Alzheimer's & Dementia: The Journal of the Alzheimer's Association

Efficacy of a medical food in mild Alzheimer's disease: A randomized, controlled trial

2010-01-01

Abstract: Objective: To investigate the effect of a medical food on cognitive function in people with mild Alzheimer's disease (AD).Methods: A total of 225 drug-naïve AD patients participated in this randomized, double-blind controlled trial. Patients were randomized to active product, Souvenaid, or a control drink, taken once-daily for 12 weeks. Primary outcome measures were the delayed verbal recall task of the Wechsler Memory Scale–revised, and the 13-item modified Alzheimer's Disease Assessment Scale–cognitive subscale at week 12.Results: At 12 weeks, significant improvement in the delayed verbal recall task was noted in the active group compared with control (P = .021). Modified Alzheimer's Disease Assessment Scale–cognitive subscale and other outcome scores (e.g., Clinician Interview Based Impression of Change plus Caregiver Input, 12-item Neuropsychiatric Inventory, Alzheimer's disease Co-operative Study–Activities of Daily Living, Quality of Life in Alzheimer's Disease) were unchanged. The control group neither deteriorated nor improved. Compliance was excellent (95%) and the product was well tolerated.Conclusions: Supplementation with a medical food including phosphatide precursors and cofactors for 12 weeks improved memory (delayed verbal recall) in mild AD patients. This proof-of-concept study justifies further clinical trials.

Outcome over seven years of healthy adults with and without subjective cognitive impairment

Barry Reisberg, Melanie B. Shulman, Carol Torossian, Ling Leng, Wei Zhu — 2010-01-01

Abstract: Background: Subjective cognitive impairment (SCI) in older persons without manifest symptomatology is a common condition with a largely unclear prognosis. We hypothesized that (1) examining outcome for a sufficient period by using conversion to mild cognitive impairment (MCI) or dementia would clarify SCI prognosis, and (2) with the aforementioned procedures, the prognosis of SCI subjects would differ significantly from that of demographically matched healthy subjects, free of SCI, termed no cognitive impairment (NCI) subjects.Methods: A consecutive series of healthy subjects, aged ≥40 years, presenting with NCI or SCI to a brain aging and dementia research center during a 14-year interval, were studied and followed up during an 18-year observation window. The study population (60 NCI, 200 SCI, 60% female) had a mean age of 67.2 ± 9.1 years, was well-educated (mean, 15.5 ± 2.7 years), and cognitively normal (Mini-Mental State Examination, 29.1 ± 1.2).Results: A total of 213 subjects (81.9% of the study population) were followed up. Follow-up occurred during a mean period of 6.8 ± 3.4 years, and subjects had a mean of 2.9 ± 1.6 follow-up visits. Seven NCI (14.9%) and 90 SCI (54.2%) subjects declined (P < .0001). Of NCI decliners, five declined to MCI and two to probable Alzheimer's disease. Of SCI decliners, 71 declined to MCI and 19 to dementia diagnoses. Controlling for baseline demographic variables and follow-up time, Weibull proportional hazards model revealed increased decline in SCI subjects (hazard ratio, 4.5; 95% confidence interval, 1.9–10.3), whereas the accelerated failure time model analysis with an underlying Weibull survival function showed that SCI subjects declined more rapidly, at 60% of the rate of NCI subjects (95% confidence interval, 0.45–0.80). Furthermore, mean time to decline was 3.5 years longer for NCI than for SCI subjects (P = .0003).Conclusions: These results indicate that SCI in subjects with normal cognition is a harbinger of further decline in most subjects during a 7-year mean follow-up interval. Relevance for community populations should be investigated, and prevention studies in this at-risk population should be explored.

