Factors associated with the presence, and longitudinal progression of, perivascular spaces: An Exposome-Wide Analysis in the UK Biobank
Shizuka Hayashi, Jing Du, Lei Fan, Jiyang Jiang, Yang Song, Dadong Wang, Perminder S. Sachdev, Wei WenBackground:
Perivascular spaces (PVS) are markers of cerebral small vessel disease (cSVD). While some vascular risk factors are known, broader determinants of regional PVS burden and progression remain unclear.
Aim:
This study aimed to identify exposome-wide determinants of cross-sectional regional PVS burden in the basal ganglia (BG) and centrum semiovale (CSO) and examine associations of identified exposures with PVS progression.
Methods:
We analysed 44,938 UK Biobank participants (4,568 with repeat imaging after 2.6 ± 1.0 years). Of 3,767 candidate exposures across eight domains, 1,289 were retained after preprocessing. The cross-sectional Exposome-Wide Association Study (ExWAS) used negative binomial regression with false discovery rate (FDR) correction. Surviving exposures were further examined with weighted quantile sum (WQS) regression to assess relative importance, Conway-Maxwell-Poisson longitudinal models, and structural equation modelling (SEM) linking exposures to cognition via PVS.
Results:
ExWAS identified 80 exposures for BG-PVS and 89 for CSO-PVS (PFDR-corrected < 0.01). Higher diastolic blood pressure (BG: Incident rate ratio (IRR)=1.04, 95% CI: 1.03–1.05; CSO: IRR=1.07, 1.05–1.08) and greater left ventricular (LV) myocardial mass (BG: IRR=1.05, 1.04–1.07; CSO: IRR=1.09, 1.06–1.11) were associated with greater burden. WQS weights were dominated by cardiovascular exposures in BG (54.5%) but were more broadly distributed in CSO, including cardiovascular (31.9%), sociodemographic (20.9%) and environmental (12.7%). Longitudinally, cardiovascular and adiposity exposures were nominally associated with faster BG-PVS progression, with stronger effects in females. SEM demonstrated cardiovascular exposures linked to cognition through BG-PVS, but not CSO-PVS.
Discussion:
Determinants of PVS burden and progression showed regional heterogeneity: BG-PVS is more strongly associated with cardiovascular exposures and cognition, while CSO-PVS shows a broader, more heterogeneous pattern. These findings support the importance of regional PVS assessment and suggest cardiovascular risk management may be particularly relevant to BG-PVS-related cSVD.