Executive Functions and Episodic Memory are Associated with Extracellular White Matter Microstructure in Early Old Age

Abstract

BackgroundCortical surface area, cortical thickness, and hippocampal volume are well‐studied in relation to later life cognitive impairments and AD. Fewer studies have investigated how white mater microstructure relates to cognition in late life. Existing work has focused on fractional anisotropy (FA) and mean diffusivity (MD) measures that are thought to capture demyelination and axonal degradation and relate to cognitive decline in normal aging and AD. However, these measures are susceptible to partial volume effects. Here, we evaluated whether executive function and memory are associated with FA and MD after deploying a free‐water (FW) elimination post‐processing method that separates fluid (FW) from tissue (FW‐corrected FA and MD).MethodWe examined 489 non‐demented men in the Vietnam Era Twin Study of Aging (VETSA) at mean age 68. Executive function was based on 6 tasks spanning inhibition, shifting, and working memory. Memory was based on 7 subtests from the Logical Memory, Visual Reproductions, and California Verbal Learning tests. Analyses focused on 11 cortical white matter tracts across three metrics: FW, FW‐corrected FA, and FW‐corrected MD. Analyses controlled for age, scanner, diabetes, hypertension, race, and ethnicity. We used false discovery rate to account for multiple testing.ResultBetter executive functioning was associated with lower FW across all 11 tracts. Better memory was associated with lower FW in 3 tracts: the superior longitudinal fasciculus (SLF) and two sections of the inferior frontal gyrus (opercularis and triangularis). Despite widespread differences with FW, there was only one significant association with intracellular metrics (executive function and FW‐corrected FA in the SLF). Finally, indicators of cognitive reserve (education or general cognitive ability assessed in early adulthood) did not moderate these associations between cognition and white matter microstructure.ConclusionOur findings leveraged a post‐processing method that separates extracellular fluid (FW) from intracellular tissue (FA, MD). We found that cognitive abilities in early old age are associated primarily with extracellular white matter microstructure (FW), which demonstrated global associations with executive function. Finally, there was no evidence that indicators of cognitive reserve influenced the strength of the association between cognition and white matter, at least in this sample of non‐demented men.