Toward an Alzheimer's disease diagnosis via high-resolution blood gene expression

2010-01-01

Abstract: Background: There is a significant need for reliable molecular biomarkers to aid in Alzheimer's disease (AD) clinical diagnosis.Methods: We performed a genome-wide investigation of the human transcriptome, taking into account the discriminatory power of splice variations from the blood of 80 AD patients and 70 nondemented control (NDC) individuals.Results: We characterized a blood RNA signature composed of 170 oligonucleotide probe sets associated with 133 genes that can correctly distinguish AD patients from NDC with a sensitivity of 100% and specificity of 96%. Functionally, this signature highlights genes involved in pathways that were associated with macrophages and lymphocytes within AD patients: Transforming growth factor (TGF-β) signaling, oxidative stress, innate immunity and inflammation, cholesterol homeostasis, and lipid-raft perturbation, whereas other genes may also provide new insights in the biology of AD.Conclusions: This study provides proof-of-concept that whole-blood profiling can generate an AD-associated classification signature via the specific relative expression of biologically relevant RNAs. Such a signature will need to be validated with extended patient cohorts, and evaluated to learn whether it can differentiate AD from others types of dementia.

Disease progression meta-analysis model in Alzheimer's disease

2009-07-10

Abstract: Background: Various authors have evaluated disease progression in Alzheimer's disease (AD), using patient data from individual clinical studies or pooled data across various trials. We conducted a systematic review of public data sources from 1990 to 2008 for all available AChE inhibitor studies, as well as clinical studies that evaluated the rate of deterioration in AD patients. Unique to this analysis, we developed a model based on literature data to describe the longitudinal response in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog) (change from baseline) in mild to moderate severity AD patients. The model was used to estimate disease progression for both placebo-treated patients and acetylcholinesterase (AChE)-inhibitor treated patients, and factors that affected disease progression.Methods: We collected 576 mean ADAS-cog changes from baseline data points of 52 trials, representing data from approximately 19,972 patients and more than 84,000 individual observations. The model described the rate of disease progression, the evident placebo effect, and the symptomatic effect of AChE-inhibitors. Baseline ADAS-cog, Mini-Mental State Examination score, age, and year of publication were tested as covariates.Results: The disease progression in mild to moderate AD patients across all available and relevant literature sources was estimated as 5.5 points per year. An Emax-type model best described the symptomatic drug effect of AChE inhibitors. The rate of disease progression (underlying disease progression) was no different between placebo and AChE-inhibitors groups. Baseline ADAS-cog is a significant covariate in disease progression. Baseline age was also tested as a covariate in the rate of disease progression, but the model was unable to describe any effects of age, likely because of the narrow distribution of mean age (literature-level analysis). There was no significant impact of publication year in the model.Conclusions: Baseline ADAS-cog is a significant covariate affecting the rate of disease progression, and it describes or at least explains the different rates of deterioration evident in early or late stages of the disease. There was no significant impact of publication year in the model, suggesting that disease progression has not slowed in more recent trials.

White matter integrity and cortical metabolic associations in aging and dementia

2010-01-01

Abstract: Background: Studies show that white matter hyperintensities, regardless of location, primarily affect frontal lobe metabolism and function. This report investigated how regional white matter integrity (measured as fractional anisotropy [FA]) relates to brain metabolism, to unravel the complex relationship between white matter changes and brain metabolism.Objective: To elucidate the relationship between white matter integrity and gray matter metabolism using diffusion tensor imaging and fluorodeoxyglucose-positron emission tomography in a cohort of 16 subjects ranging from normal to demented (age, >55 years).Methods: Mean FA values from white matter regions underlying the medial prefrontal, inferior-lateral prefrontal, parietal association, and posterior temporal areas and the corpus callosum were regressed with glucose metabolism (by positron emission tomography), using statistical parametric mapping (P < 0.005; voxel cluster, >100). Regional cerebral glucose metabolism was the primary outcome measure. According to our hypothesis, those hypometabolic cortical regions affected by Alzheimer's disease would correlate with a lower FA of associated tracks.Results: Our data show inter-regional positive correlations between FA and gray matter metabolism for the prefrontal cortex, temporal, and parietal regions. Our results suggest that left prefrontal FA is associated with left temporal and parietal metabolism. Further, left posterior temporal FA correlated with left prefrontal metabolism. Finally, bilateral parietal FA correlated with bilateral temporal metabolism.Conclusions: These regions are associated with cognitive processes affected in Alzheimer's disease and cerebrovascular disease, suggesting a link with white matter degeneration and gray matter hypometabolism. Therefore, cortical function and white matter degeneration are related in aging and dementia.

