Important Note: The following information is provided for your education. It should not be relied upon for personal diagnosis or treatment. If you believe that a particular therapy applies to you or someone you care about, be sure to consult a doctor before trying it.
   

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Previous Alzheimer's Research: 2002-2006   
The Alzheimer's Disease File also contains summaries of past research that has shown promise and may still be standard practice among many physicians. To download earlier research findings on Alzheimer's Disease, click HERE.
 

Latest Research on
Alzheimer's Disease
  
Lancet. 2008 Jul 19;372(9634):216-23.
Comment in: Lancet. 2008 Jul 19;372(9634):180-2.
Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial.
Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA.
Division of Clinical Neurosciences, University of Southampton, Southampton, UK; Moorgreen Hospital, Hampshire Partnership Trust, Southampton, UK.

BACKGROUND: Immunisation of patients with Alzheimer's disease with full-length amyloid-beta peptide (Abeta(42)) can clear amyloid plaques from the brain. Our aim was to assess the relation between Abeta(42) immune response, degree of plaque removal, and long-term clinical outcomes. METHODS: In June, 2003, consent for long-term clinical follow-up, post-mortem neuropathological examination, or both, was sought from 80 patients (or their carers) who had entered a phase I randomised, placebo-controlled trial of immunisation with Abeta(42) (AN1792, Elan Pharmaceuticals) in September, 2000. The follow-up study was completed in September, 2006. Plaques were assessed in terms of the percentage area of the cortex with Abeta immunostaining (Abeta load) and in terms of characteristic histological features reflecting plaque removal. Survival of all 80 individuals until severe dementia or death was assessed with a Cox proportional hazard model. FINDINGS: 20 participants--15 in the AN1792 group, five in the placebo group--died before follow-up started. A further 22 patients--19 in the AN1792 group, three in the placebo group--died during follow-up. Nine of the deceased patients, all in the AN1792 group, had given consent for post-mortem analysis; one of these who did not die with Alzheimer's disease was excluded. In the remaining eight participants who received immunisation and who were examined neuropathologically, mean Abeta load was lower than in an unimmunised control group that was matched for age at death (2.1% [SE 0.7] in treated participants vs 5.1% [0.9] in controls; mean difference 3.0%, 95% CI 0.6-5.4; p=0.02). Although there was considerable variation in Abeta load and degree of plaque removal among immunised participants, the degree of plaque removal varied significantly with mean antibody response attained during the treatment study period (Kruskal-Wallis p=0.02). Seven of the eight immunised patients who underwent post-mortem assessment, including those with virtually complete plaque removal, had severe end stage dementia before death. In the whole cohort, there was no evidence of improved survival (hazard ratio 0.93, 95% CI 0.43-3.11; p=0.86) or of an improvement in the time to severe dementia (1.18, 0.45-3.11; p=0.73) in the AN1792 group versus the placebo group. INTERPRETATION: Although immunisation with Abeta(42) resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration.

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Lancet. 2008 Jul 19;372(9634):207-15. Comment in: Lancet. 2008 Jul 19;372(9634):179-80.
Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study.
Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D; dimebon investigators.
Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, TX, USA.

BACKGROUND: Although treatments for Alzheimer's disease sometimes improve cognition, functional ability, or behaviour compared with baseline levels, such improvements are inconsistent across studies and measures, and effects diminish over time. More effective treatments are needed. We assessed the safety, tolerability, and efficacy of dimebon in the treatment of patients with mild-to-moderate Alzheimer's disease. METHODS: We enrolled 183 patients with mild-to-moderate Alzheimer's disease (mini-mental state examination [MMSE] scores 10-24) at 11 sites in Russia. Patients were randomly assigned by a computer-generated randomisation scheme to receive oral dimebon, 20 mg three times a day (60 mg/day [n=89]), or matched placebo (n=94). Other antidementia drugs were not allowed. The primary outcome measure assessed cognition, the difference in mean change from baseline to week 26, or last completed observation on the cognitive subscale of the Alzheimer's disease assessment scale (ADAS-cog). All patients and study personnel were blinded throughout the study. We compared dimebon with placebo with an intention-to-treat analysis, with last observation carried forward (ITT-LOCF) imputation. Analyses were repeated on the fully evaluable population, defined as all patients in the intention-to-treat population who had an ADAS-cog at week 26 and at least 80% compliance. 134 patients (68 in dimebon group, 66 in placebo group) enrolled in the 6-month blinded extension phase of the study. This trial is registered with Clinicaltrials.gov, number NCT00377715. FINDINGS: 155 (85%) patients completed the trial (78 [88%] in dimebon group, 77 [82%] in placebo group). Treatment with dimebon resulted in significant benefits in ADAS-cog compared with placebo (ITT-LOCF) at week 26 (mean drug-placebo difference -4.0 [95% CI -5.73 to -2.28]; p<0.0001). Results of the ITT-LOCF and the evaluable population analyses were much the same for all measures. Patients given dimebon were significantly improved over baseline for ADAS-cog (mean difference -1.9 [-2.92 to -0.85]; p=0.0005). Dimebon was well tolerated: dry mouth and depressed mood or depression were the most common adverse events associated with dimebon (12 [14%] patients for each symptom by week 26). The percentage of patients who had adverse events in the two groups did not differ. INTERPRETATION: Dimebon was safe, well tolerated, and significantly improved the clinical course of patients with mild-to-moderate Alzheimer's disease.

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Neurology. 2008 Jul 15;71(3):210-6.
Cardiorespiratory fitness and brain atrophy in early Alzheimer disease.
Burns JM, Cronk BB, Anderson HS, Donnelly JE, Thomas GP, Harsha A, Brooks WM, Swerdlow RH.
Department of Neurology, Hoglund Brain Imaging Center, University of Kansas School of Medicine, 3599 Rainbow Blvd, MSN 2012, Kansas City, KS 66160, USA. jburns2@kumc.edu

OBJECTIVE: To examine the correlation of cardiorespiratory fitness with brain atrophy and cognition in early-stage Alzheimer disease (AD). BACKGROUND: In normal aging physical fitness appears to mitigate functional and structural age-related brain changes. Whether this is observed in AD is not known. METHODS: Subjects without dementia (n = 64) and subjects with early-stage AD (n = 57) had MRI and standard clinical and psychometric evaluations. Peak oxygen consumption (VO(2)(peak)), the standard measure of cardiorespiratory fitness, was assessed during a graded treadmill test. Normalized whole brain volume, a brain atrophy estimate, was determined by MRI. Pearson correlation and linear regression were used to assess fitness in relation to brain volume and cognitive performance. RESULTS: Cardiorespiratory fitness (VO(2)(peak)) was modestly reduced in subjects with AD (34.7 [5.0] mL/kg/min) vs subjects without dementia (38.1 [6.3] mL/kg/min, p = 0.002). In early AD, VO(2)(peak) was associated with whole brain volume (beta = 0.35, p = 0.02) and white matter volume (beta = 0.35, p = 0.04) after controlling for age. Controlling for additional covariates of sex, dementia severity, physical activity, and physical frailty did not attenuate the relationships. VO(2)(peak) was associated with performance on delayed memory and digit symbol in early AD but not after controlling for age. In participants with no dementia, there was no relationship between fitness and brain atrophy. Fitness in participants with no dementia was associated with better global cognitive performance (r = 0.30, p = 0.02) and performance on Trailmaking A and B, Stroop, and delayed logical memory but not after controlling for age. CONCLUSIONS: Increased cardiorespiratory fitness is associated with reduced brain atrophy in Alzheimer disease (AD). Cardiorespiratory fitness may moderate AD-related brain atrophy or a common underlying AD-related process may impact both brain atrophy and cardiorespiratory fitness.

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Arch Neurol. 2008 Jul;65(7):906-12. Comment in: Arch Neurol. 2008 Jul;65(7):875-6.
Distinct pools of beta-amyloid in Alzheimer disease-affected brain: a clinicopathologic study.
Steinerman JR, Irizarry M, Scarmeas N, Raju S, Brandt J, Albert M, Blacker D, Hyman B, Stern Y.
Departments of Neurology, Columbia University Medical Center, 630 W 168th St, P&S Box 16, New York, NY 10032, USA.

