Baseline Findings of PreventE4: A Double-Blind Placebo Controlled Clinical Trial Testing High Dose DHA in APOE4 Carriers before the Onset of Dementia.

INTRODUCTION: Lower blood levels of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) are correlated with worse cognitive functions, particularly among APOE ε4 carriers. Whether DHA supplementation in APOE ε4 carriers with limited DHA consumption and dementia risk factors can delay or slow down disease progression when started before the onset of clinical dementia is not known. METHODS: PreventE4 is a double-blind, single site, randomized, placebo-controlled trial in cognitively unimpaired individuals with limited omega-3 consumption and dementia risk factors (n=368). Its objectives are to determine (1) whether carrying the APOE ε4 allele is associated with lower delivery of DHA to the brain; and (2) whether high dose DHA supplementation affects brain imaging biomarkers of AD and cognitive function. RESULTS: 365 cognitively unimpaired individuals between 55 and 80 (mean age 66) were randomized to 2 grams of DHA per day or identically appearing placebo for a period of 2 years. Half the participants were asked to complete lumbar punctures at baseline and 6-month visits to obtain cerebrospinal fluid (CSF). The primary trial outcome measure is the change in CSF DHA to arachidonic acid ratio after 6 months of the intervention (n=181). Secondary trial outcomes include the change in functional and structural connectivity using resting state functional MRI at 24 months (n=365). Exploratory outcomes include the change in Repeatable Battery of the Assessment of Neuropsychological Status at 24 months (n=365). CONCLUSIONS: Findings from PreventE4 will clarify the brain delivery of DHA in individuals carrying the APOE ε4 allele with implications for dementia prevention strategies. Trial was registered as NCT03613844.

FDDNP binding using MR derived cortical surface maps.

OBJECTIVES: To assess quantitatively the cortical pattern profile of regional FDDNP binding to beta-amyloid and neurofibrillary tangles on MR derived cortical maps, FDDNP PET images were corrected for movement and partial volume (PV), and optimized for kernel size. METHODS: FDDNP DVR PET images from 23 subjects (7 with Alzheimer's disease (AD), 6 with mild cognitive impairment and 10 controls) were obtained from Logan analysis using cerebellum as reference. A hemispheric cortical surface model for each subject was extracted from the MRI. The same transformations were applied to the FDDNP DVR PET images to map them into the same space. The cortical map with PV correction was calculated as the ratio of the DVR cortical surface and that of the simulated map, created from the mask derived from MRI and smoothed to the PET resolution. Discriminant analysis was used to order the FDDNP DVR cortical surfaces based on subjects' disease state. Linear regression was used to assess the rate of change of DVR vs. MMSE for each hemispheric cortical surface point. RESULTS: The FDDNP DVR cortical surface corrected for movement and PV had less hemispheric asymmetry. Optimal kernel size was determined to be 9 mm. The corrected cortical surface map of FDDNP DVR showed clear spatial pattern that was consistent with the known pathological progression of AD. CONCLUSION: Correcting for movement, PV as well as optimizing kernel size provide sensitive statistical analysis of FDDNP distribution which confirms in the living brain known pathology patterns earlier observed with cognitive decline with brain specimens.

Physical activity, inflammation, and volume of the aging brain.

Physical activity influences inflammation, and both affect brain structure and Alzheimer's disease (AD) risk. We hypothesized that older adults with greater reported physical activity intensity and lower serum levels of the inflammatory marker tumor necrosis factor α (TNFα) would have larger regional brain volumes on subsequent magnetic resonance imaging (MRI) scans. In 43 cognitively intact older adults (79.3±4.8 years) and 39 patients with AD (81.9±5.1 years at the time of MRI) participating in the Cardiovascular Health Study, we examined year-1 reported physical activity intensity, year-5 blood serum TNFα measures, and year-9 volumetric brain MRI scans. We examined how prior physical activity intensity and TNFα related to subsequent total and regional brain volumes. Physical activity intensity was measured using the modified Minnesota Leisure Time Physical Activities questionnaire at year 1 of the study, when all subjects included here were cognitively intact. Stability of measures was established for exercise intensity over 9 years and TNFα over 3 years in a subset of subjects who had these measurements at multiple time points. When considered together, more intense physical activity intensity and lower serum TNFα were both associated with greater total brain volume on follow-up MRI scans. TNFα, but not physical activity, was associated with regional volumes of the inferior parietal lobule, a region previously associated with inflammation in AD patients. Physical activity and TNFα may independently influence brain structure in older adults.

Reduced cortical thickness in hippocampal subregions among cognitively normal apolipoprotein E e4 carriers.

Our objective was to investigate whether asymptomatic carriers of apolipoprotein E epsilon4 [APOE-4] demonstrate pathological differences and atrophy in medial temporal lobe (MTL) subregions. We measured cortical thickness and volume in MTL subregions (hippocampal CA fields 1, 2 and 3; dentate gyrus; entorhinal cortex; subiculum; perirhinal cortex; parahippocampal cortex; and fusiform gyrus) using a high-resolution in-plane (0.4x0.4 mm) MRI sequence in 30 cognitively normal volunteers (14 APOE-4 carriers, 16 non-carriers, mean age 57 years). A cortical unfolding procedure maximized the visibility of this convoluted cortex, providing cortical ribbon thickness measures throughout individual subregions of the hippocampus and surrounding cortex. APOE-4 carriers had reduced cortical thickness compared with non-carriers in entorhinal cortex (ERC) and the subiculum (Sub), but not in the main hippocampal body or perirhinal cortex. Average cortical thickness was 14.8% lower (p=1.0e(- 6)) for ERC and 12.6% lower (p=6.8e(- 5)) for Sub in APOE-4 carriers. Standard volumetric measures of the same regions showed similar, but non-significant trends. Cognitively intact carriers of APOE-4 show regionally specific thinning of the cortical ribbon compared to APOE-3 carriers; cortical thickness may be a more sensitive measure of pathological differences in genetic risk subjects than standard volumetry.