Subtypes of depression among patients with Alzheimer's disease and other dementias

Ruby C. Castilla-Puentes, Miguel E. Habeych — 2010-01-01

Abstract: Objectives: We compared the prevalence of subtypes of depression in patients with Alzheimer's disease (AD), vascular dementia (VaD), and unspecified dementia (UD).Methods: Using the Integrated Healthcare Information Services database, we conducted an analysis of subtypes of depression (major depressive disorder, depressive disorder not otherwise specified, dysthymic disorder; depressive psychosis, and adjustment disorder depressive) among patients with AD, VaD, and UD. Six thousand four hundred and forty patients aged 60 years or older with dementia (2947 with AD, 725 with VaD, and 2768 with UD) were identified from January 1 to December 31, 2001. Both subtypes of depression and dementia subgroups were diagnosed using criteria from the International Classification of Diseases, 9th version.Results: The overall prevalence of depressive disorders was 27.41%. The prevalence of depressive disorders was significantly higher in VaD (44.14%) and UD (32.48%) patients compared with AD (18.53%, P < .0001) patients. The AD patients had the lowest prevalence of all subtypes of depression. The VaD patients, compared with both AD and UD (P < .005), had a significantly higher prevalence of: 1) depressive disorder not otherwise specified, 2) major depressive disorder, and 3) dysthymic disorder. Adjustment disorder with depressive symptoms was more common in the UD subgroup, whereas the rate of depressive psychosis was similar in all dementia subgroupsConclusions: This study supports the view that depressive disorders are more prevalent in VaD compared with UD and AD, and provides indicators to the clinician for further evaluation of depression in dementia subgroups

Rivastigmine for the treatment of dementia in patients with progressive supranuclear palsy: Clinical observations as a basis for power calculations and safety analysis

2010-01-01

Abstract: Cognitive decline and dementia are present in about 50% of patients with progressive supranuclear palsy (PSP). Based on the known involvement of the cholinergic system in PSP patients, and because rivastigmine, in contrast to other cholinesterase inhibitors, inhibits both acetylcholinesterase and butyrylcholinesterase, we discuss clinical observations of five patients suffering from PSP and dementia who were all treated with rivastigmine over a period of 3 to 6 months. We found a slight improvement in specific cognitive function that may justify further controlled studies. A calculation of sample size revealed that a study on the effect of rivastigmine in PSP should include about 31 patients to detect a significant effect. In subtests, meaningful results can be obtained with even lower numbers (five patients for a verbal fluency test, and 14 patients for a logical memory task).

Early dementia diagnosis and the risk of suicide and euthanasia

Brian Draper, Carmelle Peisah, John Snowdon, Henry Brodaty — 2010-01-01

Abstract: Background: Diagnosis of dementia is occurring earlier, and much research concerns the identification of predementia states and the hunt for biomarkers of Alzheimer's disease. Reports of suicidal behavior and requests for euthanasia in persons with dementia may be increasing.Methods: We performed a selective literature review of suicide risk in persons with dementia and the ethical issues associated with euthanasia in this population.Results: In the absence of any effective treatments for Alzheimer's disease or other types of dementia, there is already evidence that persons with mild cognitive change and early dementia are at risk of suicidal behavior, often in the context of comorbid depression. The ensuing clinical, ethical, and legal dilemmas associated with physician-assisted suicide and euthanasia in the context of dementia are a subject of intense debate. By analogy, the preclinical and early diagnoses of Huntington's disease are associated with an increased risk of suicidal behavior. Thus there is the potential for a preclinical and early diagnosis of Alzheimer's disease (through biomarkers, neuroimaging, and clinical assessment) to result in increased suicide risk and requests for physician-assisted suicide.Conclusions: Although dementia specialists have long recognized the importance of a sensitive approach to conveying bad news to patients and families and the possibility of depressive reactions, suicidal behavior has not been regarded as a likely outcome. Such preconceptions will need to change, and protocols to monitor and manage suicide risk will need to be developed for this population.

