Assessment of Risk Factors and Clinical Importance of Enlarged Perivascular Spaces by Whole-Brain Investigation in the Multi-Ethnic Study of Atherosclerosis

Abstract

ImportanceEnlarged perivascular spaces (ePVSs) have been associated with cerebral small-vessel disease (cSVD). Although their etiology may differ based on brain location, study of ePVSs has been limited to specific brain regions; therefore, their risk factors and significance remain uncertain.ObjectiveToperform a whole-brain investigation of ePVSs in a large community-based cohort.Design, Setting, and ParticipantsThis cross-sectional study analyzed data from the Atrial Fibrillation substudy of the population-based Multi-Ethnic Study of Atherosclerosis. Demographic, vascular risk, and cardiovascular disease data were collected from September 2016 to May 2018. Brain magnetic resonance imaging was performed from March 2018 to July 2019. The reported analysis was conducted between August and October 2022. A total of 1026 participants with available brain magnetic resonance imaging data and complete information on demographic characteristics and vascular risk factors were included.Main Outcomes and MeasuresEnlarged perivascular spaces were quantified using a fully automated deep learning algorithm. Quantified ePVS volumes were grouped into 6 anatomic locations: basal ganglia, thalamus, brainstem, frontoparietal, insular, and temporal regions, and were normalized for the respective regional volumes. The association of normalized regional ePVS volumes with demographic characteristics, vascular risk factors, neuroimaging indices, and prevalent cardiovascular disease was explored using generalized linear models.ResultsIn the 1026 participants, mean (SD) age was 72 (8) years; 541 (53%) of the participants were women. Basal ganglia ePVS volume was positively associated with age (β = 3.59 × 10−3; 95% CI, 2.80 × 10−3 to 4.39 × 10−3), systolic blood pressure (β = 8.35 × 10−4; 95% CI, 5.19 × 10−4 to 1.15 × 10−3), use of antihypertensives (β = 3.29 × 10−2; 95% CI, 1.92 × 10−2 to 4.67 × 10−2), and negatively associated with Black race (β = −3.34 × 10−2; 95% CI, −5.08 × 10−2 to −1.59 × 10−2). Thalamic ePVS volume was positively associated with age (β = 5.57 × 10−4; 95% CI, 2.19 × 10−4 to 8.95 × 10−4) and use of antihypertensives (β = 1.19 × 10−2; 95% CI, 6.02 × 10−3 to 1.77 × 10−2). Insular region ePVS volume was positively associated with age (β = 1.18 × 10−3; 95% CI, 7.98 × 10−4 to 1.55 × 10−3). Brainstem ePVS volume was smaller in Black than in White participants (β = −5.34 × 10−3; 95% CI, −8.26 × 10−3 to −2.41 × 10−3). Frontoparietal ePVS volume was positively associated with systolic blood pressure (β = 1.14 × 10−4; 95% CI, 3.38 × 10−5 to 1.95 × 10−4) and negatively associated with age (β = −3.38 × 10−4; 95% CI, −5.40 × 10−4 to −1.36 × 10−4). Temporal region ePVS volume was negatively associated with age (β = −1.61 × 10−2; 95% CI, −2.14 × 10−2 to −1.09 × 10−2), as well as Chinese American (β = −2.35 × 10−1; 95% CI, −3.83 × 10−1 to −8.74 × 10−2) and Hispanic ethnicities (β = −1.73 × 10−1; 95% CI, −2.96 × 10−1 to −4.99 × 10−2).Conclusions and RelevanceIn this cross-sectional study of ePVSs in the whole brain, increased ePVS burden in the basal ganglia and thalamus was a surrogate marker for underlying cSVD, highlighting the clinical importance of ePVSs in these locations.

A Systematic Review and Meta-Analysis of Automated Methods for Quantifying Enlarged Perivascular Spaces in the Brain

“…A study on chronic traumatic brain injury did not find PVS burden being associated with brain age (Hicks et al, 2023). Studies that analysed the PVS association with age in different regions had conflicting results, with the majority reporting a positive association/correlation with age in all regions, and one study finding a negative association between age and PVS volume in the temporal region (Charisis et al, 2023; N=1026).…”

“…Eleven out of thirteen studies identified a positive association between hypertension and PVS burden (Ballerini et al, 2019; Huang, Zhu, et al, 2021b; Wang et al, 2021; Wang, Chappell, et al, 2016; Cheng et al, 2022; Hadad et al, 2022; Charisis et al, 2023; Evans et al, 2023; Tachibana et al, 2024; Zebarth et al, 2023; Duperron et al, 2023). Duperron et al, (2023), the largest study amongst the ones included, found causal associations of high blood pressure with BG and hippocampal PVS, and of BG PVS and hippocampal PVS with stroke, accounting for blood pressure, even after Mendelian randomisation.…”

“…Factors identified in common among application studies included age, sex, hypertension, diabetes, WMH, sleep, and cognition, although comparable results were only available for a modest number of studies per factor. Other factors, like ethnicity, are starting to emerge, with two studies (Charisis et al, 2023; Shih et al, 2023) reporting differences in the spatial distribution (Charisis et al, 2023) and volume fraction (Shih et al, 2023) of PVS across racial/ethnic groups. Computational PVS measures used varied, but commonly included PVS count and volume, often segregated by region (e.g., basal ganglia PVS, centrum semiovale/white matter PVS).…”

“…The three most frequently applied computational PVS quantification approaches identified in this review were the one firstly proposed by Ballerini et al (2016) (Charisis et al, 2023;Shih et al, 2023) reporting differences in the spatial distribution (Charisis et al, 2023) and volume fraction (Shih et al, 2023) of PVS across racial/ethnic groups. Computational PVS measures used varied, but commonly included PVS count and volume, often segregated by region (e.g., basal ganglia PVS, centrum semiovale/white matter PVS).…”

Pericytes and Resident Perivascular Macrophages Play a Key Role in the Development of Enlarged Perivascular Spaces in Obesity, Metabolic Syndrome and Type 2 Diabetes Mellitus

“…When neuroinflammation is discussed, the CNS resident immune microglia cell(s) (MGC) most often comes to mind and is discussed extensively in the literature [52][53][54][55][56]; however, in this narrative review the focus has been primarily on the rPVMΦ that reside within the PVS by TEM studies. This is not only because PVS and EPVS are important [2,8,57] but also because both MGCs and PVMΦs have been rapidly gaining interest over the past decade. For example, PubMed (NIH National Library of Medicine) reference entries regarding MGCs have increased from 68/year in 2008 to 374/year in 2022 an increase 306/year.…”