Coronary Artery Disease Is Linked with Demyelination and Iron Deposition in White Matter Watershed Areas

Coronary artery disease is associated with white matter alterations. However, the biological basis of these changes remains unclear, specifically in normal-appearing white matter. Myelin and iron content are crucial measures of white matter health and can be measured with quantitative MRI. This study investigated whether myelin and iron alterations occur in coronary artery disease, and their relationship with cognition. In this cross-sectional study, 46 individuals with coronary artery disease and 40 healthy controls aged > 50 years, with normal cognition underwent 3T MRI and cognitive assessments. Quantitative MRI metrics (susceptibility, magnetization transfer saturation (MTsat), R2* and R1 relaxation rates) were calculated in the border zones between adjacent arterial territories (watershed regions) and in the areas outside these borders (non-watershed regions) in normal-appearing white matter. Relative to controls, the coronary artery disease group showed lower myelin and higher iron content, as measured by lower MTsat and R1, and higher susceptibility specifically in watershed regions. Importantly, these microstructural alterations were associated with poorer cognitive performance in the coronary artery disease group with lower MTsat and R1 related to poorer global cognition and with higher magnetic susceptibility with poorer verbal memory. These findings suggest that coronary artery disease is associated with demyelination and iron deposition in normal-appearing white matter, most prominently in watershed regions, which are known for their susceptibility to stroke. The association of these microstructural alterations with cognition highlights the role of normal-appearing white matter as a key vulnerable region and a promising focus for future mechanistic and therapeutic studies.