Leveraging longitudinal, multi‐site diffusion MRI data in conjunction with free‐water analysis to characterize patterns of white matter neurodegeneration in aging

Abstract

BackgroundSeveral prior studies have used diffusion MRI to investigate the relationship between white matter microstructure and aging; however, many of these studies used conventional diffusion MRI measures and single site data. The goal of the study is to leverage multi‐site harmonized diffusion MRI data in conjunction with a novel post‐processing technique [i.e., free‐water (FW) correction] to quantify the aging related tract‐specific changes in white matter microstructure.MethodThe dataset used in this study was collated using several well‐established longitudinal cohorts of aging [Alzheimer’s Neuroimaging Initiative (ADNI), Baltimore Longitudinal Study of Aging (BLSA), Vanderbilt Memory & Aging Project (VMAP)]. In total, this dataset included 1,909 participants (mean age at baseline: 72±9 years, 59% female) and 4,844 imaging sessions (mean number of visits: 4 ± 2 years, interval range: 1–12 years). Data was processed using standard approaches and uncorrected fractional anisotropy (FAU) was quantified with seven white matter tractography atlases (see Figure 1A). Data was then post‐processed using the FW correction technique and FW and FW‐corrected FA (FAT) values were quantified. Data were then harmonized using the ComBat technique and linear mixed‐effects regression was conducted on each microstructural measure, covarying for age at baseline, sex, cognitive status, education, APOE‐ε4 carrier status, and APOE‐ε2 carrier status. The effect of aging was modelled using an Age_at_Baseline x Interval interaction term.ResultAge was associated with lower FAU in all seven tracts (pFDR range: 4.77x10‐10 to ‐0.01). In the FW analysis, age was associated with higher FW in all seven tracts (pFDR range: 7.81x10‐12 to 1.33x10‐6). For FAT, however, age was only associated with lower FAT in the limbic tracts (pFDR=0.024) in addition to the occipital (pFDR=1.19x10‐8), parietal (pFDR=2.32x10‐4), and prefrontal (pFDR=0.024) TC tracts. Figure 1B‐D illustrates our findings.ConclusionThis study suggests that while there are global associations with FAU and age, these associations are attenuated once correcting for partial volume effects. Leveraging FW analysis, we found a global association with FW and age, whereby age is associated with higher FW. Further, we found that age is associated with reductions in FAT in the limbic and occipital/parietal/prefrontal TC tracts.

Sex, racial, andAPOE-ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer’s disease

“…Projection tracts connect the cortex to subcortical structures and help integrate sensory, motor, and cognitive functions.Our findings support previous cross-sectional work that found that females had lower FA values in sensory and motor projections 10 and a greater decline in FA over time compared to males. 11 Previous work has consistently found that association tracts are affected in the aging process 10,28 and these tracts show a greater decline in FA and FA FWcorr in individuals with cognitive impairment relative to cognitively unimpaired adults. 28,53 While some studies have shown that projection fibers are also associated with abnormal cognitive aging, these associations are less robust.…”

“…11 Previous work has consistently found that association tracts are affected in the aging process 10,28 and these tracts show a greater decline in FA and FA FWcorr in individuals with cognitive impairment relative to cognitively unimpaired adults. 28,53 While some studies have shown that projection fibers are also associated with abnormal cognitive aging, these associations are less robust. 10,28,49 Given that females are disproportionately affected by AD, the observed sex differences in FA FWcorr in our study suggest that white matter integrity may contribute to this disparity.…”

“…28,53 While some studies have shown that projection fibers are also associated with abnormal cognitive aging, these associations are less robust. 10,28,49 Given that females are disproportionately affected by AD, the observed sex differences in FA FWcorr in our study suggest that white matter integrity may contribute to this disparity. However, we also found that in tracts with sex differences in FW, females tended to have lower values than males longitudinally.…”

“…Consistent with prior work, 28,48-51 we used freely accessible tractography templates (https://github.com/VUMC-VMAC/Tractography_Templates) to assess the white matter microstructure in our cohort ( Figure 1 ). In total, we used 48 tract templates from seven different tract types, including association, limbic, projection, motor transcallosal, occipital transcallosal, parietal transcallosal, and prefrontal transcallosal areas.…”

“…Importantly, FW metrics are considered more sensitive to abnormal brain aging. 28-30 While previous studies have found loss of white matter integrity in limbic, association, and transcallosal (TC) tracts 28,29,31-35 associated with cognitive impairment and AD, there has yet to be a large-scale analysis leveraging FW measures to understand how sex, race, and APOE- ε4 carrier status are associated with longitudinal white matter integrity.…”