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Alzheimer's Research:
2002-2006
Semin Neurol. 2006 Nov;26(5):499-506.
Alzheimer's disease.
Turner RS.
Neurology Service, VA Ann Arbor Healthcare System, Michigan.
Alzheimer's disease (AD) is the most commonly diagnosed etiology of dementia and
may be caused by the progressive accumulation and deposition of neurotoxic Abeta/amyloid
plaques and aggregates in brain with aging-the amyloid hypothesis of AD.
However, Abeta/amyloid deposition is likely necessary but not sufficient to
cause AD, and other putative downstream pathologies, including the aggregation
of phospho-tau in neurofibrillary tangles, synaptic and neuronal loss, and glial
and inflammatory responses, are likely equally important to AD pathogenesis. The
majority of AD is sporadic (> 95%) but the discovery of rare early onset
familial forms of AD has been pivotal to our understanding of its pathogenesis
and in developing novel therapeutic strategies. Currently available drugs for
patients with AD provide modest, temporary, and palliative benefits, but they
consistently demonstrate safety and efficacy on cognitive, functional,
behavioral, and global outcome measures. Novel potential disease-modifying
therapies now in preclinical research or clinical trials may be more effective
in preventing or arresting the progressive dementia of AD and will provide a
test of the amyloid hypothesis.
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Dement Geriatr Cogn Disord. 2006 Oct 26;23(1):8-21 [Epub ahead of print]
Long-Term Efficacy and Safety of Celecoxib in Alzheimer's
Disease.
Soininen H, West C, Robbins J, Niculescu L.
Department of Neurology, Kuopio University Hospital and Department of Neurology,
Brain Research Unit, Clinical Research Center, Mediteknia, University of Kuopio,
Kuopio, Finland.
Background/Aims: Cyclooxygenase-2 (COX-2) may play an important role in the
neuropathology of Alzheimer's disease (AD). The efficacy and safety of celecoxib
(200 mg bid), a COX-2 selective inhibitor, were assessed in patients >/=50 years
with established mild-to-moderate AD to determine whether treatment was
effective in retarding deterioration of cognitive function. Methods: This was a
52-week, multicenter, randomized, double-blind, placebo-controlled,
parallel-group study. The primary efficacy end points were the change from
baseline to week 52 in the Alzheimer's Disease Assessment Scale-Cognitive
Behavior (ADAS-cog) composite score and the week 52 Clinician's Interview-Based
Impression of Change Plus (CIBIC+). Results: At 52 weeks, change in ADAS-cog
scores from baseline was similar for placebo and celecoxib 200 mg bid groups
(5.00 and 4.39, respectively). CIBIC+ scores were also similar (4.83 and 4.92).
Two extension studies were conducted but were terminated early based on these
efficacy results. Safety data from all 3 studies indicated that celecoxib was
generally well-tolerated. Conclusion: Celecoxib 200 mg bid did not slow the
progression of AD in this study, and the occurrence of adverse events was as
expected for an elderly population with a complex chronic medical condition.
Copyright (c) 2007 S. Karger AG, Basel.
-----
J Neural Transm. 2006 Oct 13; [Epub ahead of print]
Alzheimer 100 - highlights in the history of Alzheimer research.
Jellinger KA.
Institute of Clinical Neurobiology, Vienna, Austria.
Alzheimer disease, a progressive neurodegenerative disorder of hitherto unknown
etiology leading progressively to severe incapacity and death, has become the
pandemic of the 21(st) century. On World Alzheimer Day, September 21, 2006, the
100(th) anniversary of the first description of the clinical and histological
findings in this disorder by A. Alzheimer, was celebrated. This retrospective
review of the most important events and advances in Alzheimer research presents
its early history in which only clinical and histologic signs of this peculiar
disease were described. Electron microscopy, quantitative morphology and modern
biochemistry emerging in the second half of the 20(th) century opened a new era
in dementia research with description of the ultrastructure and biochemistry of
senile plaques and neurofibrillary tangles, the major disease markers of AD.
Advances in the development of clinical, neuropathological, and neuroimaging
criteria, modern instruments and algorithms in the diagnosis of the disorder
followed, enabling long-term studies and more exact diagnosis of AD and related
disorders. Landmark studies were the development of operational criteria for the
post mortem diagnosis of AD based on semiquantitative assessment and
developmental patterns of its major markers. Basic research gave insight into
the molecular genetics and pathophysiology of AD, and, based on the biochemical
findings, new pharmacological treatment options were opened. Recently,
biological and other surrogate, in particular functional neuroimaging, markers
allow an early detection of presymptomatic stages of AD, their risk factors and
progression which, in the future, might be prevented or at least slowed by new
therapeutic approaches. Since the etiology of AD is hitherto unknown, causative
therapies are still not available. The paper discusses future research needs and
challenges for developing new diagnostic strategies for early and accurate
detection of neurodegenerative processes leading to dementia, better
epidemiologic and gender data as well as more insights into the pathogenic
cascade of AD and other dementing disorders which will depend on international
networks and close cooperation between clinicians, neuroscientists, caregivers,
public health institutions, and individual sponsors.
-----
N Engl J Med. 2006 Oct 12;355(15):1525-38.
Effectiveness of atypical antipsychotic drugs in patients with
Alzheimer's disease.
Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, Lebowitz
BD, Lyketsos CG, Ryan JM, Stroup TS, Sultzer DL, Weintraub D, Lieberman JA;
CATIE-AD Study Group.
Keck School of Medicine, University of Southern California, Los Angeles, CA
90033, USA. lschneid@usc.edu
BACKGROUND: Second-generation (atypical) antipsychotic drugs are widely used to
treat psychosis, aggression, and agitation in patients with Alzheimer's disease,
but their benefits are uncertain and concerns about safety have emerged. We
assessed the effectiveness of atypical antipsychotic drugs in outpatients with
Alzheimer's disease. METHODS: In this 42-site, double-blind, placebo-controlled
trial, 421 outpatients with Alzheimer's disease and psychosis, aggression, or
agitation were randomly assigned to receive olanzapine (mean dose, 5.5 mg per
day), quetiapine (mean dose, 56.5 mg per day), risperidone (mean dose, 1.0 mg
per day), or placebo. Doses were adjusted as needed, and patients were followed
for up to 36 weeks. The main outcomes were the time from initial treatment to
the discontinuation of treatment for any reason and the number of patients with
at least minimal improvement on the Clinical Global Impression of Change (CGIC)
scale at 12 weeks. RESULTS: There were no significant differences among
treatments with regard to the time to the discontinuation of treatment for any
reason: olanzapine (median, 8.1 weeks), quetiapine (median, 5.3 weeks),
risperidone (median, 7.4 weeks), and placebo (median, 8.0 weeks) (P=0.52). The
median time to the discontinuation of treatment due to a lack of efficacy
favored olanzapine (22.1 weeks) and risperidone (26.7 weeks) as compared with
quetiapine (9.1 weeks) and placebo (9.0 weeks) (P=0.002). The time to the
discontinuation of treatment due to adverse events or intolerability favored
placebo. Overall, 24% of patients who received olanzapine, 16% of patients who
received quetiapine, 18% of patients who received risperidone, and 5% of
patients who received placebo discontinued their assigned treatment owing to
intolerability (P=0.009). No significant differences were noted among the groups
with regard to improvement on the CGIC scale. Improvement was observed in 32% of
patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of
patients assigned to risperidone, and 21% of patients assigned to placebo
(P=0.22). CONCLUSIONS: Adverse effects offset advantages in the efficacy of
atypical antipsychotic drugs for the treatment of psychosis, aggression, or
agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number,
NCT00015548 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical
Society.
-----
Arch Neurol. 2006 Oct;63(10):1402-8.
Omega-3 fatty acid treatment in 174 patients with mild to
moderate Alzheimer disease: OmegAD study: a randomized double-blind trial.
Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, Basun H, Faxen-Irving G,
Garlind A, Vedin I, Vessby B, Wahlund LO, Palmblad J.
Department of Neurobiology, Caring Sciences and Society, Section of Clinical
Geriatrics, Karolinska University Hospital Huddinge, Stockholm.
BACKGROUND: Epidemiologic and animal studies have suggested that dietary fish or
fish oil rich in omega-3 fatty acids, for example, docosahexaenoic acid and
eicosapentaenoic acid, may prevent Alzheimer disease (AD). OBJECTIVE: To
determine effects of dietary omega-3 fatty acid supplementation on cognitive
functions in patients with mild to moderate AD. DESIGN: Randomized,
double-blind, placebo-controlled clinical trial. PARTICIPANTS: Two hundred four
patients with AD (age range [mean +/- SD], 74 +/- 9 years) whose conditions were
stable while receiving acetylcholine esterase inhibitor treatment and who had a
Mini-Mental State Examination (MMSE) score of 15 points or more were randomized
to daily intake of 1.7 g of docosahexaenoic acid and 0.6 g of eicosapentaenoic
acid (omega-3 fatty acid-treated group) or placebo for 6 months, after which all
received omega-3 fatty acid supplementation for 6 months more. MAIN OUTCOME
MEASURES: The primary outcome was cognition measured with the MMSE and the
cognitive portion of the Alzheimer Disease Assessment Scale. The secondary
outcome was global function as assessed with the Clinical Dementia Rating Scale;
safety and tolerability of omega-3 fatty acid supplementation; and blood
pressure determinations. RESULTS: One hundred seventy-four patients fulfilled
the trial. At baseline, mean values for the Clinical Dementia Rating Scale, MMSE,
and cognitive portion of the Alzheimer Disease Assessment Scale in the 2
randomized groups were similar. At 6 months, the decline in cognitive functions
as assessed by the latter 2 scales did not differ between the groups. However,
in a subgroup (n = 32) with very mild cognitive dysfunction (MMSE >27 points), a
significant (P<.05) reduction in MMSE decline rate was observed in the omega-3
fatty acid-treated group compared with the placebo group. A similar arrest in
decline rate was observed between 6 and 12 months in this placebo subgroup when
receiving omega-3 fatty acid supplementation. The omega-3 fatty acid treatment
was safe and well tolerated. CONCLUSIONS: Administration of omega-3 fatty acid
in patients with mild to moderate AD did not delay the rate of cognitive decline
according to the MMSE or the cognitive portion of the Alzheimer Disease
Assessment Scale. However, positive effects were observed in a small group of
patients with very mild AD (MMSE >27 points).
-----
Arch Neurol. 2006 Oct 9; [Epub ahead of print]
Mediterranean Diet, Alzheimer Disease, and Vascular Mediation.
Scarmeas N, Stern Y, Mayeux R, Luchsinger JA.
Author Affiliations: Taub Institute for Research on Alzheimer's Disease and the
Aging Brain.
OBJECTIVES: To examine the association between the Mediterranean diet (MeDi) and
Alzheimer disease (AD) in a different AD population and to investigate possible
mediation by vascular pathways.Design, Setting, Patients, and MAIN OUTCOME
MEASURES: A case-control study nested within a community-based cohort in New
York, NY. Adherence to the MeDi (0- to 9-point scale with higher scores
indicating higher adherence) was the main predictor of AD status (194 patients
with AD vs 1790 nondemented subjects) in logistic regression models that were
adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype,
caloric intake, smoking, medical comorbidity index, and body mass index
(calculated as weight in kilograms divided by height in meters squared). We
investigated whether there was attenuation of the association between MeDi and
AD when vascular variables (stroke, diabetes mellitus, hypertension, heart
disease, lipid levels) were simultaneously introduced in the models (which would
constitute evidence of mediation). RESULTS: Higher adherence to the MeDi was
associated with lower risk for AD (odds ratio, 0.76; 95% confidence interval,
0.67-0.87; P<.001). Compared with subjects in the lowest MeDi tertile, subjects
in the middle MeDi tertile had an odds ratio of 0.47 (95% confidence interval,
0.29-0.76) and those at the highest tertile an odds ratio of 0.32 (95%
confidence interval, 0.17-0.59) for AD (P for trend <.001). Introduction of the
vascular variables in the model did not change the magnitude of the association.
CONCLUSIONS: We note once more that higher adherence to the MeDi is associated
with a reduced risk for AD. The association does not seem to be mediated by
vascular comorbidity. This could be the result of either other biological
mechanisms (oxidative or inflammatory) being implicated or measurement error of
the vascular variables.Published online October 9, 2006
(doi:10.1001/archneur.63.12.noc60109).
-----
J Natl Med Assoc. 2006 Oct;98(10):1590-7.
Safety and efficacy of donepezil in African Americans with
mild-to-moderate Alzheimer's disease.
Griffith P, Lichtenberg P, Goldman R, Payne-Parrish J.
Section of Neurology, Morehouse School of Medicine, Atlanta, GA, USA. pgriffith@mmc.edu
BACKGROUND: African Americans have a higher incidence and prevalence of
Alzheimer's disease (AD) than whites but have been underrepresented in clinical
trials, including studies of cholinesterase inhibitors. PURPOSE: The purpose of
this 12-week, open-label study was to evaluate the efficacy and safety of
donepezil in African Americans with mild-to-moderate AD. METHODS: Efficacy was
assessed via the Mini-Mental State Examination (MMSE), Clinician's
Interview-Based Impression of Change-Plus interview with the patient and
caregiver (CIBIC-Plus) and Fuld Object Memory Evaluation (FOME), a measure that
has been validated for use with elderly African Americans. RESULTS: Significant
improvements were observed in cognition (MMSE), global function (CIBIC-Plus) and
memory (all four subscales of the FOME). Donepezil was well tolerated; 51% of
patients experienced adverse events, most commonly diarrhea (5.6%), hypertension
(5.6%) and urinary tract infection (4.8%). CONCLUSIONS: These results suggest
that donepezil is effective and safe in treating African Americans with
mild-to-moderate AD, and support the value of FOME in assessing efficacy in AD
trials in diverse populations.
-----
J Nutr Health Aging. 2006 Sep-Oct;10(5):416.
Editorial: treatment success in Alzheimer's disease.
Gauthier S.
S. Gauthier, McGill Center for Studies in Aging, Montreal, Canada,
Serge.gauthier@mcgill.ca.
Therapy for Alzheimer's disease (AD) has progressed significantly over the past
twenty five years, particularly in understanding the importance of multiple
symptomatic domains, including behavior, function and cognition, throughout its
course. The review by Geldmacher et al published in this issue of the JNHA (1)
offers a critical overview of the results from randomized clinical trials (RCT)
using cholinesterase inhibitors and memantine. The conclusion is clear:
stabilizing or slowing the progression of symptoms in AD using these drugs is a
clinically meaningful therapeutic goal. Whether the scales used in RCT are the
best way to measure benefit in clinical practice remains debatable: novel
approaches such as goal attainment scaling may be useful when dealing with
individual patients. Delaying emergence of behavioral symptoms is a new
perspective in the treatment of AD: agitation and aggression may be delayed by
memantine. Apathy and hallucinations clearly improve with cholinesterase
inhibitors. These non-cognitive effects of the AD drugs may translate into a
neuroleptic-sparing effect that will reduce some of the costs and side-effects
of psychotropic drugs. There are opportunities to improve the use of current and
future drugs for AD: responder analysis from RCT and careful clinical
observations may allow using the best drug class or drug within a class for slow
versus rapid decliners, for certain clinical phenotypes and for specific
genotypes. This will be particularly true for disease-modifying treatments where
benefit measured as arrest of progression will require one year or longer of
observation.The overall message for clinical investigators, clinicians, patients
and families from this evidence-based review is one of cautious optimism about
what has been achieved already and what is coming ahead: we have improved the
care for persons with AD and we will do even better in the near future.Reference.
1. Geldmacher D.S., Frolich L., Doody R.S. et al. Realistic Expectations for
Treatment Success in Alzheimer's Disease, Jour Nutr Health and Aging, vol 10, n
degrees 5, 417-429.
-----
J Am Geriatr Soc. 2006 May;54(5):777-81.
Continuous positive airway pressure reduces subjective daytime
sleepiness in patients with mild to moderate Alzheimer's disease with sleep
disordered breathing.
Chong MS, Ayalon L, Marler M, Loredo JS, Corey-Bloom J, Palmer BW, Liu L, Ancoli-Israel
S.
Department of Psychiatry, Univeristy of California at San Diego, San Diego,
California.
OBJECTIVES: Studies have reported that 33% to 70% of patients with Alzheimer's
disease (AD) have sleep-disordered breathing (SDB). Continuous positive airway
pressure (CPAP) treatment has been shown to reduce daytime sleepiness and
improve health-related quality of life in nondemented older people with SDB. The
effect of therapeutic CPAP treatment on daytime sleepiness in patients with
mild-moderate AD with SDB was assessed. DESIGN: Randomized, double-blind,
placebo-controlled trial. SETTING: Patients' home and the University of
California San Diego, General Clinical Research Center, J. Christian Gillin
Laboratory of Sleep and Chronobiology. PARTICIPANTS: Thirty-nine
community-dwelling elderly patients with mild-moderate probable AD with SDB.
INTERVENTION: Patients were randomly assigned to receive 6 weeks of therapeutic
CPAP or 3 weeks of sham CPAP followed by 3 weeks of therapeutic CPAP.
MEASUREMENTS: Epworth Sleepiness Scale (ESS) was administered at baseline, 3
weeks, and 6 weeks. Changes in daytime sleepiness in subjects who received
optimal therapeutic CPAP were compared with changes in the sham CPAP group.
RESULTS: Within the therapeutic CPAP group, ESS scores were reduced from 8.89
during baseline to 6.56 after 3 weeks of treatment (P=.04) and to 5.53 after 6
weeks of treatment (P=.004). In the sham CPAP group, there was no significant
difference after 3 weeks of sham CPAP but a significant decrease from 7.68 to
6.47 (P=.01) after 3 weeks of therapeutic CPAP. CONCLUSION: These data provide
evidence of the effectiveness of CPAP in reducing subjective daytime sleepiness
in patients with AD with SDB.
-----
JAMA. 2006 May 10;295(18):2148-57.
Effectiveness of collaborative care for older adults with
Alzheimer disease in primary care: a randomized controlled trial.
Callahan CM, Boustani MA, Unverzagt FW, Austrom MG, Damush TM, Perkins AJ, Fultz
BA, Hui SL, Counsell SR, Hendrie HC.
Indiana University Center for Aging Research, Regenstrief Institute Inc, Indiana
University School of Medicine, Indianapolis 46202, USA. ccallaha@iupui.edu
CONTEXT: Most older adults with dementia will be cared for by primary care
physicians, but the primary care practice environment presents important
challenges to providing quality care. OBJECTIVE: To test the effectiveness of a
collaborative care model to improve the quality of care for patients with
Alzheimer disease. DESIGN, SETTING, AND PATIENTS: Controlled clinical trial of
153 older adults with Alzheimer disease and their caregivers who were randomized
by physician to receive collaborative care management (n = 84) or augmented
usual care (n = 69) at primary care practices within 2 US university-affiliated
health care systems from January 2002 through August 2004. Eligible patients
(identified via screening or medical record) met diagnostic criteria for
Alzheimer disease and had a self-identified caregiver. INTERVENTION:
Intervention patients received 1 year of care management by an interdisciplinary
team led by an advanced practice nurse working with the patient's family
caregiver and integrated within primary care. The team used standard protocols
to initiate treatment and identify, monitor, and treat behavioral and
psychological symptoms of dementia, stressing nonpharmacological management.
MAIN OUTCOME MEASURES: Neuropsychiatric Inventory (NPI) administered at baseline
and at 6, 12, and 18 months. Secondary outcomes included the Cornell Scale for
Depression in Dementia (CSDD), cognition, activities of daily living, resource
use, and caregiver's depression severity. RESULTS: Initiated by caregivers'
reports, 89% of intervention patients triggered at least 1 protocol for
behavioral and psychological symptoms of dementia with a mean of 4 per patient
from a total of 8 possible protocols. Intervention patients were more likely to
receive cholinesterase inhibitors (79.8% vs 55.1%; P = .002) and antidepressants
(45.2% vs 27.5%; P = .03). Intervention patients had significantly fewer
behavioral and psychological symptoms of dementia as measured by the total NPI
score at 12 months (mean difference, -5.6; P = .01) and at 18 months (mean
difference, -5.4; P = .01). Intervention caregivers also reported significant
improvements in distress as measured by the caregiver NPI at 12 months; at 18
months, caregivers showed improvement in depression as measured by the Patient
Health Questionnaire-9. No group differences were found on the CSDD, cognition,
activities of daily living, or on rates of hospitalization, nursing home
placement, or death. CONCLUSIONS: Collaborative care for the treatment of
Alzheimer disease resulted in significant improvement in the quality of care and
in behavioral and psychological symptoms of dementia among primary care patients
and their caregivers. These improvements were achieved without significantly
increasing the use of antipsychotics or sedative-hypnotics. TRIAL REGISTRATION:
clinicaltrials.gov Identifier: NCT00246896.
-----
Rev Neurol. 2006 May 1-15;42(9):542-8.
[Ropinirole in the treatment of Alzheimer's disease: an update.]
[Article in Spanish]
Vivancos-Matellano F.
Hospital Universitario La Paz, 28046 Madrid, Espana.
INTRODUCTION. Ropinirole is a non-ergot dopaminergic agonist with a high
affinity for D2 dopaminergic receptors which improves the symptoms of
Parkinson's disease (PD) and delays the appearance of motor complications. It is
different to the first generation of dopaminergic agonists in that, because it
lacks an ergolinic structure, it does not have the side effects that usually
appear with the use of this pharmacological group. DEVELOPMENT. Recent
functional neuroimaging studies suggest a possible neuroprotector effect of the
drug, although this aspect is still under discussion. The question as to when
and how early treatment of PD must be started has been a controversial issue for
many years now. Dopaminergic agonists have been used in monotherapy in patients
with de novo disease with the intention of deferring treatment with levodopa
and, in consequence, postponing the onset of the complications stemming from its
use. Ropinirole has been evaluated in different studies both in monotherapy and
as adjunctive therapy with levodopa. CONCLUSIONS. In the numerous clinical
trials that were carried out, it would seem clear that ropinirole can be
administered for years as sole early treatment for PD and that it offers a
notable reduction in the appearance of dyskinesias. Given the linear
dose-response relation it presents, the drug has a wide 'therapeutic window'
that allows the dosage to be increased as the disease progresses.
-----
Psychiatr Serv. 2006 May;57(5):617-9.
Innovations: geriatric psychiatry: diagnosis and treatment of
neuropsychiatric symptoms in Alzheimer's disease.
Lavretsky H, Nguyen LH.
the University of California, Los Angeles.
The authors review research on the treatment of behavioral disturbances and
psychiatric symptoms of patients with dementia, including pharmacological
treatment with antipsychotics, antidepressants, cholinesterase inhibitors, and
other psychotropic drugs. They conclude that although these medications have
some beneficial effects, no intervention is currently able to eradicate
behavioral disturbances and psychiatric symptoms of demented patients. Research
suggests that multiple interventions for an individual patient are likely to
replace the use of a single treatment. Such interventions include caregiver
training and support, antipsychotics, antidepressants, and cholinesterase
inhibitors, along with other drugs developed for the treatment of Alzheimer's
disease.
-----
J Clin Psychiatry. 2006;67 Suppl 3:15-22; quiz 23.
Contemporary issues in the treatment of Alzheimer's disease:
tangible benefits of current therapies.
Tariot PN.
Memory Disorders Center, Banner Alzheimer's Disease Institute, Phoenix, AZ
85006, USA. pierre.tariot@bannerhealth.com
Because of the mild symptomatology associated with its earlier stages,
Alzheimer's disease (AD) is most commonly diagnosed in an intermediate to late
stage of progression. Patients with moderate to severe AD at diagnosis have
already experienced appreciable losses in cognition and functioning. However,
such patients may still benefit greatly from the use of antidementia agents such
as cholines-terase inhibitors (ChEIs) and the N-methyl-D-aspartate (NMDA)
receptor open-channel antagonist memantine. Monotherapy regimens involving a
ChEI or memantine have been shown to slow the progression of cognitive symptoms
in patients with moderate to severe AD, although memantine is currently the only
agent approved for use in this setting. Furthermore, combination therapy
involving memantine and a ChEI has been shown to yield increased cognitive
benefits relative to ChEI monotherapy, a result that is believed to be
attributable to the distinct therapeutic mechanisms associated with NMDA
receptor open-channel antagonists and ChEIs. Nonetheless, recent findings
indicate that the therapeutic effects of these antidementia agents are not
limited to cognition. For example, emerging data highlight the efficacy of ChEIs
and memantine, used either alone or in combination, in improving outcomes
related to patient functioning and behavior, 2 domains that may have a great
deal of significance for patients and caregivers. Furthermore, recent clinical
trial data suggest that antidementia agents may significantly delay nursing home
placement, a unique endpoint that can be tremendously distressing to patients
with AD and their caregivers. Thus, it is clear that the ChEIs and memantine
provide substantial benefits that extend across the spectrum of symptoms of AD,
improving outcomes for those who are affected, either directly or indirectly, by
this debilitating condition.
-----
J Geriatr Psychiatry Neurol. 2006 Mar;19(1):13-5.
Beneficial effect of cholinesterase inhibitor medications on
recognition memory performance in mild to moderate Alzheimer's disease:
preliminary findings.
Crowell TA, Paramadevan J, Abdullah L, Mullan M.
Roskamp Institute Memory Clinic, Tampa, Florida. TACrowell@excite.com.
Cholinesterase inhibitor (ChEI) medications (ie, donepezil, rivastigmine, and
galantamine) have been useful in slowing the progression of the mild to moderate
stages of Alzheimer's disease (AD). Findings supporting this have largely relied
on a global error score from the Alzheimer's Disease Assessment Scale and have
not described the nature of the memory problems. We examined this issue by
comparing learning, recall, and recognition scores among 2 groups of mild to
moderately demented AD patients. Participants were patients from a memory clinic
who either were on ChEI treatment (AD+ChEI, n = 14) or had never taken a ChEI
(AD-ChEI, n = 14). Participants underwent a comprehensive neuropsychological
evaluation, including administration of the CERAD Word List Memory test. Results
indicated no significant group difference for learning and delayed free recall,
but the AD+ChEI group had significantly fewer errors than the AD-ChEI group on
the CERAD Recognition test. Our findings provide preliminary evidence that the
aspect of memory that is most affected by ChEIs appears to be facilitation of
retention of new information in memory. The implications of this on clinical
care and functional abilities as well as future directions are discussed.
-----
Alzheimer Dis Assoc Disord. 2006 Jan-Mar;20(1):23-9.
Efficacy and Safety of Memantine in Moderate-to-Severe Alzheimer
Disease: The Evidence to Date.
Bullock R.
>From the Kingshill Research Centre, Victoria Hospital, Swindon, UK.
Memantine, a moderate-affinity, uncompetitive N-methyl-D-aspartate receptor
antagonist, is currently the only agent approved for moderately severe to severe
Alzheimer disease (AD) in Europe and for moderate-to-severe Alzheimer disease in
the United States. In clinical trials, memantine has consistently demonstrated a
reduced rate of deterioration on global, cognitive, functional, and behavioral
measures, across a range of outcome measures compared with usual care. Notably,
improvements versus placebo were seen in individual activities of daily living
and behavior, particularly agitation. Efficacy was demonstrated in patients with
newly diagnosed Alzheimer disease, patients previously or currently receiving
acetylcholinesterase inhibitors, and both institutionalized and
community-dwelling Alzheimer disease patients. Memantine has a tolerability
profile similar to placebo. This review presents the results of key clinical
trials, and includes clinically relevant analyses, such as
numbers-needed-to-treat and effect sizes. Increased dependency and
institutionalization are significant cost drivers in Alzheimer disease.
Memantine is able to reduce dependency, caregiver time required, and mean
monthly caregiver and societal costs. Recent studies of the relationship between
Alzheimer disease progression, caregiver burden, and healthcare costs emphasize
the need for treatments such as memantine that can slow the rate of decline in
Alzheimer disease.
-----
Int Psychogeriatr. 2006 Feb 15;:1-3 [Epub ahead of print]
Observations from a 14-week open label trial with memantine
suggest variable response on behavioural symptoms and cognition, depending on
former treatment of AD.
Dautzenberg PL, Wouters CJ, Bootsma JE.
Department of Geriatrics, Jeroen Bosch Hospital, GV's-Hertogenbosch, The
Netherlands. E-mail: p.dautzenberg@jbz.nl.
Memantine, an uncompetitive N-methyl D-aspartate (NMDA) receptor antagonist, is
currently the only treatment licenced for moderately severe to severe
Alzheimer's Disease (AD). Memantine is effective on cognitive symptoms (Reisberg
et al., 2003 Tariot et al., 2004 Winblad and Portis, 1999), and in a post-hoc
analysis of behavioural symptoms, memantine showed beneficial effects
particularly on agitation/aggression (Gauthier et al., 2005).
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CNS Drugs. 2006;20(2):85-98.
Is there a Future for Cyclo-Oxygenase Inhibitors in Alzheimer's
Disease?
Ho L, Qin W, Stetka BS, Pasinetti GM.
Department of Psychiatry, The Mount Sinai School of Medicine, Neuroinflammation
Research Laboratories, New York, New York, USA.
Several epidemiological studies have indicated that the long-term use of NSAIDs,
most of which are cyclo-oxygenase (COX) inhibitors, may reduce the risk of
Alzheimer's disease. For this reason, anti-inflammatory COX-inhibiting NSAIDs
have received increased attention in experimental and therapeutic trials for
Alzheimer's disease. However, several recent efforts attempting to demonstrate a
therapeutic effect of NSAIDs in Alzheimer's disease have largely failed.
Clinicians and scientists currently believe that this lack of success may be
attributable to two key problems: (i) clinical trials of NSAIDs have been
conducted in patients with late-stage Alzheimer's disease, wherein advanced
neurodegeneration may be refractory to anti-inflammatory drug treatment; and
(ii) it is not known which of the large family of NSAIDs (i.e. COX-1, COX-2 or
mixed inhibitors) is most efficacious in preventing Alzheimer's disease.The wide
list of putative functions for COX in the brain, and the significant functional
heterogeneity of NSAIDs, which appear to influence the beta-amyloid (Abeta)
neuropathology associated with Alzheimer's disease via both COX-dependent and
COX-independent pathways, complicate the interpretation of the mechanisms
through which COX-inhibiting NSAIDs may beneficially influence Alzheimer's
disease. As discussed in this review, for patients at high risk of developing
Alzheimer's disease (e.g. those with mild cognitive impairment), preventative
treatment with COX-inhibiting NSAIDs may ultimately represent a viable strategy
in the management of clinical Alzheimer's disease. However, the recent evidence
showing an increased risk of major cardiovascular events among patients treated
with certain COX-1 and COX-2 inhibitors leaves many questions unanswered. We
suggest that further investigation into the physiological role(s) of COXs in
normal health and in disease conditions, and the identification of safer and
better tolerated COX inhibitors, will provide renewed impetus to the application
of anti-inflammatory strategies for the prevention and treatment of Alzheimer's
disease.
-----
Pharmacopsychiatry. 2006 Jan;39(1):16-9.
Transdermal rivastigmine treatment does not worsen impaired
performance of complex motions in patients with Alzheimer's disease.
Muhlack S, Przuntek H, Muller T.
Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum,
Germany.
BACKGROUND: There is a debate about the deterioration of fine motor behavior
during treatment with cholinesterase inhibitors. METHODS: We used an
instrumental motor test, which demands a complex motion series. Thereby we
assessed motor function in patients with Alzheimer's disease (AD), in patients
with mild cognitive impairment (MCI), and in controls. We also performed this
task and a complex reaction time paradigm (CRT) during a six-week open-label
safety study using transdermal delivery of the cholinesterase inhibitor
rivastigmine. OBJECTIVES: To investigate (1) the performance of complex
movements during deterioration of cognitive function and (2) the impact of
rivastigmine on fine motor behavior and CRT outcomes in AD patients. RESULTS:
There were significant differences in the motor test outcomes, particularly when
performed with the left non-dominant hand, between controls and patients with AD
and MCI. Rivastigmine did not deteriorate assessed fine motor skills and CRT
results. CONCLUSION: Our study shows an impaired carrying out of complex motion
series during neurodegeneration associated with cognitive dysfunction.
Rivastigmine selectively inhibits the predominant cortical and hippocampal G1
cholinesterase isoform; therefore, hypothetically no deterioration of fine motor
behavior appeared during transdermal rivastigmine treatment. We assume that a
putative drug-induced increase in speed and attention did not offset a
deterioration of motion performance because we found no significant changes in
the CRT results.
-----
Pharmacogenomics J. 2006 Jan 31; [Epub ahead of print]
Efficacy of rosiglitazone in a genetically defined population
with mild-to-moderate Alzheimer's disease.
Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zvartau-Hind
ME, Hosford DA, Roses AD.
1World Wide Development, Research and Development, GlaxoSmithKline, Research
Triangle Park, NC, USA.
Mild-to-moderate AD patients were randomized to placebo or rosiglitazone (RSG)
2, 4 or 8 mg. Primary end points at Week 24 were mean change from baseline in AD
Assessment Scale-Cognitive (ADAS-Cog) and Clinician's Interview-Based Impression
of Change Plus Caregiver Input global scores in the intention-to-treat
population (N=511), and results were also stratified by apolipoprotein E (APOE)
genotype (n=323). No statistically significant differences on primary end points
were detected between placebo and any RSG dose. There was a significant
interaction between APOE varepsilon4 allele status and ADAS-Cog (P=0.014).
Exploratory analyses demonstrated significant improvement in ADAS-Cog in APOE
varepsilon4-negative patients on 8 mg RSG (P=0.024; not corrected for
multiplicity). APOE varepsilon4-positive patients did not show improvement and
showed a decline at the lowest RSG dose (P=0.012; not corrected for
multiplicity). Exploratory analyses suggested that APOE varepsilon4 non-carriers
exhibited cognitive and functional improvement in response to RSG, whereas APOE
varepsilon4 allele carriers showed no improvement and some decline was noted.
These preliminary findings require confirmation in appropriate clinical
studies.The Pharmacogenomics Journal advance online publication, 31 January
2006; doi:10.1038/sj.tpj.6500369.
-----
Cochrane Database Syst Rev. 2006 Jan 25;(1):CD005593.
Cholinesterase inhibitors for Alzheimer's disease.
Birks J.
BACKGROUND: Since the introduction of the first cholinesterase inhibitor (ChEI)
in 1997, most clinicians and probably most patients would consider the
cholinergic drugs, donepezil, galantamine and rivastigmine, to be the first line
pharmacotherapy for mild to moderate Alzheimer's disease.The drugs have slightly
different pharmacological properties, but they all work by inhibiting the
breakdown of acetylcholine, an important neurotransmitter associated with
memory, by blocking the enzyme acetylcholinesterase. The most that these drugs
could achieve is to modify the manifestations of Alzheimer's disease. Cochrane
reviews of each ChEI for Alzheimer's disease have been completed (Birks 2005,
Birks 2005b and Loy 2005). Despite the evidence from the clinical studies and
the intervening clinical experience the debate on whether ChEIs are effective
continues. OBJECTIVES: To assess the effects of donepezil, galantamine and
rivastigmine in people with mild, moderate or severe dementia due to Alzheimer's
disease. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Improvement
Group's Specialized Register was searched using the terms 'donepezil', 'E2020' ,
'Aricept' , galanthamin* galantamin* reminyl, rivastigmine, exelon, "ENA 713"
and ENA-713 on 12 June 2005. This Register contains up-to-date records of all
major health care databases and many ongoing trial databases. SELECTION
CRITERIA: All unconfounded, blinded, randomized trials in which treatment with a
ChEI was compared with placebo or another ChEI for patients with mild, moderate
or severe dementia due to Alzheimer's disease. DATA COLLECTION AND ANALYSIS:
Data were extracted by one reviewer (JSB), pooled where appropriate and
possible, and the pooled treatment effects, or the risks and benefits of
treatment estimated. MAIN RESULTS: The results of 13 randomized, double blind,
placebo controlled trials demonstrate that treatment for periods of 6 months and
one year, with donepezil, galantamine or rivastigmine at the recommended dose
for people with mild, moderate or severe dementia due to Alzheimer's disease
produced improvements in cognitive function, on average -2.7 points (95%CI -3.0
to -2.3), in the midrange of the 70 point ADAS-Cog Scale. Study clinicians blind
to other measures rated global clinical state more positively in treated
patients. Benefits of treatment were also seen on measures of activities of
daily living and behaviour. None of these treatment effects are large.There is
nothing to suggest the effects are less for patients with severe dementia or
mild dementia, although there is very little evidence for other than mild to
moderate dementia.More patients leave ChEI treatment groups, approximately 29 %,
on account of adverse events than leave the placebo groups (18%).There is
evidence of more adverse events in total in the patients treated with a ChEI
than with placebo. Although many types of adverse event were reported, nausea,
vomiting, diarrhoea, were significantly more frequent in the ChEI groups than in
placebo.There are four studies, all supported by one of the pharmaceutical
companies, in which two ChEIs were compared, two studies of donepezil compared
with galantamine, and two of donepezil compared with rivastigmine. In three
studies the patients were not blinded to treatment, only the fourth, DON vs RIV/Bullock
is double blind. Two of the studies provide little evidence, they are of 12
weeks duration, which is barely long enough to complete the drug titration.
There is no evidence from DON vs GAL/Wilcock of a treatment difference between
donepezil and galantamine at 52 weeks for cognition, activities of daily living,
the numbers who leave the trial before the end of treatment, the number who
suffer any adverse event, or any specific adverse event.There is no evidence
from DON vs RIV/Bullock of a difference between donepezil and rivastigmine for
cognitive function, activities of daily living and behavioural disturbance at
two years. Fewer patients suffer adverse events on donepezil than rivastigmine.
AUTHORS' CONCLUSIONS: The three cholinesterase inhibitors are efficacious for
mild to moderate Alzheimer's disease. It is not possible to identify those who
will respond to treatment prior to treatment. There is no evidence that
treatment with a ChEI is not cost effective. Despite the slight variations in
the mode of action of the three cholinesterase inhibitors there is no evidence
of any differences between them with respect to efficacy. There appears to be
less adverse effects associated with donepezil compared with rivastigmine. It
may be that galantamine and rivastigmine match donepezil in tolerability if a
careful and gradual titration routine over more than three months is used.
Titration with donepezil is more straightforward and the lower dose may be worth
consideration.
-----
Cochrane Database Syst Rev. 2006 Jan 25;(1):CD005380.