OBJECTIVE: To determine whether beta-amyloid (Abeta) peptides segregated into distinct biochemical compartments would differentially correlate with clinical severity of Alzheimer disease (AD). DESIGN: Clinicopathologic correlation study. PARTICIPANTS: Twenty-seven patients from a longitudinal study of AD and 13 age- and sex-matched controls without a known history of cognitive impairment or dementia were included in this study. INTERVENTIONS: Temporal and cingulate neocortex were processed using a 4-step extraction, yielding biochemical fractions that are hypothesized to be enriched with proteins from distinct anatomical compartments: TRIS (extracellular soluble), Triton (intracellular soluble), sodium dodecyl sulfate (SDS) (membrane associated), and formic acid (extracellular insoluble). Levels of Abeta(40) and Abeta(42) were quantified in each biochemical compartment by enzyme-linked immunosorbent assay. RESULTS: The Abeta(42) level in all biochemical compartments was significantly elevated in patients with AD vs controls (P < .01). The Abeta(40) levels in the TRIS and formic acid fractions were elevated in patients with AD (temporal, P < .01; cingulate, P = .03); however, Triton and SDS Abeta(40) levels were similar in patients with AD and in controls. Functional impairment proximal to death correlated with Triton Abeta(42) (r = 0.48, P = .02) and SDS Abeta(42) (r = 0.41, P = .04) in the temporal cortex. Faster cognitive decline was associated with elevated temporal SDS Abeta(42) levels (P < .001), whereas slower decline was associated with elevated cingulate formic acid Abeta(42) and SDS Abeta(42) levels (P = .02 and P = .01, respectively). CONCLUSION: Intracellular and membrane-associated Abeta, especially Abeta(42) in the temporal neocortex, may be more closely related to AD symptoms than other measured Abeta species.

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Cell. 2008 Jun 27;133(7):1149-61.
A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk.
Dreses-Werringloer U, Lambert JC, Vingtdeux V, Zhao H, Vais H, Siebert A, Jain A, Koppel J, Rovelet-Lecrux A, Hannequin D, Pasquier F, Galimberti D, Scarpini E, Mann D, Lendon C, Campion D, Amouyel P, Davies P, Foskett JK, Campagne F, Marambaud P.
Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY 11030, USA.

Alzheimer's disease (AD) is a genetically heterogeneous disorder characterized by early hippocampal atrophy and cerebral amyloid-beta (Abeta) peptide deposition. Using TissueInfo to screen for genes preferentially expressed in the hippocampus and located in AD linkage regions, we identified a gene on 10q24.33 that we call CALHM1. We show that CALHM1 encodes a multipass transmembrane glycoprotein that controls cytosolic Ca(2+) concentrations and Abeta levels. CALHM1 homomultimerizes, shares strong sequence similarities with the selectivity filter of the NMDA receptor, and generates a large Ca(2+) conductance across the plasma membrane. Importantly, we determined that the CALHM1 P86L polymorphism (rs2986017) is significantly associated with AD in independent case-control studies of 3404 participants (allele-specific OR = 1.44, p = 2 x 10(-10)). We further found that the P86L polymorphism increases Abeta levels by interfering with CALHM1-mediated Ca(2+) permeability. We propose that CALHM1 encodes an essential component of a previously uncharacterized cerebral Ca(2+) channel that controls Abeta levels and susceptibility to late-onset AD.

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PLoS Comput Biol. 2008 Jun 27;4(6):e1000100.
Network analysis of intrinsic functional brain connectivity in Alzheimer's disease.
Supekar K, Menon V, Rubin D, Musen M, Greicius MD.
Graduate Program in Biomedical Informatics, Stanford University School of Medicine, Stanford, California, USA.

Functional brain networks detected in task-free ("resting-state") functional magnetic resonance imaging (fMRI) have a small-world architecture that reflects a robust functional organization of the brain. Here, we examined whether this functional organization is disrupted in Alzheimer's disease (AD). Task-free fMRI data from 21 AD subjects and 18 age-matched controls were obtained. Wavelet analysis was applied to the fMRI data to compute frequency-dependent correlation matrices. Correlation matrices were thresholded to create 90-node undirected-graphs of functional brain networks. Small-world metrics (characteristic path length and clustering coefficient) were computed using graph analytical methods. In the low frequency interval 0.01 to 0.05 Hz, functional brain networks in controls showed small-world organization of brain activity, characterized by a high clustering coefficient and a low characteristic path length. In contrast, functional brain networks in AD showed loss of small-world properties, characterized by a significantly lower clustering coefficient (p<0.01), indicative of disrupted local connectivity. Clustering coefficients for the left and right hippocampus were significantly lower (p<0.01) in the AD group compared to the control group. Furthermore, the clustering coefficient distinguished AD participants from the controls with a sensitivity of 72% and specificity of 78%. Our study provides new evidence that there is disrupted organization of functional brain networks in AD. Small-world metrics can characterize the functional organization of the brain in AD, and our findings further suggest that these network measures may be useful as an imaging-based biomarker to distinguish AD from healthy aging.

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Neuron. 2008 Jun 26;58(6):871-83.
Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating.
Cheung KH, Shineman D, Müller M, Cárdenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM, Foskett JK.
Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.

Mutations in presenilins (PS) are the major cause of familial Alzheimer's disease (FAD) and have been associated with calcium (Ca2+) signaling abnormalities. Here, we demonstrate that FAD mutant PS1 (M146L)and PS2 (N141I) interact with the inositol 1,4,5-trisphosphate receptor (InsP3R) Ca2+ release channel and exert profound stimulatory effects on its gating activity in response to saturating and suboptimal levels of InsP3. These interactions result in exaggerated cellular Ca2+ signaling in response to agonist stimulation as well as enhanced low-level Ca2+signaling in unstimulated cells. Parallel studies in InsP3R-expressing and -deficient cells revealed that enhanced Ca2+ release from the endoplasmic reticulum as a result of the specific interaction of PS1-M146L with the InsP3R stimulates amyloid beta processing,an important feature of AD pathology. These observations provide molecular insights into the "Ca2+ dysregulation" hypothesis of AD pathogenesis and suggest novel targets for therapeutic intervention.

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Tohoku J Exp Med. 2008 Jun;215(2):133-40.
Memory impairment and awareness of memory deficits in early-stage Alzheimer's disease.
Mimura M.
Department of Neuropsychiatry, Showa University School of Medicine, Tokyo, Japan. mimura@med.showa-u.ac.jp

In addition to their memory impairment, individuals with Alzheimer's disease (AD) often suffer from deficits in self-awareness. Awareness of memory deficits or metamemory is a multifaceted function, comprising on-line self-monitoring, generalized self-beliefs of memory efficacy, and generalized knowledge about memory functions. Awareness of memory problems in early-stage AD is a matter of clinical importance from a humanistic point of view, because higher levels of awareness may be associated with better future outcomes. Current methods of measuring awareness tend to fall into two categories, i.e., to introduce a questionnaire assessing patient/caregiver discrepancies; or to ask a patient to prospectively predict or retrospectively postdict their own memory performances. Characteristics of each measure as well as relationship between the two measures were discussed. For the performance prediction/postdiction paradigm, we used recognition memory of auditory verbal learning tests and awareness of memory deficits were examined in 24 individuals with early-stage AD. In addition to their significantly impaired recognition memory, individuals with AD displayed underawareness of memory deficits even at this early stage. They retrospectively overestimated memory performance after actual performance, but appeared to benefit from feedback and displayed intact on-line awareness of memory dysfunction, leading to normal prediction of the second session. However, individuals with AD again failed to retrospectively incorporate incidents of memory failure into generalized self-belief systems. Brain/behavior correlational analyses suggest that the prefrontal cortex and posterior dorsomedial regions including the precuneus may be involved in self-awareness.

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Am J Cardiol. 2008 May 22;101(10A):43D-49D.
Natural products as a robust source of new drugs and drug leads: past successes and present day issues.
Rishton GM.
Channel Islands Alzheimer's Institute, California State University, Camarillo, CA 93012, USA. gilbert.rishton@csuci.edu

The history of drug development has its foundation firmly set in the study of natural remedies used to treat human disease over centuries. Analysis of medicinal plants, bioactive cultures, and increased understanding of micronutrients in the food chain opened the door to the development of purified and defined chemical compounds as dose-controlled medicines. Thus, with the early discovery of cardiotonics in foxglove, salicylic acid in willow bark, morphine in poppies, and penicillin in mold, the pharmaceutical industry was launched. Such natural small molecules served as treatments for disease and ultimately, as pharmacologic tools to enable the understanding of the biochemical pathways and mechanisms of disease. In contrast, modern drug discovery technologies coupled with the powerful tools of biotechnology have prompted drug discovery organizations to focus on target-driven drug discovery at the molecular level by launching high-throughput screening programs using artificial biochemical assays. At a time when the pharmaceutical industry has come under scrutiny for high rates of drug development failure, it is interesting to see that natural products drug discovery has been marginalized in favor of this high-throughput biochemical screening paradigm. If modern drug development is once again to benefit from natural products as a source, then the limitations of artificial biochemical assays as applied to the screening of natural extracts must be realized in order to capitalize on the vast natural molecular diversity and rich ethnobotanic data that has emerged worldwide. Natural compounds can again become central players in the treatment of disease and in the understanding of disease mechanisms.