Alzheimer's disease and infection: Do infectious agents contribute to progression of Alzheimer's disease?

Ruth F. Itzhaki, Matthew A. Wozniak — 2010-01-01

We thank Honjo et al. for their interesting and balanced report on the possible role of herpes simplex virus type 1 (HSV1) in Alzheimer's disease (AD) in their recent review. However, we would like to mention that several additional recent publications indirectly support the case for HSV1, in the brains of apolipoprotein (APOE)-ε4 carriers, conferring a strong risk for the disease. These include studies by Miller and Federoff and Bhattacharjee et al. on the APOE modulation of HSV1 effects, Zambrano et al. linking HSV1 to τ hyperphosphorylation, and Bullido et al. and Pandey on the genes relevant to HSV1 and AD. Moreover, we recently published two papers that link HSV1 directly to the two main pathological features of AD brains . One of the papers described our finding, using immunocytochemistry, enzyme-linked immunosorbent assays, and Western blotting, that HSV1 infection of cultured cells leads to the phosphorylation of τ at a number of sites that were shown to be phosphorylated in AD, and that there is a consistent increase in the amount of the relevant enzymes, i.e., glycogen synthase kinase 3β and protein kinase A .

Commentary on the letter for Alzheimer's disease and infection: Do infectious agents contribute to progression of Alzheimer's disease?

Kie Honjo, Robert van Reekum, Nicolaas P.L.G. Verhoeff — 2010-01-01

We thank Professor Itzhaki and Dr Wozniak for their interest in our article and for updating our review with recent publications with regards to the association between herpes simplex virus type 1 (HSV-1) and Alzheimer's disease (AD). We agree that these latest results of HSV-1 are very important to confirm our hypothesis because previous studies have not consistently shown positive results. Knowing that APOEε4 affects the brain vulnerability to many other brain injuries and that APOEε4 is a well-established genetic risk factor for sporadic AD, this interaction is strong evidence.

Alzheimer's Association Update

2010-01-01

We need you to join advocates from across the nation on Capitol Hill during the Alzheimer's Association Advocacy Forum, March 7–9. Alzheimer's disease (AD) must be a top issue as legislators discuss research funding and funding for the care required by people with AD. The best way to get our message to lawmakers is with your support.

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2010-01-01

Editorial Board

2010-01-01

Medical and Scientific Advisory Council

2010-01-01

Alzheimer's & Dementia: The Journal of the Alzheimer's Association

Efficacy of a medical food in mild Alzheimer's disease: A randomized, controlled trial

Outcome over seven years of healthy adults with and without subjective cognitive impairment

Toward an Alzheimer's disease diagnosis via high-resolution blood gene expression

Disease progression meta-analysis model in Alzheimer's disease

White matter integrity and cortical metabolic associations in aging and dementia

Subtypes of depression among patients with Alzheimer's disease and other dementias

Rivastigmine for the treatment of dementia in patients with progressive supranuclear palsy: Clinical observations as a basis for power calculations and safety analysis

Early dementia diagnosis and the risk of suicide and euthanasia

Alzheimer's disease and infection: Do infectious agents contribute to progression of Alzheimer's disease?

Commentary on the letter for Alzheimer's disease and infection: Do infectious agents contribute to progression of Alzheimer's disease?

Alzheimer's Association Update

Subscriber information

Contents

Editorial Board

Medical and Scientific Advisory Council