Clioquinol for the treatment of Alzheimer's Disease.
Jenagaratnam L, McShane R.
BACKGROUND: Alzheimer's disease (AD) may result in senile plaques being formed
outside the brain as accumulation of beta-amyloid (Ass). OBJECTIVES: To evaluate
the efficacy of clioquinol for the treatment of cognitive impairment due to
Alzheimer's disease. SEARCH STRATEGY: The Cochrane Dementia and Cognitive
Improvement Group's Specialized Register was searched on 20 May 2005 using the
terms clioquinol and PBT1. The Register contains records from major health care
databases and many ongoing trial databases and is updated regularly. The
Internet was searched using the term: clioquinol PBT1 Alzheimer*. SELECTION
CRITERIA: Randomised double-blind trials in which treatment with clioquinol was
administered to participants with Alzheimer's disease in parallel group
comparison with placebo are included. DATA COLLECTION AND ANALYSIS: Two
reviewers (RM, LJ) independently assessed the quality of trials according to the
Cochrane Collaboration Handbook.The primary outcome measures of interest were
cognitive function (as measured by psychometric tests) and global impression.
The secondary outcome measures of interest were in the following areas: quality
of life, functional performance, effect on carer, safety and adverse effects,
and death. MAIN RESULTS: There was one included trial of clioquinol compared
with placebo in 36 patients. AUTHORS' CONCLUSIONS: It is not clear from the
trial that clioquinol shows any positive clinical result on patients with AD.
The two statistically significant positive results were seen for the more
severely affected subgroup of patients. This effect was not maintained at the 36
week end-point. The sample size was small. Details of randomisation procedure or
blinding were not reported. Further studies are needed to evaluate the potential
for clioquinol as a treatment of AD. Trials of longer duration are also
required, particularly because information about the side-effects of long-term
use of clioquinol is limited.
-----
Cochrane Database Syst Rev. 2006 Jan 25;(1):CD003476.
The effectiveness of atypical antipsychotics for the treatment of
aggression and psychosis in Alzheimer's disease.
Ballard C, Waite J.
BACKGROUND: Aggression, agitation or psychosis occur in the majority of people
with dementia at some point in the illness. There have been a number of trials
of atypical antipsychotics to treat these symptoms over the last five years, and
a systematic review is needed to evaluate the evidence in a balanced way.
OBJECTIVES: To determine whether evidence supports the use of atypical
antipsychotics for the treatment of aggression, agitation and psychosis in
people with Alzheimer's disease. SEARCH STRATEGY: The trials were identified
from a last updated search of the Specialized Register of the Cochrane Dementia
and Cognitive Improvement Group on 7 December 2004 using the terms olanzapine,
quetiapine, risperidone, clozapine, amisulpride, sertindole, zotepine,
aripiprazole, ziprasidone. This Register contains articles from all major
healthcare databases and many ongoing trials databases and is updated regularly.
SELECTION CRITERIA: Randomised, placebo-controlled trials, with concealed
allocation, where dementia and psychosis and/or aggression were assessed. DATA
COLLECTION AND ANALYSIS: 1. Two reviewers extracted data from included trials2.
Data were pooled where possible, and analysed using appropriate statistical
methods3. Analysis included patients treated with an atypical antipsychotic,
compared with placebo MAIN RESULTS: Sixteen placebo controlled trials have been
completed with atypical antipsychotics although only nine had sufficient data to
contribute to a meta-analysis and only five have been published in full in peer
reviewed journals. No trials of amisulpiride, sertindole or zotepine were
identified which met the criteria for inclusion. The included trials led to the
following results:1. There was a significant improvement in aggression with
risperidone and olanzapine treatment compared to placebo.2. There was a
significant improvement in psychosis amongst risperidone treated patients.3.
Risperidone and olanzpaine treated patients had a significantly higher incidence
of serious adverse cerebrovascular events (including stroke), extra-pyramidal
side effects and other important adverse outcomes.4. There was a significant
increase in drop-outs in risperidone (2 mg) and olanzapine (5-10 mg) treated
patients.5. The data were insufficient to examine impact upon cognitive
function. AUTHORS' CONCLUSIONS: Evidence suggests that risperidone and
olanzapine are useful in reducing aggression and risperidone reduces psychosis,
but both are associated with serious adverse cerebrovascular events and
extra-pyramidal symptoms. Despite the modest efficacy, the significant increase
in adverse events confirms that neither risperidone nor olanzapine should be
used routinely to treat dementia patients with aggression or psychosis unless
there is marked risk or severe distress. Although insufficient data were
available from the considered trials, a meta-analysis of seventeen placebo
controlled trials of atypical neuroleptics for the treatment of behavioural
symptoms in people with dementia conducted by the Food and Drug Administration
(using data not in the public domain) suggested a significant increase in
mortality (OR 1.7).
-----
Cochrane Database Syst Rev. 2006 Jan 25;(1):CD001747.
Galantamine for Alzheimer's disease and mild cognitive
impairment.
Loy C, Schneider L.
BACKGROUND: Galantamine is a specific, competitive, and reversible
acetylcholinesterase inhibitor. OBJECTIVES: To assess the clinical effects of
galantamine in patients with mild cognitive impairment (MCI), probable or
possible Alzheimer's disease (AD), and potential moderators of effect. SEARCH
STRATEGY: The trials were identified from a search of the Specialized Register
of the Cochrane Dementia and Cognitive Improvement Group, last updated on 25
April 2005 using the terms galanthamin*, galantamin* and Reminyl. Published
reviews were inspected for further sources. Additional information was collected
from unpublished clinical research reports for galantamine obtained from Janssen
and from http://www.clinicalstudyresults.org/. SELECTION CRITERIA: Trials
selected were randomised, double-blind, parallel-group comparisons of
galantamine with placebo for a treatment duration of greater than 4 weeks in
subjects with MCI or AD. DATA COLLECTION AND ANALYSIS: Data were extracted
independently by the reviewers and pooled where appropriate and possible.
Outcomes of interest include the clinical global impression of change (CIBIC-plus
or CGIC), Alzheimer's Disease Assessment Scale-cognitive sub scale (ADAS-cog),
Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL),
Disability Assessment for Dementia scale (DAD) and Neuropsychiatric Inventory (NPI).
Potential moderating variables of treatment effect assessed included trial
duration, dose, and diagnosis of possible versus probable Alzheimer's disease.
MAIN RESULTS: Ten trials with a total 6805 subjects were included in the
analysis. Treatment with galantamine led to a significantly greater proportion
of subjects with improved or unchanged global rating scale rating (k = 8
studies), at all dosing levels except for 8 mg/d . Confidence intervals for the
ORs overlapped across the dose range of 16 mg to 36 mg per day, with point
estimates of 1.6 - 1.8 when analysed with the intention-to-treat
sample.Treatment with galantamine also led to significantly greater reduction in
ADAS-cog score at all dosing levels (k = 8), with greater effect over six months
compared to three months. Confidence intervals again overlapped. Point estimate
of effect was lower for 8 mg/d but similar for 16 mg to 36 mg per day. For
example, treatment effect for 24 mg/d over six months was 3.1 point reduction in
ADAS-cog (95%CI 2.6-3.7, k = 4, ITT).ADCS-ADL, DAD and NPI were reported only in
a small proportion of trials: all showed significant treatment effect in some
individual trials at least. Confidence interval of treatment effect for the one
trial recruiting patients with possible AD overlapped with the other seven
recruiting patients with probable AD. Galantamine's adverse effects appeared
similar to those of other cholinesterase inhibitors and to be dose
related.Prolong release / once daily formulation of galantamine at 16 - 24mg/d
was found to have similar efficacy and side-effect profile as the equivalent
twice-daily regime. Data from the two MCI trials suggest marginal clinical
benefit, but a yet unexplained excess in death rate. AUTHORS' CONCLUSIONS:
Subjects in these trials were similar to those seen in earlier anti dementia AD
trials, consisting primarily of mildly to moderately impaired outpatients.
Galantamine's effect on more severely impaired subjects has not yet been
assessed.Nevertheless, this review shows consistent positive effects for
galantamine for trials of three to six months' duration. Although there was not
a statistically significant dose-response effect, doses above 8 mg/d were, for
the most part, consistently statistically significant. Galantamine's safety
profile in AD is similar to that of other cholinesterase inhibitors with respect
to cholinergically mediated gastrointestinal symptoms. It appears that doses of
16 mg/d were best tolerated in the single trial where medication was titrated
over a four week period, and because this dose showed statistically
indistinguishable efficacy with higher doses, it is probably most preferable
initially. Longer term use of galantamine has not been assessed in a controlled
fashion.Galantamine use in MCI is not recommended due to its association with an
excess death rate.
-----
Cochrane Database Syst Rev. 2006 Jan 25;(1):CD001190.
Donepezil for dementia due to Alzheimer's disease.
Birks J, Harvey R.
BACKGROUND: Alzheimer's disease is the most common cause of dementia in older
people. One of the aims of therapy is to inhibit the breakdown of a chemical
neurotransmitter, acetylcholine, by blocking the relevant enzyme. This can be
done by a group of chemicals known as cholinesterase inhibitors. OBJECTIVES: The
objective of this review is to assess whether donepezil improves the well-being
of patients with dementia due to Alzheimer's disease. SEARCH STRATEGY: The
Cochrane Dementia and Cognitive Improvement Group's Specialized Register was
searched using the terms 'donepezil', 'E2020' and 'Aricept' on 12 June 2005.
This Register contains up-to-date records of all major health care databases and
many ongoing trial databases.Members of the Donepezil Study Group and Eisai Inc
were contacted. SELECTION CRITERIA: All unconfounded, double-blind, randomized
controlled trials in which treatment with donepezil was compared with placebo
for patients with mild, moderate or severe dementia due to Alzheimer's disease.
DATA COLLECTION AND ANALYSIS: Data were extracted by one reviewer (JSB), pooled
where appropriate and possible, and the pooled treatment effects, or the risks
and benefits of treatment estimated. MAIN RESULTS: 23 trials are included,
involving 5272 participants. Most trials were of 6 months or less duration in
selected patients. Available outcome data cover domains including cognitive
function, activities of daily living, behaviour , global clinical state and
health care resource costs.For cognition there is a statistically significant
improvement for both 5 and 10 mg/day of donepezil at 24 weeks compared with
placebo on the ADAS-Cog scale (-2.01 points MD, 95%CI -2.69 to -1.34,
p<0.00001); -2.80 points, MD 95% CI -3.74 to -2.10, p<0.00001) and for 10 mg/day
donepezil compared with placebo at 52 weeks (1.84 MMSE points, 95% CI, 0.53 to
3.15, p=0.006).The results show some improvement in global clinical state
(assessed by a clinician) in people treated with 5 and 10 mg/day of donepezil
compared with placebo at 24 weeks for the number of patients showing improvement
or no change (OR 2.18, 95% CI 1.53 to 3.11, p=<0.0001, OR 2.38, 95% CI 1.78 to
3.19, p<0.00001). Benefits of treatment were also seen on measures of activities
of daily living and behaviour, but not on the quality of life score .There were
significantly more withdrawals before the end of treatment from the 10 mg/day
(but not the 5 mg/day) donepezil group compared with placebo which may have
resulted in some overestimation of beneficial changes at 10 mg/day. Benefits on
the 10 mg/day dose were marginally larger than on the 5 mg/day dose. Two studies
presented results for health resource use, and the associated costs. There were
no significant differences between treatment and placebo for any item, the cost
of any item, and for the total costs, and total costs including the informal
carer costs. A variety of adverse effects were recorded, with more incidents of
nausea, vomiting, diarrhoea, muscle cramps, dizziness, fatigue and anorexia
(significant risk associated with treatment) in the 10 mg/day group compared
with placebo but very few patients left a trial as a direct result of the
intervention. AUTHORS' CONCLUSIONS: People with mild, moderate or severe
dementia due to Alzheimer's disease treated for periods of 12, 24 or 52 weeks
with donepezil experienced benefits in cognitive function, activities of daily
living and behaviour. Study clinicians rated global clinical state more
positively in treated patients, and measured less decline in measures of global
disease severity. There is some evidence that use of donepezil is neither more
nor less expensive compared with placebo when assessing total health care
resource costs. Benefits on the 10 mg/day dose were marginally larger than on
the 5 mg/day dose. Taking into consideration the better tolerability of the 5
mg/day donepezil compared with the 10 mg/day dose, together with the lower cost,
the lower dose may be the better option. The debate on whether donepezil is
effective continues despite the evidence of efficacy from the clinical studies
because the treatment effects are small and are not always apparent in practice
.
-----
Int J Geriatr Psychiatry. 2005 Dec 2; [Epub ahead of print]
A systematic review of the clinical effectiveness of donepezil,
rivastigmine and galantamine on cognition, quality of life and adverse events in
Alzheimer's disease.
Takeda A, Loveman E, Clegg A, Kirby J, Picot J, Payne E, Green C.
Southampton Health Technology Assessments Centre (SHTAC), University of
Southampton, Southampton, UK.
BACKGROUND: The use of cholinesterase inhibiors for Alzheimer's disease (AD) is
currently being appraised by the National Institute for Clintical Evidence
(NICE). This article provides the latest evidence that NICE will be using as
part of this appraisal process. OBJECTIVE: To provide a systematic review of the
best quality evidence of the effects of donepezil, rivastigmine and galantamine
on cognition, quality of life and adverse events in people with mild to
moderately-severe AD. DESIGN: Electronic databases were searched, references of
all retrieved articles were checked, and experts were contacted for advice, peer
review and to identify additional references. Randomised controlled trials (RCTs)
were included if they fulfilled pre-specified criteria. Data were synthesised
through a narrative review. RESULTS: Twenty-six RCTs that compared any one of
the cholinesterase inhibitors with either a control group or with another
cholinesterase inhibitor were included. The quality of reporting and methodology
was varied. Treatment with donepezil, rivastigmine or galantamine resulted in
significantly better cognitive performance using the ADAS-cog scale when
compared with placebo. These findings were generally supported using the MMSE
scale. Results from head to head comparisons were limited by the low number of
studies and the study quality; generally showing no robust support for any one
drug. Few studies evaluated quality of life. Adverse events were generally
related to the gastrointestinal system, with a tendency for these to be more
common in the treatment arms. CONCLUSIONS: The cholinesterase inhibitors
donepezil, rivastigmine, and galantamine can delay cognitive impairment in
patients with mild to moderately-severe AD for at least 6 months duration.
Copyright (c) 2005 John Wiley & Sons, Ltd.
-----
Ann Pharmacother. 2005 Dec;39(12):2065-71. Epub 2005 Nov 15.
Vitamin e supplementation in Alzheimer's disease, Parkinson's
disease, tardive dyskinesia, and cataract: part 2.
Pham DQ, Plakogiannis R.
1 Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island
University, Brooklyn, NY; Internal Medicine Pharmacotherapy Specialist, Kings
County Hospital Center, Brooklyn.
OBJECTIVE: To review clinical trials evaluating the safety and efficacy of
vitamin E supplementation in Alzheimer's disease, Parkinson's disease, tardive
dyskinesia, and cataract. DATA SOURCES: Using the MeSH terms alpha-tocopherol,
tocopherols, vitamin E, Parkinson disease, tardive dyskinesia, Alzheimer
disease, cataract, and clinical trials, a literature review was conducted to
identify peer-reviewed articles in MEDLINE (1966-July 2005). STUDY SELECTION AND
DATA EXTRACTION: Published materials including original research, review
articles, and meta-analyses were reviewed. Only English-language articles and
trials that included vitamin E alone or in combination with other vitamins or
minerals were reviewed. Emphasis was placed on prospective, randomized,
double-blind, placebo-controlled clinical trials. DATA SYNTHESIS: The clinical
studies demonstrated contradicting results regarding the benefits of vitamin E
in Parkinson's disease, tardive dyskinesia, and cataract. The study reviewed for
Alzheimer's disease seemed to show benefit when vitamin E was used; however, the
statistical methods employed are questionable. There is enough evidence from
large, well-designed studies to discourage the use of vitamin E in Parkinson's
disease, cataract, and Alzheimer's disease. We recommend that vitamin E be
considered a treatment option in patients with tardive dyskinesia only if they
are newly diagnosed. CONCLUSIONS: We encourage patients to supplement with
vitamin E-rich foods. The use of a daily multivitamin, which usually contains 30
IU of alpha-tocopherol, may be beneficial; however, we discourage individual
vitamin E supplements that usually contain 400 IU of alpha-tocopherol.
-----
J Neurol Neurosurg Psychiatry. 2005 Dec;76(12):1624-9.
Lipid lowering agents are associated with a slower cognitive
decline in Alzheimer's disease.
Masse I, Bordet R, Deplanque D, Al Khedr A, Richard F, Libersa C, Pasquier F.
Department of Neurology, University Hospital, 59037 Lille, France.
BACKGROUND: Data from epidemiological studies and animal models imply that
disturbances in cholesterol metabolism are linked to Alzheimer's disease
susceptibility. Lipid lowering agents (LLAs) may have implications for the
prevention of Alzheimer's disease. OBJECTIVE: To investigate whether LLAs are
associated with a slower cognitive decline in Alzheimer's disease. METHODS: An
observational study in 342 Alzheimer patients followed in a memory clinic for
34.8 months (mean age 73.5 years, mini-mental state examination score (MMSE)
21.3 at entry); 129 were dyslipaemic treated with LLAs (47% with statins), 105
were untreated dyslipaemic, and 108 were normolipaemic. The rate of cognitive
decline was calculated as the difference between the first and last MMSE score,
divided by the time between the measurements, expressed by year. Patients were
divided into slow and fast decliners according to their annual rate of decline
(lower or higher than the median annual rate of decline in the total
population). RESULTS: Patients treated with LLAs had a slower decline on the
MMSE (1.5 point/year, p = 0.0102) than patients with untreated dyslipaemia (2.4
points/year), or normolipaemic patients (2.6 points/year). Patients with a
slower decline were more likely to be treated with LLAs. Logistic regression
analysis, with low annual cognitive decline as the dependent variable, showed
that the independent variable LLA (treated with or not) was positively
associated with the probability of lower cognitive decline (odds ratio = 0.45, p
= 0.002). CONCLUSIONS: LLAs may slow cognitive decline in Alzheimer's disease
and have a neuroprotective effect. This should be confirmed by placebo
controlled randomised trials in patients with Alzheimer's disease and no
dyslipaemia.
-----
Neurologia. 2005 Dec;20(10):686-91.
[Efficacy of memantine in the treatment of Alzheimer's disease.]
[Article in Spanish]
Molinuevo J, Llado A.
Unitat de Memoria-Alzheimer, ICMSN. Hospital Clinic. Barcelona.
Alzheimer's disease (AD) is a neurodegenerative disorder clinically
characterized by cognitive loss with impairment of daily living activities. The
benefits presently observed with the approved treatments are mainly symptomatic
without clear evidence of neuroprotection. N-methyl- D-aspartate (NMDA)
glutamate receptor antagonists have very extensive therapeutic potential in
several central nervous system disorders and can be used in chronic
neurodegenerative diseases and in other neurological diseases such as epilepsy.
Memantine, a moderatelow affinity, uncompetitive NMDA receptor antagonist, is
the only antiglutamatergic drug currently approved for the treatment of moderate
to severe AD. Several studies have demonstrated that treatment with memantine
has cognitive and functional benefits through all disease stages, while it is
safe and well tolerated. Additionally, memantine generates an indirect positive
effect on the caregiver, which results in some social benefits. This fact,
together with a delay on the transition towards a greater dependence stage is
probably associated with a decrease in the number of patients institutionalized.
From a socio-economic perspective, these effects mean lower global cost of
disease, therefore being a cost-effective drug. <p><b> Neurologia
2005;20(10):686-691</b></p>
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Am J Geriatr Psychiatry. 2005 Nov;13(11):950-8.
Preserved cognition in patients with early Alzheimer disease and
amnestic mild cognitive impairment during treatment with rosiglitazone: a
preliminary study.
Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Fishel MA,
Kulstad JJ, Green PS, Cook DG, Kahn SE, Keeling ML, Craft S.
correspondence and reprint requests to Dr. Suzanne Craft, VAPSHCS, S-182-GRECC,
1660 S. Columbian Way, Seattle, WA 98108. scraft@u.washington.edu.
OBJECTIVE: Insulin resistance (impaired insulin action) has been associated with
Alzheimer disease (AD) and memory impairment, independent of AD. Peroxisome
proliferator-activated receptor-gamma (PPAR-gamma) agonists improve insulin
sensitivity and regulate in-vitro processing of the amyloid precursor protein
(APP). Authors evaluated the effects of the PPAR-gamma agonist rosiglitazone on
cognition and plasma levels of the APP derivative beta-amyloid (Abeta) in
humans. Methods: In a placebo-controlled, double-blind, parallel-group pilot
study, 30 subjects with mild AD or amnestic mild cognitive impairment were
randomized to a 6-month course of rosiglitazone (4 mg daily; N=20) or placebo
(N=10). Primary endpoints were cognitive performance and plasma Abeta levels.
Results: Relative to the placebo group, subjects receiving rosiglitazone
exhibited better delayed recall (at Months 4 and 6) and selective attention
(Month 6). At Month 6, plasma Abeta levels were unchanged from baseline for
subjects receiving rosiglitazone but declined for subjects receiving placebo,
consistent with recent reports that plasma Abeta42 decreases with progression of
AD. CONCLUSIONS: Findings provide preliminary support that rosiglitazone may
offer a novel strategy for the treatment of cognitive decline associated with
AD. Future confirmation in a larger study is needed to fully demonstrate
rosiglitazone's therapeutic potential.
-----
Int J Geriatr Psychiatry. 2005 Nov 28;20(12):1153-1157 [Epub ahead of print]
Risperidone for psychosis of Alzheimer's disease and mixed
dementia: results of a double-blind, placebo-controlled trial.
Brodaty H, Ames D, Snowdon J, Woodward M, Kirwan J, Clarnette R, Lee E,
Greenspan A.
Academic Department of Psychogeriatrics, School of Psychiatry, University of New
South Wales, Sydney, Australia.
OBJECTIVE: To evaluate the efficacy and safety of low-dose risperidone in
treating psychosis of Alzheimer's disease (AD) and mixed dementia (MD) in a
subset of nursing-home residents who had dementia and agression and who were
participating in a randomized placebo-controlled trial of risperidone for
agreesion. METHOD: This post-hoc analysis included only patients diagnosed with
AD or MD with psychosis, defined by a score of >/= 2 on any item of the
Behavioral Pathology of Alzheimer's Disease (BEHAVE-AD) psychosis subscale at
both screening and baseline. Co-primary efficacy endpoints were changes in
scores on BEHAVE-AD psychosis subscale and Clinical Global Impression of Change
(CGI-C). RESULTS: Overall, 93 patients (46 risperidone and 47 placebo) fulfilled
the psychosis of AD criteria. Mean change at endpoint in BEHAVE-AD psychosis
subscale with risperidone was superior to placebo (-5.2 vs -3.3; p = 0.039).
Distribution of CGI-C at endpoint also favoured risperidone (p < 0.001). The
superior improvement with risperidone compared with placebo occured as early as
the first two weeks and persisted to the end of the treatment period. At
endpoint, 59% of risperidone-treated patients were responders (i.e. were 'very
much' or 'much' improved) compared with 26% of patients receiving placebo. The
mean risperidone dose was 1.03 +/- 0.61 mg/day. Twelve weeks of treatment were
completed by 37 patients treated with risperidone (80%) and 35 with placebo
(74%). A total of 46 (98%) placebo- and 44 (96%) risperidone-treated patients
experienced at least one adverse event, with only somnolence occurring more
frequently in the risperidone group. CONCLUSION: Risperidone effectively reduces
psychosis and improves global functioning in elderly patients with
moderate-to-severe psychosis of AD and MD. Copyright (c) 2005 John Wiley & Sons,
Ltd.
-----
Proc Nutr Soc. 2005 Nov;64(4):565-70.
Micronutrients and Alzheimer's disease.
Staehelin HB.
Geriatric University Clinic, University Hospital, Basel, Switzerland.
Hannes-B.Staehelin@unibas.ch
The current high life expectancy is overshadowed by neurodegenerative illnesses
that lead to dementia and dependence. Alzheimer's disease (AD) is the most
common of these conditions, and is considered to be a proteinopathy, with
amyloid-beta42 as a key factor, leading via a cascade of events to
neurodegeneration. Major factors involved are oxidative stress, perturbed Ca
homeostasis and impaired energy metabolism. Protection against oxidative stress
by micronutrients (including secondary bioactive substances) has been shown in
transgenic Alzheimer model systems to delay AD. Epidemiological evidence is less
conclusive, but the vast majority of the evidence supports a protective effect
on cognitive functions in old age and AD. Thus, a diet rich in fruits and
vegetables but also containing meat and fish is the most suitable to provide
adequate micronutrients. The strong link between cardiovascular risk and AD may
be explained by common pathogenetic mechanisms mediated, for example, by
homocysteine and thus dependant on B-vitamins (folate and vitamins B(12) and
B(6)). However, micronutrients may also be harmful. The high affinity of amyloid
for metals (Fe, Al and Zn) favours the generation of reactive oxygen species and
triggers an inflammatory response. Micronutrients in a balanced diet have a
long-lasting, albeit low, protective impact on brain aging, hence prevention
should be life long.
-----
J Alzheimers Dis. 2005 Nov;8(2):147-54.
Calcium in Alzheimer's disease pathogenesis: Too much, too little
or in the wrong place?
Canzoniero LM, Snider BJ.
Department of Biology and Environmental Sciences, University of Sannio,
Benevento, Italy.
Our understanding of the molecular genetics and biochemical pathology of
Alzheimer's disease has progressed tremendously in the past decade. The
metabolism of amyloid beta-peptide is being unraveled, and specific anti-amyloid
therapies are now in clinical trials worldwide. The precise biophysical
structure of the amyloid beta-peptide that causes neuronal dysfunction remains
under investigation, as does the interaction between amyloid peptides and tau
hyperphosphorylation, but these two molecules likely play key roles in neuronal
dysfunction in Alzheimer's disease. Despite these advances, the cell biology of
neuronal dysfunction and cell death in the Alzheimer's disease brain remains
poorly understood. This brief review will explore the role of calcium (Ca;{2+})
in neuronal death occurring during Alzheimer's disease. The evidence for
glutamate receptor-mediated Ca;{2+} overload, or excitotoxicity, and other
derangements of Ca;{2+} homeostasis in cell culture and animal models of
Alzheimer's disease is reviewed. Finally, we raise the possibility that some of
the neuronal death observed in Alzheimer's disease might be associated with a
reduction in rather than an increase in cytosolic Ca;{2+} levels, an idea with
potentially important therapeutic implications.
-----
CNS Spectr. 2005 Nov;10 Suppl 18(11):17-21.
Rationalizing Therapeutic Approaches in Alzheimer's Disease.
Grossberg GT.
Department of Psychiatry and Human Behavior, Saint Louis University Health
Science Center, Saint Louis, MO, USA.
Deficits in cholinergic and glutamatergic neurotransmission have been linked to
the symptomatology of Alzheimer's disease, and current therapies for
Alzheimer's, including cholinesterase inhibitors (ChEIs) and the N-methyl-d-aspartate
receptor antagonist memantine, have been developed to compensate for these
deficits. This article reviews the results of clinical trials involving agents
approved by the United States Food and Drug Administration for use in the
treatment of Alzheimer's disease (namely, ChEIs for mild to moderate Alzheimer's
and memantine for moderate to severe Alzheimer's). In particular, the efficacy
of current monotherapy strategies in the treatment of cognitive and functional
symptoms of Alzheimer's disease will be addressed. In addition, data from a
clinical trial examining the use of a ChEI in combination with memantine will
also be discussed, as it has been hypothesized that ChEIs and memantine may
offer synergistic benefits due to their distinct mechanisms of action.
-----
CNS Spectr. 2005 Nov;10 Suppl 18(11):22-25.
Behavioral and Neuropsychiatric Outcomes in Alzheimer's Disease.
Cummings JL.
Alzheimer's Disease Research Center, Department of Neurology, University of
California, Los Angeles, Los Angeles, CA, USA.
Behavioral and psychological symptoms of dementia pose significant challenges in
the management of patients with Alzheimer's disease. Neuropsychiatric symptoms
are associated with cognitive decline, highly impaired activities of daily
living, and frontal lobe pathology. Moreover, behavioral and psychological
symptoms can diminish patient quality of life, increase caregiver distress, and
accelerate nursing home placement. Although these symptoms are often associated
with the later stages of Alzheimer's disease, a high percentage of individuals
with mild cognitive impairment or mild Alzheimer's report symptoms as well. This
article provides an overview of behavioral and neuropsychiatric symptoms
associated with Alzheimer's disease and discusses nonpharmacologic and
pharmacologic approaches to the management of such symptoms. For patients with
severe behavioral and psychological symptoms of dementia, pychotropic agents may
be warranted, whereas approved therapies for Alzheimer's, including
cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist
memantine, may be appropriate in less severe cases.
-----
Int J Neuropsychopharmacol. 2005 Sep 5;:1-10 [Epub ahead of print]
Treatment of behavioural, cognitive and circadian rest-activity
cycle disturbances in Alzheimer's disease: haloperidol vs. quetiapine.
Savaskan E, Schnitzler C, Schroder C, Cajochen C, Muller-Spahn F, Wirz-Justice
A.
Geriatric Psychiatry, University Psychiatric Hospitals, CH-4025 Basel,
Switzerland.
this 5-wk, open-label, comparative study investigated the effects of quetiapine
and haloperidol on behavioural, cognitive and circadian rest-activity cycle
disturbances in patients with alzheimer's disease (ad). out of a total of 30
patients enrolled in the study, there were 22 completers, 11 in the quetiapine
group (mean age 81.9+/-1.8 yr, mean baseline mmse 19.9+/-1.3, mean dose 125 mg)
and 11 in the haloperidol group (mean age 82.3+/-2.5 yr, mean baseline mmse
18.1+/-1.3, mean dose 1.9 mg). as shown in the neuropsychiatric inventory, both
medications reduced delusion and agitation, whereas quetiapine additionally
improved depression and anxiety. haloperidol worsened aberrant motor behaviour
and caused extrapyramidal symptoms. in the consortium to establish a registry
for alzheimer's disease (cerad) neuropsychological test battery which assessed
cognitive parameters, quetiapine improved word recall; significant interaction
terms revealed differences between quetiapine and haloperidol in word-list
memory and constructional praxis. according to the nurses' observation scale for
geriatric patients (nosger) quetiapine improved instrumental activities of daily
living. actimetry documented the circadian rest-activity cycle before and after
treatment. sleep analysis revealed that patients receiving quetiapine had
shorter wake bouts during the night, whereas patients receiving haloperidol had
fewer though longer immobile phases. the study provides evidence that quetiapine
at a moderate dose may be efficacious in treating behavioural disturbances in
ad, with better tolerability than haloperidol.
-----
Curr Drug Targets CNS Neurol Disord. 2005 Aug;4(4):383-403.
Alzheimer's disease-associated neurotoxic mechanisms and
neuroprotective strategies.
Pereira C, Agostinho P, Moreira PI, Cardoso SM, Oliveira CR.
Center for Neuroscience and Cell Biology and Institute of Biochemistry, Faculty
of Medicine of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal.
catarina@cnc.cj.uc.pt
The characteristic hallmarks of Alzheimer's disease (AD), the most common form
of dementia in the elderly, include senile plaques, mainly composed of beta-amyloid
(Abeta) peptide, neurofibrillary tangles and selective synaptic and neuronal
loss in brain regions involved in learning and memory. Genetic studies, together
with the demonstration of Abeta neurotoxicity, led to the development of the
amyloid cascade hypothesis to explain the AD-associated neurodegenerative
process. However, a modified version of this hypothesis has emerged, the Abeta
cascade hypothesis, which takes into account the fact that soluble oligomeric
forms and protofibrils of Abeta and its intraneuronal accumulation also play a
key role in the pathogenesis of the disease. Recent evidence posit that synaptic
dysfunction triggered by non fibrillar Abeta species is an early event involved
in memory decline in AD. The current understanding of the molecular mechanisms
responsible for impaired synaptic function and cognitive deficits is outlined in
this review, focusing on oxidative stress and disturbed metal ion homeostasis,
Ca(2+) dysregulation, mitochondria and endoplasmic reticulum dysfunction,
cholesterol dyshomeostasis and impaired neurotransmission. The activation of
apoptotic cell death as a mechanism of neuronal loss in AD, and the prominent
role of neuroinflammation in this neurodegenerative disorder, are also reviewed
herein. Furthermore, we will focus on the more relevant therapeutical strategies
currently used, namely those involving antioxidants, drugs for neurotransmission
improvement, hormonal replacement, gamma- and beta- secretase inhibitors, Abeta
clearance agents (Abeta immunization, disruption of Abeta fibrils, modulation of
the cholesterol-mediated Abeta transport), non-steroidal anti-inflammatory drugs
(NSAIDs), microtubules stabilizing drugs and kinase inhibitors.
-----
Annu Rev Med. 2005 Aug 11; [Epub ahead of print]
Current Pharmacotherapy for Alzheimer's Disease.
Lleo A, Greenberg SM, Growdon JH.
Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts
02114.
Alzheimer's disease (AD) is an age-related neurodegenerative disease that
affects approximately 4.5 million people in the United States. The mainstays of
current pharmacotherapy for AD are compounds aimed at increasing the levels of
acetylcholine in the brain, thereby facilitating cholinergic neurotransmission
through inhibition of the cholinesterases. These drugs, known as
acetylcholinesterase inhibitors (AChEIs), were first approved by the U.S. Food
and Drug Administration (FDA) in 1995 based on clinical trials showing modest
symptomatic benefit on cognitive, behavioral, and global measures. In 2004 the
FDA approved memantine, an NMDA antagonist, for treating dementia symptoms in
moderate to severe AD cases. In clinical practice, memantine may be
co-administered with an AChEI, although neither drug individually or in
combination affects the underlying pathophysiology of dementia. Dementia in AD
results from progressive synaptic loss and neuronal death. As knowledge of the
mechanisms responsible for neurodegeneration in AD increases, it is anticipated
that neuroprotective drugs to slow or prevent neuronal dysfunction and death
will be developed to complement current symptomatic treatments. Expected online
publication date for the Annual Review of Medicine Volume 57 is January 7, 2006.
Please see http://www.annualreviews.org/catalog/pub_dates.asp for revised
estimates.
-----
Dement Geriatr Cogn Disord. 2005;20(2-3):192-7. Epub 2005 Aug 3.
Efficacy of rivastigmine in Alzheimer's disease patients with
rapid disease progression: results of a meta-analysis.
Farlow MR, Small GW, Quarg P, Krause A.
Indiana University School of Medicine, Indianapolis, Ind., USA.
Background: Alzheimer's disease (AD) patients experiencing more rapid symptom
progression are likely to have a poorer prognosis than those experiencing slow
symptom progression. In a recent retrospective analysis, treatment effects of
rivastigmine were more pronounced in AD patients with rapid cognitive decline
than in those with slow cognitive decline. This warranted further investigation.
Methods: Rapidly and slowly progressing patients were identified by rates of
cognitive decline [>/=4 points and <4 points, respectively, on the Alzheimer's
Disease Assessment Scale - cognitive subscale (ADAS-cog)] during 26 weeks of
placebo treatment in four randomized controlled trials (weeks 0-26). This
meta-analysis evaluated rates of cognitive decline in both subgroups during
subsequent open-label rivastigmine 26-week extension studies (weeks 26-52). A
longitudinal mixed effects model compared cognitive decline in rapidly and
slowly progressing patients, including correction for possible regression to the
mean. Results: 180 (75%) rapidly and 337 (78%) slowly progressing patients
provided ADAS-cog data after 26 weeks of open-label rivastigmine treatment.
Improvements in cognitive symptoms were observed during the first 12 weeks,
which were more pronounced in patients with rapid progression than in those with
slow progression. Rapidly progressing patients experienced significantly greater
cognitive benefits than slowly progressing patients (p = 0.029), who experienced
a modest decline in cognitive symptoms at the end of the study. Comment:
Patients experiencing rapid symptom progression may receive greater benefit from
rivastigmine than those with slow progression. In this study, cholinesterase
inhibition appeared to be of particular utility in the management of AD patients
whose symptoms were rapidly worsening. Copyright (c) 2005 S. Karger AG, Basel.
-----
Arch Intern Med. 2005 Aug 8-22;165(15):1737-42.
The prevention of hip fracture with risedronate and
ergocalciferol plus calcium supplementation in elderly women with Alzheimer
disease: a randomized controlled trial.
Sato Y, Kanoko T, Satoh K, Iwamoto J.
Department of Neurology, Mitate Hospital, Tagawa, Japan. y-sato@ktarn.or.jp
BACKGROUND: A high incidence of fractures, particularly of the hip, represents
an important problem in patients with Alzheimer disease (AD), who are prone to
falls and have osteoporosis. We previously found that deficiency of
25-hydroxyvitamin D and compensatory hyperparathyroidism cause reduced bone
mineral density in female patients with AD. We address the possibility that
treatment with risedronate sodium and ergocalciferol plus calcium
supplementation may reduce the incidence of nonvertebral fractures in elderly
women with AD. METHODS: A total of 500 elderly women with AD were randomly
assigned to daily treatment with 2.5 mg of risedronate sodium or a placebo,
combined with 1000 IU of ergocalciferol and 1200 mg of elementary calcium, and
followed up for 18 months. RESULTS: At baseline, patients of both groups showed
25-hydroxyvitamin D deficiency with compensatory hyperparathyroidism. During the
study period, bone mineral density in the risedronate group increased by 4.1%
and decreased by 0.9% in the control group. Vertebral fractures occurred in 29
patients (24 hip fractures) in the control group and 8 patients (5 hip
fractures) in the risedronate group. The relative risk in the risedronate group
compared with the control group was 0.28 (95% confidence interval, 0.13-0.59).
CONCLUSIONS: Elderly patients with AD hypovitaminosis D are at increased risk
for hip fracture. Treatment with risedronate and ergocalciferol may be safe and
effective in reducing the risk of a fracture in elderly patients with AD.
-----
Curr Med Res Opin. 2005 Aug;21(8):1317-27.
Rivastigmine and donepezil treatment in moderate to
moderately-severe Alzheimer's disease over a 2-year period.
Bullock R, Touchon J, Bergman H, Gambina G, He Y, Rapatz G, Nagel J, Lane R.