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Cleve Clin J Med. 2008 Mar;75 Suppl 2:S87-93.
Hippocampal volume change in the Alzheimer Disease Cholesterol-Lowering Treatment trial.
Sparks DL, Lemieux SK, Haut MW, Baxter LC, Johnson SC, Sparks LM, Sampath H, Lopez JE, Sabbagh MH, Connor DJ.
Roberts Laboratory for Neurodegenerative Disease Research, Sun Health Research Institute, Sun City, AZ, USA. Larry.Sparks@sunhealth.org

Numerous clinical studies suggest a link between elevated cholesterol and increased risk of Alzheimer disease (AD), and the preponderance of data suggests that statin therapy may reduce the risk of AD later in life. The first clinical investigation of statin therapy in patients with AD, the AD Cholesterol-Lowering Treatment (ADCLT) trial, found that atorvastatin 80 mg/day was associated with improvements relative to placebo on some, but not all, cognitive measures after 6 months and 1 year of therapy. We report here findings from a pilot ADCLT substudy showing a nonsignificant reduction in total hippocampal volume with 1 year of atorvastatin therapy compared with placebo, driven by a highly significant reduction in right hippocampal volume with atorvastatin therapy.

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Endocr Metab Immune Disord Drug Targets. 2008 Jun;8(2):132-42.
Lipoic acid: a novel therapeutic approach for multiple sclerosis and other chronic inflammatory diseases of the CNS.
Salinthone S, Yadav V, Bourdette DN, Carr DW.
Portland Veterans Affairs Medical Center, VAMC RD-8, 3710 Portland, OR 97239, USA.

The naturally occurring antioxidant lipoic acid (LA) was first described as an essential cofactor for the conversion of pyruvate to Acetyl-CoA, a critical step in respiration. LA is now recognized as a compound that has many biological functions. Along with its reduced form dihydrolipoic acid (DHLA), LA reduces and recycles cellular antioxidants such as glutathione, and chelates zinc, copper and other transition metal ions in addition to heavy metals. LA can also act as a scavenger of reactive oxygen and nitrogen species. By acting as an insulin mimetic agent, LA stimulates glucose uptake in many different cell types and can also modulate insulin signaling. The p38 and ERK MAP kinase pathways, AKT and NFkappaB are all regulated by LA. In addition, LA activates the prostaglandin EP2 and EP4 receptors to stimulate the production of the small molecule cyclic adenosine 5' monophosphate (cAMP). These diverse actions suggest that LA may be therapeutically effective in treating oxidative stress associated diseases. This review discusses the known biochemical properties of LA, its antioxidant properties, its ability to modulate signal transduction pathways, and the recent progress made in the utilization of LA as a therapeutic alternative for multiple sclerosis, Alzheimer's disease and diabetic neuropathy.

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Expert Opin Emerg Drugs. 2008 Jun;13(2):255-71.
Emerging amyloid beta (Ab) peptide modulators for the treatment of Alzheimer's disease (AD).
Lukiw WJ.
Louisiana State University Health Sciences Center, LSU Neuroscience Center of Excellence, 2020 Gravier Street, Suite 8B8, New Orleans, LA 70112-2272, USA. wlukiw@lsuhsc.edu

BACKGROUND: According to the 'amyloid cascade hypothesis' of Alzheimer's disease (AD), abnormal processing of beta-amyloid precursor protein (betaAPP) into toxic amyloid beta (Abeta)-peptides is central to the etiopathology of this uniquely human brain disorder. OBJECTIVE: To review current AD drugs, pharmacological approaches and strategies aimed at modulating Abeta-peptide generation and/or aggregation in the treatment of AD. METHODS: Data searches at various websites: Alzheimer Research Forum; individual drug company databases; Medline; Pharmaprojects database; unpublished research; inter-University research communications. RESULTS/CONCLUSION: Considerable research effort has focused on secretase-mediated mechanisms of betaAPP processing, and the latest pharmacological strategies have used selective Abeta-peptide-lowering agents (SALA) to provide therapeutic benefit against Abeta-initiated neurodegenerative pathology. Currently, dedicated anticholinesterase, glutamatergic agonist and Abeta-peptide immunization have had little impact in the clinical treatment of AD. One unexpected benefit of statins (HMG-CoA inhibitors), besides their cholesterol lowering abilities, has been their ancillary effects in potentiating the enzymatic mechanisms that generate Abeta-peptides. The long-term benefits or complications of statin-based therapies for use in the clinical management of AD are not known.

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PLoS ONE. 2008 Jan 23;3(1):e1475.
No effect of one-year treatment with indomethacin on Alzheimer's disease progression: a randomized controlled trial.
de Jong D, Jansen R, Hoefnagels W, Jellesma-Eggenkamp M, Verbeek M, Borm G, Kremer B.
Department of Neurology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
 
BACKGROUND: The objective of this study was to determine whether treatment with the nonselective nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows cognitive decline in patients with Alzheimer's disease (AD). METHODOLOGY/PRINCIPAL FINDINGS: This double-blind, randomized, placebo-controlled trial was conducted between May 2000 and September 2005 in two hospitals in the Netherlands. 51 patients with mild to moderate AD were enrolled into the study. Patients received 100 mg indomethacin or placebo daily for 12 months. Additionally, all patients received omeprazole. The primary outcome measure was the change from baseline after one year of treatment on the cognitive subscale of the AD Assessment Scale (ADAS-cog). Secondary outcome measures included the Mini-Mental State Examination, the Clinician's Interview Based Impression of Change with caregiver input, the noncognitive subscale of the ADAS, the Neuropsychiatric Inventory, and the Interview for Deterioration in Daily life in Dementia. Considerable recruitment problems of participants were encountered, leading to an underpowered study. In the placebo group, 19 out of 25 patients completed the study, and 19 out of 26 patients in the indomethacin group. The deterioration on the ADAS-cog was less in the indomethacin group (7.8+/-7.6), than in the placebo group (9.3+/-10.0). This difference (1.5 points; CI -4.5-7.5) was not statistically significant, and neither were any of the secondary outcome measures. CONCLUSIONS/SIGNIFICANCE: The results of this study are inconclusive with respect to the hypothesis that indomethacin slows the progression of AD. TRIAL REGISTRATION: ClinicalTrials.gov NCT00432081.
 
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Internist (Berl). 2008 Jan 23 [Epub ahead of print]
[Antidementia drugs - response or non-response?]
[Article in German]
Förstl H.
Klinik und Poliklinik für Psychiatrie und Psychotherapie, TU München, Klinikum rechts der Isar, Ismaningerstraße 22, 81675, München, Deutschland, hans.foerstl@lrz.tu-muenchen.de.
 
Due to the heterogeneous course of illness in individual cases, efficacy or "treatment-response" can not be measured in single patients; therefore a clinical distinction between response and non-response is not meaningful. Constructs which are valid for research projects become misnomers in clinical practice. To date there are two groups of antidementia drugs, memantine—an NMDA-receptor modulator licensed for the moderate to severe stages—and the cholinesterase inhibitors donepezil, galantamine, and rivastigmine, licensed for mild to moderate stages of Alzheimer's disease. These substances exert a moderate symptomatic effect on cognition and activities of daily living or clinical global impression, which corresponds to a parallel shift of the natural course of dementia. A low number of contraindications and few serious adverse events are the advantages of memantine. The extensive evidence for their efficacy and safety are the advantages of cholinesterase inhibitors. Symptoms of "cholinopathy" (a severe lack of acetylcholine) predict a favorable treatment response to cholinesterase inhibitors in groups of demented patients with attention deficit disorders, fluctuating course of illness, visual hallucinations, and superimposed states of confusion.
 
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Qual Health Res. 2008 Jan;18(1):31-42.
Losing one's memory in early Alzheimer's disease.
Parsons-Suhl K, Johnson ME, McCann JJ, Solberg S.
Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
 
A Heideggerian hermeneutical phenomenological research method was used to investigate the experience of memory loss in twelve individuals with early Alzheimer's disease or mild cognitive impairment. Data analysis proceeded as described by Diekelmann, Allen, and Tanner (1989), and incorporated the methods of Benner (1994), Thomas and Pollio (2002), and van Manen (1990). Three constitutive patterns with relational themes were identified. The first pattern, experiencing breakdown, consisted of two themes: awakening to breakdown and living with forgetting. The second pattern, temporality, consisted of three themes: being in the nothing, forgetting the past, and looking ahead. The third pattern, managing forgetting, consisted of the themes: remembering with cues, writing things down, recognizing what made remembering better or worse, and using laughter. The finding show that early Alzheimer's disease is more than an illness of cognitive losses and that forgetting is significant in light of the meaning that it has within everyday life.

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Curr Alzheimer Res. 2007 Dec;4(5):550-2.
Perispinal etanercept for treatment of Alzheimer's disease.
Tobinick E.
Assistant Clinical Professor of Medicine, UCLA, Director, Institute for Neurological Research, a Private Medical Group, Inc., 100 UCLA Medical Plaza, Suites 205-210, Los Angeles, California 90095, USA. etmd@ucla.edu.

