Impaired glymphatic system as evidenced by low diffusivity along perivascular spaces is associated with cerebral small vessel disease: a population-based study

Abstract

Objective: This study aims to investigate the associations of glymphatic system with the presence, severity and neuroimaging phenotypes of cerebral small vessel disease (CSVD) in a community-based population.

Method: This report included 2219 community-dwelling people aged 50-75 years who participated in the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events cohort. The diffusivity along perivascular spaces based on diffusion tensor imaging (DTI-ALPS index) was measured to assess glymphatic pathway. The presence and severity of CSVD were estimated using a CSVD score (points from 0 to 4) and a modified CSVD score (points from 0 to 4), which were driven by 4 neuroimaging features of CSVD, including white matter hyperintensity (WMH), enlarged perivascular spaces (EPVS), lacunes, cerebral microbleeds. Brain atrophy (BA) was also evaluated. Binary or ordinal logistic regression analyses were carried out to investigate the relationships of DTI-ALPS index with CSVD.

Result: The mean age was 61.3 (SD 6.6) years, and 1019 (45.9%) participants were men. The average DTI-ALPS index was 1.67±0.14. Individuals in the first quartile (Q1) of the DTI-ALPS index had higher risks of the presence of CSVD (OR 1.77, 95% CI 1.33 to 2.35, p<0.001), modified presence of CSVD (odds ratio (OR) 1.80, 95% CI 1.38 to 2.34, p<0.001), total burden of CSVD (common OR (cOR) 1.89, 95% CI 1.43 to 2.49, p<0.001) and modified total burden of CSVD (cOR 1.95, 95% CI 1.51 to 2.50, p<0.001) compared with those in the fourth quartile (Q4). Additionally, individuals in Q1 of the DTI-ALPS index had increased risks of WMH burden, modified WMH burden, lacunes, basal ganglia-EPVS and BA (all p<0.05).

Conclusion: A lower DTI-ALPS index underlay the presence, severity and typical neuroimaging markers of CSVD, implying that glymphatic impairment may interact with CSVD-related pathology in the general ageing population.

Trial registration number: NCT03178448.

Keywords: cerebrovascular circulation; cerebrovascular disorders; cognitive dysfunction; magnetic resonance imaging; stroke.

Figure 1

The assessment of glymphatic system by calculating the DTI-ALPS index. DTI-ALPS, diffusivity along the perivascular spaces based on diffusion tensor imaging; FA, fractional anisotropy; FLAIR, fluid-attenuated inversion recovery; ROI, regions of interest; SWI, susceptibility-weighted imaging.

Figure 2

The flow chart of 2219 included individuals. DTI, diffusion tensor imaging; DTI-ALPS, diffusivity along perivascular spaces based on diffusion tensor imaging; PRECISE, PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events.

Figure 3

The DTI-ALPS index in association with the presence and severity of CSVD. Forest plots present ORs/cORs for the associations of the DTI-ALPS index with the presence of CSVD (A), modified presence of CSVD (B), total CSVD burden (C) and modified total CSVD burden (D). The colourful lines indicate 95% CIs of ORs/cORs. Model 1 adjusted for age and sex; model 2, vascular risk factors; model 3, current medications. cOR, common OR; CSVD, cerebral small vessel disease; DTI-ALPS, diffusivity along the perivascular spaces based on diffusion tensor imaging.

Figure 4

Restricted cubic spline plots for the associations of the DTI-ALPS index with the presence and severity of CSVD. Adjusted ORs/cOR for presence of CSVD (A), modified presence of CSVD (B), total CSVD burden (C) and modified total CSVD burden (D) based on restricted cubic spines with 5 knots at 5th, 25th, 50th, 75th and 95th percentiles of the DTI-ALPS index. The solid line indicates adjusted ORs/cORs, and the dashed lines the 95% CI bands. Reference is the first quartile of ALPS index. The vertical dashed lines indicate the 25th, 50th and 75th percentiles of DTI-ALPS index. Data were fitted using a binary/ordinal logistic regression model of restricted cubic spline with five knots (the 5th, 25th, 50th, 75th, 95th percentiles) for the DTI-ALPS index after adjusting for all potential confounders. The lowest 5% and highest 5% of participants are not shown. cOR, common OR; CSVD, cerebral small vessel disease; DTI-ALPS, diffusivity along the perivascular spaces based on diffusion tensor imaging.

Figure 5

The DTI-ALPS index in association with neuroimaging phenotypes of CSVD. Forest plots present ORs/cORs for the associations of the DTI-ALPS index with different neuroimaging marker of CSVD. The black lines indicate 95% CIs of ORs/cORs. Multivariable logistic regression model adjusted for all potential confounders. BG-EPVS, basal ganglia-EPVS; CSO-EPVS, centrum semiovale-EPVS; CMBs, cerebral microbleeds; cOR, common OR; CSVD, cerebral small vessel disease; DTI-ALPS, diffusivity along the perivascular spaces based on diffusion tensor imaging; EPVS, enlarged perivascular space; GCA, global cortical atrophy scale; WMH, whiter matter hyperintensity.