Determinants of Perivascular Spaces in the General Population: A Pooled Cohort Analysis of Individual Participant
Tavia E Evans1, Maria J Knol1, Petra Schwingenschuh1
1From the Departments of Clinical Genetics (T.E.E., M.J.K., H.H.H.A.), Radiology and Nuclear Medicine (T.E.E., F.D., K.M.H.W., P.Y., M.B., H.H.H.A., M.W.V.), Epidemiology (M.J.K., M.A.I., P.Y., M.K.I., M.W.V.), and Neurology (M.K.I.), Erasmus MC, Rotterdam, the Netherlands; Department of Neurology (P.S., P.K., R.S.), Medical University of Graz, Austria; German Center for Neurodegenerative Diseases (DZNE) (K.W., M.H., H.J.G.), Site Rostock/Greifswald; Department of Psychiatry and Psychotherapy (K.W., H.J.G.) and Institute of Diagnostic Radiology and Neuroradiology (S.L.), University Medicine Greifswald, Germany; Department of Pharmacology (S.H., C.C.), National University of Singapore; Memory Aging & Cognition Centre (MACC) (S.H., C.C., M.K.I.), National University Health System, Singapore; Saw Swee Hock School of Public Health (S.H.), National University of Singapore; Department of Biomedical Data Sciences (F.D.), Stanford University, CA; J. Philip Kistler Stroke Research Center (P.Y.), Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston; The Machine Learning Section (M.B.), Department of Computer Science, University of Copenhagen, Denmark; Neuroimage Analytics Laboratory (NAL) and the Biggs Institute Neuroimaging Core (BINC) (M.H.), Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center San Antonio (UTHSCSA), TX; and Latin American Brain Health (BrainLat) (H.H.H.A.), Universidad Adolfo Ibáñez, Santiago, Chile.
Background And Objectives:
Perivascular spaces (PVS) are emerging markers of cerebral small vessel disease (CSVD), but research on their determinants has been hampered by conflicting results from small single studies using heterogeneous rating methods. In this study, we therefore aimed to identify determinants of PVS burden in a pooled analysis of multiple cohort studies using 1 harmonized PVS rating method.
Methods:
Individuals from 10 population-based cohort studies with adult participants from the Uniform Neuro-Imaging of Virchow-Robin Spaces Enlargement consortium and the UK Biobank were included. On MRI scans, we counted PVS in 4 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, APOE genotypes, and other imaging markers of CSVD. 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 4 regions increased from the age 20 years (0-1 PVS) to 90 years (2-7 PVS). Men had more mesencephalic PVS (OR [95% CI] = 1.13 [1.08-1.18] compared with women), but less hippocampal PVS (0.82 [0.81-0.83]). Higher blood pressure, particularly diastolic pressure, was associated with more PVS in all regions (ORs between 1.04-1.05). Hippocampal PVS showed higher counts with higher high-density lipoprotein cholesterol levels (1.02 [1.01-1.02]), glucose levels (1.02 [1.01-1.03]), and APOE ε4-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 toward 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.
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