Spatial coupling of enlarged perivascular spaces and white matter lesions across the Alzheimer's disease continuum.

Introduction: Emerging evidence suggests that impaired waste-clearance systems contribute to Alzheimer's disease pathogenesis, yet the etiology of clearance dysfunction markers, such as enlarged perivascular spaces, remains unclear. Because enlarged perivascular spaces and white matter lesions are both consequences of microvascular injury involving neuroinflammation and impaired cerebrovascular function, we hypothesize that these markers may be spatially coupled through local interstitial fluid stagnation, where impaired perivascular clearance associates with white matter injury. Methods: We assessed global perivascular space differences and correlations across diagnostic and biomarker-informed groups in the Alzheimer's Disease Neuroimaging Initiative dataset within whole brain, white matter, and basal ganglia regions, as well as within and outside of white matter lesions. To assess the spatial relationships between enlarged perivascular spaces and white matter lesions, we examined perivascular space distribution at distances away from white matter lesions. Results: Group-wise analyses revealed greater perivascular space counts and volumes within the white matter lesions and the basal ganglia in the mild cognitively impaired versus cognitively unimpaired group. Perivascular space counts and volumes and white matter lesion volumes correlated significantly within basal ganglia and white matter lesion regions across the cohort, with no differences in this relationship across diagnostic groups. Spatial analyses demonstrated greater perivascular space density within 5-15 mm of white matter lesions in mild cognitively impaired-amyloid positive and all amyloid positive groups compared to cognitively unimpaired-amyloid negative groups and all amyloid negative groups respectively, but reduced density ≥30 mm from white matter lesions in the Alzheimer's diagnosed-amyloid positive versus cognitively unimpaired-amyloid negative groups. White matter lesion volume consistently predicted perivascular spaces counts across all distance bins, with associations weakening as distance from white matter lesions increased. These results were all age and sex adjusted, indicating that the observed changes may reflect pathological processes beyond normal aging. Discussion: These findings demonstrate spatial coupling between enlarged perivascular spaces and white matter lesions across the Alzheimer's disease continuum, with coupling changes emerging early in disease stages, supporting the hypothesis that local perivascular clearance dysfunction and white matter injury represent interacting pathological processes that may serve as early biomarkers of Alzheimer's disease.