Kingshill Research Centre, Victoria Hospital, Swindon, UK. roger.bullock@kingshill-research.org
OBJECTIVES: Randomised controlled trials that directly compare cholinesterase
inhibitors for the treatment of Alzheimer's disease have been characterised by
significant methodological limitations. As a consequence, they have failed to
establish whether there are differences between agents in this class. To help
address this question, a double-blind, randomised, controlled, multicentre trial
was designed to evaluate the efficacy and tolerability of cholinesterase
inhibitor treatment in patients with moderate to moderately-severe Alzheimer's
disease over a 2-year period. METHODS: Patients were randomly assigned to
rivastigmine 3-12 mg/day or donepezil 5-10 mg/day. Efficacy measures comprised
assessments of cognition, activities of daily living, global functioning and
behavioural symptoms. Safety and tolerability assessments included adverse
events and measurement of vital signs. RESULTS: In total, 994 patients received
cholinesterase inhibitor treatment (rivastigmine, n = 495; donepezil, n = 499),
and 57.9% of patients completed the study. The most frequent reason for
premature discontinuation in both treatment groups was adverse events, primarily
gastrointestinal. Adverse events were more frequent in the rivastigmine group
during the titration phase, but similar in the maintenance phase. Serious
adverse events were reported by 31.7% of rivastigmine- and 32.5% of donepezil-treated
patients, respectively. Rivastigmine and donepezil had similar effects on
measures of cognition and behaviour, but rivastigmine showed a statistically
significant advantage on measures of activities of daily living and global
functioning in the ITT-LOCF population. However, this was not maintained in the
non-ITT-LOCF populations. In secondary subgroup analyses, AD patients who had
genotypes that encoded for full expression of the butyrylcholinesterase enzyme (BuChE
wt/wt; n = 226/340), who were < 75 years of age (n = 362/994) or who had
symptoms suggestive of concomitant Lewy body disease (n = 49/994) showed
significantly greater benefits from rivastigmine treatment. CONCLUSIONS:
Cholinesterase inhibitor treatment may offer continued therapeutic benefit for
up to 2 years in patients with moderate AD. Although both drugs performed
similarly on cognition and behaviour, rivastigmine may provide greater benefit
in activities of daily living and global functioning.
-----
BMJ. 2005 Aug 6;331(7512):321-7.
Cholinesterase inhibitors for patients with Alzheimer's disease:
systematic review of randomised clinical trials.
Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, van den Bussche H.
Department of Primary Medical Care, Center of Psychosocial Medicine, University
Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany.
kaduszki@uke.uni-hamburg.de
OBJECTIVES: Pharmacological treatment of Alzheimer's disease focuses on
correcting the cholinergic deficiency in the central nervous system with
cholinesterase inhibitors. Three cholinesterase inhibitors are currently
recommended: donepezil, rivastigmine, and galantamine. This review assessed the
scientific evidence for the recommendation of these agents. DATA SOURCES: The
terms "donepezil", "rivastigmine", and "galantamine", limited by
"randomized-controlled-trials" were searched in Medline (1989-November 2004),
Embase (1989-November 2004), and the Cochrane Database of Systematic Reviews
without restriction for language. STUDY SELECTION: All published, double blind,
randomised controlled trials examining efficacy on the basis of clinical
outcomes, in which treatment with donepezil, rivastigmine, or galantamine was
compared with placebo in patients with Alzheimer's disease, were included. Each
study was assessed independently, following a predefined checklist of criteria
of methodological quality. RESULTS: 22 trials met the inclusion criteria.
Follow-up ranged from six weeks to three years. 12 of 14 studies measuring the
cognitive outcome by means of the 70 point Alzheimer's disease assessment
scale--cognitive subscale showed differences ranging from 1.5 points to 3.9
points in favour of the respective cholinesterase inhibitors. Benefits were also
reported from all 12 trials that used the clinician's interview based impression
of change scale with input from caregivers. Methodological assessment of all
studies found considerable flaws--for example, multiple testing without
correction for multiplicity or exclusion of patients after randomisation.
CONCLUSION: Because of flawed methods and small clinical benefits, the
scientific basis for recommendations of cholinesterase inhibitors for the
treatment of Alzheimer's disease is questionable.
-----
Br J Psychiatry. 2005 Aug;187:143-7.
Brief psychotherapy in Alzheimer's disease: randomised controlled
trial.
Burns A, Guthrie E, Marino-Francis F, Busby C, Morris J, Russell E, Margison F,
Lennon S, Byrne J.
Department of Psychiatry, 2nd Floor, Education and Research Centre, Wythenshawe
Hospital, Southmoor Road, Manchester M23 9LT, UK. Alistair.Burns@manchester.ac.uk
BACKGROUND: Although there is good evidence that interventions for carers of
people with Alzheimer's disease can reduce stress, no systematic studies have
investigated psychotherapeutic intervention for patients themselves. This may be
important in the earlier stages of Alzheimer's disease, where insight is often
preserved. AIMS: The aim was to assess, in a randomised controlled trial,
whether psychotherapeutic intervention could benefit cognitive function,
affective symptoms and global well-being. METHOD: Individuals were randomised to
receive six sessions of psychodynamic interpersonal therapy or treatment as
usual; cognitive function, activities of daily living, a global measure of
change, and carer stress and coping were assessed prior to and after the
intervention. RESULTS: No improvement was found on the majority of outcome
measures. There was a suggestion that therapy had improved the carers' reactions
to some of the symptoms. CONCLUSIONS: There is no evidence to support the
widespread introduction of brief psychotherapeutic approaches for those with
Alzheimer's disease. However, the technique was acceptable and helpful
individually.
-----
Cochrane Database Syst Rev. 2005 Jul 20;(3):CD003154.
Memantine for dementia.
Areosa SA, Sherriff F, McShane R.
BACKGROUND: Memantine, a low affinity antagonist to glutamate NMDA receptors,
may prevent excitatory neurotoxicity in dementia. OBJECTIVES: To determine
efficacy and safety of memantine for people with Alzheimer's disease (AD),
vascular (VD) and mixed dementia. SEARCH STRATEGY: The Specialized Register of
the Cochrane Dementia and Cognitive Improvement Group was searched on 20 May
2005. This register contains references from all major healthcare databases and
many ongoing trial databases and is updated regularly. In addition the search
engines Copernic and Google were used to identify unpublished trials through
inspection of the websites of licensing bodies like the FDA , EMEA and NICE and
of companies' websites (Lundbeck, Merz, Forest, Suntori etc) and clinical trials
registries. SELECTION CRITERIA: Double-blind, parallel group,
placebo-controlled, randomized trials of memantine in people with dementia. DATA
COLLECTION AND ANALYSIS: Data were pooled where possible. Intention-to-treat
(ITT) and observed case (OC) analyses are reported. MAIN RESULTS: 1. Moderate to
severe AD. Two out of three six month studies show a small beneficial effect of
memantine. Pooled data indicate a beneficial effect at six months on cognition
(4.12 points on the 100 point SIB , 95% CI 2.14 to 5.74, P < 0.00001),
activities of daily living (1.27 points on the 54 point ADCS-ADLsev, 95% CI 0.44
to 2.09, P = 0.003) and behaviour (2.76 points on the 144 NPI, 95% CI 0.88 to
4.63, P = 0.004), supported by clinical impression of change (0.28 points on the
7 point CIBIC+, 95% CI 0.15 to 0.41, P < 0.0001).2. Mild to moderate AD. In a
single six month trial, memantine had a beneficial effect on ITT analysis of
cognition, (1.9 ADAS-Cog points, 95% CI 0.35 to 3.45, P = 0.02) and behaviour
(3.50 NPI points 95% CI 0.15 to 6.85, P = 0.04) supported by clinical global
impression of change (0.30 CIBIC+ points, 95% CI 0.09 to 0.51, P = 0.005), but
no effect on activities of daily living or OC analysis of cognition. The
statistical significance of these benefits could be overturned by data from two
unpublished studies which are known to show no significant effect. 3. Mild to
moderate vascular dementia. In two six month studies, memantine improved
cognition (1.85 ADAS-Cog points, 95% CI 0.88 to 2.83, P = 0.0002), and behaviour
(0.84 95% CI 0.06 to 0.91, P = 0.03) but this was not supported by clinical
global measures.4. Patients taking memantine appeared to be less likely to
develop agitation (93/1167 [8%] versus 134/1141 [12%] (Peto odds ratio (OR):
0.65, 95% CI 0.49 to 0.86, P = 0.002). This was consistently seen in moderate to
severe dementia. There were no data which suggested an effect on agitation which
is already present.5. Memantine is well tolerated. AUTHORS' CONCLUSIONS:
Published data suggest a small beneficial effect of memantine at six months in
moderate to severe AD. The beneficial effect on cognition in patients with mild
to moderate vascular dementia was not detectable on global assessment at six
months. Whether memantine has any effect in mild to moderate AD is unknown.
-----
Nervenarzt. 2005 Jul 19; [Epub ahead of print]
[Direct neuronal effects of statins.]
[Article in German]
Bosel J, Endres M.
Neurologische Klinik und Poliklinik, Charite - Universitatsmedizin Berlin, .
Statins, i.e. HMG-CoA reductase inhibitors, reduce the risk of stroke and may
have therapeutic potential for other neurologic diseases, including multiple
sclerosis and Alzheimer's disease. In addition to lowering cholesterol levels,
statins exert a number of cholesterol-independent (pleiotropic) effects. While
endothelial, anti-thrombotic, anti-inflammatory, and immunomodulatory, i.e.
peripheral, effects of statins are well known, little is known about the direct
effects on neurons. This may be of clinical relevance because some statins are
able to cross the blood-brain barrier. Recent experimental studies demonstrate
that statins reduce the activity of neuronal glutamate receptors and protect
neurons from excitotoxic insults. At higher doses, however, statins may also
inhibit neurite sprouting and even induce neuronal apoptosis.
-----
Int Psychogeriatr. 2005 Jun;17(2):221-36.
Effect of morning bright light treatment for rest-activity
disruption in institutionalized patients with severe Alzheimer's disease.
Dowling GA, Hubbard EM, Mastick J, Luxenberg JS, Burr RL, Van Someren EJ.
University of California, San Francisco, Department of Physiological Nursing, 2
Koret Way, Room N631, San Francisco, CA 94143-0610, USA. glenna.dowling@nursing.ucsf.edu
BACKGROUND: Disturbances in rest-activity rhythm are prominent and disabling
symptoms in Alzheimer's disease (AD). Nighttime sleep is severely fragmented and
daytime activity is disrupted by multiple napping episodes. In most
institutional environments, light levels are very low and may not be sufficient
to enable the circadian clock to entrain to the 24-hour day. The purpose of this
randomized, placebo-controlled, clinical trial was to test the effectiveness of
morning bright light therapy in reducing rest-activity (circadian) disruption in
institutionalized patients with severe AD. METHOD: Subjects (n = 46, mean age 84
years) meeting the NINCDS-ADRDA (National Institute of Neurological and
Communicative Disorders and Stroke--the Alzheimer's Disease and Related
Disorders Association) AD diagnostic criteria were recruited from two large,
skilled nursing facilities in San Francisco, California. The experimental group
received one hour (09:30-10:30) of bright light exposure (> or = 2500 lux in
gaze direction) Monday through Friday for 10 weeks. The control group received
usual indoor light (150-200 lux). Nighttime sleep efficiency, sleep time, wake
time and number of awakenings and daytime wake time were assessed using
actigraphy. Circadian rhythm parameters were also determined from the
actigraphic data using cosinor analysis and nonparametric techniques. Repeated
measures analysis of variance (ANOVA) was used to test the primary study
hypotheses. RESULTS AND CONCLUSION: Although significant improvements were found
in subjects with aberrant timing of their rest-activity rhythm, morning bright
light exposure did not induce an overall improvement in measures of sleep or the
rest-activity in all treated as compared to control subjects. The results
indicate that only subjects with the most impaired rest-activity rhythm respond
significantly and positively to a brief (one hour) light intervention.
-----
Geriatrics. 2005 Jun;Suppl:14-20.
Refining treatment guidelines in Alzheimer's disease.
Doody RS.
Baylor College of Medicine, Houston, Texas, USA.
The introduction of new therapies into the clinical arena often requires that
prescribing clinicians determine how these new treatments should be integrated
into an existing standard of care, typically with little more than clinical
trial data to guide them. However, trial outcome measures may not always
translate easily into useful information for the practicing physician. Since the
publication of dementia treatment guidelines in 2001, new data on Alzheimer's
disease (AD) therapies have become available. Notably, memantine has emerged as
the first medication indicated for the moderate-to-severe stages of AD. This
review summarizes pivotal clinical trial data on memantine in the treatment of
moderate-to-severe AD and describes how these results may be interpreted for use
in the clinical treatment setting. The studies showed that memantine, both alone
and in combination with donepezil, was associated with positive, clinically
relevant effects on cognitive and functional ability. Further, memantine in
combination with donepezil also was significantly better than donepezil alone in
management of behavioral symptoms. This review will conclude with a discussion
of how new data on AD treatments will potentially change current treatment
parameters.
-----
Clin Nutr. 2005 Jun;24(3):390-7.
Effect of oral administration of a whole formula diet on
nutritional and cognitive status in patients with Alzheimer's disease.
Salas-Salvado J, Torres M, Planas M, Altimir S, Pagan C, Gonzalez ME, Johnston
S, Puiggros C, Bonada A, Garcia-Lorda P.
Unitat de Nutricio Humana, Facultat de Medicina de Reus, Universitat Rovira i
Virgili, C/San Llorenc 21, 43201 Reus (Tarragona), Spain; Nutrition and
Dietetics, Hospital Universitari de Sant Joan, Reus, Spain.
Aims: To evaluate the effect of a whole formula diet on nutritional and
cognitive status in Alzheimer's disease patients. Methods: Patients were
randomly assigned to two interventions: a whole formula diet based on
lyophilised foods (Treatment Group, n=24) or nutritional advice (Control Group,
n=29). Energy intake, body weight, biochemistry, Mini Nutritional Assessment (MNA)
and Pfeiffer's tests were determined at baseline and at 3 months of treatment.
Results: No differences were observed between groups at baseline. Energy intake
tended to increase in the Treatment Group and to decrease in the Control Group,
although differences were not significant. The improvement in MNA and Pfeiffer
test scores was not significantly different between groups. Body weight
increased by 2.06+/-1.9kg in the Treatment Group and by 0.32+/-3.04kg in the
Control Group (P=0.007). The increases in albumin (P=0.007), haemoglobin
(P=0.002) and serum ferritin (P=0.009) were higher in the Treatment Group than
in controls. A similar rate of serious adverse events (hospitalisation or death)
was observed in both groups. Conclusions: Administration of this whole formula
has a positive impact on nutritional status. The great diversity in textures and
tastes enable these formulations to be administered to a wide range of patients
with or without liquid dysphagia.
-----
Eur Arch Psychiatry Clin Neurosci. 2005 May 20; [Epub ahead of print]
Risk factors and early signs of Alzheimer's disease in a family
study sample Risk of AD.
Heun R, Kolsch H, Jessen F.
Dept. of Psychiatry, University of Bonn, Venusberg, 53105, Bonn, Germany.
OBJECTIVE : Several predictors of Alzheimer's disease (AD) have been identified.
However, the relevance and independent contribution of risk factors and of
possible early signs such as mild cognitive impairment and subjective memory
impairment on the development of AD has not been investigated prospectively in a
cohort of non-demented elderly including first-degree relatives of AD subjects.
METHOD : The development of AD was investigated in 757 non-demented elderly.
Initial diagnoses were made from personal interviews. Information on 633
subjects after 4.7 +/- 1.2 years (mean +/- SD) was obtained either from personal
or family history interviews. Using forward logistic regression analysis,
predictors were identified by comparing their presence in 38 subjects who
developed AD and 577 subjects who remained non-demented. RESULTS : The most
important predictors of later Alzheimer's disease were increased age (Odds ratio
OR = 1.086/additional year, p < 0.001), initial subjective memory complaints (OR
= 2.68, p = 0.019), initial mild cognitive impairment (OR = 2.51, p = 0.032) and
female gender (OR = 2.84, p = 0.069). Exploratory analysis revealed that
previous depression after the age of 60 years (OR = 2.37, p = 0.033) and the
presence of the apolipoprotein E4 allele (OR = 2.49, p = 0.043) individually
predicted new AD during follow-up. A positive family history of AD (i. e. being
a first degree relative of a subject suffering from AD) did not significantly
influence the development of AD (p > 0.2). CONCLUSIONS : Increased age, the
presence of mild cognitive impairment, subjective memory impairment and gender
are the most relevant independent predictors of later Alzheimer's disease that
may be used in combination for clinical prediction of AD.
-----
Curr Med Chem. 2005;12(10):1137-47.
Therapeutic opportunities in Alzheimer disease: one for all or
all for one?
Marlatt MW, Webber KM, Moreira PI, Lee HG, Casadesus G, Honda K, Zhu X, Perry G,
Smith MA.
Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road,
Cleveland, Ohio 44106, USA.
In recent years, Alzheimer disease (AD) has received great attention as an
incurable and fatal disease that threatens the lives of aging individuals.
Debates regarding areas of research and treatment designs have made headlines as
scientists in the field question ongoing work. Despite these academic quarrels,
significant insights concerning the cellular and molecular basis of AD have
illuminated the potential causes and consequences of AD pathogenesis in the
human brain. Additionally, assigning relationships among scientific evidence is
difficult due to the nature of the disease. It is crucial to note that all
findings do not constitute causality as AD has many stages of progression, and
therefore a particular finding may reflect disease epiphenomenon. Determining
the primary causes of disease are even more problematic when considering that a
succinct timeline in which a normal aging brain develops AD-like changes due to
a single cause may not be appropriate, as increasing lines of evidence indicate
that multiple factors likely contribute to the clinical manifestation of AD.
Implications for therapeutic strategies are dramatically affected by viewing AD
as a multi-factorial disease state, one specific treatment may not be able to
prevent or reverse AD if this is indeed the case. In this regard, the current
focus on individual therapeutic targets may prove to be ineffective in the
successful treatment of AD; however, if taken in combination, these singular
therapies may likely result in the global suppression of AD. In this review, the
scientific basis for common AD therapeutics as well as the efficacy of these
treatments will be discussed.
-----
Arch Neurol. 2005 May;62(5):753-7.
Atorvastatin for the treatment of mild to moderate Alzheimer
disease: preliminary results.
Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Browne P, Wasser D,
Johnson-Traver S, Lochhead J, Ziolwolski C.
Author Affiliations: Sun Health Research Institute, Sun City, AZ 85351, USA.
larry.sparks@sunhealth.org
BACKGROUND: Laboratory evidence of cholesterol-induced production of amyloid
beta as a putative neurotoxin precipitating Alzheimer disease, along with
epidemiological evidence, suggests that cholesterol-lowering statin drugs may
favorably influence the progression of the disorder. OBJECTIVE: To determine if
treatment with atorvastatin calcium affects the cognitive and/or behavioral
decline in patients with mild to moderate Alzheimer disease. DESIGN: Pilot
intention-to-treat, proof-of-concept, double-blind, placebo-controlled,
randomized (1:1) trial with a 1-year exposure to once-daily atorvastatin calcium
(80 mg; two 40-mg tablets) or placebo using last observation carried forward
analysis of covariance as the primary method of statistical assessment.
PARTICIPANTS: Individuals with mild to moderate Alzheimer disease (Mini-Mental
State Examination score of 12-28) were recruited. Of the 98 participants
providing informed consent, 71 were eligible for randomization, 67 were
randomized, and 63 subjects completed the 3-month visit and were considered
evaluable. MAIN OUTCOME MEASURES: The primary outcome measures were change in
Alzheimer's Disease Assessment Scale-cognitive subscale and the Clinical Global
Impression of Change Scale scores. The secondary outcome measures included
scores on the Mini-Mental State Examination, Geriatric Depression Scale, the
Neuropsychiatric Inventory Scale, and the Alzheimer's Disease Cooperative
Study-Activities of Daily Living Inventory. The tertiary outcome measures
included total cholesterol, low-density lipoprotein cholesterol, and very
low-density lipoprotein cholesterol levels. RESULTS: Atorvastatin reduced
circulating cholesterol levels and produced a positive signal on each of the
clinical outcome measures compared with placebo. This beneficial effect reached
significance for the Geriatric Depression Scale and the Alzheimer's Disease
Assessment Scale-cognitive subscale at 6 months and was significant at the level
of a trend for the Alzheimer's Disease Assessment Scale-cognitive subscale,
Clinical Global Impression of Change Scale, and Neuropsychiatric Inventory Scale
at 12 months assessed by analysis of covariance with last observation carried
forward. CONCLUSION: Atorvastatin treatment may be of some clinical benefit and
could be established as an effective therapy for Alzheimer disease if the
current findings are substantiated by a much larger multicenter trial.
-----
J Am Geriatr Soc. 2005 May;53(5):793-802.
Nighttime insomnia treatment and education for Alzheimer's
disease: a randomized, controlled trial.
McCurry SM, Gibbons LE, Logsdon RG, Vitiello MV, Teri L.
Department of Psychosocial and Community Health, University of Washington,
Seattle, Washington.
Objectives: To evaluate whether a comprehensive sleep education program
(Nighttime Insomnia Treatment and Education for Alzheimer's Disease (NITE-AD))
could improve sleep in dementia patients living at home with their family
caregivers. Design: A randomized, controlled trial. Participants: Thirty-six
community-dwelling patients with Alzheimer's disease (AD) and their family
caregivers. Intervention: All participants received written materials describing
age- and dementia-related changes in sleep and standard principles of good sleep
hygiene. Caregivers in active treatment (n=17) received specific recommendations
about setting up and implementing a sleep hygiene program for the dementia
patient and training in behavior management skills. Patients in active treatment
were also instructed to walk daily and increase daytime light exposure with the
use of a light box. Control subjects (n=19) received general dementia education
and caregiver support. Measurements: Primary sleep outcomes were derived for
patients and caregivers from 1 week of sleep-wake activity measured at baseline,
posttest (2 months), and 6-month follow-up using an Actillume wrist-movement
recorder. Secondary patient outcomes included the Epworth Sleepiness Scale, the
Cornell Depression Scale, and the Revised Memory and Behavior Problem Checklist.
Caregiver self-reports included the Pittsburgh Sleep Quality Index and the
Center for Epidemiological Study of Depression Scale. Results: Patients
participating in NITE-AD showed significantly greater (P<.05) posttest
reductions in number of nighttime awakenings, total time awake at night, and
depression, and increases in weekly exercise days than control subjects. At
6-month follow-up, treatment gains were maintained, and additional significant
improvements in duration of night awakenings emerged. When cognitive level was
controlled, NITE-AD patients had lower longitudinal ratings of daytime
sleepiness than controls. There was a trend for control subjects to spend more
time in bed at 6 months than NITE-AD patients. Conclusion: This study provides
the first evidence that patients with AD who are experiencing sleep problems can
benefit from behavioral techniques (specifically, sleep hygiene education, daily
walking, and increased light exposure) that are known to improve sleep in
nondemented, institutionalized older adults.
-----
Psychol Neuropsychiatr Vieil. 2005 Mar;3 Suppl 1:S42-50.
[Non-pharmacologic approach in severe dementia]
[Article in French]
Pancrazi MP, Metais P.
Departement medico-gerontologique Paris, France. mp.pancrazi@wanadoo.fr
Care for patients with Alzheimer's disease, particularly with severe dementia,
requires a global therapeutic strategy integrating pharmacological approach into
the environmental dimensions, psychotherapeutics and rehabilitation. The
objective is to maintain autonomy as long as possible but also to improve the
quality of life by reducing the psychological suffering of patients and
families. In severe dementia, behavioral techniques and organization of the
environment are possible at home but, actually, most of the patients are
institutionalized. Structures having a specific project of life, of care and
specific architectural design should be preferred. Education and support for
caregivers as well as training of the nursing staff are essential to develop
better attitudes toward the patient, improve communication and optimize the
quality of life. In spite of the low level of evidence in the evaluation of
these strategies on account of the lack of adapted indicators and rarity of
specific research, widely spread techniques can confer special purport to this
difficult stage for the patients and their family.
-----
J Am Osteopath Assoc. 2005 Mar;105(3):145-58.
Cholinesterase inhibitors in the treatment of dementia.
Ellis JM.
Director, Neuroscience Research of the Berkshires, 100 Wendell Ave, Pittsfield,
MA 01201-6941. IMdocjay@aol.com.
Dementia associated with probable Alzheimer's disease (AD) is one of the most
common types of dementia. Patients with AD often have cholinergic deficits in
association with the disease. The cholinesterase inhibitors donepezil
hydrochloride, galantamine hydrobromide, and rivastigmine tartrate are the
current mainstays of symptomatic treatment for patients with AD. In clinical
trials for all three agents, beneficial effects on standard measures of
cognitive and global function have been observed in patients with mild to
moderate AD. Although none of the cholinesterase inhibitors has been approved
for treatment of patients in advanced stages of AD, all three agents have had
beneficial cognitive effects among patients with less severe forms of the
disease. The author provides information on recommended dosing for all three
medications, noting that cholinesterase inhibitors must be titrated carefully.
When administered with caution, galantamine, rivastigmine, and donepezil are
generally well-tolerated pharmacologic treatment options. The author notes that,
after patients and their caregivers understand that no change in status is
considered an "improvement" and a desirable clinical outcome for patients with
AD, if no benefits are achieved with the use of one cholinesterase inhibitor,
switching to another medication in this class might be beneficial. The author
further suggests that the benefits found in cholinesterase inhibitors for
patients with AD might also be applicable to patients with other types of
dementia such as vascular dementia and dementia with Lewy bodies as cholinergic
deficits have been reported in association with these types of dementia as well.
-----
J Gerontol A Biol Sci Med Sci. 2005 Mar;60(3):368-74.
Maintenance of effects of the home environmental skill-building
program for family caregivers and individuals with Alzheimer's disease and
related disorders.
Gitlin LN, Hauck WW, Dennis MP, Winter L.
Suite 513, Philadelphia, PA 19107. laura.gitlin@jefferson.edu.
BACKGROUND: Few studies evaluate whether short-term intervention effects are
maintained over time for families caring for persons with dementia. This article
examines whether treatment effects found at 6 months following active treatment
were sustained at 12 months for 127 family caregivers who participated in an
occupational therapy intervention tested as part of the National Institutes of
Health Resources for Enhancing Alzheimer's Caregiver Health (REACH) initiative.
METHODS: A randomized two-group design was implemented with three assessment
points: baseline, 6 months, and 12 months. Caregivers were randomly assigned to
a usual care control group or intervention that consisted of six occupational
therapy sessions to help families modify the environment to support daily
function of the person with dementia and reduce caregiver burden. Following
6-month active treatment, a maintenance phase consisted of one home and three
brief telephone sessions to reinforce strategy use and obtain closure.
Noninferiority statistical analysis was used to evaluate whether intervention
caregivers maintained treatment benefits from 6 to 12 months in comparison to
controls. RESULTS: For the sample of 127 at 6 months, caregivers in intervention
reported improved skills (p =.028), less need for help providing assistance (p
=.043), and fewer behavioral occurrences (p =.019) compared to caregivers in
control. At 12 months, caregiver affect improved (p =.033), and there was a
trend for maintenance of skills and reduced behavioral occurrences, but not for
other outcome measures. CONCLUSION: An in-home skills training program helps
sustain caregiver affect for those enrolled for more than 1 year. More frequent
professional contact and ongoing skills training may be necessary to maintain
other clinically important outcomes such as reduced upset with behaviors.
-----
Behav Brain Res. 2005 Mar 30;158(2):349-57.
Effects of transcutaneous electrical nerve stimulation (TENS) on
memory in elderly with mild cognitive impairment.
Luijpen MW, Swaab DF, Sergeant JA, van Dijk KR, Scherder EJ.
Department of Clinical Neuropsychology, Vrije Universiteit, Van der
Boechorststraat 1, 1081 BT Amsterdam, The Netherlands.
In previous studies, transcutaneous electrical nerve stimulation (TENS) was
shown to have a positive effect on memory in Alzheimer's disease (AD) patients.
Moreover, the reported effects appeared to be more beneficial in early stages of
Alzheimer's disease compared to later stage intervention. Based on this
stage-dependency, the present study examined the effects of TENS on memory in a
preclinical stage of AD, i.e. in subjects with mild cognitive impairment (MCI).
Our results suggest that TENS did not improve memory in a MCI population.
Mechanisms that might underlie the absence of positive effects of the TENS
treatment in a MCI population are discussed.
-----
Hum Psychopharmacol. 2005 Feb 7; [Epub ahead of print]
A comparison of donepezil and galantamine in the treatment of
cognitive symptoms of Alzheimer's disease: a meta-analysis.
Harry RD, Zakzanis KK.
University of Toronto at Scarborough, Toronto, Canada.
This review was conducted in order to determine the efficacy of donepezil and
galantamine in the treatment of cognitive symptoms of Alzheimer's disease, and
also to determine whether galantamine was a superior pharmacological
intervention. Meta-analytic methods were used to analyse the data from eight
empirical studies which met the inclusion criteria specified. By finding the
mean effect sizes of the treatment on the outcome measures of cognition, it was
determined that neither drug was greatly efficacious. However, this result does
not necessarily diminish the practical value of the drug. It was also found that
galantamine was no better than donepezil at treating cognitive decline in AD.
Copyright (c) 2005 John Wiley & Sons, Ltd.
-----
Med Sci (Paris). 2005 Feb;21(2):216-21.
[Omega-3 fatty acids in psychiatry.]
[Article in French]
Bourre JM.
Laboratoire de Neuro-pharmacologie-nutrition, Inserm, Hopital Fernand-Widal,
200, rue du Faubourg Saint-Denis, 75475 Paris Cedex 10, France. jean-marie.bourre@
fwidal.inserm.fr.
The brain is one of the organs with the highest level of lipids (fats). Brain
lipids, formed of fatty acids, participate in the structure of membranes, for
instance 50 % fatty acids are polyunsaturated in the gray matter, 1/3 are of the
omega-3 family, and are thus of dietary origin. The omega-3 fatty acids (mainly
alpha-linolenic acid, ALA) participated in one of the first experimental
demonstration of the effect of dietary substances (nutrients) on the structure
and function of the brain. Experiments were first of all carried out on ex vivo
cultured brain cells, then on in vivo brain cells (neurons, astrocytes and
oligodendrocytes) from animals fed ALA deficient diet, finally on
physicochemical (membrane fluidity), biochemical, physiological, neurosensory
(vision an auditory responses), and behavioural or learning parameters. These
findings indicated that the nature of polyunsaturated fatty acids (in particular
omega-3) present in formula milks for human infants determines to a certain
extend the visual, neurological, and intellectual abilities. Thus, in view of
these results and of the high polyunsaturated fatty acid content of the brain,
it is normal to consider that they could be involved in psychiatric diseases and
in the cognitive decline of ageing. Omega-3 fatty acids appear effective in the
prevention of stress, however their role as regulator of mood is a matter for
discussion. Indeed, they play a role in the prevention of some disorders
including depression (especially post partum), as well as in dementia,
particularly Alzheimer's disease. Their role in major depression and bipolar
disorder (manic-depressive disease), only poorly documented, is not clearly
demonstrated. The intervention of omega-3 in dyslexia, autism, and schizophrenia
has been suggested, but it does not necessarily infer a nutritional problems.
The respective importance of the vascular system (where the omega-3 are actually
active) and the cerebral parenchyma itself, remain to be resolved. However, the
insufficient supply of omega-3 fatty acids in today diet in occidental (less
than 50 % of the recommended dietary intakes values for ALA) raises the problem
of how to correct inadequate dietary habits, by prescribing mainly rapeseed
(canola) and walnut oils on the one hand, fatty fish (wild, or farmed, but the
nature of fatty acids present in fish flesh is the direct consequence of the
nature of fats with which they have been fed), and eggs from laying hens fed
omega-3 fatty acids.
-----
J Neural Transm. 2005 Jan 31; [Epub ahead of print]
Statins: drugs for Alzheimer's disease?
Eckert GP, Wood WG, Muller WE.
Department of Pharmacology, Biocenter Niederursel, ZATES, University of
Frankfurt, Germany.
Evidences from cell culture experiments and animal studies suggest a strong link
between cholesterol and Alzheimer's disease (AD). This relationship is supported
by retrospective epidemiological studies demonstrating that statin treatment
reduced the prevalence of AD in patients suffering from hypercholesterolaemia.
The alternative processing of the amyloid-precursor protein (APP) in the brain
of AD patients leads to the production of the neurotoxic amyloid-beta protein (Abeta),
a causative factor for AD pathology. In vitro, this mechanism is modulated by
alterations in cellular cholesterol levels. Moreover, lowering cholesterol in
animal experiments reduced the production of Abeta in most but not all studies.
These findings led to prospective clinical trials of cholesterol-lowering
statins in AD patients, even if many studies do not support elevated cholesterol
levels in serum and brain as a risk factor for Alzheimer's disease. Most of
these studies were negative. Thus, up to date there is insufficient evidence to
suggest the use of statins for treatment in patients with AD.
-----
Dement Geriatr Cogn Disord. 2005 Jan 25;19(4):189-195 [Epub ahead of print]
Differential Efficacy of Treatment with Acetylcholinesterase
Inhibitors in Patients with Mild and Moderate Alzheimer's Disease over a 6-Month
Period.
Lopez-Pousa S, Turon-Estrada A, Garre-Olmo J, Pericot-Nierga I, Lozano-Gallego
M, Vilalta-Franch M, Hernandez-Ferrandiz M, Morante-Munoz V, Isern-Vila A,
Gelada-Batlle E, Majo-Llopart J.
Unitat de Valoracio de la Memoria i les Demencies (UVaMiD), Hospital Santa
Caterina, Girona, Espanya.
There are various anticholinesterase inhibitors (AChEIs) for the symptomatic
treatment of mild to moderate Alzheimer's disease (AD). All AChEIs have shown
greater efficacy than placebo in randomized, double-blind, parallel-group
clinical trials. No differential studies have yet been made of the efficacy
between all AChEIs. The study aims to determine the differential efficacy of the
AChEIs with respect to a historical sample of patients with AD that were not
treated with AChEIs. An open-label, prospective, observational study with a
retrospective control group was undertaken to examine the evolution of the
cognitive function over a 6-month period. The patients were assessed with the
Mini-Mental State Examination (MMSE) at study entry and at 6 months. A general
linear model was applied for repeated measurements with the MMSE score as the
dependent variable, treatment type as an independent variable and the severity
of the deterioration, age and the MMSE baseline score as covariables. Of the
sample of 147 patients, 40 initiated treatment with donepezil, 32 with
galantamine, 30 with rivastigmine and 45 were part of a historical sample of the
memory clinic patients between 1991 and 1996 that had not been treated with
AChEIs. The average age was 73.7 years (SD = 6.9; range = 52-86), 67.3% were
women, 78.2% of the cases were mild and the MMSE baseline score was 18.1 points
(range = 11-27). No significant intergroup differences were observed in these
variables. The average doses of donepezil, galantamine and rivastigmine were
5.87 mg/day (SD = 1.92), 14.81 mg/day (SD = 6.25) and 6.41 mg/day (SD = 1.82),
respectively. At 6 months, the difference in the MMSE score with respect to the
untreated group was 1.6 points for donepezil (95% CI 0.79-2.37; p < 0.001), 0.99
points for galantamine (95% CI 0.14-1.85; p = 0.01) and 0.90 points for
rivastigmine (95% CI 0.05-1.74; p = 0.03). No significant differences were
observed in the efficacy among the groups treated with AChEIs (p > 0.05).
Treatment with AChEIs significantly delays the global cognitive impairment
associated with AD for at least 6 months. Our study found no significant
differences in efficacy between donepezil, galantamine and rivastigmine. Further
studies in the context of daily clinical practice will determine the clinical
significance of the changes observed. An important variability of the response
to the treatment was observed in treated patients. Copyright (c) 2005 S. Karger
AG, Basel.
-----
Immun Ageing. 2004 Nov 12;1(1):3.
Is immunotherapy an effective treatment for Alzheimer's disease?
Licastro F, Caruso C.
Dipartimento di Patologia Sperimentale, Universita di Bologna, Via S, Giacomo
14, 40126 Bologna, Italy. licastro@alma.unibo.it.
Immunotherapy in patients with Alzheimer's disease (AD) is rapidly becoming a
hot topic of modern geriatric and clinical gerontology. Current views see
immunization with Abeta peptide, the amyloidogenic protein found in senile
plaque of AD patient's brains, or the infusion of preformed antibody specific
for human Abeta, as possible therapeutic approaches to improve the cognitive
status in the disease. Animal models of the disease have provided positive
results from both approaches. Thus, an initial clinical trial using immunization
with human Abeta in AD patients was started, but then shortly halted because of
an unusually high incidence (6%) of meningoencephalitis. A long and currently
ongoing debate in the scientific community about the pro or contra of
vaccination or passive immunization with Abeta in AD is thereafter started.
Here, the authors would like to stress few points of concern regarding these
approaches in clinical practice.
-----
Immun Ageing. 2004 Nov 12;1(1):2.
The immunotherapy of Alzheimer's disease.
Weksler ME.
Department of Medicine, Weill Medical College of Cornell University, 1300 York
Avenue, New York, NY 10021, USA. weksler@med.cornell.edu.
Only a small percentage of patients with Alzheimer's disease benefit from
current drug therapy and for only a relatively short time. This is not
surprising as the goal of these drugs is to enhance existing cerebral function
in Alzheimer patients and not to block the progression of cognitive decline. In
contrast, immunotherapy is directed at clearing the neurotoxic amyloid beta
peptide from the brain that directly or indirectly leads to cognitive decline in
patients with Alzheimer's disease. The single trial of active immunization with
the amyloid beta peptide provided suggestive evidence of a reduction in cerebral
amyloid plaques and of stabilization in cognitive function of half the patients
who developed good antibody responses to the amyloid beta peptide. However, 6%
of actively immunized Alzheimer patients developed sterile meningoencephalitis
that forced the cessation of the clinical trial. Passive immunotherapy in animal
models of Alzheimer's disease has provided similar benefits comparable to those
seen with active immunotherapy and has the potential of being effective in the
half of Alzheimer's disease patients who do not make a significant anti-amyloid
beta peptide antibody response and without inducing T-cell-mediated
encephalitis. Published studies of 5 patients with sporadic Alzheimer disease
treated with intravenous immunoglobulin containing anti-amyloid beta peptide
antibodies showed that amyloid beta peptide was mobilized from the brain and
cognitive decline was interrupted. Further studies of passive immunotherapy are
urgently required to confirm these observations.
