Differential tractography suggests a "left-to-whole" white matter degeneration pattern in aging

We aim to investigate the progression of aging-related white matter (WM) degeneration, measured by fractional anisotropy (FA), in cognitively normal, healthy individuals over a long-term follow-up of 8.68 years. The study population consisted of 177 right-handed, healthy participants aged 21–89 years. Participants underwent cognitive assessments and MRI scans at three time points (Wave 1 = baseline; Wave 2 = approximately 4 years after Wave 1; Wave 3 = approximately 8 years after Wave 1). Three distinct Differential Tractography Analyses (DTA) were performed using the “Wave – previous Wave” scheme to evaluate long-term (Wave 3 – Wave 1) and short-term (Wave 2 – Wave 1 and Wave 3 – Wave 2) changes in FA. Correlational tractography with a nonparametric Spearman partial correlation was used for each DTA to visualize WM pathways that shown longitudinal change in FA, and the effects of covariates (including age and sex) were controlled for using a multiple regression model. For each analysis, a T-score threshold of 3.5 was applied in the fiber tracking algorithm, and a p-value corrected for False Discovery Rate (p-FDR) threshold of 0.001 was used to select tracks. FA decreased significantly over time in all three DTA (p-FDR < 0.001), showing a distinct left-dominant pattern characterized by initial involvement of the left hemisphere (mainly the temporal lobe) and later spreading to the entire brain. The results of this study suggest a “left-to-whole” pattern of WM degeneration during physiological aging, which may partially explain the loss of brain lateralization observed in aging.