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

Abstract

AbstractBackgroundSeveral 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.