Background: Increasing basic science and clinical evidence implicates inflammatory processes and resulting glial activation in the pathogenesis of Alzheimer's Disease. Excess TNF-alpha, a cytokine with pleotropic effects in the CNS, has been suggested to be involved in the pathogenesis of AD. In addition to its pro-inflammatory effects, TNF-alpha affects synaptic transmission; and glutamate, NMDA, and amyloid pathways. More specifically, TNF-alpha, produced by glia, has been shown to affect both synaptic strength and to mediate synaptic scaling, a homeostatic mechanism important to the control of neural networks. A recently published small, open-label pilot study suggested that inhibition of the inflammatory cytokine TNF-alpha utilizing the perispinal administration of etanercept may lead to sustained cognitive improvement for six months in patients with mild, moderate, and severe Alzheimer's disease. Results: Continued open-label clinical experience with this new treatment modality, now for more than two years, suggests that weekly maintenance treatment with perispinal etanercept may have a sustained positive effect. In addition, rapid clinical improvement, within minutes of dosing, has been observed on a repeated basis in multiple patients. Discussion: It is hypothesized that perispinal administration of etanercept may enable rapid delivery to the CNS via the cerebrospinal venous system, resulting in improvement in synaptic mechanisms which have been dysregulated by excess TNF-alpha. TNF-alpha modulation in Alzheimer's disease may also act by influencing glutamate, NMDA, amyloid and other inflammatory pathways. Methods of perispinal administration, as described in the pilot study, may prove useful for delivering other therapeutics, particularly large molecules, to the CNS. Further study in randomized, placebo-controlled clinical trials and in basic science studies is merited.

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Am J Manag Care. 2007 Dec;13 Suppl 8:S198-202.
Current issues in dementia pharmacotherapy.
Daiello LA.
Pharmacotherapy Solutions, 2115 Ivanhoe Rd, Orlando, FL 32804, USA. ldaiello@cox.net

Diagnosis and treatment of dementia in nursing homes and assisted living facilities remains challenging since response to treatment and disease course varies for the common degenerative dementias. Four cholinesterase inhibitors and an N-methyl-D-aspartate glutamate receptor antagonist are approved by the US Food and Drug Administration for the treatment of Alzheimer's disease (AD). Treatment with AD medications is clinically efficacious and associated with reduced caregiver burden. Some controlled trials have reported that cholinesterase inhibitors and memantine ameliorate dementia-related behavioral symptoms. Antipsychotic therapy is often used for intractable behavioral symptoms or psychosis not responding to nonpharmacologic interventions and antidementia medications; however, the risk/benefit ratio for each patient should be critically evaluated, because treatment with atypical antipsychotics has been associated with serious adverse events, including increased risk for death in older adults with dementia.

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Recent Patents CNS Drug Discov. 2007 Nov;2(3):108-87.
Therapeutic treatment of Alzheimer's disease using metal complexing agents.
Price KA, Crouch PJ, White AR.
Department of Pathology and the Centre for Neuroscience, The University of Melbourne, Victoria 3010 and The Mental Health Research Institute, Parkville, Victoria 3052, Australia. arwhite@unimelb.edu.au.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by deposition of extracellular amyloid plaques, formation of intracellular neurofibrillary tangles and neuronal dysfunction in the brain. A growing body of evidence indicates a central role for biometals such as copper in many critical aspects of AD. The amyloid beta (Abeta) peptide and its parental molecule, the amyloid precursor protein (APP) both modulate Cu and Zn metabolism in the brain. Therefore, aberrant changes to APP or Abeta metabolism could potentially alter biometal homoestasis in AD, leading to increased free radical production and neuronal oxidative stress. Modulation of metal bioavailability in the brain has been proposed as a potential therapeutic strategy for treatment of AD patients. The lipid permeable metal complexing agent, clioquinol (CQ), has shown promising results in animal models of AD and in small clinical trials involving AD patients. Moreover, a new generation of metal-ligand based therapeutics is currently under development. Patents now cover the generation of novel metal ligand structures designed to modulate metal binding to Abeta and quench metal-mediated free radical generation. However, the mechanism by which CQ and other metal complexing agents slows cognitive decline in AD animal models and patients is unknown. Increasing evidence suggests that ligand-mediated redistribution of metals at a cellular level in the brain may be important. Further research will be necessary to fully understand the complex pathways associated with efficacious metal-based pharmaceuticals for treatment of AD.

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Consult Pharm. 2007 Sep;22(9):754-62.
The use of cognitive enhancers in behavioral disturbances of Alzheimer's disease.
Miller LJ.
Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas 77030, USA. lisaj.miller@med.va.gov

OBJECTIVE: To review the literature for double-blind, placebo-controlled trials that examined the efficacy of cognitive enhancers in the psychopathology of Alzheimer's disease. DATA SOURCES: Literature searches were conducted using MEDLINE and EMBASE databases and clinicaltrials.gov. STUDY SELECTION: Overall, 55 articles were reviewed for inclusion. Several open-label studies and case reports were found on this topic, but only those involving both tacrine and use of the Neuropsychiatric Inventory were included. Regarding other drugs, only double-blind, placebo-controlled trials were selected for inclusion. DATA SYNTHESIS: Limited data suggest that the anticholinesterase inhibitors and memantine offer an alternative or adjunct to the antipsychotics for the treatment of moderate-to-severe behaviors. The author reviewed the literature for pharmacological management of behavioral and psychological symptoms of dementia (BPSD) using these cognitive enhancers. CONCLUSION: The majority of patients with Alzheimer's disease will experience behavioral disturbances during the course of their disease. Atypical antipsychotics are used routinely in these situations to treat the psychotic features and agitation. However, atypicals now carry a "black box" warning issued by the Food and Drug Administration on the basis of evidence that their use in geriatric patients with dementia-related psychosis may put patients at increased risk of mortality as a result of cardiovascular or infectious events. An alternative to the atypicals may be the acetylcholinesterase inhibitors and memantine, which have been shown to stabilize cognitive as well as behavioral issues in patients, utilizing the "gold standard" for behavior, the Neuropsychiatric Inventory. Efficacy varies among agents, with the greatest positive effects seen with donepezil, which also has the greatest number of studies. Drug benefits were harder to demonstrate for mild-to-moderate BPSD compared with moderate-to-severe symptoms.
 
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Int J Geriatr Psychiatry. 2007 Sep 26; [Epub ahead of print]
A 2-year follow-up of 233 very mild (CDR 0.5) Alzheimer's disease patients (REAL.FR cohort).
Nourhashemi F, Ousset PJ, Gillette-Guyonnet S, Cantet C, Andrieu S, Vellas B.
CHU Toulouse, Hopital Casselardit, Service de medecine interne et gerontologie clinique, Toulouse, France.

OBJECTIVES: Making an early diagnosis of Alzheimer's Disease (AD) is becoming increasingly important. The Clinical Dementia Rating scale (CDR), a semi-structured interview with patient and caregiver, is a global rating scale designed for use in staging dementia. The primary objective of our study was to examine the evolution of AD in individuals with very mild AD (CDR 0.5) across a 2-year follow up. METHODS: A cohort of AD patients (n = 682) living in the community were followed during 2 years in 16 centres of the French AD network. Each subject underwent extensive medical examination including the MMSE and CDR every 6 months. RESULTS: Two hundred and thirty-three AD patients were rated CDR 0.5 at baseline (mean MMSE score: 23.15 +/- 2.57). They were younger and reported an average duration of symptoms of approximately 0.8 years less than patients with CDR >/= 1.During the 2-year follow-up, none of the AD CDR 0.5 subjects improved; 65% of them showed an increase in the CDR score. The rate of cognitive decline was similar between the AD CDR 0.5 and CDR >/= 1 groups. The ADL decline was more significant in patients with CDR >/= 1 at inclusion. CONCLUSIONS: It is certainly possible to identify AD at a very early stage focusing on intra individual change in cognitive and functional impairment. Criteria with a high sensitivity and specificity for detecting AD at an early stage will help to further develop effective pharmacological and behavioural interventions for delaying the onset and progression of the disease. Copyright (c) 2007 John Wiley & Sons, Ltd.

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Aging Ment Health. 2007 Sep;11(5):526-31.
Personality changes in Alzheimer's disease.
Talassi E, Cipriani G, Bianchetti A, Trabucchi M.
Department of Medicine, Istituto Clinico S. Anna, Hospital, Brescia, Italy.

