Citations

It is recognized that individuals with mild cognitive impairment (MCI) already demonstrate difficulty in aspects of daily functioning, which predicts disease progression. This study examined the relationship between self‐ versus informant‐report of functional ability, and how those reports relate to objective disease measures across the disease spectrum (i.e. cognitively normal, MCI, Alzheimer's disease). A total of 1080 subjects with self‐ and/or informant‐rated Everyday Cognition questionnaires were included. Objective measures included cognitive functioning, structural brain atrophy, cerebrospinal fluid abnormalities, and a marker of amyloid deposition using positron emission tomography with [ 18 F]AV45 (florbetapir). Overall, informant‐report was consistently more associated with objective markers of disease than self‐report although self‐reported functional status may still have some utility in early disease.

AbstractBackgroundInexpensive, non‐invasive tools for assessing Alzheimer‐type pathophysiologies are needed. Computerized cognitive assessments are prime candidates.MethodsCognitively normal participants, aged 51–71, with magnetic resonance imaging, fluorodeoxyglucose‐positron emission tomography (FDG‐PET), amyloid PET, CogState computerized cognitive assessment, and standard neuropsychological tests were included. We first examined the association between the CogState battery and neuroimaging measures. We then compared that association to the one between standard neuropsychological z‐scores and neuroimaging.ResultsSlower reaction times for CogState Identification and One Back, and lower memory and attention z‐scores, were associated (P < .05) with FDG‐PET hypometabolism. Slower time on the Groton Maze Learning Task and worse One Card Learning accuracy were associated (P < .05) with smaller hippocampal volumes. There were no associations with amyloid PET. Associations of CogState and neuropsychological Z‐scores with neuroimaging were small and of a similar magnitude.ConclusionsCogState subtests were cross‐sectionally comparable to standard neuropsychological tests in their relatively weak associations with neurodegeneration imaging markers.

ABSTRACT Insulin resistance causes diminished glucose uptake in similar regions of the brain in Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2). Brain tissue studies suggested that insulin resistance is caused by low insulin receptor signaling attributable to its abnormal association with more phospho (P)‐serine‐type 1 insulin receptor substrate (IRS‐1) and less P‐tyrosine‐IRS‐1. Plasma exosomes enriched for neural sources by immunoabsorption were obtained once from 26 patients with AD, 20 patients with DM2, 16 patients with frontotemporal dementia (FTD), and matched case control subjects. At 2 time points, they were obtained from 22 others when cognitively normal and 1 to 10 yr later when diagnosed with AD. Mean exosomal levels of extracted P‐serine 312‐IRS‐1 and P‐pan‐tyrosine‐IRS‐1 by ELISA and the ratio of P‐serine 312‐IRS‐1 to P‐pan‐tyrosine‐IRS‐1 (insulin resistance factor, R) for AD and DM2 and P‐serine 312‐IRS‐1 and R for FTD were significantly different from those for case control subjects. The levels of R for AD were significandy higher than those for DM2 or FTD. Stepwise discriminant modeling showed correct classification of 100% of patients with AD, 97.5% of patients with DM2, and 84% of patients with FTD. In longitudinal studies of 22 patients with AD, exosomal levels of P‐serine 312‐IRS‐1, P‐pan‐tyrosine‐IRS‐1, and R were significantly different 1 to 10 yr before and at the time of diagnosis compared with control subjects. Insulin resistance reflected in R values from this blood test is higher for patients with AD, DM2, and FTD than case control subjects; higher for patients with AD than patients with DM2 or FTD; and accurately predicts development of AD up to 10 yr prior to clinical onset.—Kapogiannis, D., Boxer, A., Schwartz, J. B., Abner, E. L., Biragyn, A., Masharani, U., Frassetto, L., Petersen, R. C., Miller, B. L., Goetzl, E. J. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural‐derived blood exosomes of preclinical Alzheimer's disease. FASEB J . 29, 589‐596 (2015). www.fasebj.org

AbstractWith increasing numbers of people with Alzheimer's and other dementias across the globe, many countries have developed national plans to deal with the resulting challenges. In the United States, the National Alzheimer's Project Act, signed into law in 2011, required the creation of such a plan with annual updates thereafter. Pursuant to this, the US Department of Health and Human Services (HHS) released the National Plan to Address Alzheimer's Disease in 2012, including an ambitious research goal of preventing and effectively treating Alzheimer's disease by 2025. To guide investments, activities, and the measurement of progress toward achieving this 2025 goal, in its first annual plan update (2013) HHS also incorporated into the plan a set of short, medium and long‐term milestones. HHS further committed to updating these milestones on an ongoing basis to account for progress and setbacks, and emerging opportunities and obstacles. To assist HHS as it updates these milestones, the Alzheimer's Association convened a National Plan Milestone Workgroup consisting of scientific experts representing all areas of Alzheimer's and dementia research. The workgroup evaluated each milestone and made recommendations to ensure that they collectively constitute an adequate work plan for reaching the goal of preventing and effectively treating Alzheimer's by 2025. This report presents these Workgroup recommendations.

IntroductionLittle is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer's disease (AD).MethodsWe analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n = 405, 24 months) and (2) simvastatin in mild to moderate AD (n = 225, 18 months).ResultsBaseline plasma Aβ was not related to cognitive or clinical progression. We observed a decrease in plasma Aβ40 and 42 among apolipoprotein E epsilon 4 (APOE ε4) carriers relative to noncarriers in the mild cognitive impairment trial. Patients treated with simvastatin showed a significant increase in Aβ compared with placebo. We found significant storage time effects and considerable plate‐to‐plate variation.DiscussionWe found no support for the utility of plasma Aβ as a prognostic factor or correlate of cognitive change. Analysis of stored specimens requires careful standardization and experimental design, but plasma Aβ may prove useful in pharmacodynamic studies of antiamyloid drugs.