Relationship of Perivascular Space Markers With Incident Dementia in Cerebral Small Vessel Disease

Abstract

Background: Recent studies, using diffusion tensor image analysis along the perivascular space (DTI-ALPS), suggest impaired perivascular space (PVS) function in cerebral small vessel disease, but they were cross-sectional, making inferences on causality difficult. We determined associations between impaired PVS, measured using DTI-ALPS and PVS volume, and cognition and incident dementia.

Methods: In patients with lacunar stroke and confluent white matter hyperintensities, without dementia at baseline, recruited prospectively in a single center, magnetic resonance imaging was performed annually for 3 years, and cognitive assessments, including global, memory, executive function, and processing speed, were performed annually for 5 years. We determined associations between DTI-ALPS and PVS volume with cerebral small vessel disease imaging markers (white matter hyperintensity volume, lacunes, and microbleeds) at baseline and with changes in imaging markers. We determined whether DTI-ALPS and PVS volume at baseline and change over 3 years predicted incident dementia. Analyses were controlled for conventional diffusion tensor image metrics using 2 markers (median mean diffusivity [MD] and peak width of skeletonized MD) and adjusted for age, sex, and vascular risk factors.

Results: A total of 120 patients, mean age 70.0 years and 65.0% male, were included. DTI-ALPS declined over 3 years, while no change in PVS volume was found. Neither DTI-ALPS nor PVS volume was associated with cerebral small vessel disease imaging marker progression. Baseline DTI-ALPS was associated with changes in global cognition (β=0.142, P=0.032), executive function (β=0.287, P=0.027), and long-term memory (β=0.228, P=0.027). Higher DTI-ALPS at baseline predicted a lower risk of dementia (hazard ratio, 0.328 [0.183-0.588]; P<0.001), and this remained significant after including median MD as a covariate (hazard ratio, 0.290 [0.139-0.602]; P<0.001). Change in DTI-ALPS predicted dementia conversion (hazard ratio, 0.630 [0.428-0.964]; P=0.048), but when peak width of skeletonized MD and median MD were entered as covariates, the association was not significant. There was no association between baseline PVS volume, or PVS change over 3 years, and conversion to dementia.

Conclusions: DTI-ALPS predicts future dementia risk in patients with lacunar strokes and confluent white matter hyperintensities. However, the weakening of the association between change in DTI-ALPS and incident dementia after controlling for peak width of skeletonized MD and median MD suggests part of the signal may represent conventional diffusion tensor image metrics. PVS volume is not a predictor of future dementia risk.

Keywords: cerebral small vessel disease; cognitive dysfunction; dementia; white matter.

Figure 1.

Diffusion tensor image (DTI) analysis along the perivascular space (DTI-ALPS) workflow. dtifit: command provided by FSL used to calculate fractional anisotropy (FA) and V1 images from DTI. flirt: command provided by FSL used for registering individual images to a standardized space. V1 is the first eigenvector image derived from DTI, indicating the primary direction of fiber pathways in specific brain regions. Blue color denotes superior to inferior fibers, green indicates anterior to posterior fibers, and red signifies left to right fibers. Dxx indicates diffusivity along the perivascular space, signifying left to right directional diffusion; Dyy, diffusivity along projection fibers, indicating superior to inferior directional diffusion; Dzz, diffusivity along association fibers, depicting anterior to posterior directional diffusion; FSL, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain Software Library; and ROI, region of interest.

Figure 2.

Survival curves according to baseline diffusion tensor image analysis along the perivascular space (DTI-ALPS).