Aging and white matter microstructure and macrostructure: a longitudinal multi-site diffusion MRI study of 1,184 participants

Abstract

Quantifying the microstructural and macrostructural geometrical features of the human brain's connections is necessary for understanding normal aging and disease. Here, we examine brain white matter diffusion magnetic resonance imaging data from one cross-sectional and two longitudinal datasets totaling in 1184 subjects and 2236 sessions of people aged 50-97 years. Data was drawn from well-established cohorts, including the Baltimore Longitudinal Study of Aging dataset, Cambridge Centre for Ageing Neuroscience dataset, and the Vanderbilt Memory & Aging Project. Quantifying 4 microstructural features and, for the first time, 11 macrostructure-based features of volume, area, and length across 120 white matter pathways, we apply linear mixed effect modeling to investigate changes in pathway-specific features over time, and document large age associations within white matter. Conventional diffusion tensor microstructure indices are the most age-sensitive measures, with positive age associations for diffusivities and negative age associations with anisotropies, with similar patterns observed across all pathways. Similarly, pathway shape measures also change with age, with negative age associations for most length, surface area, and volume-based features. A particularly novel finding of this study is that while trends were homogeneous throughout the brain for microstructure features, macrostructural features demonstrated heterogeneity across pathways, whereby several projection, thalamic, and commissural tracts exhibited more decline with age compared to association and limbic tracts. The findings from this large-scale study provide a comprehensive overview of the age-related decline in white matter and demonstrate that macrostructural features may be more sensitive to heterogeneous white matter decline. Therefore, leveraging macrostructural features may be useful for studying aging and could have widespread implications for a variety of neurodegenerative disorders.

Superficial white matter across the lifespan: volume, thickness, change, and relationship with cortical features

“…For example, well characterized waves of brain growth occur, with gray matter volume increasing until middle childhood (~ 6 years), followed by volume decreases from young adulthood and into late adulthood, while white matter reaches peak volume in adulthood (20-40 years), again leveling off and decreasing into late adulthood, with both tissues experiencing accelerated atrophy during late adulthood (Bethlehem et al, 2022; Hedman et al, 2012; Lebel et al, 2012; Scahill et al, 2003). Within each tissue type, changes are heterogenous, with different growth trajectories in different cortical regions and white matter pathways (Lebel et al, 2012; Lebel et al, 2008; Schilling et al, 2022a), and different associations with axonal myelination (Grydeland et al, 2019) and densities (Beck et al, 2021; Cox et al, 2016; Giorgio et al, 2010; Schilling et al, 2022a). These studies have driven hypotheses that aim to relate structure and function and determine structural mediators or cognition (Armstrong et al, 2020; Frangou et al, 2022; Winter et al, 2021), or may serve as a benchmark of normative trajectories that might be used to reveal patterns of abnormal variation or vulnerability in disease and disorder (Bethlehem et al, 2022; Fjell and Walhovd, 2010; Shafer et al, 2022).…”

White matter tract microstructure, macrostructure, and associated cortical gray matter morphology across the lifespan

“…These changes continue into adulthood with similar regional patterns [4,44]. In healthy aging, this pattern inverts, with decreases in FA and increase in diffusivities throughout much of the white matter [45][46][47][48], and more pronounced changes in frontal regions [7,[49][50][51]. These changes likely reflect degradation of white matter microstructure -including demyelination, disruption of axonal structure/coherence, and increased water content.…”

Short superficial white matter and aging: a longitudinal multi-site study of 1,293 subjects and 2,711 sessions

“…In the gray matter, structural MRI studies have shown heterogenous patterns of normal agerelated changes in cortical volume and thickness [23][24][25][26][27][28][29][30], with detectable differences in abnormal aging and disease [30][31][32][33][34][35]. In the white matter, diffusion tensor imaging (DTI) analysis has shown that fractional anisotropy (FA) is negatively associated with age and mean diffusivity (MD) is positively associated with age across several white matter pathways [36][37][38][39], and tractography analysis has shown that the volume and surface areas of many pathways decreases with age [40]. These findings have been attributed to myelin loss and/or decreased axonal densities and volumes.…”