Neuropathological Basis of Age-Associated Brain Atrophy (P05.053)

Abstract

Objective: To examine the association between brain volume trajectories measured during life and postmortem neuropathology in the oldest old. Background Better understanding of the neuropathological basis of age-related brain atrophy is needed to optimize use of brain volume as a biomarker in Alzheimer disease studies. Design/Methods: Seventy-one participants of a longitudinal aging study were followed until death. All volunteers had ≥ 2 MRI scans, with the last scan within 36 months of death, and cognitive evaluations within 24 months of death. Mixed effects models, which allow random intercept and age slope, with each brain volume (ventricular, total brain and hippocampal) as the outcome were run with the following dependent variables: Braak stage (3 categories), senile plaque burden (2 categories), age at each MRI assessment, presence of gross infarcts, APOE genotype (coded as the presence of one or more e4 versus none), cognitive status at the last evaluation before death (cognitively impaired versus not cognitively impaired), presence of Lewy Bodies and terms for the interactions of these variables with time (age at each MRI assessment). Age at death and duration of follow-up were also controlled for as potential confounders. Results: The mean age at death was 94.72 (±5.46) years old. Of the 71 subjects 44 developed cognitive impairment before death. In the mixed-effects models presence of infarcts, having a high Braak or senile plaque score, and the e4 allele were all significantly associated with greater ventricular enlargement over time independent of cognitive status. Presence of infarcts was also significantly associated with greater total brain atrophy. None of the pathological measures was significantly associated with hippocampal atrophy. Conclusions: Ventricular enlargement over time, is a good marker of accruing age-associated neuropathology independent of the presence of cognitive impairment. Presence of high burdens of both neurofibrillary tangles and senile plaques correlate with ventricular enlargement over time. Supported by: Funding from the Research & Development Office of the Department of Veterans Affairs (Career Development Award and Merit Review Grant) and the National Institute on Aging, National Institute of Health, AG08017. Disclosure: Dr. Erten-Lyons has nothing to disclose. Dr. Woltjer has nothing to disclose. Dr. Dodge has nothing to disclose. Dr. Silbert has nothing to disclose. Dr. Kramer has nothing to disclose. Dr. Kaye has received personal compensation for activities with Eli Lilly & Company as a participant on a data safety and monitoring board. Dr. Kaye has received research support from Elan Corporation, Danone Medical, Bristol-Myers Squibb Company, Satoris, and Intel.