Determinants of Perivascular Spaces in the General Population

Abstract

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.

Perivascular space enlargement accelerates with hypertension, white matter hyperintensities, chronic inflammation, and Alzheimer’s disease pathology: evidence from a three-year longitudinal multicentre study

“…Sex and education were also tied to PVS enlargement. CSO-PVS volumes were greater in men, as described in previous cross-sectional studies(23,61). Despite the usage of fractional PVS volumes, this observation could be influenced by sex-dependent head size differences: individuals with larger heads require longer or thicker blood vessels to sustain adequate blood supply to the brain(62).…”

Cerebral small vessel disease: Recent advances and future directions

“…They are frequently seen in patients with SVD and are associated with other markers of SVD including lacunes, WMH, CMB, and cortical microinfarcts. 48 , 49 However, their independent contribution to the etiology of SVD needs to be established, as does their role in cognitive decline. 48 It has been hypothesized that failure of brain fluid transport, via the glymphatic system, plays a key role in initiation and progression of SVD, and that stagnation of glymphatic transport may drive loss of brain fluid homeostasis leading to transient white matter edema, perivascular dilation, and ultimately demyelination.…”

Deep learning applications in vascular dementia using neuroimaging

“…CNN models have been showing promising results in the quantification and segmentation of PVS [38]. In addition, CNN models can also quantify PVS in four different brain regions: midbrain, hippocampi, basal ganglia and centrum semiovale [39], and these region-specific PVS can be influenced by sex, cardiovascular risk factors, APOE gene and imaging biomarkers [40 ▪▪ ].…”