Background: Assessment of personality changes in patients with dementia has received little systematic investigation, although caregivers report personality modifications in every phase of dementia. Methods: A group of 52 patients with probable Alzheimer's disease (AD) vs. a group of fifteen control subjects were selected for these personality tests before and after the manifestation of dementia using an Italian version of Brooks and McKinaly's Personality Inventory (PI). Results: After the onset of AD, a significant shift from positive to negative characteristics in PI was observed in 12 of 18 bipolar pairs of adjectives constituting the instrument and the total mean PI score decreased significantly (p < 0.001), indicating a substantial worsening of personality profile. In the control group however, evaluated before and after retirement, personality traits and total mean PI score did not show a significant change. The association of personality traits and total PI score with demographic, cognitive and functional characteristics of AD patients was calculated. Conclusion: Personality changes have been depicted to be influenced by severity of cognitive, functional and behavioural complaints rather than age, sex, education and disease duration. These first applications of the Italian version of PI confirmed that personality modifications make a consistent aspect of the phenomenology of AD although in the negative direction. Further studies are needed to understand the nature of personality changes in dementia and the utility of PI to investigate these changes.

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Int J Geriatr Psychiatry. 2007 Sep 18; [Epub ahead of print]
Quetiapine treatment for behavioural and psychological symptoms of dementia in Alzheimer's disease patients: a 6-week, double-blind, placebo-controlled study.
Paleacu D, Barak Y, Mirecky I, Mazeh D.
Neurology Service and Memory Clinic, Abarbanel Mental Health Center, Bat Yam, Israel, Affiliated with the Sackler School of Medicine, Tel Aviv University, Israel.

SETTING: Treating elderly patients with Alzheimer's disease (AD) and behavioral and psychological symptoms of dementia (BPSD) is challenging due to the increased risk of iatrogenic movement disorders with old neuroleptics and the seemingly increasing risk of cardiovascular events with newer atypical agents. Quetiapine is an atypical antipsychotic agent that warrants further investigation. OBJECTIVES: To assess tolerability, safety, and clinical benefit of quetiapine in AD patients with BPSD. PARTICIPANTS AND DESIGN: AD patients with BPSD participated in a 6-week randomized, double-blind, placebo-controlled trial. Quetiapine was increased on the basis of clinical response and tolerability. Primary efficacy assessments included the Neuropsychiatric Inventory (NPI) and Clinical Global Impression of Change (CGI-C). Secondary efficacy measures included the Mini-Mental State Examination (MMSE), the Simpson-Angus Scale (SAS) and the Abnormal Involuntary Movement Scale (AIMS). RESULTS: Forty patients (26 women), mean age 82.2 (SD 6.4) years were enrolled, 27 completed treatment. Median dose of quetiapine was 200 mg/day. Significant NPI total scores reductions (79% for placebo and 68.5% for quetiapine) were observed. The CGI-C score decreased significantly in the quetiapine group (p = 0.009 at 6 weeks) and did not change significantly in the placebo group (p = 0.48). The MMSE, AIMS, SAS scores and adverse events did not differ significantly between the two arms. CONCLUSIONS: Quetiapine did not significantly improve psychosis scores. It did not cause cognitive and motor deterioration. These results might possibly be due to small sample size. Copyright (c) 2007 John Wiley & Sons, Ltd.

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J Alzheimers Dis. 2007 Sep;12(1):37-52.
One hundred years after the discovery of Alzheimer's disease. A turning point for therapy?
Giacobini E, Becker RE.
Department of Rehabilitation and Geriatrics, University of Geneva Medical School, Geneva, Switzerland.

Following the introduction of cholinesterase inhibitors in 1986 and a 20-yr long period of successful clinical application in mild, moderate and severe patients, the treatment of AD has turned to modify the course of pathological processes thought to comprise the disease. Several active and passive vaccines are presently under investigation for efficacy, reducing amyloid-beta in the brain of patients with mild-moderately advanced disease. Three large international immunization trials are in progress in US and Europe on mild-moderate AD patients. Among these, the most advanced trial in time is the humanized antibody trial. In addition, drugs aiming to reduce tauphosphorylation (GSK3 inhibitors) are about to enter clinical phases of development. Due to intrinsic difficulties, the developments of gamma-and beta-secretase inhibitors have not yet reached clinical stages. Only one anti-amyloid-aggregation, an aminoglycan compound, and one anti-APO-E approach with rosiglitazone are currently in clinical testing. Stem-cell therapy and gene-replacing therapy remain experimental and far from clinical application. Based on experimental evidence that NGF (nerve growth factor) treatment could provide prolonged protection of the central cholinergic system, i.c.v. infusion of NGF, with genetically modified fibroblasts or gene therapy are under current investigation. NGF treatment could probably double the clinical effect of ChEIs in time. Given the level of scientific and clinical activity it is reasonable to expect that within the next five to ten years a new therapy for AD will, by blocking disease progression, both produce long term stabilization of at least 5 years in patients with AD and prevent or delay emergence in persons at risk for AD.

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Neurology. 2007 Sep 11;69(11):1084-93.
Mediterranean diet and Alzheimer disease mortality.
Scarmeas N, Luchsinger JA, Mayeux R, Stern Y.
Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA. ns257@columbia.edu

BACKGROUND: We previously reported that the Mediterranean diet (MeDi) is related to lower risk for Alzheimer disease (AD). Whether MeDi is associated with subsequent AD course and outcomes has not been investigated. OBJECTIVES: To examine the association between MeDi and mortality in patients with AD. METHODS: A total of 192 community-based individuals in New York who were diagnosed with AD were prospectively followed every 1.5 years. Adherence to the MeDi (0- to 9-point scale with higher scores indicating higher adherence) was the main predictor of mortality in Cox models that were adjusted for period of recruitment, age, gender, ethnicity, education, APOE genotype, caloric intake, smoking, and body mass index. RESULTS: Eighty-five patients with AD (44%) died during the course of 4.4 (+/-3.6, 0.2 to 13.6) years of follow-up. In unadjusted models, higher adherence to MeDi was associated with lower mortality risk (for each additional MeDi point hazard ratio 0.79; 95% CI 0.69 to 0.91; p = 0.001). This result remained significant after controlling for all covariates (0.76; 0.65 to 0.89; p = 0.001). In adjusted models, as compared with AD patients at the lowest MeDi adherence tertile, those at the middle tertile had lower mortality risk (0.65; 0.38 to 1.09; 1.33 years' longer survival), whereas subjects at the highest tertile had an even lower risk (0.27; 0.10 to 0.69; 3.91 years' longer survival; p for trend = 0.003). CONCLUSION: Adherence to the Mediterranean diet (MeDi) may affect not only risk for Alzheimer disease (AD) but also subsequent disease course: Higher adherence to the MeDi is associated with lower mortality in AD. The gradual reduction in mortality risk for higher MeDi adherence tertiles suggests a possible dose-response effect.

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Curr Neurol Neurosci Rep. 2007 Sep;7(5):366-372.
Diet and Alzheimer's Disease.
Luchsinger JA, Noble JM, Scarmeas N.
Taub Institute for Research of Alzheimer’s Disease and the Aging Brain, Columbia University, PH9E-105, 630 West 168th Street, New York, NY 10032, USA. jal94@columbia.edu.

Alzheimer's disease (AD) is increasing in prevalence. There are no known preventive or curative measures. There is evidence that oxidative stress, homo-cysteine-related vitamins, fats, and alcohol have a role in the pathogenesis of AD. Some epidemiologic studies suggest that higher dietary intake of antioxidants, vitamins B(6), B(12), and folate, unsaturated fatty acids, and fish are related to a lower risk of AD, but reports are inconsistent. Modest to moderate alcohol intake, particularly wine, may be related to a lower risk of AD. The Mediterranean diet may also be related to lower AD risk. However, randomized clinical trials of supplements of vitamins E, B(12), B(6), and folate have shown no cognitive benefit, and randomized trials for other nutrients or diets in AD are not available. The existing evidence does not support the recommendation of specific supplements, foods, or diets for the prevention of AD.

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Aging Clin Exp Res. 2007 Aug;19(4):316-22.
Cognitive stimulation intervention for elders with mild cognitive impairment compared with normal aged subjects: preliminary results.
Wenisch E, Cantegreil-Kallen I, De Rotrou J, Garrigue P, Moulin F, Batouche F, Richard A, De Sant'anna M, Rigaud AS.
Department of Gerontology, Broca Hospital, 75013 Paris, France. emilie.wenisch@brc.aphp.fr.

BACKGROUND AND AIMS: Cognitive training programs have been developed for Alzheimer's disease patients and the healthy elderly population. Collective cognitive stimulation programs have been shown to be efficient for subjects with memory complaint. The aim of this study was to evaluate the benefit of such cognitive programs in populations with Mild Cognitive Impairment (MCI). METHODS: Twelve patients with MCI and twelve cognitively normal elders were administered a cognitive stimulation program. Cognitive performance (Logical Memory, Word paired associative learning task, Trail Making Test, verbal fluency test) were collected before and after the intervention. A gain score [(post-score - prescore)/pre-score] was calculated for each variable and compared between groups. RESULTS: The analysis revealed a larger intervention size effect in MCI than in normal elders' performances on the associative learning task (immediate recall: p<0.05, delayed recall: p<0.01). The intervention was more beneficial in improving associative memory abilities in MCI than in normal subjects. At the end of the intervention, the MCI group had lower results than the normal group only for the delayed recall of Logical Memory. CONCLUSIONS: Although further studies are needed for more details on the impact of cognitive stimulation programs on MCI patients, this intervention is effective in compensating associative memory difficulties of these patients. Among non-pharmacological interventions, cognitive stimulation therapy is a repeatable and inexpensive collective method that can easily be provided to various populations with the aim of slowing down the rate of decline in elderly persons with cognitive impairment.