-----
Folia Neuropathol. 2004;42(4):251-5.
New therapeutic approaches in Alzheimer's disease.
Barcikowska M.
Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre,
Warszawa. mariab@cmdik.pan.pl
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that
affects a large proportion of the elderly population. It causes a progressive
decline in memory and other cognitive functions. There is no effective treatment
of AD despite the great effort in trying to find one. Herein new therapeutic
approaches including those closely targeting the pathogenesis of the disease
have been discussed. Potential disease modifying treatments that are being
considered as future treatment of AD include avaccination, secretase inhibitors,
cholesterol lowering drugs, metal chelators and anti- inflammatory agents.
According to Evidence Based Dementia Practice, only inhibitors of
acetylcholinesterase (AChE) are approved in mild and moderate stages of AD
treatment. From the end of 2003, FDA also approved memantine for much severer
phases of AD. When all the presented possibilities are taken into account, the
most important target for scientists and physicians is not only to find ways for
causative cure of AD, but also to be ready for that moment. There is a great
need for finding routine biomarkers and sensitive enough clinical tests for
diagnosis of AD in which the lasting pathological process does not destroy too
many neurones.
-----
Curr Opin Lipidol. 2004 Dec;15(6):667-72.
Cholesterol, statins and dementia.
Wolozin B.
Department of Pharmacology, Boston University School of Medicine, L-603, Boston,
MA 02118-2526, USA.
PURPOSE OF REVIEW: Advances in cholesterol biology suggest that cholesterol
metabolism modulates beta-amyloid production, and that pharmaceuticals that
inhibit cholesterol metabolism might be valuable in therapy of Alzheimer's
disease. Although the genetics and cell biology continue to support the link
between cholesterol and Alzheimer's disease, recent clinical studies suggest
that the animal studies might not directly translate to clinical studies in
humans. RECENT FINDINGS: This review will highlight advances in genetics, cell
biology and clinical sciences investigating the relationship between cholesterol
and Alzheimer's disease. SUMMARY: Cholesterol, its catabolites and proteins that
regulate cholesterol levels all modulate processing of amyloid precursor
protein. Statins hold promise in therapy of Alzheimer's disease, but the current
data are more consistent with a model of statins that act as neuroprotective
agents rather than inhibitors of beta-amyloid production.
-----
Drugs Aging. 2004;21(14):931-7.
Rivastigmine in frontotemporal dementia : an open-label study.
Moretti R, Torre P, Antonello RM, Cattaruzza T, Cazzato G, Bava A.
Dipartimento di Fisiologia e Patologia, Universita di Trieste, Triste,
ItalyDipartimento di Medicina Clinica e Neurologia, UCO di Neurologia, Sezione
Disturbi Cognitivi, Universita di Trieste, Trieste, Italy.
OBJECTIVE: This preliminary open-label study aims to investigate the effects of
rivastigmine, an inhibitor of acetylcholinesterase (AChE) and
butyrylcholinesterase (BuChE), in 20 patients diagnosed with frontotemporal
dementia (FTD). PATIENTS AND METHODS: Study subjects were men and women 60-75
years of age diagnosed with probable FTD. The rivastigmine group received doses
of 3-9 mg/day. The control group included matched patients receiving
antipsychotics, benzodiazepines and selegiline (deprenyl). All patients
completed a 12-month follow-up period. RESULTS: Rivastigmine treatment was well
tolerated. At 12 months, there was a general amelioration of behavioural changes
as demonstrated by reductions in Neuropsychiatric Inventory (p < 0.001 vs
baseline and control), Behavioral Pathology in Alzheimer's Disease Rating Scale
(p < 0.001 vs baseline and control) and Cornell Scale for Depression in Dementia
scores (p < 0.05 vs baseline, p < 0.001 vs control) in the rivastigmine group.
Caregiver burden was reduced, as shown by reduced Relative Stress Scale scores
(p < 0.001 vs baseline and control). Mean scores on outcome measures evaluating
executive function stabilised in the rivastigmine group (p < 0.05 vs controls).
Rivastigmine did not prevent the disease-related deterioration of cognition as
assessed using the Mini-Mental State Examination. CONCLUSION: In this open-label
study, rivastigmine-treated patients were less behaviourally impaired, and
caregiver burden was reduced, at 12 months, compared with baseline. The use of
cholinesterase inhibitors in FTD warrants further research.
-----
Curr Med Res Opin. 2004 Nov;20(11):1815-20.
Effects of galantamine in patients with mild Alzheimer's disease.
Orgogozo JM, Small GW, Hammond G, Van Baelen B, Schwalen S.
Universite de Bordeaux 2 - Hopital Pellegrin, Bordeaux, France.
BACKGROUND: Galantamine is an acetylcholinesterase inhibitor that modulates
nicotinic receptors. It is effective in mild to moderate Alzheimer's disease
(AD) but no trial has focused exclusively on mild AD. We performed a post-hoc
sub-set analysis using data from four randomised trials to explore the efficacy
of galantamine versus placebo in mild AD. METHODS: Participants in all studies
met NINCDS-ADRDA criteria for probable AD. We examined data from patients with
baseline Mini Mental State Examination (MMSE) 21-24 who received galantamine 24
mg/day (GAL) or placebo (PLAC). Scores for the Alzheimer's Disease Assessment
Scale-cognitive subset (ADAS-cog), Clinician's Interview-Based Impression of
Change (CIBIC), Disability Assessment for Dementia (DAD), and ACDS-ADL scales
were compared. RESULTS: Of the 694 patients (362 GAL, 332 PLAC, mean baseline
MMSE 22.4 +/- 1.1, mean age 74 +/- 7.9 years), 65% completed 6 months treatment
(223 GAL, 229 PLAC). Mean change in ADAS-cog at 6 months was -1.5 (95%
confidence interval -2.2, -0.8, p < 0.001) for GAL and + 0.2 (-0.6, 0.9, p =
0.72) for PLAC. This difference was statistically significant (p = 0.001).
Significantly more patients receiving galantamine were classified as 'improved'
using the CIBIC (26.9% GAL vs 14.3% PLAC, p < 0.001). Galantamine was generally
well tolerated; most common adverse events were nausea, vomiting and diarrhoea.
CONCLUSIONS: Pooled data from four randomised trials of patients with mild AD
indicate that patients who received galantamine 24 mg/day for 6 months improved
cognition more often than those who received placebo and that a higher
proportion receiving galantamine were globally improved. This suggests that
patients with mild AD benefit from galantamine treatment.
-----
Eur J Neurol. 2004 Nov;11(11):734-41.
Long-term efficacy and safety of galantamine in patients with
mild-to-moderate Alzheimer's disease: multicenter trial.
Pirttila T, Wilcock G, Truyen L, Damaraju CV.
Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland.
In clinical trials, short-term galantamine treatment produces consistent
positive effects on global ratings, cognitive tests, and assessments of
activities of daily living and behavior in patients with mild-to-moderate
Alzheimer's disease (AD), providing the rationale for longer-term, open-label
treatment. In this continuation trial following enrollment in previous 12-month
trials, patients received galantamine 24 mg/day for a total of 24 months (total
exposure up to 36 months). Primary efficacy measures were the ADAS-cog/11 and
DAD. Adverse events (AEs) were coded to WHO preferred terms, including AEs begun
in previous trials. Initial improvement in cognitive function was followed by a
gradual decline, as measured by increased ADAS-cog/11 scores. At 36 months, ADAS-cog/11
scores increased by a mean (SEM) of 12.4 (0.80) points (P < 0.001) versus a
projected 22-point increase for untreated patients. Functional abilities, as
measured by the DAD, had decreased significantly at each time point versus
baseline (P < 0.001). The most common treatment-emergent AEs were agitation
(16.1%), insomnia (12.4%), fall (11.2%), and urinary tract infection (10.2%).
AEs were mainly mild to moderate, appropriate for an elderly population, with
few judged treatment related. Galantamine 24 mg/day is safe and effective for
long-term treatment of mild-to-moderate AD. Potential exists for prolonged
benefit with galantamine therapy versus lack of treatment for the long-term.
-----
CNS Drugs. 2004;18(13):827-44.
Combination therapy in Alzheimer's disease : a review of current
evidence.
Schmitt B, Bernhardt T, Moeller HJ, Heuser I, Frolich L.
Division of Geriatric Psychiatry, Central Institute of Mental Health Mannheim,
University of Heidelberg, Mannheim, Germany.
Treating dementia has become a major challenge in clinical practice. Presently,
acetylcholinesterase inhibitors are the first-line drugs in the treatment of
Alzheimer's disease (AD). These options are now complemented by memantine, which
is approved for the treatment of moderate-to-severe AD. Altogether, a minimum of
six agent classes already exist, all of which are approved for clinical use and
are either already being tested or ready for phase III clinical trials for the
treatment of AD. These include cholinesterase inhibitors, blockers of the NMDA
receptor, antioxidants or blockers of oxidative deamination (including Gingko
biloba), anti-inflammatory agents, neurotrophic factors (including hormone
replacement therapy and drugs acting on insulin signal transduction) and
antiamyloid agents (including cholesterol-lowering therapy). These approaches
hold promise for disease modification and have a potential to be used as
combination therapy for cognitive enhancement.Presently, only nine clinical
studies have been published that have investigated the effects of a combination
regimen on cognitive performance or AD. Among those, one study was conducted in
elderly cognitively intact persons; the others involved patients with AD. Only
five of the treatment studies followed a randomised, controlled design. Not all
studies favoured the superior efficacy of combination therapy over monotherapy.
Some studies, however, showed some evidence for synergistic combination effects
of symptomatic therapy, including delay or prevention of disease progression in
AD patients. In addition, six studies investigated the effects of AChE inhibitor
in combination with antipsychotic or antidepressant therapy on behavioural
aspects of AD symptomatology. In four of those studies there were indications
that combination therapy had greater efficacy over monotherapy.The treatment of
AD patients requires optimised options for all stages of illness based on the
available drugs. There is a great need for further well designed studies on
combination therapy in AD.
-----
Am J Alzheimers Dis Other Demen. 2004 Sep-Oct;19(5):275-8.
Statin use and hippocampal volumes in elderly subjects at risk
for Alzheimer's disease: a pilot observational study.
Doraiswamy PM, Steffens DC, McQuoid DR.
Department of Psychiatry and Medicine (Geriatrics), Duke University Medical
Center, Durham, North Carolina, USA.
Statins are investigational therapies for preventing or treating Alzheimer's
disease (AD) and mild cognitive impairment (MCI). Hippocampal atrophy is a
characteristic feature of MCI and AD. This study analyzed cross-sectional data
from 246 nondemented elderly subjects to test the effect of lipid lowering agent
(LLA) therapy on cognition and brain magnetic resonance imaging (MRI) measures
of white matter lesions and hippocampal volume. The study also compared rates of
hippocampal volume change over two and four years in a smaller subset. At
baseline, LLA users were younger, better educated, more likely to be male, and
had higher cognitive scores. Cognitive performance also varied by age and
gender, and MRI measures varied by age. After adjusting for these differences,
the effect of LLA use on baseline cognition, baseline hippocampal volume, and
baseline white matter lesion scores was not significant. The effect of LLA use
on hippocampal volume loss at two-year and four-year follow-ups was also not
significant. This study is the first to examine statin effects on brain atrophy
measured by MRI. In this cohort, statin use was not associated with rate of
change of hippocampal volume. While the study was limited by a relatively small
number of statin users, the findings seem consistent with three prior randomized
trials that found no cognitive benefits for statins in nondemented subjects.
Prospective studies in both nondemented and AD subjects may provide more
conclusive answers.
-----
Curr Pharm Des. 2004;10(25):3177-84.
New classes of AChE inhibitors with additional pharmacological
effects of interest for the treatment of Alzheimer's disease.
Villarroya M, Garcia AG, Marco JL.
Instituto Teofilo Hernando, Departamento de Farmacologia y Terapeutica, Facultad
de Medicina, Universidad Autonoma de Madrid, 28029-Madrid, Spain.
mercedes.villarroya@uam.es
Alzheimer's disease (AD) is associated to a gradual loss of attention and memory
that have been associated to impairment of brain cholinergic neurotransmission,
particularly a deficit of cholinergic neurons in the nucleus basalis of Meynert.
Thus, it is not surprising that the first therapeutic target that has
demonstrated therapeutic efficacy on cognition, behaviour and functional daily
activities has been the inhibitors of acetylcholinesterase (AChE), i.e. tacrine,
donepezil, rivastigmine and galanthamine. But not all inhibitors of AChE have
the same potency to block the enzyme and have a different pharmacological
profile. For instance, rivastigmine is a dual inhibitor of AChE and
butyrylcholinesterase (BuChE), and galanthamine is a mild inhibitor of AChE and
an allosteric potentiating ligand of neuronal nicotinic receptors for
acetylcholine (nAChRs). In addition, we have recently found that galanthamine
has neuroprotective effects by inducing calcium signals and the induction of the
antiapoptotic protein Bcl-2. In this frame, we have been synthesizing new
tacrine derivatives that keep their ability to inhibit AChE but that interfere
with neuronal calcium overloading and prevent apoptosis. Some of these compounds
exhibit neuroprotecting properties and thus, could be useful in the treatment of
neurodegenerative and ischaemic brain diseases.
-----
Am J Geriatr Pharmacother. 2004 Jun;2(2):119-32.
Pharmacotherapeutic approaches to the prevention of Alzheimer's
disease.
Standridge JB.
Department of Family Medicine, University of Tennessee Health Science Center
College of Medicine, Chattanooga Unit, Chattanooga, Tennessee, USA.
Background: Alzheimer's disease (AD) is the most common cause of cognitive
impairment in older patients and is expected to increase greatly in prevalence.
Interventions that could delay disease onset would have a major public health
impact. Objective: The objective of this article is to review evidence from
epidemiologic studies and controlled trials addressing whether AD can be
prevented. Methods: Data were gathered through a comprehensive, systematic
search of MEDLINE using focused search criteria and spanning a 6-year period
from January 1998 through January 2004; a hand search of reference lists from
these studies and reviews; a review of the Cochrane Database of Systematic
Reviews; and a hand search of relevant journals. Selection of articles was based
on the clinical focus. Additional inclusion criteria were used to select key
articles that contained higher-level evidence in accordance with explicit,
validated criteria. Results: Preventive interventions for AD include vitamins,
nonsteroidal anti-inflammatory drugs, and agents that protect the endothelium (eg,
statins). Good control of hypertension with angiotensin-converting enzyme
inhibitors and long-acting dihydropyridines also confers neuroprotective
benefits. Conclusions: The paradigm that AD is pharmacologically unresponsive is
shifting as more effective pharmacotherapies for prevention and treatment
rapidly emerge. Our understanding of the molecular mechanisms of
neurodegeneration will soon allow us to more specifically target and interrupt
the processes that contribute to this progressive dementia.
-----
Psychoneuroendocrinology. 2004 Nov;29(10):1326-34.
Intranasal insulin improves memory in humans.
Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W.
Department of Neuroendocrinology, University of Lubeck, Ratzeburger Allee 160,
Haus 23a, 23538 Lubeck, Germany.
Previous studies have suggested an acutely improving effect of insulin on memory
function. To study changes in memory associated with a prolonged increase in
brain insulin activity in humans, here we used the intranasal route of insulin
administration known to provide direct access of the substance to the
cerebrospinal fluid compartment. Based on previous results indicating a
prevalence of insulin receptors in limbic and hippocampal regions as well as
improvements in memory with systemic insulin administration, we expected that
intranasal administration of insulin improves primarily hippocampus dependent
declaration memory function. Also, improvements in mood were expected. We
investigated the effects of 8 weeks of intranasal administration of insulin
(human regular insulin 4 x 40 IU/d) on declarative memory (immediate and delayed
recall of word lists), attention (Stroop test), and mood in 38 healthy subjects
(24 males) in a double blind, between-subject comparison. Blood glucose and
plasma insulin levels did not differ between the placebo and insulin conditions.
Delayed recall of words significantly improved after 8 weeks of intranasal
insulin administration (words recalled, Placebo [Formula: see text], Insulin
[Formula: see text], [Formula: see text] ). Moreover, subjects after insulin
reported signs of enhanced mood, such as reduced anger ( [Formula: see text] )
and enhanced self-confidence ( [Formula: see text] ). Results indicate a direct
action of prolonged intranasal administration of insulin on brain functions,
improving memory and mood in the absence of systemic side effects. These
findings could be of relevance for the treatment of patients with memory
disorders like in Alzheimer's disease.
-----
Dement Geriatr Cogn Disord. 2004;18(2):227-32. Epub 2004 Jul 14.
Specific functional effects of memantine treatment in patients
with moderate to severe Alzheimer's disease.
Doody R, Wirth Y, Schmitt F, Mobius HJ.
Department of Neurology, Baylor College of Medicine, Houston, Tex., USA.
Treatment of Alzheimer's disease (AD) that combats progressive functional
deterioration can improve the patient's quality of life and reduce caregiver
burden. Memantine, a moderate affinity N-methyl-D-aspartate receptor antagonist,
reduces global deterioration in AD patients and provides cognitive and
functional benefits relative to placebo. Two previous studies reported
statistically significant benefits of memantine for overall functional ability
on the Alzheimer Disease Cooperative Study Activities of Daily Living Inventory
modified for severe dementia (ADCS-ADL(19)), Functional Assessment Staging, and
G2 scale. The present study reports a single-item analysis of the ADL scales
from the two trials and shows that patients treated with memantine demonstrated
a numerical advantage over placebo on all items assessed. These results help to
translate the positive effects of memantine into specific aspects of functional
ability, information that is relevant to AD patients and their families as well
as to researchers interested in the assessment of functional ability in AD
clinical trials. Copyright 2004 S. Karger AG, Basel
-----
Neuroepidemiology. 2004 Jul-Aug;23(4):159-69.
Nonsteroidal anti-inflammatory drugs for the prevention of
Alzheimer's disease: a systematic review.
Szekely CA, Thorne JE, Zandi PP, Ek M, Messias E, Breitner JC, Goodman SN.
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
cszekely@jhsph.edu
OBJECTIVE: Alzheimer's disease, the most prevalent dementia, is a prominent
source of chronic illness in the elderly. Laboratory evidence suggests that
nonsteroidal anti-inflammatory drugs (NSAIDs) might prevent the onset of
Alzheimer's disease. Since the early 1990s numerous observational
epidemiological studies have also investigated this possibility. The purpose of
this meta-analysis is to summarize and evaluate available evidence regarding
exposure to nonaspirin NSAIDs and risk of Alzheimer's disease using
meta-analyses of published studies. METHODS: A systematic search was conducted
using Medline, Biological Abstracts, and the Cochrane Library for publications
1960 onwards. All cross-sectional, retrospective, or prospective observational
studies of Alzheimer's disease in relation to NSAID exposure were included in
the analysis. At least 2 of 4 independent reviewers characterized each study by
source of data and design, including method of classifying exposure and outcome,
and evaluated the studies for eligibility. Discrepancies were resolved by
consensus of all 4 reviewers. RESULTS: Of 38 publications, 11 met the
qualitative criteria for inclusion in the meta-analysis. For the 3 case-control
and 4 cross-sectional studies, the combined risk estimate for development of
Alzheimer's disease was 0.51 (95% Cl=0.40-0.66) for NSAID exposure. In the
prospective studies, the estimate was 0.74 (95% Cl=0.62-0.89) for 4 studies
reporting lifetime NSAID exposure and it was 0.42 (95% Cl=0.26-0.66) for the 3
studies reporting a duration of use of 2 or more years. CONCLUSIONS: Based on
analysis of prospective and nonprospective studies, NSAID exposure was
associated with decreased risk of Alzheimer's disease. An issue that requires
further exploration in future trials or observational studies is the temporal
relationship between NSAID exposure and protection against Alzheimer's disease.
-----
Neurol Res. 2004 Jul;26(5):603-5.
Treatment of vascular dementia-evidence from clinical trials with
cholinesterase inhibitors.
Erkinjuntti T, Roman G, Gauthier S.
Helsinki University Central Hospital, Helsinki, Finland.
Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from
cardiovascular disease, are common causes of dementia and cognitive decline in
the elderly. Also, CVD frequently contributes to cognitive loss in patients with
Alzheimer's disease (AD). Progress in understanding the pathogenetic mechanism
involved in vascular cognitive impairment and vascular dementia (VaD) has
resulted in promising treatments of these conditions. Cholinergic deficits in
VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways
and can be treated with the use of the cholinesterase inhibitors used in AD.
Controlled clinical trials with donepezil, galantamine, and rivastigmine in VaD,
as well as in patients with AD plus CVD, have demostrated improvement in
cognition, behavior and activites of daily living.
-----
Neurol Res. 2004 Jul;26(5):598-602.
Antioxidants for the treatment of mild cognitive impairment.
Mecocci P, Mariani E, Cornacchiola V, Polidori MC.
Department of Gerontology and Geriatrics, University of Perugia, Perugia, Italy.
The isolated deficit in recent memory frequently associated with decline to
Alzheimer's disease (AD) is defined as mild cognitive impairment (MCI). The
observed progression of MCI to AD suggests a common pathogenesis between these
two clinical syndromes, and several neuroimaging, neuropsychological and
biological methods are applied with the purpose of identifying subjects at risk
of AD. Among these methods, the evaluation of a condition of oxidative stress is
gaining increasing attention. Since oxidative stress seems to be involved in the
earliest phases of AD, and MCI may be considered as a prodromal phase of
dementia, it is an attractive issue to focus therapeutic interventions on the
early phase of the disease.
-----
J Clin Psychiatry. 2004;65 Suppl 11:11-5.
Efficacy of atypical antipsychotics in elderly patients with
dementia.
Tariot PN, Profenno LA, Ismail MS.
Department of Psychiatry and Neurobehavioral Therapeutics, Monroe Community
Hospital, University of Rochester Medical Center, Rochester, NY 14620, USA.
pierre_tariot@urmc.rochester.edu
Pharmacotherapy in patients with dementia aims to improve distressing behavioral
and psychological signs of dementia after nonpharmacologic interventions fail,
without causing unacceptable side effects or exacerbating underlying cognitive
impairment. We review data describing risperidone (3 published
placebo-controlled trials), olanzapine (1 abstract regarding a
placebo-controlled trial and a published placebo-controlled trial), quetiapine
(1 published open-label trial and an abstract regarding a placebo-controlled
trial), and aripiprazole (1 abstract regarding a placebo-controlled trial). For
example, a 12-week study of risperidone in patients with Alzheimer's disease
showed a dose-related improvement in psychosis and agitation. The frequency of
extrapyramidal symptoms (EPS) was also significantly greater in patients
receiving the highest doses. A 6-week study of olanzapine showed greater
improvement than placebo in agitation/aggression and psychosis with doses of 5
and 10 mg/day, but not 15 mg/day, with side effects including gait disturbance
and sedation at all doses. A 52-week, open-label trial of quetiapine (median
dose = 138 mg/day) in elderly patients with psychosis suggested good
tolerability with apparent behavioral benefit; EPS improved or remained
unchanged in most patients. Limited data describing aripiprazole have shown
inconclusive evidence regarding relief of psychosis in elderly patients with
Alzheimer's disease-related dementia, with apparently good tolerability over the
short term. It appears that, in the aggregate, atypical antipsychotics are
efficacious for treatment of agitation in dementia, with less clear impact on
psychosis, but their tolerability profiles clearly differ. The National
Institute of Mental Health-funded Clinical Antipsychotic Trials of Intervention
Effectiveness in Alzheimer's Disease project will provide the first head-to-head
comparisons of atypicals in dementia and will examine possible drug-drug
differences between efficacy and effectiveness.
-----
Int J Geriatr Psychiatry. 2004 Jul;19(7):624-33.
Donepezil for the symptomatic treatment of patients with mild to
moderate Alzheimer's disease: a meta-analysis of individual patient data from
randomised controlled trials.
Whitehead A, Perdomo C, Pratt RD, Birks J, Wilcock GK, Evans JG.
The University of Reading, Medical and Pharmaceutical Statistics Research Unit,
Reading, UK. P.A.Whitehead@reading.ac.uk
BACKGROUND: The objective was to evaluate the efficacy and tolerability of
donepezil (5 and 10 mg/day) compared with placebo in alleviating manifestations
of mild to moderate Alzheimer's disease (AD). METHOD: A systematic review of
individual patient data from Phase II and III double-blind, randomised,
placebo-controlled studies of up to 24 weeks and completed by 20 December 1999.
The main outcome measures were the ADAS-cog, the CIBIC-plus, and reports of
adverse events. RESULTS: A total of 2376 patients from ten trials were
randomised to either donepezil 5 mg/day (n = 821), 10 mg/day (n = 662) or
placebo (n = 893). Cognitive performance was better in patients receiving
donepezil than in patients receiving placebo. At 12 weeks the differences in
ADAS-cog scores were 5 mg/day-placebo: - 2.1 [95% confidence interval (CI), -
2.6 to - 1.6; p < 0.001], 10 mg/day-placebo: - 2.5 ( - 3.1 to - 2.0; p < 0.001).
The corresponding results at 24 weeks were - 2.0 ( - 2.7 to - 1.3; p < 0.001)
and - 3.1 ( - 3.9 to - 2.4; p < 0.001). The difference between the 5 and 10
mg/day doses was significant at 24 weeks (p = 0.005). The odds ratios (OR) of
improvement on the CIBIC-plus at 12 weeks were: 5 mg/day-placebo 1.8 (1.5 to
2.1; p < 0.001), 10 mg/day-placebo 1.9 (1.5 to 2.4; p < 0.001). The
corresponding values at 24 weeks were 1.9 (1.5 to 2.4; p = 0.001) and 2.1 (1.6
to 2.8; p < 0.001). Donepezil was well tolerated; adverse events were
cholinergic in nature and generally of mild severity and brief in duration.
CONCLUSION: Donepezil (5 and 10 mg/day) provides meaningful benefits in
alleviating deficits in cognitive and clinician-rated global function in AD
patients relative to placebo. Increased improvements in cognition were indicated
for the higher dose. Copyright 2004 John Wiley & Sons, Ltd.
-----
CNS Spectr. 2004 Jul;9(7 Suppl 5):6-12.
What is the rationale for new treatment strategies in Alzheimer's
disease?
Rogawski MA.
Epilepsy Research Section, National Institute of Neurological Disorders and
Stroke, National Institutes of Health, Bethesda, MD, USA.
Alzheimer's disease (AD) is characterized by the abnormal extracellular
accumulation of amyloid beta-peptide (Abeta) into neuritic plaques and the
intraneuronal aggregation of the microtubule-associated protein tau to form
neurofibrillary tangles. These molecular events are implicated in the selective
damage to neural systems critical for the brain functions that are impaired in
AD. Impairment of cholinergic neurotransmission may be an important factor
underlying the defects in cognition and memory that characterize AD.
Cholinesterase (ChE) inhibitors, such as donepezil, rivastigmine, and
galantamine, cause symptomatic improvement by inhibiting the breakdown of the
neurotransmitter acetylcholine to increase its synaptic availability and, in the
case of galantamine, by also allosterically potentiating nicotinic cholinergic
receptors. Other agents, including vitamin E, monoamine oxidase inhibitors, and
statins, have shown some benefit in epidemiological studies and clinical trials
although compelling evidence of their efficacy is lacking. Memantine, shown to
cause cognitive and functional improvement, is not an ChE inhibitor and does not
interact with marketed ChE inhibitors. While the mechanism of action of
memantine in AD is not known, the principal pharmacologic actions at therapeutic
dose are inhibition of ionotropic neurotransmitter receptors, specifically
N-methyl-D-aspartate (NMDA), 5-HT3, and nicotinic receptors. Like other NMDA
antagonists, memantine causes behavioral activation associated with enhanced
cerebral glucose utilization. Studies have shown that memantine can reverse the
decreased metabolic activity associated with AD, possibly accounting for its
beneficial effects on cognition and global functioning. Memantine also has
neuroprotective properties and can inhibit Abeta-induced neurodegeneration.
-----
Dement Geriatr Cogn Disord. 2004 Apr 6;18(1):50-54. Epub 2004
Apr 06.
Effects of Cholinergic Drugs and Cognitive Training
on Dementia.
Requena C, Lopez Ibor MI, Maestu F, Campo P, Lopez Ibor
JJ, Ortiz T.
Universidad de Leon (Area de Psicologia), Leon, Madrid, Spain.
A study was performed on patients with Alzheimer's disease
(AD) in order to evaluate the efficacy of a combined treatment
(donepezil plus cognitive training) in both cognitive processes
and affective states. Eighty-six subjects, 25 men and 61 women,
with an average age of 75.58 years, were studied. Almost all the
subjects had a basic educational level. Donezepil was administered
at a dose of 10 mg daily along with cognitive treatment involving
images of everyday life and reminiscent music; the sessions took
place on Monday to Friday and lasted three quarters of an hour.
The study lasted 12 months. Subjects underwent test-retest with
the following tests: Mini-Mental State Examination (MMSE), the
cognitive subscale of the Alzheimer's Disease Assessment Scale
(ADAS-cog); the Geriatric Depression Scale (GDS) and the overall
deterioration scale (FAST). The results showed that subjects receiving
the combined treatment had a better response than those who did
not receive any cognitive training. These subjects' MMSE score
decreased by 3.24 on average. The affective symptomatology of
those receiving only drug treatment improved whereas the cognitive
processes did not. Copyright 2004 S. Karger AG, Basel
-----
Dement Geriatr Cogn Disord. 2004 Apr 6;18(1):37-43. Epub 2004
Apr 06.
Donepezil for Alzheimer's Disease in Clinical
Practice—The DONALD Study. A Multicenter 24-Week Clinical
Trial in Germany.
Froelich L, Gertz HJ, Heun R, Heuser I, Jendroska K, Kornhuber
J, Kurz A, Mueller-Thomsen T, Ries F, Waechtler C, Metz M, Goebel
C.
Division of Geriatric Psychiatry, Central Institute for Mental
Health Mannheim, University of Heidelberg, Germany.
This multicenter open-label clinical trial was designed to
investigate the safety and efficacy of donepezil, a selective
acetylcholinesterase inhibitor, in the treatment of Alzheimer's
disease (AD) in routine clinical practice in Germany. A total
of 237 patients with mild-to-moderate AD were treated with donepezil
for 24 weeks, 186 completed the study according to the protocol.
In the completer group, mean MMSE score for efficacy showed an
improvement from baseline of +1.6 points at week 12 (95% CI +1.1
to +2.1) and of +1.1 points at week 24 (95% CI +0.5 to +1.7).
In more than 80% of the patients, global tolerability was rated
to be very good or good. There were only insignificant effects
on ECG parameters. This study confirms the results obtained in
previous double-blind trials, which showed that donepezil is effective
and well tolerated in patients with mild-to-moderately severe
AD. Copyright 2004 S. Karger AG, Basel
-----
Drugs Aging. 2004;21(6):395-403.
Risk of antipsychotic drug use in patients with
Alzheimer's disease treated with rivastigmine.
Suh DC, Arcona S, Thomas SK, Powers C, Rabinowicz AL, Shin
H, Mirski D.
Ernest Mario School of Pharmacy, Rutgers University, Piscataway,
New Jersey, USA.
BACKGROUND AND OBJECTIVE: Cholinesterase inhibitors may offer
some improvement in the behavioural symptoms of Alzheimer's disease.
The dual inhibitory mechanism of action of rivastigmine (inhibition
of acetylcholinesterase and butyrylcholinesterase) may improve
behavioural symptoms and may delay the need for antipsychotics.
This study was conducted to investigate the effect of rivastigmine
on the time to first antipsychotic drug use among patients with
Alzheimer's disease, compared with patients with Alzheimer's disease
not treated with a cholinesterase inhibitor.DESIGN AND METHODS:
This study used MarketScan((R)) research databases from 1 January
1999 to 31 March 2002. Patients were included if they: (a) were
diagnosed with Alzheimer's disease on two occasions or filled
a prescription for rivastigmine for the first time during the
index period from 1 July 2000 to 31 December 2001; (b) were 65
years of age and older; (c) had continuous health and prescription
insurance coverage during the entire study period; and (d) had
not used an antipsychotic medication within 18 months prior to
their index Alzheimer's disease prescription or diagnosis. The
'no cholinesterase inhibitor' group included patients who were
newly diagnosed with Alzheimer's disease, but did not use any
cholinesterase inhibitors. Chi-square, Student's t-, and log-rank
tests were used to test differences in study variables between
groups. Cox proportional hazards models were used to estimate
predicted risk of first antipsychotic drug use.RESULTS: The study
included 497 patients in the rivastigmine group and 749 patients
in the 'no cholinesterase inhibitor' group. The rivastigmine group
patients were younger compared with the 'no cholinesterase inhibitor'
group patients (p < 0.01). The overall usage of antipsychotics
was considerably lower for patients taking rivastigmine (9.8%)
compared with those not taking cholinesterase inhibitors (25.6%).
Patients taking rivastigmine were 64% less likely (relative risk
= 0.36; p < 0.0001) to take antipsychotics compared with patients
not taking cholinesterase inhibitors, after adjusting for demographic
covariates, comorbid conditions, and use of other CNS drugs and
anticonvulsants. Age was the only other factor that influenced
antipsychotic use; older patients were significantly more likely
to start antipsychotics than younger patients.CONCLUSION: This
study provides initial evidence that patients with Alzheimer's
disease treated with rivastigmine have a reduced risk of initiating
therapy with an antipsychotic drug compared with patients who
receive no cholinesterase inhibitor treatment. These findings
may imply that rivastigmine use could delay the onset of behavioural
symptoms that require treatment with antipsychotic medications.
-----
J Am Geriatr Soc. 2004 Mar;52(3):381-387.
A Randomized, Controlled Trial of Doxycycline
and Rifampin for Patients with Alzheimer's Disease.
Loeb MB, Molloy D, Smieja M, Standish T, Goldsmith CH,
Mahony J, Smith S, Borrie M, Decoteau E, Davidson W, McDougall
A, Gnarpe J, O'donnell M, Chernesky M.
Departments ofPathology and Molecular Medicine Clinical Epidemiology
and Biostatistics Hamilton Regional Laboratory Medicine Program,
Hamilton, Ontario, Canada Geriatric Research Group, St. Peter's
Hospital, Department of Medicine, McMaster University, Hamilton,
Ontario, Canada Parkwood Hospital, University of Western Ontario,
London Chronic Care, London, Ontario, Canada Department of Medicine,
University of Saskatchewan, Saskatoon, Saskatchewan The Moncton
Hospital, Moncton, New Brunswick, Canada Grey Bruce Medical Center,
Owen Sound, Ontario, Canada Department of Medical Microbiology
and Immunology, University of Alberta, Edmonton, Alberta, Canada.
OBJECTIVES: : To assess whether doxycycline and rifampin have
a therapeutic role in patients with Alzheimer's disease (AD).
DESIGN: : Randomized, triple-blind, controlled trial. SETTING:
: Three tertiary care and two community geriatric clinics in Canada.
PARTICIPANTS: : One hundred one patients with probable AD and
mild to moderate dementia. INTERVENTION: : Oral daily doses of
doxycycline 200 mg and rifampin 300 mg for 3 months. MEASUREMENTS:
: The primary outcome was a change in Standardized Alzheimer's
Disease Assessment Scale cognitive subscale (SADAScog) at 6 months.
Secondary outcomes were changes in the SADAScog at 12 months and
tests of dysfunctional behavior, depression, and functional status.
RESULTS: : There was significantly less decline in the SADAScog
score at 6 months in the antibiotic group than in the placebo
group, (-2.75 points, 95% confidence interval (CI)=-5.28 to -0.22,
P=.034). At 12 months, the difference between groups in the SADAScog
was -4.31 points (95% CI=-9.17-0.56, P=.079). The antibiotic group
showed significantly less dysfunctional behavior at 3 months.
There was no significant difference in adverse events between
groups (P=.34). There were no differences in Chlamydia pneumoniae
detection using polymerase chain reaction or antibodies (immunoglobulin
(Ig)G or IgA) between groups. CONCLUSION: : Therapy with doxycycline
and rifampin may have a therapeutic role in patients with mild
to moderate AD. The mechanism is unlikely to be due to their effect
on C. pneumoniae. More research is needed to investigate these
agents.
-----
Am J Psychiatry. 2004 Mar;161(3):532-8.
Reduction of behavioral disturbances and caregiver
distress by galantamine in patients with
Alzheimer's disease.
Cummings JL, Schneider L, Tariot PN, Kershaw PR, Yuan W.
OBJECTIVE: Alzheimer's disease pathology includes both histologic
changes and neurotransmitter deficits. The cholinergic deficit
contributes to both cognitive and behavioral disturbances, and
cholinesterase inhibitors may improve behavior in Alzheimer's
disease patients. This analysis was conducted to assess the impact
of galantamine, a cholinesterase inhibitor with nicotinic-receptor-modulating
properties, on the pattern and evolution of behavioral disturbances
in patients with Alzheimer's disease and on caregiver distress
related to patients' behavior. METHOD: Data from 978 patients
with mild to moderate Alzheimer's disease who were randomly assigned
to placebo or galantamine (8, 16, or 24 mg/day) were analyzed.
Behavioral changes were assessed with the Neuropsychiatric Inventory,
and alterations in caregiver distress were measured by the Neuropsychiatric
Inventory distress scale. Data collected at baseline and 12 and
21 weeks postbaseline were analyzed. RESULTS: Neuropsychiatric
Inventory scores worsened with placebo, whereas patients treated
with 16 or 24 mg/day of galantamine had no change in total Neurospcyhiatric
Inventory scores. Treated patients, asymptomatic or symptomatic
at baseline, had better Neuropsychiatric Inventory subscale scores
than did patients receiving placebo. Behavioral improvement in
patients symptomatic at baseline ranged from 29% to 48%. Changes
were evident in patients receiving 16 or 24 mg/day of galantamine.
High-dose galantamine was associated with a significant reduction
in caregiver distress. CONCLUSIONS: Galantamine therapy was associated
with reduced emergence of behavioral disturbances and improvement
in existing behavioral problems in patients with mild to moderate
Alzheimer's disease, with a concomitant reduction in reported
caregiver distress.
-----
J Nutr. 2004 Mar;134(3):489-492.
Glutathione Metabolism and Its Implications for
Health.
