Abstract

White matter (WM) tracts play a crucial role in enabling efficient neural transmission, which is essential for optimal brain function. Once overlooked, WM is now recognized for its constant remodeling throughout life, responding to both enriching and adverse factors. These alterations in WM microstructure can enhance cognitive and motor performance through more efficient transmission, or conversely, contribute to functional decline. Notably, WM changes are among the earliest alterations observed in neurodegenerative disorders such as Alzheimer’s disease (AD) and other dementias, highlighting the potential for WM as a target for early interventions.
However, our current knowledge is limited regarding: 1) the time scales at which plastic changes occur and 2) the biological mechanisms driving microstructural changes. This is largely due to the physiological non-specificity of commonly used neuroimaging techniques and the predominantly univariate focus of most studies in the field.
This Ph.D. thesis presents four original studies focused on investigating early WM changes in health and disease. The first study examines longitudinal plastic changes in WM following short-term motor learning in young, healthy participants, providing insights into activity-dependent WM remodeling. The second study introduces MVComp, an open-source toolbox developed to compute a multivariate distance metric—the Mahalanobis distance (D2). MVComp allows the integration of various imaging features, yielding individualized scores of deviation from a reference.
The latter half of the thesis focused on the investigation of early pathological changes in WM among older adults at risk of dementia, using the multivariate framework developed in study two. The third study explored the relationship between WM alterations and cardiometabolic risk factors in older adults with a family history of AD. Individuals at higher genetic risk of AD (Apolipoprotein E (ApoE) ε4) displayed a distinct pattern where LDL-cholesterol negatively impacted WM health, with myelination changes as the primary underlying mechanism. Finally, the fourth study assessed WM deviations in coronary artery disease patients, linking higher D2 scores in specific arterial territories to lower fitness levels and poorer cognition.
Together, these findings underscore the dynamic nature of WM changes and demonstrate that multivariate approaches offer a comprehensive characterization, shedding light on the biological mechanisms at play.