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Neurology. 2007 Aug 28;69(9):878-85.
Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease.
Li G, Larson EB, Sonnen JA, Shofer JB, Petrie EC, Schantz A, Peskind ER, Raskind MA, Breitner JC, Montine TJ.
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. gli@u.washington.edu

BACKGROUND: Treatment with 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors ("statins") has been associated in some epidemiologic studies with reduced risk of Alzheimer disease (AD). However, direct evidence of statin effects on neuropathologic markers of AD is lacking. We investigated whether antecedent statin exposure is associated with neuritic plaque (NP) or neurofibrillary tangle (NFT) burden in a population-based sample of human subjects. METHODS: Brain autopsies were performed on 110 subjects, ages 65 to 79 years, who were cognitively normal at enrollment into the Adult Changes in Thought Study. Neuropathologic findings were compared between statin users with > or =3 prescriptions of > or =15 pills of simvastatin, pravastatin, lovastatin, or atorvastatin vs nonusers, based on pharmacy dispensing records. RESULTS: After controlling for age at death, gender, cognitive function at study entry, brain weight, and presence of cerebral microvascular lesions, the odds ratio (OR) for each unit increase in Braak NFT stage in statin users vs nonusers was 0.44 (95% CI: 0.20 to 0.95). The OR for each unit increase in Consortium to Establish a Registry for Alzheimer's Disease (CERAD) staging of NPs did not deviate significantly from unity (OR 0.69; 95% CI: 0.32 to 1.52). However, the risk for typical AD pathology (Braak stage > or = IV and CERAD rating > or = moderate) was reduced in statin users (OR 0.20; 95% CI: 0.05 to 0.86). CONCLUSIONS: These findings demonstrate an association between antecedent statin use and neurofibrillary tangle burden at autopsy. Additional study is needed to examine whether statin use may be causally related to decreased development of Alzheimer disease-related neuropathologic changes.

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Am J Psychiatry. 2007 Jun;164(6):910-915.
Nursing Home Placement, Day Care Use, and Cognitive Decline in Alzheimer's Disease.
Wilson RS, McCann JJ, Li Y, Aggarwal NT, Gilley DW, Evans DA.
Rush Alzheimer’s Disease Center, Rush University Medical Center, 600 S. Paulina St., Suite 1038, Chicago, IL 60612. rwilson@rush.edu.

OBJECTIVE: People with Alzheimer's disease are often placed in a nursing home, sometimes after using adult day care services. How affected persons function during this potentially difficult transition is not well understood. The aim of this study was to examine the associations of day care use and nursing home placement with the rate of cognitive decline in Alzheimer's disease. METHOD: The participants were 432 older persons with Alzheimer's disease who were recruited from health care settings in the Chicago area. At baseline, they lived in the community and were using day care services a mean 1.7 days per week. At 6-month intervals for up to 4 years, they completed nine cognitive tests from which a composite measure of global cognition was derived. RESULTS: On average, cognition declined at a gradually increasing rate during the study period. Nursing home placement was associated with a decrease in the level of cognition and an acceleration in the rate of cognitive decline. Day care use at baseline was not related to cognitive decline in initial analyses, but it interacted with nursing home placement such that higher level of day care use substantially reduced association of placement with accelerated cognitive decline. Education interacted with placement such that more schooling was associated with a greater increase in cognitive decline upon nursing home placement, but prior day care use also attenuated this association. CONCLUSIONS: Nursing home placement is associated with accelerated short-term cognitive decline in Alzheimer's disease. Prior experience in adult day care may lessen this association.

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Dtsch Med Wochenschr. 2007 Jun 1;132(22):1207-13.
[Cholinesterase inhibitors and Alzheimer's disease: demonstrable efficacy, origin and bias of published studies.]
[Article in German]
Egert S, Wagenpfeil S, Förstl H.
Münchner Studienzentrum.

BACKGROUND AND OBJECTIVE: The cholinesterase-inhibitors (AChE-I) donepezil, galantamine and rivastigmine are currently used in the symptomatic treatment of patients with Alzheimer's dementia (AD) and the associated cholinergic deficits as well as those with other forms of dementia. Threee aspects were analysed: (1) data on their clinical efficacy, (2) differences between North-American and international studies, and (3) potential publication biases. METHODS: Included were data from randomized, placebo-controlled, double-blind parallel group trials on more than 100 patients who had been treated for >/=12 weeks for AD, VaD, dementia with Lewy bodies, dementia with Parkinson's disease or with mild cognitive impairment. RESULTS: These large published trials support the clinical efficacy of AChE-I in patients with mild to moderate AD and other forms of dementia with regard to cognition and global impression. there was a trend towards greater beneficial cognitive effects in North-American studies, but this was non-significant. There was no evidence of a publication bias. CONCLUSIONS: Published data provide evidence for the clinical efficacy of donepezil, galantamine and rivastigmine in patients with mild to moderate AD. There is no indication that these results are critically influenced by the origin or a bias of the publication.

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Expert Opin Investig Drugs. 2007 Jun;16(6):819-28.
Clinical immunologic approaches for the treatment of Alzheimer's disease.
Solomon B.
George S. Wise Faculty of Life Sciences, Department of Molecular Microbiology & Biotechnology, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel. beka@post.tau.ac.il

Recent clinical trials of active vaccination against beta-amyloid (Abeta) have succeeded in clearing Abeta plaques; however, further understanding of immunization with regards to inflammation and other hallmarks of Alzheimer's disease pathology is required. Antibodies generated with this first-generation vaccine may not have had the desired therapeutic properties or targeted the 'correct' mechanism, but they have opened the way for new clinical approaches, which are now under consideration. Passive administration of monoclonal antibodies directed to various regions of Abeta peptide and/or administration of immunoconjugates of only small fragments of the N-terminal region may lead to the development of an improved second generation of Abeta vaccines. Amyloid immunotherapy offers genuine opportunities for disease treatment; however, such an approach towards treating and preventing Alzheimer's disease patients requires careful antigen and antibody selection to maximize efficacy and minimize adverse events.

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Expert Opin Pharmacother. 2007 May;8(7):1011-23.
Donepezil: an update.
Seltzer B.
V.A. Boston Healthcare System, Department of Neurology, Harvard Medical School, Geriatric Research Center, Boston, MA 02130, USA. bseltzer@partners.org

Donepezil hydrochloride is the most widely prescribed drug for Alzheimer's disease (AD). The main mechanism of action through which it influences cognition and function is presumed to be the inhibition of acetylcholinesterase enzyme in the brain; however, donepezil may also impact the pathophysiology of AD at several other points. Officially approved for mild-to-moderate and severe AD, donepezil has also been shown to be effective in early-stage AD, vascular dementia, Parkinson's disease dementia/Lewy body disease and cognitive symptoms associated with multiple sclerosis. In addition, one study suggested that donepezil may delay the onset of AD in subjects with mild cognitive impairment, a prodrome to AD. The pharmacokinetics, pharmacodynamics, safety/tolerability profile and drug interaction properties of donepezil make it an easy and safe agent to use. However, in general, the efficacy of donepezil is limited, and ongoing studies are investigating other agents that may ultimately overtake its present position as the mainstay of anti-AD therapy.

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Neurology. 2007 May 1;68(18):1509-14.
Cognitive decline in Alzheimer disease: Impact of spirituality, religiosity, and QOL.
Kaufman Y, Anaki D, Binns M, Freedman M.
Behavioural Neurology Program, Division of Neurology, Baycrest, Canada. ykaufman@herzoghospital.org

OBJECTIVE: To assess effects of quality of life (QOL), spirituality, and religiosity on rate of progression of cognitive decline in Alzheimer disease (AD). METHODS: In this longitudinal study, we recruited 70 patients with probable AD. The Mini-Mental State Examination was used to monitor the rate of cognitive decline. Religiosity and spirituality were measured using standardized scales that assess spirituality, religiosity, and organizational and private religious practices. We conducted a simultaneous multiple linear regression analysis for factors contributing to rate of cognitive decline. RESULTS: After controlling for baseline level of cognition, age, sex, and education, a slower rate of cognitive decline was associated with higher levels of spirituality (p < 0.05) and private religious practices (p < 0.005). These variables accounted for 17% of the total variance [F(11,58) = 2.24, p < 0.05]. There was no correlation between rate of cognitive decline and QOL. CONCLUSION: Higher levels of spirituality and private religious practices, but not quality of life, are associated with slower progression of Alzheimer disease.

