Background and Objectives:Perivascular spaces (PVS) are emerging markers of cerebral small vessel disease, but research on their determinants has been hampered by conflicting results from small single studies employing heterogeneous rating methods. In this study we therefore aimed to identify determinants of PVS burden in a pooled analysis of multiple cohort studies using one harmonized PVS rating method.Methods:Individuals from ten population-based cohort studies with adult participants from the UNIVRSE consortium and the UK Biobank were included. On magnetic resonance imaging scans, we counted PVS in four brain regions (mesencephalon, hippocampus, basal ganglia, and centrum semiovale) according to a uniform and validated rating protocol, both manually and automated using a deep learning algorithm. As potential determinants, we considered demographics, cardiovascular risk factors,APOEgenotypes, and other imaging markers of cerebral small vessel disease. Negative binomial regression models were used to examine the association between these determinants and PVS counts.Results:In total, 39,976 individuals were included (age range 20-96 years). The average count of PVS in the four regions increased from the age of 20 years (0-1 PVS) to 90 years (2-7 PVS). Men had more mesencephalic PVS (odds ratio [95% confidence interval] = 1.13 [1.08-1.18] compared to women), but less hippocampal PVS (0.82 [0.81-0.83]). Higher blood pressure, in particular diastolic pressure, was associated with more PVS in all regions (odds ratios between 1.04-1.05). Hippocampal PVS showed higher counts with higher HDL cholesterol levels (1.02 [1.01-1.02]), and glucose levels (1.02 [1.01-1.03]), as well asAPOEε4-alleles (1.02 [1.01-1.04]). Furthermore, white matter hyperintensity volume and presence of lacunes were associated with PVS in multiple regions, but most strongly with the basal ganglia (1.13 [1.12-1.14] and 1.10 [1.09-1.12], respectively).Discussion:Various factors are associated with the burden of PVS, in part regionally-specific, which points towards a multifactorial origin beyond what can be expected from PVS-related risk factor profiles. This study highlights the power of collaborative efforts in population neuroimaging research.