White matter regions with low microstructure in young adults spatially coincide with white matter hyperintensities in older adults

Microstructural and macrostructural white matter damage occurs frequently with aging, is associated with negative health outcomes, and can be imaged non-invasively as fractional anisotropy (FA) and white matter hyperintensities (WMH), respectively. The extent to which diminished microstructure precedes or results from macrostructural white matter damage is poorly understood. This study evaluated the hypothesis that white matter areas with normatively lower microstructure in young adults are most susceptible to develop WMH in older adults. Forty-nine younger participants (age = 25.8 ± 2.8 years) underwent diffusion-weighted imaging (DWI), and 557 older participants (age = 73.9 ± 5.7 years) underwent DWI and T2-weighted magnetic resonance imaging (MRI). In older adults, WMH had a mostly periventricular distribution with higher frequency in frontal regions. We found lower FA in areas of frank WMH compared to normal-appearing white matter (NAWM) in older adults. Then, to determine if areas of normatively lower white matter microstructure spatially overlap with areas that frequently develop macrostructural damage in older age, we created a WMH frequency map in which each voxel represented the percentage of older adults with a WMH in that voxel. We found lower normative FA in young adults with regions frequently segmented as WMH in older adults. We conclude that low white matter microstructure is observed in areas of white matter macrostructural damage, but white matter microstructure is also normatively low (i.e., at ages 20–30) in regions with high WMH frequency, prior to white matter macrostructural damage

Relative contribution of white matter hyperintensity to amyloid and neurodegeneration in cognitive decline over time or clinical diagnoses in a diverse, community‐based cohort of older adults

Background: The 2018 NIA‐AA Alzheimer’s disease (AD) research framework moves towards a multiple biomarker approach to explain AD development and progression more fully. This research framework has the flexibility to incorporate various biomarkers into a full or partial amyloid‐tau‐neurodegeneration (A/T/N) profile. The objective of this study was to determine the relative contribution of white matter hyperintensities (WMH) to amyloid and neurodegeneration on cognition in a diverse, community‐based cohort of older adults. Method: A subset of cognitively healthy participants (n=155; age=69‐99yrs; 65% women, 30%/44%/26% Non‐Hispanic White/Non‐Hispanic Black/Hispanic) from the Washington Heights‐Inwood Columbia Aging Project underwent baseline Florbetaben PET (amyloid SUVR), T1‐weighted (cortical thickness[mm]) and T2‐weighted FLAIR MRI (WMH volume[cm3]), as well as subsequent neuropsychological assessments and consensus diagnoses every 1.5 years (up to 6 visits). Linear mixed effects models were used to test for change over time in language, memory, executive function, and visuospatial ability, while cox proportional hazard models were used to test for risk of developing MCI or AD. Biomarkers of interest included amyloid, cortical thickness, and WMH, adjusted for demographics (sex/gender, race/ethnicity, education). Interactions between biomarkers and time (e.g., slope differences) were evaluated as significant below 0.1. Result: In A/N/V models, higher amyloid was associated with faster rates of decline in language (B [95%CI]: ‐0.08 [‐0.13, ‐0.02]), memory (‐0.13 [‐0.21, ‐0.05]), and visuospatial ability (‐0.05 [‐0.12, 0.01]), higher WMH was associated with faster rates of decline in executive function (‐0.05 [‐0.11, 0.009]) and visuospatial ability (‐0.02 [‐0.05, 0.005]), and lower cortical thickness was associated with lower executive function scores (1.6 [0.10, 3.0]). Individuals were more likely to develop MCI or AD with higher amyloid (Hazard Ratio=4.2, [1.1, 15.9]), but not with higher WMH (1.2 [0.83, 1.7]) or lower cortical thickness (0.03 [4E‐4, 2]). Conclusion: In this imaging subsample of older community‐dwelling adults, cognitive decline is differentially associated by domain with amyloid or vascular burden, while broader, multi‐domain cognitive impairment necessary for MCI or AD diagnoses is associated with amyloid, one of the hallmark AD pathologies. Results support the use of complementary information from biomarker profiles, including traditional AD, vascular, and neurodegenerative biomarkers, to investigate AD and related dementias

Regional white matter hyperintensities predict Alzheimer’s‐like neurodegeneration

BackgroundSmall vessel cerebrovascular disease, best visualized as white matter hyperintensities (WMH) on T2‐weighted MRI scanning, is associated with cognitive decline and increases risk for clinical Alzheimer’s disease (AD), particularly when it is distributed in posterior brain regions. There is much debate, however, about whether cerebrovascular disease represents a comorbidity or whether it is more fundamental to the pathogenesis of AD. The purpose of this study was to examine whether regional WMH volume predicts neurodegeneration, operationally‐defined as longitudinal decline in cortical thickness, among community‐dwelling older adults.MethodTwo hundred thirty‐eight participants(73.18+5.23 years old, 60% women, 35% APOE‐ε4 carriers, 30% non‐Hispanic White/32% Hispanic/38% Black, 14% with MCI) from the Washington Heights Inwood Columbia Aging Project (WHICAP) received high‐resolution structural 3T MRI scans at baseline and 4.09+1.57 years later. Regional WMH volume was derived with in house developed software and the FreeSurfer (v6.0) longitudinal processing stream was used to calculate change in cortical thickness. Using QDEC, we examined the relationship of total and regional WMH volume with annualized rate of decline in cortical thickness (symmetrized across the two visits) with vertex‐wise general linear models adjusted for age, sex, and APOE status. We additionally adjusted for a baseline marker of AD‐related atrophy (entorhinal cortex thickness).ResultBaseline total WMH volume predicted widespread cortical atrophy in a pattern consistent with AD‐associated atrophy, which included parahippocampal, temporal, and parietal regions. When examined regionally, the effects were most prominent for parietal lobe WMH, which predicted entorhinal cortex atrophy predominantly. Adjusting for baseline entorhinal cortical thickness did not alter the findings. In stratified analyses, the effects were strongest among Hispanic and Black participants compared with White participants, and similar across APOE groups.ConclusionWhite matter hyperintensity volume, especially in the parietal lobes, predicts Alzheimer’s‐like neurodegeneration, suggesting that small vessel cerebrovascular disease contributes to the ‘N’ aspect of the ‘A/T/N’ pathogenic models of AD. The results were independent of and stronger than baseline atrophy measures, suggesting that WMH are not simply a result of neurodegeneration. These effects may manifest differently across racial/ethnic groups, with small vessel cerebrovascular disease playing a more prominent role in future neurodegeneration among racial/ethnic minorities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163839/1/alz044776.pd