OBJECTIVE
Magnetic resonance imaging (MRI)-visible enlarged perivascular spaces (PVS) are markers of cerebral small vessel disease (SVD) and aging, processes implicated in both neurodegenerative and cerebrovascular pathologies. However, longitudinal positron emission tomography (PET) studies examining PVS as a mechanism underlying Alzheimer's disease (AD) pathophysiological progression are lacking. Our overall objective was to investigate the associations of baseline PVS burden with white matter hyperintensity (WMH) volume, amyloid-PET, and tau-PET, both cross-sectionally and longitudinally.
METHODS
We examined 2,229 participants across the aging-AD spectrum from the Mayo Clinic Study of Aging (MCSA) and the Mayo Alzheimer's Disease Research Center (ADRC) (mean age = 68.59 ± 12.70 and 48.94% women). PVS and WMH were quantified using a novel in-house algorithm. Amyloid on [11C]Pittsburgh Compound B (PiB)-PET and tau on AV1451-PET were measured. Cross-sectional regional and global associations were examined using canonical correlation analysis (CCA). Longitudinal associations were examined using age- and sex-adjusted linear mixed effect (LME) models with natural splines and subject-wise 10-fold cross-validation.
RESULT
Three distinct associations were observed: (1) PVS in the basal ganglia (PVS-BG) was associated with greater WMH volume both cross-sectionally and longitudinally; (2) PVS-BG covaried with higher PiB standardized uptake value ratio (SUVR) cross-sectionally, with longitudinal trajectory associations limited to amyloid-negative individuals; (3) PVS in the centrum semiovale (PVS-CSO) was not associated with amyloid or tau, but was associated with occipital WMH, a pattern characteristic of CAA.
INTERPRETATION
Findings lend support for PVS-BG as an early indicator of small vessel dysfunction and WMH pathogenesis. Individuals with higher PVS-BG burden exhibited higher WMH burden and faster WMH progression, suggesting that PVS-BG may identify individuals at increased risk of progressive SVD. Evidence linking PVS to downstream AD biomarker progression was weaker. Findings support the relevance of PVS-CSO to CAA, suggesting that they may reflect changes occurring early in the disease process. ANN NEUROL 2026.
Audrey Low, J. Gunter, Mingzhao Hu et al.· Annals of Neurology· 0 citations
BACKGROUND: White matter hyperintensities (WMH) are widely used to assess cerebral small vessel disease but reflect late-stage injury. Diffusion magnetic resonance imaging (MRI) biomarkers have been proposed to capture earlier small vessel disease-related microstructural damage but their temporal progression relative to WMH and risk factors associated with progression remain unexplored. METHODS: We identified 2077 participants from the population-based cohort study of the Mayo Clinic Study of Aging in Olmsted County, Minnesota (aged 50–101 years) collected between 05/2005 and 09/2024 with longitudinal neuroimaging. Using multioutput nonlinear mixed-effects models in those with at least 2 fluid-attenuated inversion recovery-MRI and diffusion MRI scans, we characterized the temporal progression of WMH and 4 diffusion MRI biomarkers: fractional anisotropy of the genu of the corpus callosum, peak width of skeletonized mean diffusivity, free water, and Arteriolosclerosis-score, which were automatically estimated. Models incorporated participant-specific time shifts, correlations between biomarkers, and effects of risk factors (sex, education, APOE ε4 status, cardiometabolic conditions). RESULTS: The study population had a mean age of 78 years, 47% were women, 28% were APOE ε4 allele carriers, and 80% were cognitively unimpaired, with an average follow-up of 5.2 years (SD, 4.3 years) for fluid-attenuated inversion recovery-MRI and 4.3 years (SD, 3.9 years) for diffusion MRI. Arteriolosclerosis-score, fractional anisotropy of the genu of the corpus callosum, free water, and peak width of skeletonized mean diffusivity became abnormal in 50% of the study population 16, 12, 10, and 7 years before WMH become abnormal (half-width of CI <1 year), respectively. Global markers (Arteriolosclerosis-score, free water, peak width of skeletonized mean diffusivity, and WMH) were correlated, indicating shared substrates of widespread white matter injury. Fractional anisotropy of the genu of the corpus callosum, a vascular risk microstructural injury biomarker, was weakly coupled with WMH and had an earlier but more linear worsening across adulthood. Cardiometabolic conditions predicted earlier worsening of all biomarkers. Female participants showed earlier WMH, fractional anisotropy of the genu of the corpus callosum, and Arteriolosclerosis-score abnormalities, whereas male participants exhibited earlier peak width of skeletonized mean diffusivity and free water abnormalities. CONCLUSIONS: Diffusion MRI biomarkers were abnormal at least a decade before WMH become abnormal in the population, revealing a prolonged phase of early small vessel disease and highlighting their potential for small vessel disease prevention.
P. Vemuri, Mingzhao Hu, Emily S. Lundt et al.· Stroke· 0 citations