The HOPE4MCI study: A randomized double-blind assessment of AGB101 for the treatment of MCI due to AD.

INTRODUCTION: In addition to the accumulation of amyloid plaques and neurofibrillary tangles, the presence of excess neural activity is a pathological hallmark of Alzheimer's disease (AD) and a prognostic indicator for progression of AD pathology and clinical/cognitive worsening in mild cognitive impairment due to Alzheimer's disease (MCI due to AD). The HOPE4MCI clinical study tested the efficacy of a therapeutic with demonstrated ability to normalize heightened neural activity in the hippocampus in a randomized controlled trial of 78 weeks duration in patients with MCI due to AD. METHODS: One hundred and sixty-four participants were randomized to placebo (n = 83) or AGB101 (n = 81), an extended-release formulation of low dose (220 mg) levetiracetam. The primary endpoint was the change in Clinical Dementia Rating Scale Sum of Boxes score (CDR-SB) comparing follow up at 18 months to baseline. The goal of the primary efficacy analysis was to estimate the difference between the AGB101 and placebo arms in the mean change of the primary endpoint. RESULTS: The mean change in CDR-SB was estimated to be 1.12 (95% confidence interval [CI]: 0.66, 1.69) for the AGB101 arm and 1.22 (95% CI: 0.75, 1.78) for the placebo arm. The estimated difference between arms is -0.10 (95% CI: -0.85, 0.58), which was not statistically significant. In a prespecified analysis, the difference was -0.45 (95% CI: -1.43, 0.53) for ApoE-4 noncarriers and -0.10 (95% CI: -0.92, 0.72) for apolipoprotein E (ApoE)-4 carriers. DISCUSSION: The possibility that ApoE-4 carriers and noncarriers will respond differently to therapeutic intervention is consistent with recently reported findings from biologics and the present results show further testing of AGB101 in patients with MCI due to AD who are noncarriers of the ApoeE-4 allele is warranted. Conclusions from the HOPE4MCI study are limited primarily due to the small sample size and results can only be regarded as a guide to future research.

Dementia in late-onset epilepsy: The Atherosclerosis Risk in Communities study.

OBJECTIVE: To determine the risk of dementia after the development of late-onset epilepsy. METHODS: We used data from the Atherosclerosis Risk in Communities (ARIC) cohort study, which started in 1987 to 1989 with 15,792 mostly Black and White men and women from 4 US communities. We identified late-onset epilepsy (LOE; seizures starting at age 67 or later) from linked Medicare claims data. We used a Cox proportional hazards regression model to evaluate associations between LOE and dementia through 2017 as ascertained from neuropsychological testing, interviews, and hospital discharge surveillance, and we used multinomial logistic regression to assess the risk of dementia and mild cognitive impairment in the subset with full neuropsychological assessments available. We adjusted for demographics and vascular and Alzheimer disease risk factors. RESULTS: Of 9,033 ARIC participants with sufficient Medicare coverage data (4,980 [55.1%] female, 1993 [22.1%] Black), 671 met the definition of LOE. Two hundred seventy-nine (41.6%) participants with and 1,408 (16.8%) without LOE developed dementia (p < 0.001). After a diagnosis of LOE, the adjusted hazard ratio for developing subsequent dementia was 3.05 (95% confidence interval 2.65-3.51). The median time to dementia ascertainment after the onset of LOE was 3.66 years (quartile 1-3, 1.28-8.28 years). INTERPRETATION: The risk of incident dementia is substantially elevated in individuals with LOE. Further work is needed to explore causes for the increased risk of dementia in this growing population.

Impact of the Baltimore Experience Corps Trial on cortical and hippocampal volumes.

INTRODUCTION: There is a substantial interest in identifying interventions that can protect and buffer older adults from atrophy in the cortex and particularly, the hippocampus, a region important to memory. We report the 2-year effects of a randomized controlled trial of an intergenerational social health promotion program on older men's and women's brain volumes. METHODS: The Brain Health Study simultaneously enrolled, evaluated, and randomized 111 men and women (58 interventions; 53 controls) within the Baltimore Experience Corps Trial to evaluate the intervention impact on biomarkers of brain health at baseline and annual follow-ups during the 2-year trial exposure. RESULTS: Intention-to-treat analyses on cortical and hippocampal volumes for full and sex-stratified samples revealed program-specific increases in volumes that reached significance in men only (P's ≤ .04). Although men in the control arm exhibited age-related declines for 2 years, men in the Experience Corps arm showed a 0.7% to 1.6% increase in brain volumes. Women also exhibited modest intervention-specific gains of 0.3% to 0.54% by the second year of exposure that contrasted with declines of about 1% among women in the control group. DISCUSSION: These findings showed that purposeful activity embedded within a social health promotion program halted and, in men, reversed declines in brain volume in regions vulnerable to dementia. CLINICAL TRIAL REGISTRATION: NCT0038.

Assessment of cognition in mild cognitive impairment: a comparative study.

The demand for rapidly administered, sensitive, and reliable cognitive assessments that are specifically designed for identifying individuals in the earliest stages of cognitive decline (and to measure subtle change over time) has escalated as the emphasis in Alzheimer's disease clinical research has shifted from clinical diagnosis and treatment toward the goal of developing presymptomatic neuroprotective therapies. To meet these changing clinical requirements, cognitive measures or tailored batteries of tests must be validated and determined to be fit-for-use for the discrimination between cognitively healthy individuals and persons who are experiencing very subtle cognitive changes that likely signal the emergence of early mild cognitive impairment. We sought to collect and review data systematically from a wide variety of (mostly computer-administered) cognitive measures, all of which are currently marketed or distributed with the claims that these instruments are sensitive and reliable for the early identification of disease or, if untested for this purpose, are promising tools based on other variables. The survey responses for 16 measures/batteries are presented in brief in this review; full survey responses and summary tables are archived and publicly available on the Campaign to Prevent Alzheimer's Disease by 2020 Web site (http://pad2020.org). A decision tree diagram highlighting critical decision points for selecting measures to meet varying clinical trials requirements has also been provided. Ultimately, the survey questionnaire, framework, and decision guidelines provided in this review should remain as useful aids for the evaluation of any new or updated sets of instruments in the years to come.

Assessment of cognition in early dementia.

Better tools for assessing cognitive impairment in the early stages of Alzheimer's disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer's Association convened a meeting to discuss state of the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real-world situations in order to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.

A roadmap for the prevention of dementia II: Leon Thal Symposium 2008.

This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.