Wu G, Fang YZ, Yang S, Lupton JR, Turner ND.
Faculty of Nutrition, Texas A&M University, College Station,
TX, 77843. Department of Biochemistry and Molecular Biology, Beijing
Institute of Radiation Medicine, Beijing, China 100850. Department
of Animal Nutrition, China Agricultural University, Beijing, China
100094.
Glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is the
most abundant low-molecular-weight thiol, and GSH/glutathione
disulfide is the major redox couple in animal cells. The synthesis
of GSH from glutamate, cysteine, and glycine is catalyzed sequentially
by two cytosolic enzymes, gamma-glutamylcysteine synthetase and
GSH synthetase. Compelling evidence shows that GSH synthesis is
regulated primarily by gamma-glutamylcysteine synthetase activity,
cysteine availability, and GSH feedback inhibition. Animal and
human studies demonstrate that adequate protein nutrition is crucial
for the maintenance of GSH homeostasis. In addition, enteral or
parenteral cystine, methionine, N-acetyl-cysteine, and L-2-oxothiazolidine-4-carboxylate
are effective precursors of cysteine for tissue GSH synthesis.
Glutathione plays important roles in antioxidant defense, nutrient
metabolism, and regulation of cellular events (including gene
expression, DNA and protein synthesis, cell proliferation and
apoptosis, signal transduction, cytokine production and immune
response, and protein glutathionylation). Glutathione deficiency
contributes to oxidative stress, which plays a key role in aging
and the pathogenesis of many diseases (including kwashiorkor,
seizure, Alzheimer's disease, Parkinson's disease, liver disease,
cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart
attack, stroke, and diabetes). New knowledge of the nutritional
regulation of GSH metabolism is critical for the development of
effective strategies to improve health and to treat these diseases.
-----
J Biol Chem. 2004 Feb 25 [Epub ahead of print]
Copper depletion down-regulates expression of
Alzheimer's disease Amyloid-beta precursor protein gene.
Bellingham SA, Lahiri DK, Maloney B, La Fontaine S, Multhaup
G, Camakaris J.
Genetics Dept., The University of Melbourne, Melbourne, Victoria
3010.
Alzheimers disease is characterised by the accumulation of
amyloid-beta peptide, which is cleaved from the amyloid-beta precursor
protein (APP). Reduction in levels of the potentially toxic amyloid
has emerged as one of the most important therapeutic goals in
Alzheimers disease. Key targets for this goal are factors that
affect the regulation of the APP gene. Recent in vivo and in vitro
studies have illustrated the importance of copper in Alzheimers
disease neuropathogenesis and suggested a role for the amyloid-beta
precursor protein in copper homeostasis as a copper detoxification/efflux
protein. We hypothesised that metals and in particular copper
might alter APP gene expression. To test the hypothesis, we utilised
human fibroblasts over-expressing the Menkes protein (MNK), a
major mammalian copper efflux protein. MNK deletion fibroblasts
have high intracellular copper, while MNK over-expressing fibroblasts
have severely depleted intracellular copper. We demonstrate that
copper depletion significantly reduced APP protein levels and
down-regulated APP gene expression. Furthermore, APP promoter
deletion constructs identified the copper-regulatory region between
490 to +104 of the APP gene promoter in both basal MNK over-expressing
cells and in copper-chelated MNK deletion cells. Overall these
data support the hypothesis that copper can regulate APP expression
and further support a role for APP to function in copper homeostasis.
Copper-regulated APP expression may also provide a potential therapeutic
target in Alzheimers disease.
-----
Aging Ment Health. 2004 Feb;8(2):117-25.
Special Section--Behavioral symptoms of dementia:
their measurement and intervention.
Colling KB.
Passive behavior (PB) in persons with Alzheimer's disease (PWAD)
has been overlooked despite recognition that it occurs on a daily
basis and is often resistant to interventions. The purpose of
this study was to describe how the experience of passivity was
for the caregiver and the PWAD, factors that precipitated PB,
caregiver responses that promoted engagement, and caregiver responses
that intensified PB, as well as activities initiated by caregivers
over the past month that reduced passivity in the person with
dementia (PWD). Fifty caregivers of community-dwelling persons
with mild (n = 15), moderate (n = 16), and severe (n = 19) Alzheimer's
disease participated in a semi-structured interview. Data were
analyzed using Colaizzi's Phenomenological Thematic Extraction
and descriptive statistics. Caregivers identified decreased levels
of activity, decreased verbalization, withdrawal, less socialization,
and decreased interest in activities as examples of PBs. For caregivers,
the experience of coping with PBs engendered frustration with
their loved ones' cognitive deterioration, difficulty in watching
and accepting loss of function, fatigue, sadness, and using coping
skills. Paradoxically, both being alone and increased environmental
stimuli precipitated PB. Feelings of helplessness and loss of
control by the person also caused PB. The most successful interventions
to promote engagement were: giving cues and assistance, initiating
the task, giving guidance, and providing enjoyable activities.
Responses that hindered engagement included: 'correcting' or putting
stress on the person, rushing activities, and repeating directions.
Faith, humor, patience, and contact with friends and family were
identified as positive approaches. Caregiver interventions demonstrated
synchrony with selected background and proximal variables in the
Need-driven Dementia-compromised Behavior (NDB) model.
-----
Cochrane Database Syst Rev. 2004;(1):CD004395.
Donepezil for vascular cognitive impairment.
Malouf R, Birks J.
Department of Public Health Sciences, Cochrane Airways Group,
St George's Hospital Medical School, Cranmer Terrace, London,
UK, SW17 ORE.
BACKGROUND: Vascular disease is the second commonest cause
of dementia after Alzheimer's disease. There are difficulties
in classifying patients with this type of cognitive impairment
owing to varied clinical presentation and different types of arterial
disease. There is some degree of overlap in the neuropathology
of Alzheimer's and vascular dementia. Deficient cholinergic neurotransmission,
a characteristic of Alzheimer's disease, has been postulated to
contribute to the cognitive impairment of vascular disease of
the brain. Cholinesterase inhibitors, such as donepezil, may therefore
be a rational treatment. OBJECTIVES: To assess the clinical efficacy
and tolerability of donepezil on cognitive function, clinical
global impression, activities of daily living and social functioning
of people with vascular cognitive impairment. SEARCH STRATEGY:
Relevant randomized controlled trials were identified from a search
of the Cochrane Dementia and Cognitive Improvement Group Specialized
Register on 21 July 2003 using the terms donepezil, E2020 and
Aricept. This Register consists of records from all major healthcare
databases and many ongoing trials databases. Unpublished trials
were requested from the drug company Eisai Inc and they provided
us with the required data. SELECTION CRITERIA: All unconfounded
randomized double-blind trials comparing donepezil with placebo
were eligible for inclusion. Trials using combinations of donepezil
with other pharmacological interventions were excluded. DATA COLLECTION
AND ANALYSIS: Both reviewers assessed studies against the criteria
for inclusion and extracted data. Data were pooled where appropriate,
and weighted mean differences or Peto odds ratios with 95% confidence
intervals calculated. Intention-to-treat analysis was undertaken
when possible. MAIN RESULTS: Two large-scale, randomized, double-blind,
parallel-group controlled trials were identified for inclusion.
A total of 1219 people with mild to moderate cognitive decline
due to probable or possible vascular dementia (according to the
NINCDS/AIREN criteria and the Hachinski Ischemia Scale) were recruited.
Donepezil, at doses of 5 or 10 mg a day was compared with placebo
for 24 weeks. For each outcome measure, mean change from baseline
at weeks 12 and 24, using a last observation carried forward analysis,
was calculated. Cognitive function: The donepezil groups showed
statistically significantly better performance than the placebo
groups on the cognitive subscale of the Alzheimer's Disease Assessment
Scale (ADAS-Cog) at 12 and 24 weeks. The donepezil groups produced
statistically significantly better scores than the placebo groups
on the Mini-Mental State Examination (MMSE) at 12 and 24 weeks.
Global function: The sum of the boxes of the Clinical Dementia
Rating (CDR-SB) showed at 24 weeks a statistically significant
benefit of 10 mg donepezil daily over both placebo and a 5 mg
daily dosage. The Clinician's Interview-Based Impression of Change-plus
version (CIBIC-plus) showed improved global function of participants
taking 5 mg of donepezil daily compared with the placebo group
but this was not seen in the higher dose group. Activities of
daily living and social behaviour: On the Instrumental Activity
of Daily Living (IADL) scale, there was no statistically significant
difference between the groups taking donepezil 5mg per day donepezil
and placebo, but the group taking 10 mg of donepezil a day showed
benefit compared with placebo There were statistically significant
benefit for donepezil at either dosage compared with placebo on
the Alzheimer's Disease Functional Assessment and Change Scale
(ADFACS). Tolerability and adverse effects: Broad range of adverse
events were reported in the studies and data confirmed that donepezil
was well tolerated, and most of the side effects were transient
and were resolved by stopping the medication. Some of these events,
especially nausea, diarrhoea, anorexia and cramp appeared more
frequently on the 10 mg dose where there was a statistically significant
difference compared with placebo. Drop-out: Thetatistically significant
difference compared with placebo. Drop-out: The drop-out rate
was similar between the groups, 84.2% (330) patients completed
the studies. The withdrawal rate was low and due mainly to side
effects. REVIEWER'S CONCLUSIONS: Evidence from the available studies
support the benefit of donepezil in improving cognition function,
clinical global impression and activities of daily living in patients
with probable or possible mild to moderate vascular cognitive
impairment after 6 months treatment. Extending studies for longer
periods would be desirable to establish the efficacy of donepezil
in patients with advanced stages of cognitive impairment. Moreover,
there is an urgent need for establishing specific clinical diagnostic
criteria and rating scales for vascular cognitive impairment.
-----
Cochrane Database Syst Rev. 2004;(1):CD004244.
Alpha lipoic acid for dementia.
Sauer J, Tabet N, Howard R.
Section of Old Age Psychiatry, Institute of Psychiatry, De Crespigny
Park, London, UK, SE5 8AF.
BACKGROUND: Oxidative processes have been implicated in the
pathogenesis of neurodegenerative dementias including Alzheimer's
disease. Protecting the central nervous system against these damaging
mechanisms may be a useful therapeutic approach. Alpha lipoic
acid (ALA) is an endogenous antioxidant that interrupts cellular
oxidative processes in both its oxidized and reduced forms. These
properties might qualify ALA for a modulatory role in the treatment
of people with dementia. OBJECTIVES: To assess the role and clinical
efficacy of alpha lipoic acid in the treatment of dementia. SEARCH
STRATEGY: A search of the Specialized Register of the Cochrane
Dementia and Cognitive Improvement Group (CDCIG) on 3 February
2003 using the terms 'alpha lipoic acid' and 'thioctic'. The CDCIG
Specialized register is updated regularly and contains records
from all major health care databases (MEDLINE, EMBASE, PsycInfo,
CINAHL) as well as from many trials databases. SELECTION CRITERIA:
All double-blind randomized placebo-controlled trials examining
the efficacy of alpha lipoic acid in dementia DATA COLLECTION
AND ANALYSIS: No trials were found that met the selection criteria
MAIN RESULTS: No meta-analysis could be performed. A systematic
search of the Specialized Register of the Cochrane Dementia and
Cognitive Improvement Group, as well as registers of ongoing and
unpublished trials could not identify any studies investigating
the use of ALA for dementia. REVIEWER'S CONCLUSIONS: In the absence
of randomized double-blind placebo-controlled trials investigating
ALA for dementia, no evidence exists to explore any potential
effects. Until data from trials become available for analysis,
ALA cannot be recommended for people with dementia.
-----
Arch Neurol. 2004 Feb;61(2):252-6.
The cognitive benefits of galantamine are sustained
for at least 36 months: a long-term extension trial.
Raskind MA, Peskind ER, Truyen L, Kershaw P, Damaraju CV.
Department of Psychiatry and Behavioral Sciences, University of
Washington School of Medicine and VISN 20 Mental Illness Research,
Education and Clinical Center, VA Puget Sound Health Care System,
Seattle 98108, USA. murray.raskind@med.va.gov
BACKGROUND: Alzheimer disease (AD) causes progressive cognitive
and functional decline over years. Although cholinesterase inhibitors
have demonstrated efficacy in studies lasting 3 to 6 months, little
is known about long-term therapy. OBJECTIVE: To report the long-term
cognitive effects of galantamine hydrobromide given continuously
for 36 months in AD patients. PARTICIPANTS: Subjects were 194
US patients with mild to moderate AD who had been randomized to
continuous galantamine therapy in either of 2 double-blind placebo-controlled
trials. Subjects subsequently received open-label continuous galantamine
therapy for up to 36 months. MAIN OUTCOME MEASURES: Effects on
cognition were analyzed as change from study enrollment baseline
in scores on the Alzheimer's Disease Assessment Scale-11-item
cognitive subscale. Cognitive decline in galantamine-treated subjects
was compared with that in a clinically similar historical control
sample of AD patients who had received placebo for 12 months and
with the mathematically predicted decline of untreated patients
over 36 months. The rate of cognitive decline of patients who
completed the entire 36-month trial (n = 119) was compared with
that of patients who withdrew for any reason during the long-term
open-label extension (n = 75). An inverted responder analysis
was also performed in 36-month completers. RESULTS: Patients treated
continuously with galantamine for 36 months increased a mean +/-
SE of 10.2 +/- 0.9 points on the Alzheimer's Disease Assessment
Scale-11-item cognitive subscale-a substantially smaller cognitive
decline (approximately 50%) than that predicted for untreated
patients. Patients discontinuing galantamine therapy before 36
months had declined at a similar rate before discontinuation as
those completing 36 months of treatment. Almost 80% of patients
who received galantamine continuously for up to 36 months seemed
to demonstrate cognitive benefits compared with those predicted
for untreated patients. CONCLUSIONS: Cognitive decline over 36
months of continuous galantamine treatment was substantially less
than the predicted cognitive decline of untreated patients with
mild to moderate dementia. Thus, the cognitive benefits of galantamine
seemed to be sustained for at least 36 months. These findings
suggest that galantamine slows the clinical progression of AD.
-----
JAMA. 2004 Jan 21;291(3):317-24.
Memantine treatment in patients with moderate
to severe Alzheimer disease already receiving donepezil: a randomized
controlled trial.
Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald
S, Gergel I; Memantine Study Group.
Department of Psychiatry, University of Rochester Medical Center,
Monroe Community Hospital, Rochester, NY 14620, USA. pierre_tariot@urmc.rochester.edu
CONTEXT: Memantine is a low- to moderate-affinity, uncompetitive
N-methyl-D-aspartate receptor antagonist. Controlled trials have
demonstrated the safety and efficacy of memantine monotherapy
for patients with moderate to severe Alzheimer disease (AD) but
no controlled trials of memantine in patients receiving a cholinesterase
inhibitor have been performed. OBJECTIVE: To compare the efficacy
and safety of memantine vs placebo in patients with moderate to
severe AD already receiving stable treatment with donepezil. DESIGN,
SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled
clinical trial of 404 patients with moderate to severe AD and
Mini-Mental State Examination scores of 5 to 14, who received
stable doses of donepezil, conducted at 37 US sites between June
11, 2001, and June 3, 2002. A total of 322 patients (80%) completed
the trial. INTERVENTIONS: Participants were randomized to receive
memantine (starting dose 5 mg/d, increased to 20 mg/d, n = 203)
or placebo (n = 201) for 24 weeks. MAIN OUTCOME MEASURES: Change
from baseline on the Severe Impairment Battery (SIB), a measure
of cognition, and on a modified 19-item AD Cooperative Study-Activities
of Daily Living Inventory (ADCS-ADL19). Secondary outcomes included
a Clinician's Interview-Based Impression of Change Plus Caregiver
Input (CIBIC-Plus), the Neuropsychiatric Inventory, and the Behavioral
Rating Scale for Geriatric Patients (BGP Care Dependency Subscale).
RESULTS: The change in total mean (SE) scores favored memantine
vs placebo treatment for SIB (possible score range, 0-100), 0.9
(0.67) vs -2.5 (0.69), respectively (P<.001); ADCS-ADL19 (possible
score range, 0-54), -2.0 (0.50) vs -3.4 (0.51), respectively (P
=.03); and the CIBIC-Plus (possible score range, 1-7), 4.41 (0.074)
vs 4.66 (0.075), respectively (P =.03). All other secondary measures
showed significant benefits of memantine treatment. Treatment
discontinuations because of adverse events for memantine vs placebo
were 15 (7.4%) vs 25 (12.4%), respectively. CONCLUSIONS: In patients
with moderate to severe AD receiving stable doses of donepezil,
memantine resulted in significantly better outcomes than placebo
on measures of cognition, activities of daily living, global outcome,
and behavior and was well tolerated. These results, together with
previous studies, suggest that memantine represents a new approach
for the treatment of patients with moderate to severe AD.
-----
Neurology. 2004 Jan 13;62(1):66-71.
Rofecoxib: no effect on Alzheimer's disease in
a 1-year, randomized, blinded, controlled study.
Reines SA, Block GA, Morris JC, Liu G, Nessly ML, Lines
CR, Norman BA, Baranak CC; Rofecoxib Protocol 091 Study Group.
Merck Research Laboratories, 10 Sentry Parkway, Blue Bell, PA
19422, USA.
BACKGROUND: Inflammatory mechanisms have been implicated in
the pathogenesis of Alzheimer's disease (AD) and may be mediated
via the cyclo-oxygenase-2 enzyme. This study sought to evaluate
the effect of rofecoxib, a nonsteroidal anti-inflammatory drug
that selectively inhibits cyclo-oxygenase-2, in slowing the progression
of dementia in patients with established AD. METHODS: A double-blinded,
multicenter trial was conducted in which 692 patients with mild
or moderate AD aged 50 years or older were randomly assigned to
receive 25 mg rofecoxib or placebo daily for 12 months. The key
efficacy measures were mean change from baseline at month 12 on
the cognitive subscale of the AD Assessment Scale (ADAS-cog) and
score on the Clinician's Interview Based Impression of Change
with caregiver input (CIBIC+). RESULTS: Four hundred eighty-one
patients (70%) completed assessments and remained on treatment
at 12 months. No significant differences between treatments were
found on the mean change from baseline error score for the ADAS-cog
(rofecoxib = 4.84; placebo = 5.44; difference = -0.60) or mean
score on the CIBIC+ (rofecoxib = 4.90; placebo = 4.87; difference
= 0.03) over 12 months. This result persisted after adjusting
for severity of dementia at baseline, presence of the APOE-epsilon4
allele, and donepezil use. Secondary analyses did not reveal any
significant differences on any other measures. CONCLUSION: The
failure of selective cyclo-oxygenase-2 inhibition to slow the
progression of AD may indicate either that the disease process
is too advanced to modify in patients with established dementia
or that cyclo-oxygenase-2 does not play a significant role in
the pathogenesis of the disorder.
-----
Prog Brain Res. 2004;146:441-9.
Nerve growth factor: from animal models of cholinergic
neuronal degeneration to gene therapy in Alzheimer's disease.
Tuszynski MH, Blesch A.
Department of Neurosciences-0626, University of California, San
Diego, La Jolla, CA 92093, USA. mtuszynski@ucsd.edu
Over the last 20 years it has been recognized that neurotrophic
factors profoundly influence the development of the nervous system
and have the potential to modify disease processes in the adult
nervous system. The ability of nervous system growth factors to
prevent or reduce neuronal degeneration in animal models of neurodegenerative
diseases has led to several clinical trials. One of the main obstacles
to the success of these trials has been the method of growth factor
delivery: sufficiently high doses of neurotrophic factors must
be achieved in the target region of the brain to efficiently modify
disease processes, but delivery must be restricted to specific
brain regions to prevent adverse effects. Recent advances in molecular
medicine have made gene therapy in the nervous system a potentially
realistic approach for the delivery of therapeutic molecules such
as growth factors. As an alternative to conventional drug delivery,
several gene therapy trials for the treatment of central nervous
system diseases have started or will start in the near future.
This chapter reviews the development of neurotrophic factor gene
therapy for neurodegenerative diseases focusing on the therapeutic
potential of nerve growth factor in Alzheimer's disease, currently
the subject of a phase I clinical trial.
-----
Appl Neuropsychol. 2003;10(4):215-23.
Results of a randomized placebo-controlled study
of memory training for mildly impaired Alzheimer's disease patients.
Cahn-Weiner DA, Malloy PF, Rebok GW, Ott BR.
Department of Psychiatry and Human Behavior, Brown Medical School,
Providence, Rhode Island, USA. deborah_cahn@brown.edu
The efficacy of a memory-training program to improve word-list
recall and recognition was evaluated in 34 patients with probable
Alzheimer's disease (AD). The patients, who were all taking donepezil
throughout the 6-week intervention, were randomly assigned to
a cognitive intervention group or a control group. The Control
group received didactic presentations but no formal memory training.
Patients were assessed on neuropsychological tests before the
6-week training program, immediately after the training, and 8
weeks after completion of the training. Caregivers, who were blind
to group assignment, completed activities of daily living (ADLs)
and everyday memory questionnaires at all three time-points. No
significant main effects of group (training vs. control) or time
were observed on any outcome measures, nor were any significant
interactions found. In terms of "process" measures during
the 6-week training program, the patients demonstrated modest
improvement on recall and recognition of test material presented
during the training sessions. These results suggest that although
modest gains in learning and memory may be evident in AD patients
who are taught specific strategies, the benefits do not generalize
to other measures of neuropsychological functioning after a brief
intervention.
-----
Neurology. 2003 Dec 9;61(11):1498-502.
Idebenone treatment fails to slow cognitive decline
in Alzheimer's disease.
Thal LJ, Grundman M, Berg J, Ernstrom K, Margolin R, Pfeiffer
E, Weiner MF, Zamrini E, Thomas RG.
Department of Neurosciences, University of California San Diego
School of Medicine, La Jolla 92093-0624, USA. lthal@ucsd.edu
OBJECTIVE: To determine the effect of idebenone on the rate
of decline in Alzheimer's disease (AD). METHODS: A 1-year, multicenter,
double-blind, placebo-controlled, randomized trial was conducted.
Subjects were over age 50 with a diagnosis of probable AD and
had Mini-Mental State Examination (MMSE) scores between 12 and
25. Subjects were treated with idebenone 120, 240, or 360 mg tid,
each of which was compared with placebo. Primary outcome measures
were the Alzheimer's Disease Assessment Scale-Cognitive Subcomponent
(ADAS-Cog) and a Clinical Global Impression of Change (CGIC).
Secondary outcome measures included measurements of activities
of daily living, the Behavioral Pathology in Alzheimer's Disease
Rating Scale, and the MMSE. RESULTS: Five hundred thirty-six subjects
were enrolled and randomized to the four groups. Except for a
slight difference in age, there were no differences in patient
characteristics at baseline. For the primary outcome measures,
there were no significant overall differences between the treatment
groups in the prespecified four-group design. In an exploratory
two-group analysis comparing all three treated groups combined
with placebo, drug-treated patients performed better on the ADAS-Cog
in both the intent-to-treat (ITT) and completers analyses. There
were no differences in the CGIC scores for the ITT or completers
analyses in either the four-group or the two-group analyses. There
were no overall differences on any of the secondary outcome measures
in any of the analyses. CONCLUSION: Idebenone failed to slow cognitive
decline in AD that was of sufficient magnitude to be clinically
significant.
-----
Prescrire Int. 2003 Dec;12(68):230-1.
Anticholinesterases in Alzheimer's disease: a
modest effect on moderately severe disease.
[No authors listed]
(1) Of the four anticholinesterases available in France for
the treatment of mild to moderate Alzheimer's disease, donepezil
is the reference agent. (2) Yet even donepezil is only moderately
effective: only about 10% of patients show a short-lived clinical
improvement. (3) Recent systematic reviews from Cochrane and NICE
confirm the moderate efficacy of anticholinesterases in this setting.
-----
Prescrire Int. 2003 Dec;12(68):203-5.
Memantine: new preparation. Poor evaluation and
uncertain benefit in Alzheimer's disease.
[No authors listed]
(1) The standard treatment for mild to moderately severe Alzheimer's
disease is donepezil, an anticholinesterase with some beneficial
effects (progression is slowed in about 10% of patients, by six
months on average) and mainly gastrointestinal adverse effects.
(2) Memantine, a drug first developed several decades ago, belongs
to the family of NMDA glutamate receptor inhibitors. Marketing
authorisation was recently granted for memantine in moderately
severe and severe Alzheimer's disease. (3) The clinical evaluation
dossier on memantine is poor. Marketing approval was obtained
thanks to only one placebo-controlled trial. It included only
252 patients treated for 28 weeks. Patients with moderately severe
Alzheimer's disease were not analyzed separately from those with
severe forms, even though the response criteria are different
for the two categories of patients. (4) According to the chosen
endpoint, 5% to 19% of patients were clinically improved by memantine.
It is not known whether this benefit persists beyond six months.
(5) The report of a trial comparing memantine + donepezil with
placebo + donepezil does not analyse the response rate. Use of
this combination is not currently justified. (6) In clinical trials
the main adverse effects of memantine were neurological (dizziness
and headache). Fairly lengthy pharmacovigilance data from Germany
are relatively reassuring. (7) In practice, donepezil remains
the reference option for moderately severe Alzheimer's disease.
Memantine is a second-line option, as its adverse effects differ
from those of anticholinesterases. There is still no drug offering
a clear benefit for patients with severe forms of the disease.
-----
Am Fam Physician. 2003 Oct 1;68(7):1365-72.
Pharmacologic treatment of Alzheimer's disease:
an update.
DeLaGarza VW.
Department of Family Medicine, Robert C. Byrd Health Sciences
Center, West Virginia University School of Medicine, Morgantown,
West Virginia 26506, USA. vdelagarza@pol.net
Alzheimer's disease is characterized by the development of
senile plaques and neurofibrillary tangles, which are associated
with neuronal destruction, particularly in cholinergic neurons.
Drugs that inhibit the degradation of acetylcholine within synapses
are the mainstay of therapy. Donepezil, rivastigmine, and galantamine
are safe but have potentially troublesome cholinergic side effects,
including nausea, anorexia, diarrhea, vomiting, and weight loss.
These adverse reactions are often self-limited and can be minimized
by slow drug titration. Acetylcholinesterase inhibitors appear
to be effective, but the magnitude of benefit may be greater in
clinical trials than in practice. The drugs clearly improve cognition,
but evidence is less robust for benefits in delaying nursing home
placement and improving functional ability and behaviors. Benefit
for vitamin E or selegiline has been suggested, but supporting
evidence is not strong. Most guidelines for monitoring drug therapy
in patients with Alzheimer's disease recommend periodic measurements
of cognition and functional ability. The guidelines generally
advise discontinuing therapy with acetylcholinesterase inhibitors
when dementia becomes severe.
-----
JAMA. 2003 Oct 15;290(15):2015-22.
Exercise plus behavioral management in patients
with Alzheimer disease: a randomized controlled trial.
Teri L, Gibbons LE, McCurry SM, Logsdon RG, Buchner DM,
Barlow WE, Kukull WA, LaCroix AZ, McCormick W, Larson EB.
Department of Psychosocial and Community Health, University of
Washington, Seattle 98195, USA. lteri@u.washington.edu
CONTEXT: Exercise training for patients with Alzheimer disease
combined with teaching caregivers how to manage behavioral problems
may help decrease the frailty and behavioral impairment that are
often prevalent in patients with Alzheimer disease. OBJECTIVE:
To determine whether a home-based exercise program combined with
caregiver training in behavioral management techniques would reduce
functional dependence and delay institutionalization among patients
with Alzheimer disease. DESIGN, SETTING, AND PATIENTS: Randomized
controlled trial of 153 community-dwelling patients meeting National
Institute of Neurological and Communicative Diseases and Stroke/Alzheimer
Disease and Related Disorders Association criteria for Alzheimer
disease, conducted between June 1994 and April 1999. INTERVENTIONS:
Patient-caregiver dyads were randomly assigned to the combined
exercise and caregiver training program, Reducing Disability in
Alzheimer Disease (RDAD), or to routine medical care (RMC). The
RDAD program was conducted in the patients' home over 3 months.
MAIN OUTCOME MEASURES: Physical health and function (36-item Short-Form
Health Survey's [SF-36] physical functioning and physical role
functioning subscales and Sickness Impact Profile's Mobility subscale),
and affective status (Hamilton Depression Rating Scale and Cornell
Depression Scale for Depression in Dementia). RESULTS: At 3 months,
in comparison with the routine care patients, more patients in
the RDAD group exercised at least 60 min/wk (odds ratio [OR],
2.82; 95% confidence interval [CI], 1.25-6.39; P =.01) and had
fewer days of restricted activity (OR, 3.10; 95% CI, 1.08-8.95;
P<.001). Patients in the RDAD group also had improved scores
for physical role functioning compared with worse scores for patients
in the RMC group (mean difference, 19.29; 95% CI, 8.75-29.83;
P<.001). Patients in the RDAD group had improved Cornell Depression
Scale for Depression in Dementia scores while the patients in
the RMC group had worse scores (mean difference, -1.03; 95% CI,
-0.17 to -1.91; P =.02). At 2 years, the RDAD patients continued
to have better physical role functioning scores than the RMC patients
(mean difference, 10.89; 95% CI, 3.62-18.16; P =.003) and showed
a trend (19% vs 50%) for less institutionalization due to behavioral
disturbance. For patients with higher depression scores at baseline,
those in the RDAD group improved significantly more at 3 months
on the Hamilton Depression Rating Scale (mean difference, 2.21;
95% CI, 0.22-4.20; P =.04) and maintained that improvement at
24 months (mean difference, 2.14; 95% CI, 0.14-4.17; P =.04).
CONCLUSION: Exercise training combined with teaching caregivers
behavioral management techniques improved physical health and
depression in patients with Alzheimer disease.
-----
Lancet Neurol. 2003 Sep;2(9):539-47.
Treatment of Alzheimer's disease: current status
and new perspectives.
Scarpini E, Scheltens P, Feldman H.
Department of Neurological Sciences, Dino Ferrari Center and CEND,
University of Milan, IRCCS Ospedale Maggiore Policlinico, Milan,
Italy. elio.scarpini@unimi.it
Alzheimer's disease (AD) is the most common neurodegenerative
disorder and the most prevalent cause of dementia with ageing.
Pharmacological treatment of AD is based on the use of acetylcholinesterase
inhibitors, which have beneficial effects on cognitive, functional,
and behavioural symptoms of the disease, but their role in AD
pathogenesis is unknown. Other pharmacological therapies are becoming
available--including the recently approved drug memantine, an
NMDA channel blocker indicated for advanced AD. Here, we review
clinical features of the available cholinesterase inhibitors (donepezil,
rivastigmine, and galantamine) including their pharmacological
properties, the evidence for switching from one agent to another,
"head to head" studies, and the emerging evidence for
the use of memantine in AD. New therapeutic approaches--including
those more closely targeted to the pathogenesis of the disease--will
also be reviewed. These potentially disease modifying treatments
include amyloid-beta-peptide vaccination, secretase inhibitors,
cholesterol-lowering drugs, metal chelators, and anti-inflammatory
agents.
-----
Int J Geriatr Psychiatry. 2003 Sep;18(Suppl 1):S7-S13.
Have cholinergic therapies reached their clinical
boundary in Alzheimer's disease?
Jones RW.
The Research Institute for the Care of the Elderly, St. Martins
Hospital, Bath, UK. r.w.jones@bath.ac.uk.
The cholinergic hypothesis suggests that Alzheimer's disease
(AD) results from a selective loss in cholinergic neurons with
decreased acetylcholine levels. Treatments that increase the level
of acetylcholine would be expected to provide clinical benefit.
Clinical trials of dietary precursors of acetylcholine and muscarinic
receptor agonists have been unsuccessful. Further research is
needed to confirm whether nicotine or nicotinic agonists are of
value. The most successful approach has been to increase acetylcholine
levels by inhibiting cholinesterase function. A number of cholinesterase
inhibitors (ChEI) show clinical efficacy including phyostigmine
but it is poorly tolerated. Tacrine, the first ChEI to be licensed
for AD, needs frequent administration and causes a specific reversible
hepatotoxicity. Three ChEI, donepezil, rivastigmine and galantamine
are widely available. They are effective in mild to moderate (and
possibly severe) AD. Tolerability is improved by slow dose titration
and there are a significant number of non-responders. Donepezil
appears to be effective, the simplest to use and the best tolerated.
Rivastigmine is effective but less well tolerated: galantamine
is also very effective with intermediate tolerability. Although
there are pharmacological differences between the three compounds,
it remains uncertain whether these are clinically relevant. There
are still unanswered questions. It is difficult to predict who
will respond to the drugs and it is unclear how long treatment
benefits last. At present there are little data to support the
suggestion of activity beyond symptomatic benefit. Trials are
also being conducted in Mild Cognitive Impairment, other dementias
and other conditions where cognitive impairment is a problem.
Copyright 2003 John Wiley & Sons, Ltd.
-----
Ann Pharmacother. 2003 Sep;37(9):1321-4.
Olanzapine for psychotic and behavioral disturbances
in Alzheimer disease.
Schatz RA.
College of Pharmacy, The University of Toledo, Toledo, OH, USA.
robinschatz@msn.com
OBJECTIVE: To evaluate the efficacy and safety of olanzapine
for the treatment of psychotic and behavioral disturbances in
Alzheimer disease. DATA SOURCES: MEDLINE (1966-January 2003) and
Science Citation Index searches were performed. Key search terms
included olanzapine, Alzheimer(s), and dementia. DATA SYNTHESIS:
Four trials of olanzapine and subsequent post hoc analyses were
reviewed. Three trials found a benefit associated with olanzapine
use, but a fourth trial did not. CONCLUSIONS: Olanzapine appears
to be effective in treating psychotic and behavioral disturbances
associated with Alzheimer disease. However, the most appropriate
dose remains to be determined. The benefit of olanzapine therapy
must be weighed against the adverse effect profiles of olanzapine
and alternative treatment options.
-----
CMAJ. 2003 Sep 16;169(6):557-64.
Efficacy and safety of cholinesterase inhibitors
in Alzheimer's disease: a meta-analysis.
Lanctot KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou
MM, Einarson TR.
Neuropharmacology Research Program, Department of Psychiatry,
Sunnybrook & Women's College Health Sciences Centre, Toronto,
ON. Krista.Lanctot@sw.ca
BACKGROUND: Cholinesterase inhibitors (ChEIs) are the only
drugs marketed for the treatment of Alzheimer's disease. Despite
numerous randomized controlled trials, the efficacy and safety
of this group of medications has not been quantified. Our objective
was to quantitatively summarize data on the efficacy and safety
of ChEIs in Alzheimer's disease in a format useful to clinicians.
METHODS: We performed a meta-analysis of randomized, double-blind,
placebo-controlled, parallel-group trials of currently marketed
ChEIs (donepezil, rivastigmine and galantamine), used in therapeutic
doses for at least 12 weeks, from which a cognitive outcome was
reported. Studies were identified through 3 electronic databases
searched to May 2002, pharmaceutical companies and journals. We
extracted the proportions of subjects who responded, experienced
adverse events, discontinued treatment for any reason or discontinued
treatment because of adverse events. RESULTS: In the 16 identified
trials that met the inclusion criteria, 5159 patients were treated
with a ChEI and 2795 received a placebo. The pooled mean proportion
of global responders to ChEI treatment in excess of that for placebo
treatment was 9% (95% confidence interval [95% CI] 6%-12%). The
rates of adverse events, dropout for any reason and dropout because
of adverse events were also higher among the patients receiving
ChEI treatment than among those receiving placebo, the excess
proportions being 8% (95% CI 5%-11%), 8% (95% CI 5%-11%) and 7%
(95% CI 3%-10%), respectively. The numbers needed to treat for
1 additional patient to benefit were 7 (95% CI 6-9) for stabilization
or better, 12 (95% CI 9-16) for minimal improvement or better
and 42 (95% CI 26-114) for marked improvement; the number needed
to treat for 1 additional patient to experience an adverse event
was 12 (95% CI 10-18). INTERPRETATION: Treatment with ChEIs results
in a modest but significant therapeutic effect and modestly but
significantly higher rates of adverse events and discontinuation
of treatment. The numbers needed to treat to benefit 1 additional
patient are small.
-----
Am J Alzheimers Dis Other Demen. 2003 Jul-Aug;18(4):205-14.
Olanzapine as a treatment of neuropsychiatric
disorders of Alzheimer's disease and other dementias: a 24-month
follow-up of 68 patients.
Moretti R, Torre P, Antonello RM, Cazzato G, Griggio S,
Bava A.
Dipartimento di Fisiologia e Patologia Generale, Dipartimento
di Medicina Clinica e Neurologia, U.C.O. di Clinica Neurologica,
Ambulatorio Disturbi Cognitivi, Universita degli Studi di Trieste,
Trieste, Italy.
Although the core feature of all types of dementia is progressive
cognitive disruption, most demented patients also express noncognitive
behavioral problems. These noncognitive problems lead to potentially
devastating disabilities, and are often a major cause of stress,
anxiety and concern for caregivers. Psychotropic drugs are frequently
used to control these symptoms, but they have the potential for
significant side effects, such as sedation, disinhibition, depression,
falls, incontinence, parkinsonisms and akathisias. For 24 months,
we monitored 68 outpatients suffering from Alzheimer's disease,
vascular dementia, frontal lobe dementia, Parkinson dementia complex,
and Lewy body disease. Our purpose was to identify the role and
efficacy of olanzapine and the side effects which emerged during
the treatment of behavioral alteration resulting from five etiological
causes. This paper will discuss the results of this study, and
will provide an overview of the existing literature.
-----
South Med J. 2003 Jul;96(7):699-701.
Orally disintegrating olanzapine for the treatment
of psychotic and behavioral disturbances associated with dementia.
Reeves RR, Torres RA.
Department of Psychiatry, University of Mississippi School of
Medicine, Jackson, MS, USA. roy.reeves@med.va.gov
Orally disintegrating olanzapine is a recently marketed form
of olanzapine that dissolves rapidly on contact with saliva. We
describe six demented patients resistant to treatment with common
oral antipsychotic medications who were successfully treated with
the formulation. The importance of these case reports is to make
physicians aware that orally disintegrating olanzapine may be
useful for the management of psychobehavioral disturbances in
demented patients who resist or have difficulty taking standard
oral medications.
-----
Fortschr Neurol Psychiatr. 2003 Jul;71 Suppl 1:S16-26.
