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BackgroundStudies have investigated white matter microstructure in relation to late-life cognitive impairments, with fractional anisotropy (FA) and mean diffusivity (MD) measures thought to capture demyelination and axonal degradation. However, new post-processing methods allow isolation of free water (FW), which captures extracellular fluid contributions such as atrophy and neuroinflammation, from tissue components. FW also appears to be highly relevant to late-life cognitive impairment. Here, we evaluated whether executive functions are associated with FW, and FA and MD corrected for FW (FAFWcorr and MDFWcorr).MethodWe examined 489 non-demented men in the Vietnam Era Twin Study of Aging (VETSA) at mean age 68. Two latent factors capturing 'common executive function' and 'working-memory specific' processes were estimated based on 6 tasks. Analyses focused on 11 cortical white matter tracts across three metrics: FW, FAFWcorr, and MDFWcorr.ResultsBetter 'common executive function' was associated with lower FW across 9 of the 11 tracts. There were no significant associations with intracellular metrics after false discovery rate correction. Effects also appeared driven by individuals with MCI (13.7% of the sample). Working memory-specific tasks showed some associations with FAFWcorr, including the triangularis portion of the inferior frontal gyrus. There was no evidence that cognitive reserve (i.e., general cognitive ability assessed in early adulthood) moderated these associations between executive function and FW or FA.DiscussionExecutive function abilities in early old age are associated primarily with extracellular fluid (FW) as opposed to white matter (FAFWcorr or MDFWcorr). Moderation analyses suggested cognitive reserve does not play a strong role in these associations, at least in this sample of non-demented men.

Objective: Abnormal white matter (AWM) on magnetic resonance imaging is associated with cognitive performance in older adults. We explored cognitive associations with AWM during late-midlife. Method: Participants were community-dwelling men (n = 242; M = 61.90 years; range = 56-66). Linear-mixed effects regression models examined associations of total, periventricular, and deep AWM with cognitive performance, controlling for multiple comparisons. Models considering specific cognitive domains controlled for current general cognitive ability (GCA). We hypothesized that total AWM would be associated with worse processing speed, executive function, and current GCA; deep AWM would correlate with GCA and periventricular AWM would relate to specific cognitive abilities. We also assessed the potential influence of cognitive reserve by examining a moderation effect of early life (mean age of 20) cognition. Results: Greater total and deep AWM were associated with poorer current GCA. Periventricular AWM was associated with worse executive function, working memory, and episodic memory. When periventricular and deep AWM were modeled simultaneously, both retained their respective significant associations with cognitive performance. Cognitive reserve did not moderate associations. Conclusions: Our findings suggest that AWM contributes to poorer cognitive function in late-midlife. Examining only total AWM may obscure the potential differential impact of regional AWM. Separating total AWM into subtypes while controlling for current GCA revealed a dissociation in relationships with cognitive performance; deep AWM was associated with nonspecific cognitive ability whereas periventricular AWM was associated with specific frontal-related abilities and memory. Management of vascular or other risk factors that may increase the risk of AWM should begin during or before early late-midlife. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

White matter disease in the brain increases with age and cardiovascular disease, emerging in midlife, and these associations may be influenced by both genetic and environmental factors. We examined the frequency, distribution, and heritability of abnormal white matter and its association with hypertension in 395 middle-aged male twins (61.9 ± 2.6 years) from the Vietnam Era Twin Study of Aging, 67% of whom were hypertensive. A multi-channel segmentation approach estimated abnormal regions within the white matter. Using multivariable regression models, we characterized the frequency distribution of abnormal white matter in midlife and investigated associations with hypertension and Apolipoprotein E-ε4 status and the impact of duration and control of hypertension. Then, using the classical twin design, we estimated abnormal white matter heritability and the extent of shared genetic overlap with blood pressure. Abnormal white matter was predominantly located in periventricular and deep parietal and frontal regions; associated with age (t = 1.9, p = 0.05) and hypertension (t = 2.9, p = 0.004), but not Apolipoprotein ε4 status; and was greater in those with uncontrolled hypertension relative to controlled (t = 3.0, p = 0.003) and normotensive (t = 4.0, p = 0.0001) groups, suggesting that abnormal white matter may reflect currently active cerebrovascular effects. Abnormal white matter was highly heritable (a2 = 0.81) and shared some genetic influences with systolic blood pressure (rA = 0.26), although there was evidence for distinct genetic contributions and unique environmental influences. Future longitudinal research will shed light on factors impacting white matter disease presentation, progression, and potential recovery., Highlights • White matter abnormalities were highly heritable and associated with hypertension. • Only some genetic influences were shared with systolic blood pressure. • There is evidence for unique environmental influences unrelated to hypertension. • Poorly controlled hypertension was associated with more abnormal white matter. • Abnormal white matter may reflect currently active cerebrovascular effects.