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Int J Geriatr Psychiatry. 2007 May;22(5):475-84.
The efficacy and safety of risperidone in the treatment of psychosis of Alzheimer's disease and mixed dementia: a meta-analysis of 4 placebo-controlled clinical trials.
Katz I, de Deyn PP, Mintzer J, Greenspan A, Zhu Y, Brodaty H.
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.

BACKGROUND: Dementia typically includes behavioral and psychological symptoms of dementia (BPSD) as well as cognitive decline. Psychosis of Alzheimer's disease (AD) is a specific component of AD, characterized by delusions, misidentifications, and hallucinations. METHODS: This study is a meta-analysis of patients with psychosis of AD from four large placebo-controlled clinical trials of risperidone in dementia. Three trials included patients diagnosed with heterogeneous symptoms of BPSD (those with psychosis of AD were included in this analysis), while one trial included only those diagnosed with psychosis of AD. Efficacy was measured using the Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD) Psychosis subscale and Clinical Global Impression (CGI). RESULTS: Primary analyses in the psychosis of AD population demonstrated that risperidone significantly improved scores on the BEHAVE-AD Psychosis subscale and CGI scale compared with placebo. Secondary analyses demonstrated that patients with more severe symptoms showed a more pronounced response to treatment with risperidone compared with placebo than those patients with less severe symptoms. Extrapyramidal symptoms and somnolence were more frequent with risperidone than placebo (p = 0.04). Cerebrovascular adverse events and all-cause mortality were observed more frequently, although not statistically significantly, with risperidone versus placebo. CONCLUSIONS: This meta-analysis of psychosis of AD showed improvement in psychotic symptoms and general clinical improvement in patients with psychosis of AD treated with risperidone compared with placebo. The benefits of treatment were most significant in patients with severe symptoms. The safety profile of risperidone in this psychosis of AD population was similar to the more general BPSD population. Copyright (c) 2007 John Wiley & Sons, Ltd.

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Can J Psychiatry. 2007 Apr;52(4):248-55.
Efficacy and safety of antidepressants for treatment of depression in Alzheimer's disease: a metaanalysis.
Thompson S, Herrmann N, Rapoport MJ, Lanctôt KL.
Department of Psychiatry, Atlantic Health Sciences Corporation, Saint John, New Brunswick.

OBJECTIVE: Depression in patients with Alzheimer's disease (AD) is common (15% to 63%) and is associated with significant morbidity and increased mortality. Our objective was to quantitatively summarize the data on the efficacy and safety of antidepressant treatment for depression complicating AD. METHOD: We performed a metaanalysis of randomized, double-blind, placebo-controlled trials of antidepressants with a database search of the English literature (up to 2006) and a manual search of references in the retrieved articles. We extracted the proportion of subjects who responded and remitted, experienced adverse events (AEs), discontinued treatment due to AEs, or discontinued treatment for any reason. Cognition scores were also extracted. RESULTS: We included 5 studies, which involved 82 subjects treated with antidepressants and 83 subjects who received placebo treatment. Antidepressants were superior to placebo for both treatment response (odds ratio [OR] 2.32; 95% confidence interval [CI], 1.04 to 5.16) and remission of depression (OR 2.75; 95% CI, 1.13 to 6.65). There were no significant differences between the 2 groups for change in cognition (weighted mean difference -0.71, 95% CI, -3.20 to 1.79), overall dropouts (OR 0.70; 95% CI, 0.29 to 1.66) or dropout due to AEs (OR 1.41; 95% CI 0.36 to 5.54). The numbers needed to treat for one additional AD patient to respond to antidepressant treatment were 5 (95% CI, 3 to 59) and 5 (95% CI, 2 to 24) for remission of depression. CONCLUSIONS: Antidepressant treatment for depression in AD is efficacious, with rates of discontinuation that are comparable to placebo. Nonetheless, clinicians must be vigilant regarding the potential side effects of antidepressants in this population.

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Am J Alzheimers Dis Other Demen. 2007 Feb-Mar;22(1):62-77.
Language-enriched exercise plus socialization slows cognitive decline in Alzheimer's disease.
Arkin S.
Department of Speech and Hearing Sciences), University of Arizona, Tucson, USA. arkinaz@earthlink.net

This article reports the effects of language-enriched physical fitness interventions provided by University of Arizona undergraduate students to 24 mild- to moderate-stage Alzheimer's disease patients (AD Rehab group). Socialization experiences consisted of supervised volunteer work and cultural/recreational activities. Changes in global functioning and neuropsychological test performance were tracked and compared to those of a similar group of untreated patients from the Consortium for the Establishment of a Registry for Alzheimer's Disease (CERAD). Cohorts completing 4 semesters or longer showed no significant between-year changes after their first year on the Clinical Dementia Rating, a measure of global functioning, and on 5 or 6 of the cognitive and language measures. Comparisons with the CERAD sample suggested a slower rate of decline for the AD Rehab group. The stabilization of global and cognitive performance was not apparent among participants who completed only 2 semesters. Significant physical fitness and mood outcomes were previously reported in this journal.

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Am J Alzheimers Dis Other Demen. 2007 Feb-Mar;22(1):42-7.
Cognitive and psychopathologic response to rivastigmine in dementia with Lewy bodies compared to Alzheimer's disease: a case control study.
Rozzini L, Chilovi BV, Bertoletti E, Conti M, Delrio I, Trabucchi M, Padovani A.
Department of Neurology, University of Brescia, Italy. lrozzini@iol.it

Cholinesterase inhibitors (ChEIs) are effective in improving cognition and behavior in patients affected by Alzheimer's disease (AD) as well as by Lewy bodies dementia (DLB). The authors compared the effect of rivastigmine in the treatment of cognitive impairment and behavioral and psychological symptoms of dementia (BPSD) in 30 AD and in 30 DLB patients. At baseline, DLB compared to AD patients showed a greater number of extrapyramidal symptoms (P < .005) and were similar regarding cognitive symptoms and BPSD. After treatment, both groups showed a comparable cognitive and psycho-behavioral improvement. A significant difference between AD and DLB patients was found for hallucinations (P < .002). Rivastigmine produces comparable cognitive benefits in patients with DLB and AD and also a significant improvement of behavioral disorders. These findings support the view that ChEIs should be considered a first-line treatment of the cognitive and psycho-behavioral symptoms of both AD and DLB.

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Am J Alzheimers Dis Other Demen. 2007 Feb-Mar;22(1):14-9.
Effectiveness of support groups for people with mild to moderate Alzheimer's disease: an evaluative survey.
Snyder L, Jenkins C, Joosten L.
University of California, San Diego, Shiley-Marcos Alzheimer's Disease Research Center, 9500 Gilman Drive 0948, La Jolla, CA 92093, USA. lsnyder@ucsd.edu

Support groups can provide a forum for socialization and learning for people with mild to moderate Alzheimer's disease. The aim of this study was to evaluate the effectiveness of these groups based on participant feedback. A survey questionnaire was administered to 70 support group participants with Alzheimer's disease from 8 well-established groups across the United States. Participants reported on the educational value, positive socialization, and improved ability to cope with symptoms and to accept the diagnosis as a result of participating in a support group. These reported outcomes suggest the importance of creating more sensitive measures to better evaluate the effectiveness of support groups and other educational or social support programs for persons with dementia.

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CNS Spectr. 2007 Feb;12(2):119-23.
Alzheimer's Disease: Progress in the Development of Anti-amyloid Disease-Modifying Therapies.
Christensen DD.
University of Utah, Salt Lake City, UT, USA.

The amyloid hypothesis-the leading mechanistic theory of Alzheimer's disease-states that an imbalance in production or clearance of amyloid beta (Abeta) results in accumulation of Abeta and triggers a cascade of events leading to neurodegeneration and dementia. The number of persons with Alzheimer's disease is expected to triple by mid-century. If steps are not taken to delay the onset or slow the progression of Alzheimer's disease, the economic and personal tolls will be immense. Different classes of potentially disease-modifying treatments that interrupt early pathological events (ie, decreasing production or aggregation of Abeta or increasing its clearance) and potentially prevent downstream events are in phase II or III clinical studies. These include immunotherapies; secretase inhibitors; selective Abeta42-lowering agents; statins; anti-Abeta aggregation agents; peroxisome proliferator-activated receptor-gamma agonists; and others. Safety and serious adverse events have been a concern with immunotherapy and gamma-secretase inhibitors, though both continue in clinical trials. Anti-amyloid disease-modifying drugs that seem promising and have reached phase III clinical trials include those that selectively target Abeta42 production (eg, tarenflurbil), enhance the activity of alpha-secretase (eg, statins), and block Abeta aggregation (eg, transiposate).