[Pathomechanisms and hypothesis-guided therapeutic
strategies for late-onset Alzheimer's disease]
[Article in German]
Hoyer S, Riederer P.
Abteilung fur Pathochemie und Allgemeine Neurochemie, Universitat
Heidelberg.
Even though the clinical effectiveness of the presently used
pharmaceutical therapy of sporadic Alzheimer Disease seems to
be proven sufficient, their effective mechanisms are much less
known or are disregarded in the evaluation of the clinical effects.
However, it seems to be inevitable to know both clinical effect
and effective mechanisms of pharmaceutics in order to be able
to judge their adversity and benefit. In reference to the pharmaceutics
implemented on sporadic AD in Germany, total different effective
mechanisms are shown. In consideration of the shown pathomechanisms
which have been recognized for sporadic AD, therapeutic rationales
on application of Ginkgo biloba extract (EGb 761) and Memantine
are evident. The application of acetylcholinesterase inhibitors,
often looked on as agent of choice, is to be considered critically
because of the danger of the occurrence of myopathological dysfunction,
resp. the Gulf War Syndrome. Sophisticated and hastily advertised
therapy strategies with statins or vaccination against beta A4
should not be used because of a lack of sufficient evidence based
on the pathophysiological pattern of damage as known in sporadic
AD. Future development must take in account that with sporadic
AD aging influences cannot or can hardly be influenced. Therapeutic
goals should consist to improve the cellular energy status and
the membrane functioning.
-----
Presse Med. 2003 Jul 26;32(25):1181-6.
[Serotonin reuptake inhibitors in depression of
Alzheimer's disease and other dementias]
[Article in French]
Lebert F.
Centre Medical des Monts de Flandres, Centre de la Memoire, CHRU
Lille, Bailleul.
RATIONALE IN ALZHEIMER'S DISEASE: Selective serotonine uptake
inhibitors (SSRI) have demonstrated their effectiveness for symptomatic
treatment of depression, as well as for behavioral and psychological
disorders in dementia patients, particularly in Alzheimer's disease.
TOLERANCE: SSRI are particularly well tolerated, particularly
in comparison with tricyclic antidepressants. Nausea and vomiting
may be a problem in old demented patients. Safety studies have
shown that tolerance is not modified in patients with Alzheimer's
disease. DRUG INTERACTIONS AND PHARMACOKINETICS: Fluoxetine and
paroxetine have an inhibiting effect on metabolism of cholinesterase
inhibitors which should be avoided. The compounds have a short
half-life and non-active metabolites should be preferred. TRAZODONE:
Studies conducted in patients with Alzheimer's disease, mixed
type dementia, or fronto-temporal dementia have shown the efficacy
of trazodone for diverse types of symptoms: sadness, emotional
disorders, irritability, fear, psychomotor instability, delirant
ideas. Efficacy of SSRI in patients with Lewy body dementia remains
to be confirmed.
-----
J Neurol. 2003 Jul;250(7):788-92.
Anti-inflammatory therapy in Alzheimer's disease:
is hope still alive?
van Gool WA, Aisen PS, Eikelenboom P.
Dept. of Neurology, H2-222.2, Academic Medical Center, P.O. Box
22700, 1100 DE, Amsterdam, The Netherlands. w.a.vangool@amc.uva.nl
Based on observations from neuropathology, epidemiology, and
in vitro and animal experiments, the inflammatory component of
Alzheimer's disease (AD) has been considered a compelling target
for therapeutic intervention. However, a summary of all published
trial reports to date suggests that AD patients do not benefit
from treatment with anti-inflammatory drugs. In this brief review,
we try to reconcile these sobering trial results with recent observations
from basic research and epidemiology that continue to strengthen
the idea that inflammatory mechanisms play an important role in
the pathogenesis of AD. We review the possibilities that (1) not
all components of the inflammatory response in AD are detrimental,
(2) beneficial effects of anti-inflammatory drugs may not be mediated
by inflammatory pathways, and (3) the timing of the intervention
should be in the earliest stages of the pathogenesis of AD, perhaps
even before the first symptoms emerge.We conclude that studies
on primary prevention of AD are the logical next step in testing
the inflammatory hypothesis of AD.
-----
BMJ. 2003 Jul 19;327(7407):128.
Effect of non-steroidal anti-inflammatory drugs
on risk of Alzheimer's disease: systematic review and meta-analysis
of observational studies.
Etminan M, Gill S, Samii A.
Department of Clinical Epidemiology, Royal Victoria Hospital,
Montreal, Quebec, Canada H3A 1A1. mahyar.etminan@mail.mcgill.ca
OBJECTIVES: To quantify the risk of Alzheimer's disease in
users of all non-steroidal anti-inflammatory drugs (NSAIDs) and
users of aspirin and to determine any influence of duration of
use. DESIGN: Systematic review and meta-analysis of observational
studies published between 1966 and October 2002 that examined
the role of NSAID use in preventing Alzheimer's disease. Studies
identified through Medline, Embase, International Pharmaceutical
Abstracts, and the Cochrane Library. RESULTS: Nine studies looked
at all NSAIDs in adults aged > 55 years. Six were cohort studies
(total of 13 211 participants), and three were case-control studies
(1443 participants). The pooled relative risk of Alzheimer's disease
among users of NSAIDs was 0.72 (95% confidence interval 0.56 to
0.94). The risk was 0.95 (0.70 to 1.29) among short term users
(< 1 month) and 0.83 (0.65 to 1.06) and 0.27 (0.13 to 0.58)
among intermediate term (mostly < 24 months) and long term
(mostly > 24 months) users, respectively. The pooled relative
risk in the eight studies of aspirin users was 0.87 (0.70 to 1.07).
CONCLUSIONS: NSAIDs offer some protection against the development
of Alzheimer's disease. The appropriate dosage and duration of
drug use and the ratios of risk to benefit are still unclear.
-----
J Am Geriatr Soc. 2003 Jul;51(7):937-44.
Donepezil is associated with delayed nursing home
placement in patients with Alzheimer's disease.
Geldmacher DS, Provenzano G, McRae T, Mastey V, Ieni JR.
University Memory and Aging Center, University Hospitals Research
Institute, Cleveland, Ohio, USA.
OBJECTIVES: To assess the relationship between donepezil treatment
and time to nursing home placement (NHP) for patients with Alzheimer's
disease (AD). DESIGN: Observational follow-up of patient NHP and
vital status. SETTING: Community. PARTICIPANTS: Patients previously
enrolled in one of three randomized, double-blind, placebo-controlled
clinical trials of donepezil and two subsequent open-label studies
(total N = 1,115); 671 patients provided complete data for analysis.
MEASUREMENTS: Data were obtained through follow-up interviews
with caregivers and chart reviews of patients with AD. Comparison
groups were defined by whether patients received an effective
dose of donepezil (>/=5 mg/d; >/=80% compliance) for specific
numbers of weeks during the double-blind or open-label trial phase,
in both phases, or in neither. Cox proportional hazards models
were used to estimate risk ratios for NHP and survival curves
from which median times to NHP were estimated for first dementia-related
placement of longer than 2 weeks and permanent placement. The
models were adjusted for age, sex, baseline Mini-Mental State
Examination score, whether the caregiver was a spouse, caregiver
continuity, and use of other cholinesterase inhibitors after the
clinical trials. RESULTS: Use of donepezil of 5 mg/d or more was
associated with significant delays in NHP. A cumulative dose-response
relationship was observed between longer-term sustained donepezil
use and delay of NHP. When donepezil was taken at an effective
dose for at least 9 to 12 months, conservative estimates of the
time gained before NHP were 21.4 months for first dementia-related
NHP and 17.5 months for permanent NHP. CONCLUSION: Use of donepezil
by AD patients resulted in significant delays in NHP. Long-term
use of donepezil may help AD patients live longer in community
settings, with consequent personal, social, and economic benefits.
-----
Rev Neurol. 2003 Jul 16-31;37(2):149-55.
[Factors that modify the natural course of Alzheimer's
disease]
[Article in Spanish]
Lopez OL, Becker JT.
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
15213, USA. lopezol@msx.upmc.edu
Alzheimer s disease (AD) is an insidious, and progressive disorder
of the nervous system that typically occurs after age 65, with
incidence rising with chronological age. The disorder is characterized
by a pronounced memory loss, due to neuropathological changes
in the mesial temporal lobes; as the pathology spreads throughout
the cerebral cortex. However, it is still unknown why some areas
are more affected than others, with the subsequent clinical heterogeneity
(or phenotypes), and variability in the clinical course. The most
salient neurobehavioral syndromes that can affect the clinical
course are extrapyramidal signs, as well as a wide variety of
psychiatric syndromes (e.g., psychotic symptoms, depression, aggression).
Similarly, medication use (e.g., antipsychotics, sedatives) have
shown to have a detrimental effect in the course of the disease.
Current palliative treatments for AD may alter the natural history
of the disease by extending the time that affected patients may
live at home.
-----
J Clin Psychiatry. 2003;64 Suppl 9:18-22.
The search for better noncholinergic treatment
options for Alzheimer's disease.
Mintzer JE.
Medical University of South Carolina and Ralph H. Johnson VA Medical
Center, Charleston, SC, USA. mintzerj@musc.edu
Alzheimer's disease is a biological process that involves the
disruption of multiple neurochemical pathways. Current treatments
for Alzheimer's disease focus on deficits in the cholinergic neurochemical
pathway. While newer generation cholinergic agents have a more
favorable side effect profile, only a limited, but consistent,
degree of efficacy is seen. Treatments are emerging that focus
on other areas of neurochemical activity such as oxidative damage,
inflammation, glutamatergic neurotransmissions, and serotonergic
and dopaminergic pathways. These treatments, supplemented with
current cholinergic therapies, may help to ease patients' suffering
and caregiver distress.
-----
Neurorehabil Neural Repair. 2003 Jun;17(2):101-8.
Effects of low-frequency cranial electrostimulation
on the rest-activity rhythm and salivary cortisol in Alzheimer's
disease.
Scherder E, Knol D, van Someren E, Deijen JB, Binnekade
R, Tilders F, Sergeant J.
Department of Clinical Neuropsychology, Vrije Universiteit, Van
der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands. EJA.Scherder@psy.vu.nl
OBJECTIVE: In previous studies, cranial electrostimulation
(CES) had positive effects on sleep in depressed patients and
in patients with vascular dementia. The present study examined
the effects of low-frequency CES on the rest-activity rhythm and
cortisol levels of patients with probable Alzheimer's disease
(AD). METHOD: It was hypothesised that a decreased level of cortisol
would parallel a positive effect of low-frequency CES on nocturnal
restlessness. Sixteen AD patients were randomly assigned to an
experimental group (n = 8) or a control group (n = 8). The experimental
group was treated with CES, whereas the control group received
sham stimulation, for 30 minutes a day, during 6 weeks. The rest-activity
rhythm was assessed by actigraphy. Cortisol was measured repeatedly
in the saliva throughout the day by means of salivette tubes.
RESULTS: Low-frequency CES did not improve the rest-activity rhythm
in AD patients. Moreover, both groups showed an increase instead
of a decrease in the level of cortisol. CONCLUSIONS: These preliminary
results suggest that low-frequency CES has no positive effect
on the rest-activity rhythm in AD patients. An alternative research
design with high-frequency CES in AD is discussed.
-----
Arch Neurol. 2003 Jun;60(6):843-8.
Analysis of outcome in retrieved dropout patients
in a rivastigmine vs placebo, 26-week, Alzheimer disease trial.
Farlow M, Potkin S, Koumaras B, Veach J, Mirski D.
Department of Neurology, Indiana University School of Medicine,
Indianapolis 46202, USA. mfarlow@iupui.edu
BACKGROUND: Treatment with cholinesterase inhibitors improves
cognition in patients with Alzheimer disease (AD). In studies
designed with a washout period at the end of the study, after
treatment with a cholinesterase inhibitor is discontinued, the
cognitive benefits of therapy are no longer apparent following
washout. The rivastigmine trials discussed in this article were
not designed with a posttreatment washout period at the end of
the study. Therefore, to evaluate the effect of discontinuing
treatment, we analyzed the retrieved dropout (RDO) population.
OBJECTIVE: To evaluate the change in cognition (at week 26 vs
baseline) observed in patients from 3 large clinical trials of
AD who prematurely discontinued treatment with placebo or rivastigmine.Design
and METHODS: Eligible patients with AD (Mini-Mental State Examination
[MMSE] score, 10-26, inclusive) were enrolled in 1 of three 26-week,
double-blind, placebo-controlled studies (Novartis US Pivotal
[dose-range] Trial, US fixed-dose study, and a Global Pivotal
[dose-range] Trial) that compared rivastigmine therapy with placebo.
Patients who discontinued study participation (for any reason)
(considered to be the RDO population) were encouraged to return
for their scheduled week 26 efficacy evaluations. Effects on cognition
were assessed using the Alzheimer's Disease Assessment Scale-Cognitive
subscale (ADAS-Cog). RESULTS: The results for the Novartis US
Pivotal Trials and for the 3 studies combined (Novartis studies
B352, B351, and B303) are reported. In the US pivotal trial, RDO
patients in the 6- to 12-mg/d group had been not receiving the
drug (to be called "off drug") for 102 (57.7) days (mean
[SD]) compared with 68 (51.7) days in the RDO placebo group. In
these RDO analyses, a statistically significantly greater worsening
on the ADAS-Cog mean change score was observed in the placebo
group (n = 17) compared with the rivastigmine 6- to 12-mg/d group
(n = 33) at week 26 (MMSE score, -8.2 vs -3.0; P =.009). In the
pooled studies, the mean (SD) number of days off treatment was
95 (52.0) days for the rivastigmine 6- to 12-mg/d group and 66
(52.7) days for the placebo group. The RDO analysis also showed
a statistically significantly greater decline in cognitive function
as measured by the ADAS-Cog mean change score in the placebo group
(n = 38) compared with the rivastigmine 6- to 12-mg/d group (n
= 88) at week 26 (MMSE score, -5.69 vs -2.5; P =.004). A significantly
greater proportion of patients in the placebo group exhibited
at least a 4-point and 7-point worsening in ADAS-Cog scores at
week 26 compared with the rivastigmine 6- to 12-mg/d group in
both the Novartis US Pivotal Trials (P =.007, P =.009) and the
pooled studies (P =.002, P =.017). CONCLUSIONS: After discontinuation
of therapy, rivastigmine-treated patients exhibited less deterioration
in cognitive function compared with placebo-treated patients.
The less severe worsening of cognition after withdrawal of treatment
in patients previously treated with rivastigmine suggests an effect
on disease progression.
-----
Cochrane Database Syst Rev. 2003;(2):CD004031.
Ibuprofen for Alzheimer's disease.
Tabet N, Feldmand H.
Postgraduate Medical School, University of Brighton, Department
of Old Age Psychiatry, Falmer, Brighton, UK. n.t.tabet@brighton.ac.uk
BACKGROUND: Non-steroidal antiinflammatory drugs such as ibuprofen
may have a role in the treatment of conditions characterized by
inflammatory processes. Ibuprofen may attenuate the effects of
modulators of inflammation that have been implicated in the pathogenesis
of Alzheimer's disease. OBJECTIVES: To investigate the efficacy
of ibuprofen treatment for people with Alzheimer's disease. SEARCH
STRATEGY: The trials were identified from a search of the Specialized
Register of the Cochrane Dementia and Cognitive Improvement Group
on 10 December 2002 using the (many) terms listed in the main
text of the review. The CDCIG Register is updated regularly and
contains records from all major health care databases and many
ongoing trials databases. In addition computerized databases and
Internet sites pertaining to ibuprofen and Alzheimer's disease
were systematically examined by two reviewers independently. Data
on ongoing trials of ibuprofen for the treatment of people with
AD were also sought. SELECTION CRITERIA: Eligibility for this
review included all single or multi centre placebo-controlled
randomized trials examining the efficacy of ibuprofen in the treatment
of people diagnosed with Alzheimer's disease according to internationally
accepted criteria. Inclusion and exclusion criteria were specified
to ensure lack of bias in selection and methodological quality
of selected trials. DATA COLLECTION AND ANALYSIS: The aim was
for the two reviewers NT and HF to collect data independently.
The data selected would reflect cognitive, behavioural, physical
and psychological domains of AD. MAIN RESULTS: A systematic search
of all available databases and other sources failed to identify
any completed randomized, double-blind and placebo-controlled
trials, assessing the efficacy of ibuprofen in AD eligible for
inclusion in the review. One double-blind placebo-controlled trial
investigating ibuprofen treatment for age-associated memory impairment
has been identified, but is yet unfinished and no data are yet
available. Other trials assessing the effect of ibuprofen on CSF
beta amyloid in cognitively unimpaired individuals and the effect
of other NSAIDs such as naproxen and rofecoxib for people with
AD are currently under way. REVIEWER'S CONCLUSIONS: No evidence
yet exists from randomized double-blind and placebo-controlled
trials on whether ibuprofen is efficacious for patients diagnosed
as having Alzheimer's disease. Ibuprofen, like other NSAIDs, has
an identifiable and in some instances a significant side-effect
profile which may include gastrointestinal bleeding. Therefore,
it needs to be shown that the benefits of such a treatment outweighs
the risk of side effects before ibuprofen can be recommended for
people with Alzheimer's disease.
-----
Cochrane Database Syst Rev. 2003;(2):CD003158.
Acetyl-L-carnitine for dementia.
Hudson S, Tabet N.
Psychiatry, Maudsley Hospital, Maudsley Hospital, London, UK,
SE5 8 AZ. s.hudson@iop.kcl.ac.uk
BACKGROUND: Dementia is a common mental health problem affecting
5% of those over 65. Various pathological processes are linked
to memory impairment in dementia, particularly those affecting
the cholinergic neurotransmitter system. Acetyl-l-carnitine (ALC)
is derived from carnitine and is described as having several properties
which may be beneficial in dementia. This includes activity at
cholinergic neurons, membrane stabilization and enhancing mitochondrial
function. Work on the effects of ALC has been ongoing since the
1980s yet the efficacy of ALC in cognitive decline remains unclear.
Early studies suggested a beneficial effect of ALC on cognition
and behaviour in aging subjects. However, later, larger studies
have not supported these findings. Some of the difficulties lie
in the early and later studies differing widely in methodology
and assessment tools used, and are therefore difficult to compare.
ALC is not currently in routine clinical use. OBJECTIVES: The
objective of this review is to establish whether Acetyl-l-carnitine
is clinically effective in the treatment of people with dementia.
SEARCH STRATEGY: The trials were identified from a search of the
Specialized Register of the Cochrane Dementia and Cognitive Improvement
Group on 8 January 2003 using the terms acetyl-l-carnitine, l-carnitine
acetyl ester, acetylcarnitine. SELECTION CRITERIA: All double-blind,
randomized, trials involving people with dementia in which treatment
with ALC was compared with a placebo group DATA COLLECTION AND
ANALYSIS: Data were extracted by a reviewer (SH) and entered into
Revman 4.1 software. Where possible intention-to-treat data were
used, but most of the analyses were of completers (people who
completed the study). MAIN RESULTS: There are 11 included trials,
all of which had restricted the participants to people with Alzheimer's
disease. All trials assessed the cognitive effects of ALC and
in addition six considered severity of dementia, six considered
functional ability and six considered clinical global impression.
There were statistically significant treatment effects in favour
of ALC at 12 and 24 weeks for the numbers showing improvement
as determined by Clinical Global Impression, [OR 2.33, 95% CI
1.25 to 4.35, P<0.01] and [OR 3.91, 95% CI 1.32 to 11.54, P=0.01]
but not as determined by the CIGIC at 52 weeks. There was no evidence
of benefit for ALC in the areas of cognition, severity of dementia,
functional ability or Clinical Global Impression as a continuous
measure. Various adverse events were reported, but from the meta-analyses
there were no statistically significant differences between treated
and placebo groups. REVIEWER'S CONCLUSIONS: There is evidence
for benefit of ALC on clinical global impression, but there was
no evidence using objective assessments in any other area of outcome.
Given the large number of comparisons made, the statistically
significant result may be due to chance. At present there is no
evidence to recommend its routine use in clinical practice. Although
the intention of the review was to access ALC for the treatment
of all dementias, the included trials had confined themselves
to participants with Alzheimer's disease. Individual patient data
may add to the findings, as would trials including other types
of dementia and other outcomes (e.g. mood and caregiver quality
of life). However, the evidence does not suggest that ALC is likely
to prove an important therapeutic agent. More work on the pharmacokinetics
of ALC in humans is also required.
-----
Cochrane Database Syst Rev. 2003;(2):CD002853.
Propentofylline for dementia.
Frampton M, Harvey RJ, Kirchner V.
4 Edwin Terrace, Mellifont Avenue, Dun Laoire, Co. Dublin, Ireland.
maria.frampton@virgin.net
BACKGROUND: Propentofylline is a novel therapeutic agent for
dementia that readily crosses the blood-brain barrier and acts
by blocking the uptake of adenosine and inhibiting the enzyme
phosphodiesterase. In vitro and in vivo its mechanism of action
appears to be twofold; it inhibits the production of free radicals
and reduces the activation of microglial cells. It therefore interacts
with the inflammatory processes that are thought to contribute
to dementia, and given its mechanism of action is a possible disease
modifying agent rather than a purely symptomatic treatment. OBJECTIVES:
To determine the clinical efficacy and safety of propentofylline
for people with dementia. SEARCH STRATEGY: The trials were identified
from a search of the Specialized Register of the Cochrane Dementia
and Cognitive Improvement Group on 5 February 2003. Aventis, the
manufacturing pharmaceutical company, was asked for data from
unpublished studies but declined to enter into correspondence.
SELECTION CRITERIA: Unconfounded double-blind randomized controlled
trials of propentofylline compared with a placebo or another treatment
group. DATA COLLECTION AND ANALYSIS: There were detailed reports
of only four of the nine included studies. The efficacy of propentofylline
was reviewed for undifferentiated dementia as there were not enough
data to attempt a subgroup analysis for the types of dementia.
MAIN RESULTS: The following statistically significant treatment
effects in favour of propentofylline are reported. Cognition at
3, 6 and 12 months including MMSE at 12 months. [MD 1.2, 95%CI
0.12 to 2.28, P=0.03] Severity of dementia at 3, 6 and 12 months
including CGI at 12 months [MD -0.21, 95%CI -0.39 to -0.03, P=0.03].
Activities of Daily Living (NAB) at 6 and 12 months [MD -1.20,
95%CI -2.22 to -0.18, P=0.02]. Global Assessment (CGI) at 3 months
[MD -0.48, 95% CI -0.75 to -0.21, P=0.0006], but not at later
times. Tolerability There were minimal data on adverse effects
and drop-outs. There were a statistically significant treatment
effects in favour of placebo at 12 months, for the number of dropouts,
[OR=1.43, 95%CI 1.04 to 1.90, P=0.03]. REVIEWER'S CONCLUSIONS:
There is limited evidence that propentofylline might benefit cognition,
global function and activities of daily living of people with
Alzheimer's disease and/or vascular dementia. The meta-analyses
reported here are far from satisfactory as a summary of the efficacy
of propentofylline, considering the unpublished information on
another 1200 patients in randomized trials that exists. Unfortunately
Aventis has been unwilling to correspond with the authors, significantly
limiting the scope of this review.
-----
Pharmacopsychiatry. 2003 Jun;36 Suppl 1:S8-14.
Pharmacological studies supporting the therapeutic
use of Ginkgo biloba extract for Alzheimer's disease.
Ahlemeyer B, Krieglstein J.
Institute for Pharmacology und Toxicology, Department of Pharmacy,
Philipps University of Marburg, Ketzerbach 63, 35032 Germany.
The standardized Ginkgo biloba extract EGb 761(definition see
editorial) has been shown to produce neuroprotective effects in
different in vivo and in vitro models. Since EGb 761 is a complex
mixture containing flavonoid glycosides, terpene lactones (non-flavone
fraction) and various other constituents, the question arises
as to which of these compounds mediates the protective activity
of EGb 761. Previous studies have demonstrated that the non-flavone
fraction was responsible for the antihypoxic activity of EGb 761.
Thus, we examined the neuroprotective and anti-apoptotic ability
of the main constituents of the non-flavone fraction, the ginkgolides
A, B, C, J and bilobalide. In focal cerebral ischemia models,
the administration of bilobalide (5-20 mg/kg, s. c.) 60 min before
ischemia dose-dependently reduced the infarct area in mouse brain
and the infarct volume in rat brain 2 days after the onset of
the injury. 30 minutes of pretreatment with ginkgolide A (50 mg/kg,
s. c.) and ginkgolide B (100 mg/kg, s. c.) reduced the infarct
area in the mouse model of focal ischemia. In primary cultures
of hippocampal neurons and astrocytes from neonatal rats, ginkgolide
B (1 microM) and bilobalide (10 microM) protected the neurons
against damage caused by glutamate (1 mM, 1 h) as evaluated by
trypan blue staining. In addition, bilobalide (0.1 microM) was
able to increase the viability of cultured neurons from chick
embryo telencepalon when exposed to cyanide (1 mM, 1h). Furthermore,
we attempted to find out whether ginkgolides A, B, and J and bilobalide
were also able to inhibit neuronal apoptosis (determined by nuclear
staining with Hoechst 33 258 and TUNEL-staining). Ginkgolide B
(10 microM), ginkgolide J (100 microM) and bilobalide (1 microM)
reduced the apoptotic damage induced by serum deprivation (24h)
or treatment with staurosporine (200 nM, 24h) in cultured chick
embryonic neurons. Bilobalide (100 microM) rescued cultured rat
hippocampal neurons from apoptosis caused by serum deprivation
(24h), whereas ginkgolide B (100 microM) and bilobalide (100 microM)
reduced apoptotic damage induced by staurosporine (300 nM, 24h).
Ginkgolide A failed to affect apoptotic damage neither in serum-deprived
nor in staurosporine-treated neurons. The results suggest that
some of the constituents of the non-flavone fraction of EGb 761
possess neuroprotective and anti-apoptotic capacity, and that
bilobalide is the most potent one. In contrast, ginkgolic acids
(100-500 microM) induced neuronal death, which showed features
of apoptosis as well as of necrosis, but these constituents were
removed from EGb 761 below an amount of 0.0005 %. Taking together,
there is experimental evidence for a neuroprotective effect of
EGb 761 that agrees with clinical studies showing the efficacy
of an oral treatment in patients with mild and moderate dementia.
-----
Coll Antropol. 2003 Jun;27(1):413-24.
Hormone replacement therapy--is there a place
for its use in neurology?
Vukovic V, Lovrencic-Huzjan A, Solter VV, Dordevic V, Demarin
V.
Department of Neurology, University Hospital Sestre Milosrdnice,
Zagreb, Croatia.
Stroke remains the third leading cause of mortality in developed
countries despite declining tendency over the past decades. As
the leading cause of disability and second cause of dementia,
primary prevention should be the main way to fight the disease,
since therapy is not efficient enough. Several observations pointed
to estrogen as a protective agent that may reduce stroke risk,
however, studies have shown conflicting data. There is no strong
evidence that hormone replacement therapy (HRT) increases stroke
risk. Several studies have shown that HRT may reduce the risk
of fatal stroke. Conflicting results have been found for Alzheimer's
disease and HRT as well. An association between higher serum concentration
of estradiol and decreased risk of cognitive decline has been
found in some studies, supporting the hypothesis that estrogen
concentration may play a significant role in brain protection.
Having in mind results of recent randomized trials, it is suggested
that HRT should not be recommended on general basis for the primary
or secondary prevention of cardiovascular/cerebrovascular diseases
or for primary prevention of degenerative diseases such as Alzheimer's
disease. Osteoporosis, cognitive decline and climacteric symptoms
that are likely to impact on quality of life, speak in favor for
recommendation of HRT use. On the other side, family history of
breast carcinoma, mastopathy, thromboembolism, in certain cases
gallbladder disease, will discourage the commencement of HRT.
Respecting the patient's preferences and having benefits and risks
in mind as well as science advisory statements, individual counseling
regarding HRT should be the leading concept in the healthcare
of postmenopausal women.
-----
Cochrane Database Syst Rev. 2003;(3):CD003154.
Memantine for dementia.
Areosa SA, Sherriff F.
BACKGROUND: Alzheimer's disease, vascular and mixed dementia
are the three commonest forms of dementia affecting older people.
There is evidence that the excitatory activity of L-glutamate
plays a role in the pathogenesis of Alzheimer's disease and in
the damage from an ischaemic stroke. A low affinity antagonist
to N-Methyl-D-aspartate (NMDA) type receptors, such as memantine,
may prevent excitatory amino acid neurotoxicity without interfering
with the physiological actions of glutamate required for memory
and learning. OBJECTIVES: To determine the clinical efficacy and
safety of memantine for people with Alzheimer's disease, or vascular
or mixed dementia. SEARCH STRATEGY: Trials were identified from
a search of the Specialized Register of the Cochrane Dementia
and Cognitive Improvement Group on 15 April 2003 using the terms:
memantin*, D-145, DMAA, DRG-0267. All major health care databases
and trial databases within the scope of the group are searched
regularly to keep this Register up to date. SELECTION CRITERIA:
Double-blind, parallel group, placebo-controlled, randomized and
unconfounded trials in which memantine was administered to people
with dementia. DATA COLLECTION AND ANALYSIS: Data were extracted,
pooled where possible, and weighted mean differences, standardized
mean differences or odds ratios were estimated. Intention-to-treat
(ITT) and observed cases (OC) analyses are reported, where data
were available. MAIN RESULTS: Effect of memantine in patients
with moderate to severe Alzheimer's disease: analysis of the change
from baseline at 28 weeks gave statistically significant results
in favour of memantine for 20 mg/day on cognition (MD: 6.1. 95%
CI 2.99 to 9.21, P=0.0001) activities of daily living (MD 2.10,
95% CI 0.46 to 3.74, p=0.01) and in the global clinical impression
of change measured by the CIBIC-Plus at 28 weeks (MD -0.30, 95%
CI -0.58 to -0.02, p=0.04), in all cases the analysis was the
ITT-LOCF population (Reisberg 2000). There were no significant
differences between memantine and placebo for the number of drop-outs
and total number of adverse effects, but a significant difference
in favour of memantine for the number who suffer agitation. Effect
of memantine in patients with mild to moderate vascular dementia:
analysis of the change from baseline at 28 weeks gave statistically
significant results in favour of memantine ( 20 mg/day ) for cognition
(MD -2.19, 95% CI -3.16 to -1.21, P<0.0001) but there was no
benefit for the clinical impression of change, or for global measures
of dementia (MMM300, and MMM500). There were no significant differences
between memantine and placebo for the number of drop-outs and
total number of adverse effects, but a significant difference
in favour of memantine for the number who suffer agitation. Effect
of memantine in patients with Alzheimer's disease and vascular
dementia at 12 weeks: there was no statistically significant difference
between memantine (10 mg/day) and placebo in activities of daily
living. There was a benefit in favour of memantine (10 mg/day)
compared with placebo at 12 weeks, for the numbers improved in
terms of clinical impression of change (60/82 compared with 38/84
- OR 3.30, 95% CI 1.72 to 6.33, P=0.0003) (Winblad 1999). Effect
of memantine in patients with vascular dementia, Alzheimer's disease
and dementia of non-specified type at 6 weeks: there were beneficial
effects on cognition (Ditzler 1991), activities of daily living
(Ditzler 1991, Pantev 1993), behaviour (Pantev 1993) and global
scales (Gortelmeyer 1992; Pantev 1993; Ditzler 1991) and in global
impression of change (Gortelmeyer 1992; Ditzler 1991). There were
no significant differences between memantine and placebo for the
number of drop-outs and total number of adverse effects, but a
significant difference in favour of placebo for the number who
suffer restlessness. REVIEWER'S CONCLUSIONS: There is a beneficial
effect of memantine (20 mg/day) for patients with moderate to
severe Alzheimer disease on cognition and functional decline but
not in the clinical impression of change. Patifor patients with
moderate to severe Alzheimer disease on cognition and functional
decline but not in the clinical impression of change. Patients
with mild to moderate vascular dementia receiving memantine 20
mg/day had less cognitive deterioration at 28 weeks but again
this effect was not clinically discernible. There is a possible
beneficial effect on cognition, function and global scales for
memantine at 6 weeks in mixed populations. The drug is well tolerated
and the incidence of adverse effects is low. More studies are
needed.
-----
Cochrane Database Syst Rev. 2003;(3):CD001394.
Validation therapy for dementia.
Neal M, Briggs M.
Research and Development, Leeds Mental Health Trust, North Wing,
St. Mary's House, St. Mary's Road, Leeds, UK, LS7 3JX.
BACKGROUND: Validation therapy was developed by Naomi Feil
between 1963 and 1980 for older people with cognitive impairments.
Initially, this did not include those with organically-based dementia,
but the approach has subsequently been applied in work with people
who have a dementia diagnosis. Feil's own approach classifies
individuals with cognitive impairment as having one of four stages
in a continuum of dementia: these stages are Mal orientation,
Time Confusion, Repetitive Motion and Vegetation. The therapy
is based on the general principle of validation, the acceptance
of the reality and personal truth of another's experience, and
incorporates a range of specific techniques. Validation therapy
has attracted a good deal of criticism from researchers who dispute
the evidence for some of the beliefs and values of validation
therapy, and the appropriateness of the techniques. Feil, however,
argues strongly for the effectiveness of validation therapy. OBJECTIVES:
To evaluate the effectiveness of validation therapy for people
diagnosed as having dementia of any type, or cognitive impairment
SEARCH STRATEGY: The trials were identified from the Specialized
Register of the Cochrane Dementia and Cognitive Improvement Group
(CDCIG) on 8 January 2003 using the terms validation therapy,
VTD and emotion-oriented care. The Specialized Register at that
time contained records from the following databases: MEDLINE,
EMBASE, CINAHL, PSYCLIT, and SIGLE and many trials databases.
SELECTION CRITERIA: All randomized controlled trials (RCTs) examining
validation therapy as an intervention for dementia were considered
for inclusion in the review. The criteria for inclusion comprised
systematic assessment of the quality of study design and the risk
of bias. DATA COLLECTION AND ANALYSIS: Data were extracted independently
by both reviewers. Authors were contacted for data not provided
in the papers. Psychological scales measuring cognition, behaviour,
emotional state and activities of daily living were examined.
MAIN RESULTS: Three studies were identified that met the inclusion
criteria (Peoples 1982; Robb 1986; Toseland 1997) incorporating
data on a total of 116 patients (42 in experimental groups, and
74 in the control groups (usual care 43 and social contact 21,
10 in reality orientation). It was not possible to pool the data
from the 3 included studies, either because of the different lengths
of treatment or choice of different control treatments, or because
the outcome measures were not comparable. Two significant results
were found:Peoples 1982 - Validation versus usual care. Behaviour
at 6 weeks [MD --5.97, 95% CI (-9.43 to -2.51) P=0.0007, completers
analysis] favours validation therapy. Toseland 1997 - Validation
versus social contact. Depression at 12 months (MOSES) [MD -4.01,
95% CI (-7.74 to - 0.28) P=0.04, completers analysis], favours
validation. There were no statistically significant differences
between validation and social contact or between validation and
usual therapy. There were no assessments of carers. REVIEWER'S
CONCLUSIONS: There is insufficient evidence from randomized trials
to allow any conclusion about the efficacy of validation therapy
for people with dementia or cognitive impairment.
-----
Cochrane Database Syst Rev. 2003;(3):CD001190.
Donepezil for dementia due to Alzheimer's disease.
Birks JS, Harvey R.
Department of Clinical Geratology, University of Oxford, Oxford,
UK, OX2 6HE.
BACKGROUND: Alzheimer's disease is the most common cause of
dementia in older people. One of the aims of therapy is to inhibit
the breakdown of a chemical neurotransmitter, acetylcholine, by
blocking the relevant enzyme. This can be done by a group of chemicals
known as cholinesterase inhibitors. However, some (like tacrine)
are associated with adverse effects such as hepatotoxicity, but
donepezil (E2020, Aricept) is safer. OBJECTIVES: The objective
of this review is to assess whether donepezil improves the well-being
of patients with dementia due to Alzheimer's disease. SEARCH STRATEGY:
The Cochrane Dementia and Cognitive Improvement Group's Specialized
Register was searched using the terms 'donepezil', 'E2020' and
'Aricept' on 9 October 2002. This Register contains up-to-date
records of all major health care databases and many ongoing trial
databases.Members of the Donepezil Study Group and Eisai Inc were
contacted. SELECTION CRITERIA: All unconfounded, double-blind,
randomized controlled trials in which treatment with donepezil
was compared with placebo for patients with mild, moderate or
severe dementia due to Alzheimer's disease. DATA COLLECTION AND
ANALYSIS: Data were extracted by one reviewer (JSB ), pooled where
appropriate and possible, and the weighted mean differences or
Peto odds ratios (95%CI) estimated. MAIN RESULTS: Sixteen trials
are included, involving 4365 participants. The trials were of
12, 24 or 52 weeks duration in selected patients. Available outcome
data cover domains including cognitive function and global clinical
state, but data on several important dimensions of outcome are
unavailable.For cognition there is a statistically significant
improvement for both 5 and 10 mg/day of donepezil at 24 weeks
compared with placebo (-2.02 points on the ADAS-Cog scale WMD,
95%CI -2.77 to -1.26, p<0.00001; -2.92 points on the ADAS-Cog
scale WMD 95% CI -3.74 to -2.10, p<0.00001)and for 10 mg/day
donepezil compared with placebo at 52 weeks (1.84MMSE points,
95% CI, 0.53 to3.15, p=0.006).The results show some improvement
in global clinical state (assessed by an independent clinician)
in people treated with 5 and 10 mg/day of donepezil compared with
placebo at 12 and 24 weeks. Benefits of treatment were also seen
on measures of activities of daily living and behaviour.There
were significantly more withdrawals before the end of treatment
from the 10 mg/day (but not the 5 mg/day) donepezil group compared
with placebo which may have resulted in some overestimation of
beneficial changes at 10 mg/day.A variety of adverse effects were
recorded, with more incidents of nausea, vomiting, diarrhoea and
anorexia in the 10 mg/day group compared with placebo and the
5 mg/day group, but very few patients left a trial as a direct
result of the intervention. REVIEWER'S CONCLUSIONS: People with
mild, moderate or severe dementia due to Alzheimer's disease treated
for periods of 12, 24 or 52 weeks with donepezil experienced benefits
in cognitive function, activities of daily living and behaviour.
Study clinicians rated global clinical state more positively in
treated patients, and measured less decline in measures of global
disease severity. Although no significant changes were measured
on a patient-rated quality of life scales, the instrument used
was crude and possibly unsuited to the task.The additional data
now available confirm the findings of the previous issue of this
review and extend the evidence for the effectiveness of treatment
to at least 52 weeks and to those with severe dementia. More evidence
is still needed for the economic efficacy of donepezil, but clinical
efficacy is confirmed.
-----
Cochrane Database Syst Rev. 2003;(3):CD001015.
Lecithin for dementia and cognitive impairment.
Higgins JP, Flicker L.
MRC Biostatistics Unit, Institute of Public Health, Robinson Way,
Cambridge, Cambridgeshire, UK, CB2 2SR.
BACKGROUND: Alzheimer's disease sufferers have been found to
have a lack of the enzyme responsible for converting choline into
acetylcholine within the brain. Lecithin is a major dietary source
of choline, so extra consumption may reduce the progression of
dementia. OBJECTIVES: To determine the efficacy of lecithin in
the treatment of dementia or cognitive impairment. SEARCH STRATEGY:
The Cochrane Dementia and Cognitive Improvement Group's Specialized
Register was searched on 15 May 2002 using the terms lecithin
and phosphaditylcholine. This contains records from all major
databases and many trials databases. Reference lists and relevant
books have been examined. SELECTION CRITERIA: All unconfounded,
randomized trials comparing lecithin with placebo in a treatment
period longer than one day, in patients with dementia of the Alzheimer
type, vascular dementia, mixed vascular and Alzheimer's disease,
unclassified or other dementia or unclassified cognitive impairment
not fulfilling the criteria for dementia are eligible for inclusion.
DATA COLLECTION AND ANALYSIS: Data were extracted by two independent
reviewers and cross-checked. Meta-analyses were performed when
more than one trial provided data on a comparable outcome on sufficiently
similar patients. Random effects analyses were performed whenever
heterogeneity between results appeared to be present. Standardised
differences in mean outcome measures were used due do the use
of different scales and periods of treatment. Odds ratios for
dichotomous data were pooled using the Mantel-Haenszel or DerSimonian
and Laird methods. MAIN RESULTS: Twelve randomized trials have
been identified involving patients with Alzheimer's disease (265
patients), Parkinsonian dementia (21 patients) and subjective
memory problems (90 patients). No trials reported any clear clinical
benefit of lecithin for Alzheimer's disease or Parkinsonian dementia.
Few trials contributed data to meta-analyses. The only statistically
significant result was in favour of placebo for adverse events,
based on one trial, which appears likely to be a spurious result.
A dramatic result in favour of lecithin was obtained in a trial
of subjects with subjective memory problems. REVIEWER'S CONCLUSIONS:
Evidence from randomized trials does not support the use of lecithin
in the treatment of patients with dementia. A moderate effect
cannot be ruled out, but results from the small trials to date
do not indicate priority for a large randomized trial.
-----
Clin Ther. 2003 Jun;25(6):1634-53.
A review of rivastigmine: a reversible cholinesterase
inhibitor.
Williams BR, Nazarians A, Gill MA.
Department of Pharmacy, University of Southern California School
of Pharmacy, Los Angeles, California 90089, USA.
BACKGROUND: Rivastigmine tartrate is a reversible cholinesterase
inhibitor indicated for the symptomatic treatment of mild to moderate
dementia. It was approved by the US Food and Drug Administration
for the treatment of Alzheimer's disease (AD) on April 21, 2000.
OBJECTIVE: The purpose of this review was to summarize the background
on dementia of the Alzheimer type and the pharmacokinetic properties,
efficacy and tolerability profiles, clinical applications, adverse
effects (AEs), drug interactions, and pharmacoeconomics of rivastigmine.
METHODS: A literature search was conducted using MEDLINE (1995-2002),
EMBASE Geriatrics and Gerontology (1995-2002), the National Institutes
of Health Alzheimer's Disease Education and Resource Center Combined
Health Information Database, and Google. Search terms included
rivastigmine, Exelon, ENA 713, and ENA-713. The bibliographies
of retrieved articles also were searched for relevant articles.
RESULTS: In clinical trials, rivastigmine has improved or maintained
cognitive function, global function (ie, activities of daily living
[ADLs]), and behavior in patients with mild to moderate AD for
up to 52 weeks. AEs are generally mild to moderate and primarily
affect the gastrointestinal (GI) tract. Clinically significant
drug interactions with rivastigmine have thus far not been reported.
Treatment with rivastigmine for up to 2 years may reduce the cost
of caring for patients with AD. Cost savings are minimal during
the first year, particularly for those with mild disease, but
increase during the second year of treatment. Cost savings occur
earlier for those with moderate AD. Most savings are realized
from a delay in the need for institutionalization. CONCLUSIONS:
Rivastigmine has been shown to improve or maintain patients' performance
in 3 major domains: cognitive function, global function (ADLs),
and behavior. The efficacy and tolerability of rivastigmine have
been proved by numerous clinical trials, with the most prominent
AE being GI irritation.
-----
Neurology 2003 Apr 8;60(7):1071-6
DHEA treatment of Alzheimer's disease: a randomized,
double-blind, placebo-controlled study.
Wolkowitz OM, Kramer JH, Reus VI, Costa MM, Yaffe K, Walton P,
Raskind M, Peskind E, Newhouse P, Sack D, De Souza E, Sadowsky
C, Roberts E; DHEA-Alzheimer's Disease Collaborative Research.
Department of Psychiatry, Center for Neurobiology and Psychiatry,
University of California San Francisco (UCSF) School of Medicine,
USA. owenw@itsa.ucsf.edu
OBJECTIVE: To compare the efficacy and tolerability of dehydroepiandrosterone
(DHEA) vs placebo in AD. METHOD: Fifty-eight subjects with AD
were randomized to 6 month's treatment with DHEA (50 mg per os
twice a day; n = 28) or placebo (n = 30) in a multi-site, double-blind
pilot trial. Primary efficacy measures assessed cognitive functioning
(the AD Assessment Scale-Cognitive [ADAS-Cog]) and observer-based
ratings of overall changes in severity (the Clinician's Interview-Based
Impression of Change with Caregiver Input [CIBIC-Plus]). At baseline,
3 months, and 6 months, the ADAS-Cog was administered, and at
3 and 6 months, the CIBIC-Plus was administered. The 6-month time
point was the primary endpoint. RESULTS: Nineteen DHEA-treated
subjects and 14 placebo-treated subjects completed the trial.
DHEA was relatively well-tolerated. DHEA treatment, relative to
placebo, was not associated with improvement in ADAS-Cog scores
at month 6 (last observation carried forward; p = 0.10); transient
improvement was noted at month 3 (p = 0.014; cutoff for Bonferroni
significance = 0.0125). No difference between treatments was seen
on the CIBIC-Plus at either the 6-month or the 3-month time points.
CONCLUSIONS: DHEA did not significantly improve cognitive performance
or overall ratings of change in severity in this small-scale pilot
study. A transient effect on cognitive performance may have been
seen at month 3, but narrowly missed significance.
-----
N Engl J Med 2003 Apr 3;348(14):1333-41
Memantine in moderate-to-severe Alzheimer's disease.
Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ;
Memantine Study Group.
Department of Psychiatry, New York University School of Medicine,
New York 10016, USA. barry.reisberg@med.nyu.edu
BACKGROUND: Overstimulation of the N-methyl-D-aspartate (NMDA)
receptor by glutamate is implicated in neurodegenerative disorders.
Accordingly, we investigated memantine, an NMDA antagonist, for
the treatment of Alzheimer's disease. METHODS: Patients with moderate-to-severe
Alzheimer's disease were randomly assigned to receive placebo
or 20 mg of memantine daily for 28 weeks. The primary efficacy
variables were the Clinician's Interview-Based Impression of Change
Plus Caregiver Input (CIBIC-Plus) and the Alzheimer's Disease
Cooperative Study Activities of Daily Living Inventory modified
for severe dementia (ADCS-ADLsev). The secondary efficacy end
points included the Severe Impairment Battery and other measures
of cognition, function, and behavior. Treatment differences between
base line and the end point were assessed. Missing observations
were imputed by using the most recent previous observation (the
last observation carried forward). The results were also analyzed
with only the observed values included, without replacing the
missing values (observed-cases analysis). RESULTS: Two hundred
fifty-two patients (67 percent women; mean age, 76 years) from
32 U.S. centers were enrolled. Of these, 181 (72 percent) completed
the study and were evaluated at week 28. Seventy-one patients
discontinued treatment prematurely (42 taking placebo and 29 taking
memantine). Patients receiving memantine had a better outcome
than those receiving placebo, according to the results of the
CIBIC-Plus (P=0.06 with the last observation carried forward,
P=0.03 for observed cases), the ADCS-ADLsev (P=0.02 with the last
observation carried forward, P=0.003 for observed cases), and
the Severe Impairment Battery (P<0.001 with the last observation
carried forward, P=0.002 for observed cases). Memantine was not
associated with a significant frequency of adverse events. CONCLUSIONS:
Antiglutamatergic treatment reduced clinical deterioration in
moderate-to-severe Alzheimer's disease, a phase associated with
distress for patients and burden on caregivers, for which other
treatments are not available. Copyright 2003 Massachusetts Medical
Society
-----
J Clin Psychiatry 2003 Feb;64(2):134-43
A randomized placebo-controlled trial of risperidone
for the treatment of aggression, agitation, and psychosis of dementia.
Brodaty H, Ames D, Snowdon J, Woodward M, Kirwan J, Clarnette
R, Lee E, Lyons B, Grossman F.
Academic Department for Old Age Psychiatry, School of Psychiatry,
University of New South Wales, Sydney, Australia. h.brodaty@unsw.edu.au
BACKGROUND: This randomized, double-blind, placebo-controlled
trial examined the efficacy and safety of risperidone in the treatment
of aggression, agitation, and psychosis in elderly nursing-home
patients with dementia. METHOD: Elderly patients with a DSM-IV
diagnosis of dementia of the Alzheimer's type, vascular dementia,
or a combination of the 2 (i.e., mixed dementia) and significant
aggressive behaviors were randomized to receive, for a period
of 12 weeks, a flexible dose of either placebo or risperidone
solution up to a maximum of 2 mg/day. Outcome measures were the
Cohen-Mansfield Agitation Inventory (CMAI), the Behavioral Pathology
in Alzheimer's Disease (BEHAVE-AD) rating scale, and the Clinical
Global Impression of Severity (CGI-S) and of Change (CGI-C) scales.
RESULTS: A total of 345 patients were randomized to treatment
with risperidone or placebo, and 337 patients received at least
one dose of study drug. The trial was completed by 67% of patients
in the placebo group and 73% of patients in the risperidone group.
The mean +/- SE dose of risperidone was 0.95 +/- 0.03 mg/day.
The primary endpoint of the study, the difference from baseline
to endpoint in CMAI total aggression score, showed a significant
reduction in aggressive behavior for risperidone versus placebo
(p <.001). A similar improvement was also seen for the CMAI
total non-aggression subscale (p <.002) and for the BEHAVE-AD
total (p <.001) and psychotic symptoms subscale (p =.004).
At endpoint, the CGI-S and the CGI-C scores indicated a significantly
greater improvement with risperidone compared with placebo (p
<.001). Overall, 94% and 92% of the risperidone and placebo
groups, respectively, reported at least 1 adverse event. Somnolence
and urinary tract infection were more common with risperidone
treatment, whereas agitation was more common with placebo. There
was no significant difference in the number of patients who reported
extrapyramidal symptoms between the risperidone (23%) and placebo
(16%) groups. CONCLUSION: Treatment with low-dose (mean = 0.95
mg/day) risperidone resulted in significant improvement in aggression,
agitation, and psychosis associated with dementia.
-----
JAMA 2003 Jan 8;289(2):210-6
Efficacy of cholinesterase inhibitors in the treatment
of neuropsychiatric symptoms and functional impairment in Alzheimer
disease: a meta-analysis.
Trinh NH, Hoblyn J, Mohanty S, Yaffe K.
Department of Psychiatry, Massachusetts General Hospital, Boston,
USA.
CONTEXT: Cholinesterase inhibitors are the primary treatment
for the cognitive symptoms of Alzheimer disease (AD). Cholinergic
dysfunction is also associated with neuropsychiatric and functional
deficits, but results from randomized controlled trials of cholinesterase
inhibitors are conflicting. OBJECTIVE: To conduct a systematic
review and meta-analysis to quantify the efficacy of cholinesterase
inhibitors for neuropsychiatric and functional outcomes in patients
with mild to moderate AD. DATA SOURCES: We performed a literature
search of trials using MEDLINE (January 1966-December 2001), Dissertations
Abstracts On-line, PSYCHINFO, BIOSIS, PubMed, and the Cochrane
Controlled Trials Register. We retrieved English- and non-English-language
articles for review and collected references from bibliographies
of reviews, original research articles, and other articles of
interest. We searched for both published and unpublished trials,
contacting researchers and pharmaceutical companies. STUDY SELECTION:
We included 29 parallel-group or crossover randomized, double-blind,
placebo-controlled trials of outpatients who were diagnosed as
having mild to moderate probable AD and were treated for at least
1 month with a cholinesterase inhibitor. Sixteen trials included
neuropsychiatric and 18 included functional measures. DATA EXTRACTION:
Two investigators (N.H.T. and J.H.) independently extracted study
methods, sources of bias, and outcomes. Neuropsychiatric outcomes
were measured with the Neuropsychiatric Inventory (NPI, 0-120
points) and the Alzheimer Disease Assessment Scale, noncognitive
(ADAS-noncog, 0-50 points) and were analyzed with the weighted
mean difference method. Functional outcomes were measured with
several activities of daily living (ADL) and instrumental activities
of daily living (IADL) scales and analyzed with the standardized
mean difference method. DATA SYNTHESIS: For neuropsychiatric outcomes,
10 trials included the ADAS-noncog and 6 included the NPI. Compared
with placebo, patients randomized to cholinesterase inhibitors
improved 1.72 points on the NPI (95% confidence interval [CI],
0.87-2.57 points), and 0.03 points on the ADAS-noncog (95% CI,
0.00-0.05 points). For functional outcomes, 14 trials used ADL
and 13 trials used IADL scales. Compared with placebo, patients
randomized to cholinesterase inhibitors improved 0.1 SDs on ADL
scales (95% CI, 0.00-0.19 SDs), and 0.09 SDs on IADL scales (95%
CI, 0.01 to 0.17 SDs). There was no difference in efficacy among
various cholinesterase inhibitors. CONCLUSIONS: These results
indicate that cholinesterase inhibitors have a modest beneficial
impact on neuropsychiatric and functional outcomes for patients
with AD. Future research should focus on how such improvements
translate into long-term outcomes such as patient quality of life,
institutionalization, and caregiver burden.
-----
Ann Intern Med 2003 Mar 4;138(5):400-10
Alzheimer disease: current concepts and emerging
diagnostic and therapeutic strategies.
Clark CM, Karlawish JH.
Memory Disorders Clinic, Penn-Ralston Center, University of Pennsylvania,
3615 Chestnut Street, Philadelphia, Pennsylvania 19104, USA.
Alzheimer disease is a complex neurodegenerative dementing
illness. It has become a major public health problem because of
its increasing prevalence, long duration, high cost of care, and
lack of disease-modifying therapy. Over the past few years, however,
remarkable advances have taken place in understanding both the
genetic and molecular biology associated with the intracellular
processing of amyloid and tau and the changes leading to the pathologic
formation of extracellular amyloid plaques and the intraneuronal
aggregation of hyperphosphorylated tau into neurofibrillary tangles.
The identification of disease-causing autosomal dominant mutations
as well as gene polymorphisms that alter the risk for pathology
indicate that Alzheimer disease is a genetically complex disorder.
This progress in our understanding of the molecular pathology
has set the stage for clinically meaningful advances in diagnosis
and treatment. Emerging diagnostic methods that are based on biochemical
and imaging biomarkers of disease-specific pathology hold the
potential for accurately diagnosing Alzheimer disease at the earliest
stage of the illness--the time when disease-modifying treatment
will be most effective. Currently available cholinesterase inhibition
therapy targets the cognitive symptoms. However, the goal of new
therapies under development is halting the pathologic cascade
and potentially reversing the course of the disease. If these
new therapies are successful, they will represent a remarkable
medical advance for patients and the families who care for them.
-----
Dement Geriatr Cogn Disord 2003;15(2):79-87
Galantamine provides sustained benefits in patients
with 'advanced moderate' Alzheimer's disease for at least 12 months.
Blesa R, Davidson M, Kurz A, Reichman W, van Baelen B, Schwalen
S.
Hospital Clinic Universitari, Barcelona, Spain. rblesa@clinic.ub.es
Galantamine (Reminyl), a novel agent with a dual mode of action,
modulates nicotinic acetylcholine receptors and inhibits acetylcholinesterase.
Galantamine has consistently demonstrated a broad range of beneficial
effects and has shown sustained benefits in cognitive and functional
abilities for at least 12 months in patients with mild-to-moderate
Alzheimer's disease (AD). As pivotal studies demonstrating the
efficacy of cholinergic drugs were designed to exclude patients
with severer AD, many patients with the advanced stage of this
condition are currently not treated due to the lack of demonstrated
efficacy in clinical trials. We aimed to investigate whether there
was any evidence for the benefits of galantamine in patients with
severer disease, by performing a post hoc analysis using data
extracted from the population of the two long-term galantamine
studies. We evaluated the efficacy of galantamine in patients
with 'advanced moderate' AD. 'Advanced moderate' patients were
those with baseline Mini Mental State Examination (MMSE) scores
</=14 or Alzheimer's Disease Assessment Scale - cognitive subscale
(ADAS-cog) scores >30. These patients were compared with matched
controls who received placebo in a different historical study.
Cognitive abilities (assessed using the ADAS-cog scale) of 'advanced
moderate' AD patients receiving galantamine for 12 months were
maintained at baseline levels after 12 months, and significantly
improved over those of placebo patients (p < 0.001). Of the
'advanced moderate' patients receiving galantamine, 51% with baseline
ADAS-cog of >30 maintained or improved their ADAS-cog scores
over baseline values, compared with 13% receiving placebo (p <
0.001). In the subgroup of 'advanced moderate' patients with baseline
MMSE </=14, 48% of those receiving galantamine and 4% of those
receiving placebo maintained or improved their ADAS-cog scores
at 12 months (p = 0.001). In both subgroups, the treatment difference
(galantamine vs. historical placebo) amounted to approximately
10 points on the ADAS-cog scale. Functional abilities, as assessed
using the Disability Assessment for Dementia scale, remained significantly
superior in galantamine-treated patients compared with historical
placebo-treated patients at 12 months (p < 0.001). In conclusion,
galantamine offered sustained efficacy to patients with 'advanced
moderate' AD, confirming the benefits seen in published studies
of patients with mild-to-moderate AD. This drug has potential
for broader use in clinical practice. Copyright 2003 S. Karger
AG, Basel
-----
Curr Drug Targets 2003 Feb;4(2):97-112
A critical analysis of new molecular targets and
strategies for drug developments in Alzheimer's disease.
Lahiri DK, Farlow MR, Sambamurti K, Greig NH, Giacobini E, Schneider
LS.
Department of Psychiatry and Neurology, Institute of Psychiatric
Research, Indiana University School of Medicine, Indianapolis,
IN 46202-4887, USA. dlahiri@iupui.edu
Alzheimer's disease (AD), a progressive, degenerative disorder
of the brain, is believed to be the most common cause of dementia
amongst the elderly. AD is characterized by the presence of amyloid
deposits and neurofibrillary tangles in the brain of afflicted
individuals. AD is associated with a loss of the presynaptic markers
of the cholinergic system in the brain areas related to memory
and learning. AD appears to have a heterogeneous etiology with
a large percentage termed sporadic AD arising from unknown causes
and a smaller fraction of early onset familial AD (FAD) caused
by mutations in one of several genes, such as the beta-amyloid
precursor protein (APP) and presenilins (PS1, PS2). These proteins
along with tau, secretases, such as beta-amyloid cleaving enzyme
(BACE), and apolipoprotein E play important roles in the pathology
of AD. On therapeutic fronts, there is significant research underway
in the development of new inhibitors for BACE, PS-1 and gamma-secretase
as targets for treatment of AD. There is also a remarkable advancement
in understanding the function of cholinesterase (ChE) in the brain
and the use of ChE-inhibitors in AD. A new generation of acetyl-
and butyryl cholinesterase inhibitors is being studied and tested
in human clinical trials for AD. The development of vaccination
strategies, anti-inflammatory agents, cholesterol-lowering agents,
anti-oxidants and hormone therapy are examples of new approaches
for treating or slowing the progression of AD. In addition, nutritional,
genetic and environmental factors highlight more effective preventive
strategies for AD. Developments of early diagnostic tools and
of quantitative markers are critical to better follow the course
of the disease and to evaluate different therapeutic strategies.
In this review, we attempt to critically examine recent trends
in AD research from molecular, genetic to clinical areas. We discuss
various neurobiological mechanisms that provide the basis of new
targets for AD drug development. All these current research efforts
should lead to a deeper understanding of the pathobiochemical
processes that occur in the AD brain in order to effectively diagnose
and prevent their occurrence.
-----
J Neuropsychiatry Clin Neurosci 2003 Winter;15(1):67-73
Patterns of change in the treatment of psychiatric
symptoms in patients with probable Alzheimer's disease from 1983
to 2000.
Lopez OL, Becker JT, Sweet RA, Klunk W, Kaufer DI, Saxton J, DeKosky
ST.
Alzheimer's Disease Research Center, University of Pittsburgh
School of Medicine, Pennsylvania, USA. Lopezol@msx.upmc.edu
The authors examined the pattern of use of psychiatric medication
as prescribed by community physicians in 1,155 patients with probable
Alzheimer's disease (AD) referred to the Alzheimer's Disease Research
Center of Pittsburgh between April 1983 and July 2000. The use
of antidepressants and of sedatives, hypnotics, and anxiolytics
(SHA) increased over time, while the use of antipsychotics decreased.
The increased use of antidepressants and decreased use of antipsychotics
may reflect the growing evidence that newer antidepressants (e.g.,
selective serotonin reuptake inhibitors) can be used to treat
not only mood-related disorders, but also abnormal behavior (e.g.,
aggression, agitation) and sleep disorders in AD. Although the
use of SHA has a proven deleterious effect on patients with AD,
their use has increased over the past two decades.
-----
J Mol Neurosci 2002 Dec;19(3):331-4
Tau therapeutics for Alzheimer's disease: the
promise and the challenges.
Gold M.
Global Clinical Research and Development, CNS/Analgesia, Johnson
& Johnson Pharmaceutical Research and Development, Titusville,
NJ 08560, USA. mgold1@prdus.jnj.com
The pathological diagnosis of Alzheimer's disease (AD) depends
on the presence of plaques consisting of the beta-amyloid peptide
as well as neurofibrillary tangles consisting of paired helical
filaments (PHFs) of the tau (tau) protein. The role of each type
of pathology in the pathogenesis and progression of AD remains
unclear. Previous hypotheses suggested that these two processes
were independent, whereas more recent data suggest that there
may be a bidirectional interaction between these two pathological
processes. The identification of the neurotoxic effects of beta-amyloid
and the discovery of mutations responsible for early-onset Alzheimer's
disease (EOAD) and their linkage to beta-amyloid overproduction,
has made the amyloid hypothesis of AD the predominant influence
for therapeutic targets. Several approaches have emerged from
preclinical testing and have entered early phases of clinical
developments. The recent identification of tau mutations and their
linkage to progressive neurodegenerative disorders provides a
counterbalancing influence on the search for therapeutic targets
for AD. Therapeutic approaches that are targeted to either beta-amyloid
or tau share certain features at the level of pharmacology and
will face many of the same challenges as they progress through
drug development paradigms. The aim of this article is to provide
a brief overview of some of the commonalities and the challenges
faced by tau-related therapeutic strategies. The issues discussed
in this article are not exhaustively dealt with in either scope
or detail.
-----
Cochrane Database Syst Rev 2003;(1):CD003154
Memantine for dementia.
Areosa SA, Sherriff F.
c/ Mauricio Legendre 17, 5-A, Madrid, Spain, 28046. almudenaareosa@hotmail.com
BACKGROUND: Alzheimer's disease, vascular and mixed dementia
are the commonest forms of dementia in older people. There is
evidence that the excitatory activity of L-glutamate plays a role
in the pathogenesis of Alzheimer's disease and in the damage from
an ischaemic stroke. A low affinity antagonist to N-Methyl-D-aspartate
(NMDA) type receptors, such as memantine, may prevent excitatory
amino acid neurotoxicity without interfering with the physiological
actions of glutamate required for memory and learning. OBJECTIVES:
To determine the clinical efficacy and safety of memantine for
people with Alzheimer's disease, vascular, or mixed dementia.
SEARCH STRATEGY: Trials were identified from a search of the Trial-based
Specialized Register of the Cochrane Dementia and Cognitive Improvement
Group on 9 October 2002 using the terms: memantin*, D-145, DMAA,
DRG-0267. All major health care databases and trial databases
within the scope of the group are searched regularly to keep this
Register up to date. SELECTION CRITERIA: Double-blind, parallel
group, placebo-controlled, randomized and unconfounded trials
in which memantine was administered to people with dementia. DATA
COLLECTION AND ANALYSIS: Data were extracted, pooled where possible,
and weighted mean differences, standardized mean differences or
odds ratios were estimated. Intention-to-treat (ITT) and observed
cases (OC) analyses are reported, where data were available. MAIN
RESULTS: There were a total of seven trials that met inclusion
criteria, of which five had sufficient data for analysis. The
analysis of change from baseline for cognition gave statistically
significant results in favour of memantine (20 mg/day) (MD: -2,83
95% CI -4.37 to -1.29, P=0.0003) at 28 weeks and for memantine
(30mg/day) at 6 weeks (MD: -3.04. 95% CI -5.68 to -0.40, P=0.02).
Effects on Activities of Daily living (ADL) were difficult to
interpret. One study provided data using a non-validated scale
for measuring five simple instrumental tasks under the guidance
of an investigator. When pooled with another study the analysis
gave statistically significant results in favour of memantine
for 30 mg/day at 6 weeks (SMD: -1.36 95% CI -1.77 to -0.96, P=0.0003).
Mood and behaviour: One trial provided data on memantine 30 mg/day
at 6 weeks using the NOSIE scale. The OC analysis found statistically
significant differences in favour of treatment (MD: 23.30 95%
CI 17.83 to 28.77, P<0.00001). Global scales: The analysis
revealed a statistically significant difference in favour of memantine
(20mg/day ) at 6 weeks (MD: -12.30 95% CI -16.90 to -7.70, P<0.00001).
Similar results were found for larger doses (memantine 30 mg/day)
at 6 weeks in a pooled meta-analysis of two other studies (WMD:
-10.77 95% CI -13.46 to -8.09, P<0.00001). With regard to the
Global Impression of Change three studies found statistically
significant results in favour of 10, 20 and 30 mg/day of memantine
compared with placebo at 6 or 12 weeks. There was a benefit in
favour of memantine (20 mg/day) compared with placebo at 6 weeks,
for the numbers improved ( 24/41 compared with 11/41)(OR, 3.85,
95% CI 1.52 to 9.75, P=0.004), in favour of memantine (30 mg/day)
compared with placebo at 6 weeks, for the numbers improved ( 20/30
compared with 8/29)(OR, 5.25, 95% CI 1.72 to 15.98, P=0.004) and
in favour of memantine (10 mg/day) compared with placebo at 12
weeks, for the numbers improved ( 60/82 compared with 38/84)(OR,
3.30, 95% CI 1.72 to 6.33, P=0.0003). In general memantine seemed
to be well tolerated. There was no statistically significant difference
between memantine and placebo for the three studies that reported
adverse events.There were some data on specific adverse events.
In one study the incidence of restlessness by the end of the treatment
at 6 weeks was statistically significantly lower in the placebo
group than in the group taking memantine 30 mg/day (15/30 compared
with 2/29) (OR 13.50, 95% CI 2.71 to 67.19, P=0.001). The number
of dropouts was similar in treatment and placebo groups at 6 or
28 weeks time for memantine 20 mg/day and at 6 weeks for memantine
30 mg/day. REVIEWER'S CONCLUSIONS: Memantine is a safe drug and
may be useful for treating Alzheimer's, vascular,and mixed dementia
of all severities. Most of the trials so far reported have been
small and not long enough to detect clinically important benefits.
However there is a possible benefit on cognition and global measures,
and an early improvement in behaviour in people with dementia.
More studies are needed.
-----
Cochrane Database Syst Rev 2003;(1):CD003119
Vinpocetine for cognitive impairment and dementia.
Szatmari SZ, Whitehouse PJ.
4300, Targu Mures, str. Gral I., Dumitrache 22, Romania. szatmari@netsoft.ro
BACKGROUND: Vinpocetine is a synthetic ethyl ester of apovincamine,
a vinca alkaloid obtained from the leaves of the Lesser Periwinkle
(Vinca minor) and discovered in the late 1960s. Although used
in human treatment for over twenty years, it has not been approved
by any regulatory body for the treatment of cognitive impairment.
Basic sciences studies have been used to claim a variety of potentially
important effects in the brain. However, despite these many proposed
mechanisms and targets, the relevance of this basic science to
clinical studies is unclear. OBJECTIVES: To assess the efficacy
and safety of vinpocetine in the treatment of patients with cognitive
impairment due to vascular disease, Alzheimer's disease, mixed
(vascular and Alzheimer's disease) and other dementias. SEARCH
STRATEGY: The Cochrane Dementia & Cognitive Improvement Group's
Specialized Register was searched using the terms vinpocetin*,
cavinton, kavinton, Rgh-4405, Tcv-3B, "ethyl apovincaminate",
vinRx, periwinkle, "myrtle vincapervinc" and cezayirmeneksesi.
The manufacturers of vinpocetine were asked for information on
trials of vinpocetine for dementia. In addition we tried to collect
articles not listed in MEDLINE or other sources on the Internet
(e.g. articles in Hungarian and Romanian). SELECTION CRITERIA:
All human, unconfounded, double-blind, randomized trials in which
treatment with vinpocetine was administered for more than a day
and compared to control in patients with vascular dementia, Alzheimer's
dementia or mixed Alzheimer's and vascular dementia and other
dementias. Non-randomized trials were excluded. DATA COLLECTION
AND ANALYSIS: Data were independently extracted by the two reviewers
(SzSz and PW) and cross-checked. Data from "washout"
periods were not used for the analysis. For continuous or ordinal
variables, such as cognitive test results, the main outcomes of
interest were the change in score from baseline. The categorical
outcome of global impression was transformed to binary data (improved
or not improved) as was the occurrence of adverse effects; here
the endpoint itself was of interest the Peto method of the "typical
odds ratio" was used. A test for heterogeneity of treatment
effects between the trials was made if appropriate. Data synthesis
and analysis were performed using the Cochrane Review Manager
software (RevMan version 4.1). MAIN RESULTS: All identified studies
were performed before the 1990s and used various terms and criteria
for cognitive decline and dementia. The three studies included
in the review involved a total of 583 people with dementia treated
with vinpocetine or placebo. The reports of these studies did
not make possible any differentiation of effects for degenerative
or vascular dementia. The results show benefit associated with
treatment with vinpocetine 30mg/day and 60 mg/day compared with
placebo, but the number of patients treated for 6 months or more
was small. Only one study extended treatment to one year. Adverse
effects were inconsistently reported and without regard for relationship
to dose. The available data do not demonstrate many problems of
adverse effects but intention-to-treat data were not available
for any of the trials. REVIEWER'S CONCLUSIONS: Although the basic
science is interesting, the evidence for beneficial effect of
vinpocetine on patients with dementia is inconclusive and does
not support clinical use. The drug seems to have few adverse effects
at the doses used in the studies. Large studies evaluating the
use of vinpocetine for people suffering from well defined types
of cognitive impairment are needed to explore possible efficacy
of this treatment.
-----
Cochrane Database Syst Rev 2003;(1):CD000442
Selegiline for Alzheimer's disease.
Birks J, Flicker L.
Department of Clinical Geratology, University of Oxford, Oxford,
UK, OX2 6HE. jacqueline.birks@geratology.ox.ac.uk
BACKGROUND: Alzheimer's disease is the most common cause of
dementia in older people accounting for some 60% of cases with
late-onset cognitive deterioration. It is now thought that several
neurotransmitter dysfunctions are involved from an early stage
in the pathogenesis of Alzheimer's disease-associated cognitive
decline. The efficacy of selegiline for symptoms of Alzheimer's
disease remains controversial and is reflected by its low rate
of prescription and the lack of approval by several regulatory
authorities in Europe and elsewhere. Reasons for this uncertainty
involve the modest overall effects observed in some trials, the
lack of benefit observed in several trials, the use of cross-over
designs which harbour methodological problems in a disease like
dementia and the difficulty in interpreting results from trials
when a variety of measurement scales are used to assess outcomes.
OBJECTIVES: The objective of this review is to assess whether
or not selegiline improves the well-being of patients with Alzheimer's
disease. SEARCH STRATEGY: The Cochrane Dementia and Cognitive
Impairment Group Register of Clinical Trials, was searched using
the terms 'selegiline', 'l-deprenyl', "eldepryl" and
"monamine oxidase inhibitor-B". MEDLINE, PsycLIT and
EMBASE electronic databases were searched with the above terms
in addition to using the group strategy (see group details) to
limit the searches to randomised controlled trials. SELECTION
CRITERIA: All unconfounded, double-blind, randomised controlled
trials in which treatment with selegiline was administered for
more than a day and compared to placebo in patients with dementia.
DATA COLLECTION AND ANALYSIS: An individual patient data meta-analysis
of selegiline, Wilcock 2002 provides much of the data that are
available for this review. Seven studies provided individual patient
data and this was pooled with summary statistics from the published
papers of the other nine studies. Where possible, intention-to-treat
data were used but usually the meta analyses were restricted to
completers' data (data on people who completed the study). MAIN
RESULTS: There are 17 included trials. There were very few significant
treatment effects and these were all in favour of selegiline;
cognition at 4-6 weeks and 8-17 weeks, and activities of daily
living at 4-6 weeks. There is little evidence of adverse effects
caused by selegiline, and few withdrew from trials, apart from
the Sano trial. The analyses were conducted on data available.
There was no attempt to correct for missing patients because there
were so few and withdrawal was probably unconnected with treatment.
All trials examined the cognitive effects of selegiline, and in
addition 12 trials examined the behavioural and mood effects.
The meta-analysis revealed benefits on memory function, shown
by improvement in the memory tests from several cognitive tests
(the Randt Memory Index from Agnoli 1990 and Agnoli 1992, the
BSRT from Sunderland 1992, prose recall from Filip 1991, ADAS-cog
from Lawlor 1997, the Wechsler Memory Scale from Loeb 1990 and
Mangoni 1991, the Rey -AVL from Piccinin 1990, and the MMSE from
Sano 1995, Tariot 1998, Filip 1991, Freedman 1996, Burke 1993
and Riekkinen 1993). The combined memory tests, and overall the
combined cognitive tests, analysed using standardised mean differences,
showed an improvement due to selegiline compared with placebo
at 4-6 weeks (SMD 0.39, 95%CI 0.07 to 0.72, P = 0.02, random effects
model ) and 8-17 weeks, ( SMD 0.44, 95%CI 0.04 to 0.84, P = 0.03,
random effects model). The meta-analyses of emotional state show
no treatment effects. Several studies assessed activities of daily
living using several different scales, the GBS-motor function
from Agnoli 1990, the NOSIE-daily living from Filip 1991, the
BDS-daily living from Loeb 1990 and Mangoni 1991, the DS from
Sano 1995 and PIADL from Tariot 1998. The combined tests, analysed
using the standardised mean difference, showed an improvement
due to selegiline at 4-6 weeks (SMD -0.27, 95% CIs -0.41 to -0.13,
P = <.001). The global rating scales, the BDS used by Burke
1993 and Tariot 1998, and the GBS used by Agnoli 1990 and Agnoli
1992, and the GDS used by Freedman 1996 and the CGI by Filip 1991,
analysed using standardised mean differences showed no effect
of selegiline. A variety of adverse effects were recorded, but
very few patients left a trial as a direct result. Four studies
reported no side effects. Mangoni 1991 reported poor tolerability
for 3 patients out of 68 on treatment and 1 out of 51 on placebo,
resulting in dropouts. Small numbers found equally in both groups
reported anxiety, agitation, dizziness, nausea and dyspepsia.
Piccinin 1990 reported that selegiline was well tolerated with
few adverse reactions (dizziness and orthostatic hypotension)
and no resulting drop outs. Burke 1993 and Loeb 1990 both reported
that selegiline was very well tolerated with no serious side effects.
Sano 1995 reported 49 categories of adverse events but found no
differences between the 4 arms of the factorial trial. Freedman
1996 reported unequal numbers of dropouts in the trial with 7
subjects withdrawing from the selegiline group and only 1 subject
from the placebo group. The meta-analyses of the numbers suffering
adverse effects, and of the numbers of withdrawals before the
end of the trial show no difference between control and selegiline.
REVIEWER'S CONCLUSIONS: Despite its initial promise, ie the potential
neuroprotective properties, and its role in the treatment of Parkinson's
disease sufferers, selegiline for Alzheimer's disease has proved
disappointing. Although there is no evidence of a significant
adverse event profile, there is also no evidence of a clinically
meaningful benefit for Alzheimer's disease sufferers. This is
true irrespective of the outcome measure evaluated, ie cognition,
emotional state, activities of daily living, and global assessment,
whether in the short, or longer term (up to 69 weeks), where this
has been assessed. There would seem to be no justification, therefore,
to use it in the treatment of people with Alzheimer's disease,
nor for any further studies of its efficacy in Alzheimer's disease.
-----
Dement Geriatr Cogn Disord 2003;15(1):26-33
Patterns of clinically detectable treatment effects
with galantamine: a qualitative analysis.
Joffres C, Bucks RS, Haworth J, Wilcock GK, Rockwood K.
Geriatric Medicine Research Unit, Queen Elizabeth II Health Sciences
Centre, Halifax, Canada.
The Clinician's Interview Based Impression of Change, plus
carer interview (CIBIC-Plus) is widely used in anti-dementia drug
trials. It includes clinicians' notes about patients' behaviour,
function, and cognition, and a 7-point clinical global impression
of change scale that summarizes patients' changes during treatment.