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Expert Opin Drug Metab Toxicol. 2007 Feb;3(1):135-141.
A brief review of the pharmacologic and therapeutic aspects of memantine in Alzheimer's disease.
Schmitt F, Ryan M, Cooper G.
1University of Kentucky, Sanders-Brown Center on Aging, and Department of Neurology, and Departments of Psychiatry, Psychology, and Behavioural Sciences, 800 S. Limestone Street, Lexington, KY 40536-0230, USA. fascom@email.uky.edu , 2University of Kentucky, Department of Neurology, and Department of Pharmacy Practice and Science, 800 S. Limestone Street, Lexington, KY 40536-0230, USA, 3University of Kentucky, Sanders-Brown Center on Aging, and Department of Neurology, 800 S. Limestone Street, Lexington, KY 40536-0230, USA, 4Lexington Clinic, Division of Neurology, Lexington, KY, USA.

The past decade has seen an increase in therapeutic options for Alzheimer's disease (AD) that target neurotransmitters, such as acetylcholine, and research continues to target abnormal proteins in the AD brain. Recently, glutamate excitotoxicity has also become a target for AD treatment with the advent of memantine. Clinical trial data reviewed for memantine show good tolerability, low side-effect profiles and a positive therapeutic impact in moderate-to-severe AD, both as monotherapy and in conjunction with donepezil. However, additional data suggest variable benefits in the mild stages of AD. Furthermore, published reports support reduced dosing in patients with significant renal disease. However, the opportunity to target a second mechanism in the treatment of AD, thereby providing added symptomatic benefit, appears to be a useful consideration for clinicians who treat this devastating neurodegenerative disorder.

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Expert Opin Pharmacother. 2007 Feb;8(2):203-14.
Memantine in the treatment of mild-to-moderate Alzheimer's disease.
Cosman KM, Boyle LL, Porsteinsson AP.
University of Rochester School of Medicine, Alzheimer's Disease Care Research and Education Program (AD-CARE), Monroe Community Hospital, 435 East Henrietta Road, Rochester, NY 14620, USA. Kelly_Cosman@urmc.rochester.edu

Memantine is the first and only medication that has been approved by European, US and Canadian regulatory agencies for the treatment of moderate-to-severe Alzheimer's disease (AD). It is an NMDA receptor antagonist that works to prevent excitotoxicity and cell death, which are mediated by the excessive influx of calcium during a sustained release of glutamate. Preclinical studies of memantine reveal that it has the potential to improve memory and learning processes after impairment has occurred, as well as to prevent further neuronal damage. Although memantine has been considered for the treatment of earlier AD, it has not yet been approved for this. Randomized controlled trials of memantine in the treatment of mild-to-moderate AD have demonstrated small treatment effects in measures of cognition, global assessment and behavior favoring the use of memantine. However, the differences between treatment groups were not consistently significant. Two ongoing long-term trials are further investigating the efficacy of memantine in the treatment of mild-to-moderate AD.

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Dement Geriatr Cogn Disord. 2007 Jan 25;23(3):194-201 [Epub ahead of print]
Prevention and Treatment of Dementia or Alzheimer's Disease by Statins: A Meta-Analysis.
Zhou B, Teramukai S, Fukushima M.
Division of Clinical Trial Design and Management, Translational Research Center, Kyoto University Hospital, Kyoto, Japan.

Background/Aim: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are thought to reduce the amount of Abeta peptides by reducing cholesterol from blood and/or cerebrospinal fluid. We performed this meta-analysis to evaluate the preventive and treatment effects of statins on dementia and Alzheimer disease onset. Methods: Relevant studies were systematically identified, and data were abstracted according to predefined criteria. We used a fixed-effects model and a random-effects model to compute pooled relative risks and to assess statistical heterogeneity. Results: The pooled crude odds ratios in statin users as compared with nonusers were 0.67 (95% confidence interval CI 0.54-0.82) in the dementia group and 0.81 (95% CI 0.64-1.02) in the Alzheimer group. The pooled adjusted relative risks calculated by random-effects model were 0.77 (95% CI 0.45-1.30) in the dementia group and 0.81 (95% CI 0.56-1.16) in the Alzheimer group. Conclusions: Statin use did not show a beneficial effect on the risk of dementia or Alzheimer's disease. Further study and independent confirmation of the association between statin use and dementia and Alzheimer's disease in larger clinical trials are warranted. Copyright (c) 2007 S. Karger AG, Basel.

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Am J Alzheimers Dis Other Demen. 2007 December-January;21(6):454-459.
Clock Drawing and Frontal Lobe Behavioral Effects of Memantine in Alzheimer's Disease: A Rater-Blinded Study.
Paskavitz JF, Gunstad JJ, Samuel JE.
Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts. James.Paskavitz@Perceptive.com.

Caregivers of Alzheimer's disease patients treated with memantine have reported improved frontal lobe behaviors. The present study examined these possible improvements in executive functioning using rater-blinded scoring of a clock-drawing test. Fifty-one Alzheimer's disease patients were treated with open-label memantine for 10 weeks. Clock drawing and Mini-Mental State Examination data were collected before and after treatment. Clock drawing improved significantly with treatment, whereas Mini-Mental State Examination data did not. Twenty-seven patients judged as improved in frontal lobe behaviors by caregivers demonstrated a statistically significant improvement in clock drawing to command, whereas 24 patients judged to be unchanged or worse with memantine in their frontal lobe behaviors had no change in their clock drawing and had worsening on their Mini-Mental State Examination. The current findings suggest that memantine improves frontal lobe behavior in some Alzheimer's disease patients and that clock drawing to command may be sensitive to these improvements.

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Am J Alzheimers Dis Other Demen. 2007 December-January;21(6):448-453.
Efficacy and Tolerability of Quetiapine in the Treatment of Behavioral and Psychological Symptoms of Dementia.
Onor ML, Saina M, Aguglia E.
University of Trieste, Italy. marialuisa.onor@libero.it.

Behavioral symptoms start to appear in mild and moderate dementia and become increasingly severe with the progression of the disease. Agitation, aggressiveness, and psychosis can be seen in Alzheimer's disease, and in particular are common manifestations in Lewy body dementia. It is the behavioral disturbances rather than the cognitive disorders that are more often the cause of the institutionalization of these patients because of the heavy assistance and emotional burden they represent for caregivers. Traditionally, these kinds of symptoms were controlled by classical antipsychotic agents, which after long-term use cause severe extrapyramidal effects, late dyskinesia, sedation, orthostatic hypotension, and cognitive function impairment. More recently, atypical antipsychotic agents have shown a better tolerability profile, with a reduced incidence of extrapyramidal effects, orthostatic hypotension, sedation, and a reduced impact on cognitive function. The aim of this study is to evaluate the efficacy and tolerability of quetiapine in a group of patients with a diagnosis of dementia and concomitant psychotic disorders. The response to treatment was evaluated by the Neuropsychiatric Inventory (NPI) and the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). The NPI and BEHAVE-AD were administered at baseline and after 4 weeks and 12 weeks of therapy. Tolerability was assessed by the incidence of clinically evident side effects. The results show that quetiapine is effective in reducing behavioral symptoms, deliria and hallucinations, aggressiveness, and sleep disturbances. Quetiapine tolerability proved to be satisfactory. The only side effect of clinical significance was orthostatic hypotension, which was, however, partially preventable by a slower drug titration.

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Curr Top Med Chem. 2007;7(1):115-26.
Disrupting beta-Amyloid Aggregation for Alzheimer Disease Treatment.
Estrada LD, Soto C.
Protein Misfolding Disorders Laboratory, George and Cynthia Mitchell Center for Alzheimer's disease research, Department of Neurology and Neurosciences and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA. clsoto@utmb.edu.

Alzheimer's disease is a devastating degenerative disorder for which there is no cure or effective treatment. Although the etiology of Alzheimer's disease is not fully understood, compelling evidence indicates that deposition of aggregates composed by a misfolded form of the amyloid beta peptide (Abeta) is the central event in the disease pathogenesis. Therefore, an attractive therapeutic strategy is to prevent or reverse Abeta misfolding and aggregation. Diverse strategies have been described to identify inhibitors of this process, including screening of libraries of small molecules chemical compounds, rational design of synthetic peptides, assessment of natural Abeta-binding proteins and stimulation of the immune system by vaccination. In this article we describe these different approaches, their principles and their potential strengths and weaknesses. Overall the available data suggest that the development of drugs to interfere with Abeta misfolding and aggregation is a feasible target that hold great promise for the treatment of Alzheimer's disease.
  
Previous Alzheimer's Research: 2002-2006   
The Alzheimer's Disease File also contains summaries of past research that has shown promise and may still be standard practice among many physicians. To download earlier research findings on Alzheimer's Disease, click HERE.

 

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