We analyzed the narrative content of clinicians' notes from a
randomized, controlled trial of galantamine, an anti-Alzheimer's
disease drug, and identified varying degrees of improvement and
decline. In general, while most patients were rated as showing
'no change', considerable changes were seen in such patients,
but were judged by clinicians to have been offset by decline in
other areas. Most patients rated as 'improved' showed combinations
of cognitive, functional and/or behavioural improvement or stability.
While patients with signs of cognitive improvement could be found
across the scale from 'very much improved' to 'minimally worse',
patients with functional improvement were rated as having improved
or not having changed. Cognitive declines in several domains or
any cognitive decline seen with functional declines were the chief
drivers of worsening ratings. The CIBIC-Plus notes have potential
value in identifying reproducible patterns of clinically relevant
treatment effects provided that data are consistent and specific,
and that seemingly contradictory information is carefully explored.
Clinicians appear to be skeptical of cognitive changes not supported
by like changes in function or behaviour. Copyright 2003 S. Karger
AG, Basel
-----
Bioessays 2003 Mar;25(3):283-8
Alzheimer vaccine: amyloid-beta on trial.
Robinson SR, Bishop GM, Munch G.
School of Psychology, Psychiatry and Psychological Medicine, Monash
University, Australia. stephen.robinson@med.moash.edu.au
A new therapeutic approach is being developed for the treatment
of Alzheimer's disease (AD). This approach involves the deliberate
induction of an autoimmune response to amyloid-beta (Abeta) peptide,
the constituent of neuritic plaques that is thought to cause the
neurodegeneration and dementia in AD. If this approach is to be
effective, antibodies must be produced that can selectively target
the toxic forms of Abeta, while leaving the functionally-relevant
forms of Abeta and its precursor protein untouched. Furthermore,
an approach needs to be found that avoids provoking an acute neuroinflammatory
response. The situation is made even more challenging by uncertainty
regarding which isoforms of Abeta contribute to the pathogenesis
of AD. Copyright 2003 Wiley Periodicals, Inc.
-----
Drugs Today (Barc) 2002 Sep;38(9):631-7
Therapeutic approaches to the treatment of Alzheimer's
disease.
Yamada K, Toshitaka N.
Laboratory of Experimental Therapeutics, Department of Clinical
Pharmacy, Faculty of Pharmaceutical Sciences, Kanazawa University,
Kanazawa, Japan.
Alzheimer's disease is the most common cause of progressive
decline of cognitive function in aged humans and is characterized
by the presence of numerous senile plaques and neurofibrillary
tangles accompanied by neuronal loss. The only treatment currently
available for the disease is pharmacotherapy with acetylcholinesterase
inhibitors, a palliative strategy aimed at the temporary improvement
of cognitive function. Other strategies with disease-modifying
potential may include the use of antiinflammatory drugs, estrogen
replacement therapy and antioxidants. Recent progress in understanding
the molecular and cellular pathophysiology of Alzheimer's disease
has suggested possible pharmacological interventions that could
modify the development and progress of the disease (disease-modifying
therapy), such as treatment with secretase inhibitors, transition
metal chelators, HMG-CoA reductase inhibitors and amyloid-b immunization.
Inhibitors of tau hyperphosphorylation may also modulate the development
and progress of the disease. Copyright 2002 Prous Science
-----
Neurosignals 2002 Sep-Oct;11(5):293-7
Cyclooxygenase as a target for the antiamyloidogenic
activities of nonsteroidal anti-inflammatory drugs in Alzheimer's
disease.
Pasinetti GM.
Neuroinflammation Research Laboratories, Department of Psychiatry,
School of Medicine, Mount Sinai Medical Center, One Gustave L.
Levy Place, New York, N.Y. 10029, USA. giulio.pasinetti@mssm.edu
A large number of epidemiological studies have addressed the
possible protective effect of anti-inflammatory drug use with
regard to Alzheimer's disease (AD). The most convincing of these
studies--the Baltimore Longitudinal Study of Aging--utilized data
collected prospectively, thereby minimizing recall bias issues.
However, despite this evidence, therapeutic studies investigating
nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-1
(COX-1) and COX-2 inhibitors and steroids, do not support this
hypothesis. This discrepancy may be due to the fact that the bulk
of epidemiological evidence has examined the likely incidence
of AD prior to the onset of clinical symptoms of disease. On the
basis of this information, the article will attempt to formulate
a possible scenario, in which optimal NSAIDs might be tested in
the most favorable clinical therapeutic conditions in order to
determine whether NSAIDs can provide beneficial treatment for
the clinical progression of AD dementia. Copyright 2003 S. Karger
AG, Basel
-----
J Mol Neurosci 2002 Dec;19(3):303-7
Neuroprotective properties of valproate: potential
benefit for AD and tauopathies.
Loy R, Tariot PN.
Department of Neurology, Program in Neurobehavioral Therapeutics,
University of Rochester School of Medicine and Dentistry, Rochester,
NY 14620, USA. becky_loy@urmc.rochester.edu
Neuropsychiatric disturbances are extremely common in Alzheimer's
disease (AD), and represent integral features of the illness,
as well as appropriate targets for therapy. We are interested
in designing trials aimed at preventing or delaying the emergence
of psychopathology in AD. For symptomatic treatment of agitation,
mood stabilizers, particularly sodium valproate, have proved to
be beneficial in some patients. Since these effects take several
weeks to emerge, we considered that they might be dependent on
potentially neuroprotective actions of valproate, such as inhibition
of apoptosis and slowing of neurofibrillary tangle formation.
In this article we present the rationale for testing the neuroprotective
potential of valproate experimentally in mouse models of tauopathy
and in a clinical trial of patients with AD who lack psychopathology
at baseline. Together, these studies will provide important tests
of the hypothesis that valproate, either through inhibition of
tau phosphorylation or some other mechanism, is a useful therapeutic
agent to modify disease progression in AD.
-----
J Neural Transm Suppl 2002;(62):277-85
Improved global function and activities of daily
living in patients with AD: a placebo-controlled clinical study
with the neurotrophic agent Cerebrolysin.
Muresanu DF, Rainer M, Moessler H.
Neurology Department, University of Cluj-Napoca, Cluj-Napoca,
Romania.
BACKGROUND: Cerebrolysin (Cere) is a peptidergic, neurotrophic
drug which has been shown to improve cognitive performance and
global function of Alzheimer's disease (AD) patients in earlier
trials. In this study, we have attempted to replicate this findings
with particular emphasis on functional improvement of the patients.
PATIENTS AND METHODS: Patients received infusions of 30 ml Cere
or placebo five days/week for six consecutive weeks. Patients
had to have a diagnosis of AD and a MMSE score of 14-25 inclusive.
Effects on cognition, global function, and activities of daily
living were evaluated 3, 6, and 18 weeks after the beginning of
the infusions. RESULTS: Significant improvement of cognitive function,
clinical global impression and activities of daily living were
seen after the end of the therapy. The effects were most pronounced
in the DAD score, a measure for the capability to perform activities
of daily living. Interestingly, and in line with the findings
of earlier studies, the treatment effect of Cere was maintained
after cessation of treatment up to the week 18 assessment. CONCLUSION:
The data confirm the findings of earlier trials and clearly demonstrates
that Cere leads to functional improvement of patients with AD.
The sustained treatment effect of Cere after withdrawal has been
confirmed.
-----
J Neural Transm Suppl 2002;(62):227-39
Can estrogen play a significant role in the prevention
of Alzheimer's disease?
Kesslak JP.
Institute for Brain Aging and Dementia, Department of Neurology,
University of California, Irvine, CA 92697-4540, USA. JPKessla@uci.edu
In women the abrupt decline estrogen levels at menopause may
be associated with cognitive deficits and increased risk for Alzheimer's
disease (AD); estrogen replacement therapy may reduce this risk.
Animal studies indicate that estrogen modulates neurotransmitter
systems, regulates synaptogenesis, and is neuroprotective. These
beneficial effects occur in brain areas critical to cognitive
function and involved in AD. Reduced estrogen levels can compromise
neuronal function and survival. Estrogen replacement therapy can
reverse cognitive deficits associated with low estrogen levels
and may reduce the risk of AD. However, clinical trials for estrogen
replacement in the treatment of AD have produced ambiguous results.
Initial, small, open-label and double blind clinical trials indicated
improved cognitive function in women with AD. Recent large trials
failed to show a beneficial effect for long-term estrogen replacement
for women with AD. There are several variables that could affect
these results, such as genetic factors, time between estrogen
loss and replacement, extent and types of AD pathology, and other
environmental and health factors. Presently large prospective
studies are being conducted as the National Institutes of Health
in the Women's Health Initiative and the Preventing Postmenopausal
Memory Loss and Alzheimer's with Replacement Estrogens studies
to provide a better assessment of the role of estrogen for age
related health issues, including dementia.
-----
Int J Clin Pract 2002 Dec;56(10):791-6
Rivastigmine in patients with Alzheimer's disease
and concurrent hypertension.
Erkinjuntti T, Skoog I, Lane R, Andrews C.
Department of Neurology, Helsinki University Central Hospital,
Hyks, Finland.
Rivastigmine has demonstrated significant benefits in patients
with mild to moderate Alzheimer's disease (AD). We aimed to confirm
whether rivastigmine was effective in patients with or without
concurrent vascular risk factors (VRF), as previously suggested.
We chose to stratify the 725 patients involved in an international
dose-ranging study according to the presence of arterial hypertension
(a marker of VRF) at baseline. Efficacy in each subgroup was assessed
using the ADAS-cog, a measure of cognitive performance, the Progressive
Deterioration Scale (PDS) and the Clinician's Interview-Based
Impression of Change (CIBIC) with caregiver input. Patients receiving
rivastigmine 6-12 mg/day showed better outcomes on the ADAS-cog
than those receiving placebo, in both the hypertensive and non-hypertensive
subgroups. Hypertensive patients receiving rivastigmine 6-12 mg/day
also showed improvement over those receiving 1-4 mg/day (p = 0.023).
Rivastigmine 6-12 mg/day also provided better outcomes than placebo
on the PDS in the hypertensive (p = 0.031) and non-hypertensive
(p = 0.035) subgroups. All patients receiving rivastigmine 6-12
mg/day had superior CIBIC-plus scores than those receiving placebo.
There was a trend for lower incidences of nausea and vomiting
in rivastigmine-treated patients with hypertension than in those
without hypertension. No cardiac adverse events or drug-drug interactions
were reported. Our data support the hypothesis that rivastigmine
provides benefits to patients with or without hypertension, and
contribute to the evidence that particular benefits may be observed
in those with vascular risk factors.
-----
Arch Women Ment Health 2002 Nov;5(3):105-10
Neuroprotective effects of estradiol-17beta: implications
for psychiatric disorders.
Kolsch H, Rao ML.
Department of Psychiatry, University of Bonn, Sigmund-Freud-Strasse
25, D-53105 Bonn, Germany. heike.koelsch@ukb.uni-bonn.de
Estradiol-17beta is the most potent female sex hormone. In
addition to its role in the control of primary and secondary sexual
characteristics, it also influences the development of the brain.
Furthermore, estradiol-17beta possesses neuroprotective properties
that are mediated via receptor action and also independently of
receptors. Several processes that are regulated by estradiol-17beta
might influence the expression of Alzheimer's disease and schizophrenia.
Differences between the sexes have been described in both disorders,
and it has been suggested that these may be due to the action
of oestrogens. Long-term oestrogen replacement has proved to be
beneficial in the prevention and treatment of Alzheimer's disease
and schizophrenia. The results, however, are controversial. Preliminary
in vitro and in vivo findings, which are summarised in this review,
encourage further studies with estradiol-17beta or its analogues
as potential adjunctive interventions particularly in "negative
syndrome" schizophrenia and in Alzheimer's disease.
-----
Nippon Yakurigaku Zasshi 2002 Nov;120(1):24P-29P
[Anti-dementia drugs for Alzheimer disease in
present and future]
[Article in Japanese]
Nabeshima T, Noda Y, Kamei H.
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya
University Graduate School of Medicine, Nagoya 466-8560, Japan.
Alzheimer disease(AD) is characterized as neurodegenerative
disease showing impairment of cognitive function, death of neuronal
cells, numerous numbers of senile plaques and tangle of neurofilaments.
There are two different hypotheses that neurotoxicity of aggregated
amyloid beta protein(A beta) and hyperphosphorylation of tau protein
are the causes of AD. The dysfunction of cholinergic neuronal
system is observed in the early stage of AD. Therefore, the strategy
to increase of acetylcholine (ACh) level in brain by using ACh
esterase inhibitor is mainstream in the present. We have tacrine,
donepezil, rivastigmine and galantamine. Tacrine, the first drug
for AD, is replaced by other drugs, because of its hepatic toxicity.
Galantamine binds allosteric sites of nicotine receptor and stimulates
it in addition to its inhibitory effect on ACh esterase. Metamantine
was approved in EU in 2002. It is non-competitive inhibitor of
NMDA receptors, and dopamine releaser, which has neuroprotective
effect. All of the above drugs improve cognitive function of patients,
and they could delay hospitalization for 7 months or more. In
the present anti-inflammatory drugs, anti-oxidative drugs and
estrogen are under investigation. As anti-A beta therapy, inhibitors
of beta -and gamma-secretase, A beta aggregation inhibitors, A
beta degradation stimulators and A beta vaccination are possible
strategies. The inhibitors of tau protein phosphorylation and
activators of phosphates could be that of anti-tau protein phosphorylation.
Additionally, it is expected to have the strategies such as neuroregeneration
by neurotorophic factors and immunopyline ligands, and supply
of neuronal cells by gene therapy and human ES cells.
-----
J Am Coll Nutr 2002 Dec;21(6):506-22
Risk factors for Alzheimer's disease: role of
multiple antioxidants, non-steroidal anti-inflammatory and cholinergic
agents alone or in combination in prevention and treatment.
Prasad KN, Cole WC, Prasad KC.
Center for Vitamins and Cancer Research, Department of Radiology,
School of Medicine, University of Colorado Health Sciences Center,
Denver, Colorado 80262, USA. Kedar.Prasad@UCHSC.edu
The etiology of Alzheimer's disease (AD) is not well understood.
Etiologic factors, chronic inflammatory reactions, oxidative and
nitrosylative stresses and high cholesterol levels are thought
to be important for initiating and promoting neurodegenerative
changes commonly found in AD brains. Even in familial AD, oxidative
stress plays an important role in the early onset of the disease.
Mitochondrial damage and proteasome inhibition represent early
events in the pathogenesis of AD, whereas increased processing
of amyloid precursor protein (APP) to beta-amyloid (Abeta) fragments
(Abeta(40) and Abeta(42)) and formation of senile plaques and
neurofibrillary tangles (NFTs) represent late events. We propose
a hypothesis that in idiopathic AD, epigenetic components of neurons
such as mitochondria, proteasomes and post-translation protein
modifications (processing of amyloid precursor protein to beta-amyloid
and hyperphosphorylation of tau), rather than nuclear genes, are
the primary targets for the action of diverse groups of neurotoxins.
Based on epidemiologic, laboratory and limited clinical studies,
we propose that a combination of non steroidal anti-inflammatory
drugs (NSAIDs) and appropriate levels and types of multiple micronutrients,
including antioxidants, may be more effective than the individual
agents in the prevention, and they, in combination with a cholinergic
agent, may be more effective in the treatment of AD than the individual
agents alone. In addition, agents, which can prevent formation
of plaques or dissolve these plaques may further enhance the efficacy
of our proposed treatment strategy.
-----
Ann N Y Acad Sci 2002 Nov;977:493-500
Responses to donepezil in Alzheimer's disease
and Parkinson's disease.
Mori S.
Department of Neurology, Kyoto Prefectural University of Medicine,
Kawaramachi-Hirokoji, Kamikyou-ku, Kyoto 602-8224, Japan. satomori@koto.kpu-m.ac.jp
Alzheimer's disease is the most common cause of dementia, but
Parkinson's disease also shows dementia in the later stages. Donepezil
is a cholinesterase inhibitor used for the treatment of Alzheimer's
disease. Variable responses to this drug suggest that Alzheimer's
disease is clinically heterogeneous. In the clinical trial of
tacrine, a first developed cholinesterase inhibitor, three cases
markedly improved and, several years later, they were pathologically
confirmed as dementia with Lewy bodies (DLB). In recent years,
another cholinesterase inhibitor, rivastigmine, has also been
reported to be effective for patients with DLB by a placebo-controlled,
double-blind, multicenter study. Parkinson's disease with dementia,
which is known to fulfill the pathological criteria of DLB, also
shows a favorable response to donepezil. In some cases, not only
does cognitive function improve, but also parkinsonism. Both DLB
and Parkinson's disease with dementia show characteristic CBF
patterns: While the parietal and temporal lobes are involved in
Alzheimer's disease, the occipital lobe is additionally affected
in these diseases. Alzheimer's disease and Parkinson's disease
have been considered discrete disease entities. However, viewed
from the aspects of response to donepezil treatment and CBF patterns,
both diseases overlapped. A brain SPECT may be a useful tool to
detect such treatable conditions.
-----
Ann N Y Acad Sci 2002 Nov;977:454-67
Treatment of Alzheimer's disease by transposition
of the omentum.
Goldsmith HS.
Department of Surgery, University of Nevada School of Medicine,
Reno, Nevada, USA. Hgldsmith@aol.com
There is increasing evidence that cerebral hypoperfusion plays
a key role in the development of Alzheimer's disease (AD). As
one ages, cerebral blood flow (CBF) decreases as a direct reflection
of a normal aging process. Coupled with this expected drop in
CBF are a host of other factors, such as hypertension, stress,
smoking, diabetes, cholesterol buildup, etc., which further decrease
blood flow to the brain. Maintaining a critical level of CBF is
essential if adequate amounts of oxygen and glucose are to be
presented to neurons to sustain their cellular energy production
(ATP). If CBF drops below a critical flow level, insufficient
ATP will be produced and, if this situation is not corrected,
neurons will deteriorate and eventually die. When a critical mass
of neurons die in areas of the brain involved with cognition and
memory, AD will result. Omentum transposition to the brain is
a surgical procedure by which a large volume of blood and other
biological agents can be delivered to the brain over an indefinite
period of time. The omentum gives metabolic support to deteriorating
neurons and its presence on the brain has resulted in the reversal
of AD symptoms. Additionally, omentum transposition to the brain
can markedly reduce senile plaque accumulation, but has no apparent
effect on reducing neurofibrillary tangles. Omental transposition
may play an important role in the future treatment of AD, especially
in early and moderate cases.
-----
J Clin Psychopharmacol 2002 Dec;22(6):615-20
Regional effects of donepezil and rivastigmine
on cortical acetylcholinesterase activity in
Alzheimer's disease.
Kaasinen V, Nagren K, Jarvenpaa T, Roivainen A, Yu M, Oikonen
V, Kurki T, Rinne JO.
Department of Neurology, University of Turku, Turku, Finland.
Donepezil and rivastigmine are acetylcholinesterase (AChE)
inhibitors used to improve cholinergic neurotransmission and cognitive
function in Alzheimer's disease (AD). This study examined direct
effects of these drugs on AChE activity in the frontal, temporal,
and parietal cortices in AD. Six AD patients were scanned with
positron emission tomography before and after 3 months of treatment
with donepezil (10 mg/day), and five AD patients were scanned
before and after 3 to 5 months of treatment with rivastigmine
(9 mg/day). Healthy unmedicated controls were imaged twice to
evaluate the reproducibility of the method. A specific AChE tracer,
[methyl-11C]N-methyl-piperidyl-4-acetate, and a 3D positron emission
tomography system with MRI coregistration were used for imaging.
Treatment with donepezil reduced the AChE activity (k3 values)
in the AD brain by 39% in the frontal (p < 0.001, Bonferroni
corrected), 29% in the temporal (p = 0.02, corrected) and 28%
in the parietal cortex (p = 0.05, corrected). The corresponding
levels of inhibition for rivastigmine were 37% (p = 0.003, corrected),
28% (p = 0.03, uncorrected) and 28% (p = 0.05, corrected). When
the treatment groups were combined, the level of AChE inhibition
was significantly greater in the frontal cortex compared to the
temporal cortex (p = 0.03, corrected). The test-retest analysis
with healthy subjects indicated good reproducibility for the method,
with a nonsignificant 0% to 7% intrasubject variability between
scans. The present study provides first evidence for the effect
of rivastigmine on cortical AChE activity. Our results indicate
that the pooled effects of donepezil and rivastigmine on brain
AChE are greater in the frontal cortex compared to the temporal
cortex in AD. This regional difference is probably related to
the prominent temporoparietal reduction of AChE in AD. We hypothesize
that the clinical improvement in behavioral and attentional symptoms
of AD due to AChE inhibitors is associated with the frontal AChE
inhibition.
-----
Curr Med Res Opin 2002;18(6):347-54
Functional, cognitive and behavioral effects of
donepezil in patients with moderate Alzheimer's disease.
Gauthier S, Feldman H, Hecker J, Vellas B, Emir B, Subbiah P;
Donepezil MSAD Study Investigators' Group.
serge.gauthier@mcgill.ca
OBJECTIVE: To investigate the efficacy and safety of donepezil
in a subgroup of patients with Alzheimer's disease (AD) of moderate
severity from a previous trial. METHODS: Two hundred and seven
patients with moderate AD (standardized Mini-Mental State Examination
[sMMSE] score 10-17) were randomized to treatment in this 24-week,
double-blind, placebo-controlled trial. Patents received either
donepezil, 5 mg/day for the first 28 days and 10 mg/day thereafter
according to the clinician's judgement (n = 102), or placebo (n
= 105). The primary outcome measure was the Clinician's Interview-Based
Impression of Change with caregiver input (CIBIC-plus) at week
24 using a last observation carried forward (LOCF) analysis. RESULTS:
Baseline patient demographics were similar between treatment groups.
Mean age was 74.3 years (range 48-92). Least-squares (LS) mean
sMMSE scores at baseline were 13.6 +/- 0.3 for the donepezil group
and 13.9 +/- 0.3 for the placebo group. LS mean CIBIC-plus scores
for donepezil-treated patients were improved from, or close to,
baseline severity at all visits, and were significantly different
from placebo at weeks 8, 12, 18, and 24 (week 24 LOCF mean difference
= 0.53, p = 0.0003). LS mean change from baseline scores on the
sMMSE and Severe Impairment Battery (SIB) for the donepezil group
improved throughout the study, and were significantly different
from placebo at each visit for the sMMSE (week 24 LOCF mean difference
= 2.06, p = 0.0002) and from week 8 for the SIB (week 24 LOCF
mean difference = -4.44, p = 0.0026). LS mean change scores on
the Disability Assessment for Dementia remained at or above baseline
levels throughout the study for the donepezil group, while the
placebo group showed a steady decline; treatment differences were
significant at each visit (week 24 LOCF mean difference = -9.25,
p < 0.0001). LS mean change scores on the Neuropsychiatric
Inventory 12-item total improved throughout the study for the
donepezil group and were significantly different from placebo
at weeks 4 and 24 (week 24 LOCF mean difference = 5.92, p = 0.0022).
Eighty-one per cent of donepezil-treated and 89% of placebo-treated
patients completed the trial, with 9% and 5%, respectively, discontinuing
due to adverse events (AEs). Eighty-two per cent of donepezil-treated
and 80% of placebo-treated patients experienced AEs, the majority
of which were rated mild in severity and, in general, were similar
between treatment groups. CONCLUSION: The significant treatment
responses observed with donepezil in these patients reinforce
the findings from earlier studies that show donepezil to have
important benefits, compared wih placebo, across functional, cognitive,
and behavioral symptoms, with good tolerability, in patients with
AD of moderate severity.
-----
Rev Neurol 2002 Nov 1-15;35(9):859-69
[Rivastigmine: a review of its clinical effectiveness]
[Article in Spanish]
Spiegel R.
Novartis Pharma AG, Basilea, Suiza.
The progression of Alzheimer s disease (AD) is linked with
the appearance of symptoms in three key domains, namely activities
of daily living (ADL), behaviour and cognition. The development
and decline of these symptoms gives rise to a loss in the patient
s functional capacity and contributes to the social, health care
and economic costs associated with the disease. Tests suggest
that the onset of these symptoms, in AD and in other types of
dementia (e.g. frontotemporal dementia, dementia in Parkinson
s disease and vascular dementia [VaD]), can be attributed to the
loss of acetylcholine and cholinergic neurons in areas of the
brain that are central to learning and memory, to execution functions
and to behavioural and emotional responses, such as the cerebral
cortex, the hippocampus and the limbic regions. There is evidence
to show that the use of cholinesterase (ChE) inhibitors, including
rivastigmine, donepezil and galanthamine, to enhance the survival
of cholinergic neurotransmission is beneficial in the treatment
of these symptoms. For example, administering rivastigmine stabilises
and improves the performance of ADL in mild to moderate stages
and slows down the decline in the capacity to carry out ADL in
patients with serious AD. There is an improvement in the behavioural
symptoms, the appearance of new symptoms diminishes and the use
of other psychotropic drugs is reduced. Cognitive deficits become
stable or improve during short term treatment and the treatment
also delays the cognitive decline associated with the progression
of the disease. A review of the available data reveals that ChE
inhibition is beneficial in the long term in the three key symptomatic
domains in different stages of the disease, as well as its perhaps
being useful in different dementias. Therefore, it is likely that
treatment with a ChE inhibitor improves quality of life and reduces
the social and economic burden of these disorders.
-----
Rev Neurol 2002 Nov 1-15;35(9):850-9
[Treatment of Alzheimer's disease]
[Article in Spanish]
Lopez OL, Becker JT.
Departamento de Nurologia. Escuela de Medicina. Universitdad de
Pettsburgh, Pennsylvania, EE.UU. lopezol@msx.upmc
OBJECTIVE: To review the experience of the last twenty years
in the treatment of Alzheimer s disease (AD). METHODS: Literature
review. RESULTS: The neuropathological bases of AD are centered
on two important pathophysiological mechanisms: 1) Structural
damage (e.g., senile plaques, neurofibrillary tangles, neuronal
loss, inflammatory processes), and 2) Loss of cholinergic neurons
(and acetylcholine depletion) in the nucleus basalis of Meynert,
which sends cholinergic projections to all areas of the neocortex,
especially the temporal lobes and frontal and parietal association
areas. The indemnity of this system is essential for normal cognitive
functioning. At this moment, the only long term treatment available
for AD are acetylcholinesterase inhibitors (CEIs) (e.g., tacrine,
donepezil, rivastigmine, galanthamine). There are being investigated
several treatments that may alter the development of neurofibrillary
tangles and neuritic plaques (e.g., peripherally administered
antibodies against beta amyloid proteins). Nerve growth factors
may have the capability of improving neuronal survival, although
their form of administration remains a problem. Amelioration of
oxidative stress and CNS inflammatory processes may slow dawn
the rate of neurodegeneration. CONCLUSION: All suspected mechanisms
of the metabolic cascade of AD have been explored with specific
and non specific treatments. Current treatments (e.g., CEIs) still
have to prove that their effects can last for long periods of
time. With the advent of further understanding of the neurodegenerative
processes that cause AD, new treatments that may slow down the
progression of the disease will be available.
-----
Rev Neurol 2002 Nov 1-15;35(9):846-50
[Treatment of neuropsychiatric symptoms in Alzheimer's
disease]
[Article in Spanish]
Kaufer D.
Departamento de Nuerologia. Escuela de Medicina de la Universidad
de Pittsburg, Pennsyvania, EE.UU. dcaufer@pitt.edu
The overall goal of all therapeutic interventions in Alzheimer
s disease (AD) is the optimisation of the adaptive functions and
quality of life of these patients. The general strategy for the
use of pharmacological interventions in the treatment of neuropsychiatric
manifestations of AD includes the following: 1) An exhaustive
evaluation of the psychiatric symptomatology; 2) Establish a hierachy
of the simptoms to treat based on their severity of symptoms and
on their impact on the caregiver; 3) The identification of an
adequate agent based on the type of symptoms and subject s characteristics;
4) The initial use of low doses with gradual titration, and 5)
Changing one drug at a time. Regarding psychotic symptons, the
introduction of new agents (e.g., risperidone) has replaced the
use of traditional treatments (e.g., thioridazine) in patients
with AD. The presence of psychomotor agitation and aggression
can be treated with great variety of drugs, such as antipsychotics,
anticonvulsants, antidepressants, and sedatives. Selective serotonine
re uptake inhibitors are the treatment of choice for depressive
symptomatology. The cholinesterase inhibitors have shown to be
useful in the treatment of hallucinations, anxiety and apathy.
-----
CNS Drugs 2002;16(12):811-24
Non-cholinergic strategies for treating and preventing
Alzheimer's disease.
Doraiswamy PM.
Department of Psychiatry, Duke University Medical Center, Durham,
North Carolina 27710, USA.
The pathophysiology of Alzheimer's disease is complex and involves
several different biochemical pathways. These include defective
beta-amyloid (Abeta) protein metabolism, abnormalities of glutamatergic,
adrenergic, serotonergic and dopaminergic neurotransmission, and
the potential involvement of inflammatory, oxidative and hormonal
pathways. Consequently, these pathways are all potential targets
for Alzheimer's disease treatment and prevention strategies. Currently,
the mainstay treatments for Alzheimer's disease are the cholinesterase
inhibitors, which increase the availability of acetylcholine at
cholinergic synapses. Since the cholinesterase inhibitors confer
only modest benefits, additional non-cholinergic Alzheimer's disease
therapies are urgently needed. Several non-cholinergic agents
are currently under development for the treatment and/or prevention
of Alzheimer's disease. These include anti-amyloid strategies
(e.g. immunisation, aggregation inhibitors, secretase inhibitors),
transition metal chelators (e.g. clioquinol), growth factors,
hormones (e.g. estradiol), herbs (e.g. Ginkgo biloba), nonsteroidal
anti-inflammatory drugs (NSAIDs, e.g. indomethacin), antioxidants,
lipid-lowering agents, antihypertensives, selective phosphodiesterase
inhibitors, vitamins (E, B12, B6, folic acid) and agents that
target neurotransmitter or neuropeptide alterations. Neurotransmitter
receptor-based approaches include agents that modulate certain
receptors (e.g. nicotinic, muscarinic, alpha-amino-3-hydroxy-5-methyl-4-isoxazole
proprionic acid [AMPA], gamma-aminobutyric acid [GABA], N-methyl-D-aspartate
[NMDA]) and agents that increase the availability of neurotransmitters
(e.g. noradrenergic reuptake inhibitors). Of these strategies,
the NMDA receptor antagonist memantine is in the most advanced
stage of development in the US and is already approved in Europe
as the first treatment for moderately severe to severe Alzheimer's
disease. Memantine is proposed to counteract cellular damage due
to pathological activation of NMDA receptors by glutamate. Results
with Ginkgo biloba have been mixed. Data for neurotrophic therapies
and vitamin E (tocopherol) appear promising but require confirmation.
NSAIDs and conjugated estrogens have not proven to be of value
to date for the treatment of Alzheimer's disease. Statins may
have a potential role in reducing the risk or delaying the onset
of Alzheimer's disease, although this has yet to be confirmed
in randomised trials. There are currently no data to support the
use of statins as a treatment for dementia. This article provides
an update on the current status of selected agents, focusing primarily
on those agents with the most extensive clinical evidence at present.
-----
Can J Psychiatry 2002 Oct;47(8):734-41
Effective use of electroconvulsive therapy in
late-life depression.
Flint AJ, Gagnon N.
University of Toronto, Geriatric Psychiatry Program, University
Health Network, Toronto, Ontario. alastair.flint@uhn.on.ca
OBJECTIVE: To review literature pertaining to the efficacy,
safety, and tolerability of electroconvulsive therapy (ECT) in
treating late-life depression. METHOD: We undertook a literature
review with an emphasis on research studies published in the last
10 years. RESULTS: There is a positive association between advancing
age and ECT efficacy. Age per se does not necessarily increase
the risk of cognitive side effects from ECT, but this risk is
increased by age-associated neurological conditions such as Alzheimer's
dementia and cerebrovascular disease. With appropriate evaluation
and monitoring, ECT can be used safely in patients of very advanced
age and in those with serious medical conditions. Several technical
factors, including dose of electricity relative to a patient's
seizure threshold, position of electrodes, frequency of administration,
and total number of treatments, have an impact on the efficacy
and cognitive side effects of ECT and need to be taken into account
when administering ECT. Naturalistic studies have found that 50%
of more of patients have a relapse of depression within 6 to 12
months of discontinuing acute ECT. CONCLUSIONS: In recent years,
there has been substantial progress in our understanding of the
effect of technical factors on the efficacy and cognitive side
effects of ECT. When administered in an optimal manner, ECT is
a safe, well-tolerated, and effective treatment in older patients.
Relapse of depression after response to ECT remains a significant
problem, and there is a need for further research into the prediction
and prevention of post-ECT relapse.
-----
Can J Psychiatry 2002 Oct;47(8):715-22
Cognitive pharmacotherapy of Alzheimer's disease
and other dementias.
Herrmann N.
Department of Psychiatry, Division of Geriatric Psychiatry, Faculty
of Medicine, University of Toronto Sunnybrook and Women's College
Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5.
nathan.herrmann@swchsc.on.ca
OBJECTIVE: The objective of this paper is to review the randomized
controlled trials (RCTs) on the pharmacotherapy of Alzheimer's
disease and other dementias and to provide evidence-based recommendations
for treatment of the cognitive impairment associated with these
disorders. METHOD: A Medline search was conducted for RCTs, using
the following key words: Alzheimer's disease, dementia, therapy,
cholinesterase inhibitor, donepezil, rivastigmine, and galantamine.
Studies were critically appraised, followed by a review of published
major clinical practice guidelines. Recommendations for treatment
were made based on best available evidence. RESULTS: The pharmacotherapy
of Alzheimer's disease should include the meticulous management
of vascular risk factors (for example, hypertension, diabetes,
cholesterol, and stroke prophylaxis) and consideration for supplementation
with folate, vitamin B complex, and vitamin E. Patients should
be offered at least 1 trial of a cholinesterase inhibitor, with
the possibility of another trial if the first is poorly tolerated
or ineffective. Patients with vascular dementia and dementia with
Lewy bodies should also be offered treatment with cholinesterase
inhibitors. At this time, we lack sufficient data to recommend
the use of hormone replacement or antiinflammatory therapy for
treatment of dementia as the primary indication. CONCLUSION: Reasonable
evidence exists to provide recommendations for the pharmacotherapy
of dementia. Treatment will likely result in modest but important
benefits to patients, caregivers, and society.
-----
J Neurol Sci 2002 Nov 15;203-204:137-9
Treatment with donepezil in Alzheimer patients
with and without cerebrovascular disease.
Frolich L, Klinger T, Berger FM.
Klinik fur Psychiatrie und Psychotherapie I, Klinikum der Universitat
Frankfurt am Main, Heinrich-Hoffmannstr. 10, D-60528, Frankfurt
am Main, Germany.
Donepezil, a selective acetylcholinesterase inhibitor, is approved
for the symptomatic treatment of mild to moderate Alzheimer's
disease (AD). In a post-marketing surveillance (PMS) study in
Germany, patients under routine treatment conditions were observed
while treatment was switched from other antidementia drugs (i.e.,
nootropics) to donepezil. A total of 913 patients were enrolled
(60.1% female, mean+/-S.D. age 73.4+/-8.6 years, mean Mini-Mental
Status Examination [MMSE] 18.0+/-5.3), and were treated with donepezil
(5 or 10 mg/day according to recommended dosing). 709/913 (77.1%)
of patients had been pretreated with other antidementive drugs
(piracetam, memantine, ginkgo, and others). In 29.6% of patients,
investigators documented concomitant cerebrovascular disease (CVD+)
according to their clinical judgment. Observation period was 3
months for the individual patient. Efficacy parameters were changes
in MMSE, global clinical (investigators) judgment of efficacy,
and a clinical judgment about the patients' quality of life (QoL).
Adverse events were also analyzed. The objective of the present
investigation was to compare-in a "real-life" setting-the
differential efficacy and tolerability of donepezil in AD patients
with and without concomitant cerebrovascular disease. After 3
months, patients had improved by a mean MMSE change from baseline
of 2.2 points (CVD+: 2.4 pts, CVD-: 2.1 pts). QoL was judged "improved"
in 70.0% of patients (CVD+: 72.5%, CVD-: 69.6%). Adverse events
were reported in 85/913 (9.3%) of patients (CVD+: 11.2%, CVD-:
7.9%). Reported adverse events were substantially less than reported
previously in controlled clinical trials. This suggests that donepezil
therapy is effective and well tolerated in AD patients, both with
and without concomitant cerebrovascular disease.
-----
J Neurol Sci 2002 Nov 15;203-204:125-30
Treatment options: the latest evidence with galantamine
(Reminyl).
Erkinjuntti T.
Memory Research Unit, Department of Clinical Neurosciences, Helsinki
University Central Hospital, P.O. Box 300, 00029 Hyks, Finland.
Timo.Erkinjuntti@hus.fi
Vascular dementia (VaD) has a great deal of overlap (in terms
of features and symptoms) with Alzheimer's disease (AD). Mixed
dementia, or AD with concomitant cerebrovascular disease (AD with
CVD), is increasingly being recognized as a distinct clinical
condition that occurs with substantial frequency. The robust evidence
for the effectiveness of cholinergic treatments such as galantamine
(Reminyl) in AD suggests its potential use in the treatment of
dementias related to CVD, and preclinical evidence supports this
rationale. Galantamine, which has a unique dual cholinergic mode
of action, may be of particular benefit in VaD and AD with CVD.
For example, behavioral symptoms, which can be more severe in
VaD than in AD and are important determinants of the impact of
dementia, may be especially benefited by galantamine. This results
from its potential to modulate systems involving other neurotransmitters
such as 5-HT (serotonin) and dopamine, which affect mood and emotional
balance. The results of a recent landmark clinical trial with
galantamine in patients with VaD, or AD with CVD, indicate that
galantamine produces benefits across a broad range of symptoms
of dementia in both patient populations. Significant cognitive
improvements over 6 months, long-term maintenance of cognition
for at least 12 months, and global benefits, as well as efficacy
in both behavioral and functional symptoms, indicate efficacy
with galantamine that is so far unsurpassed by any other drug
treatment for dementia. Galantamine therefore has potential to
benefit a wide range of patients with dementia in the clinic.
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