Longitudinal Cognitive Changes in Cerebral Small Vessel Disease: The Effect of White Matter Hyperintensity Regression and Progression

Abstract

Background and objectives: White matter hyperintensities (WMHs) are the commonest imaging marker of cerebral small vessel disease (SVD) and a major cause of cognitive decline and vascular dementia. WMHs typically accumulate over time, but recent studies show they can also regress, but potential clinical benefits have received little attention. We examined progressing, stable, and regressing WMH in people with stroke-related SVD and the effect on cognitive outcomes.

Methods: We recruited patients with minor nondisabling ischemic stroke (modified Rankin score ≤2) from stroke services into our prospective longitudinal observational study. Participants underwent cognitive assessment and brain MRI within 3-month poststroke and 1 year later. We gathered information on vascular risk factors, stroke severity, global cognition (Montreal Cognitive Assessment [MoCA]), processing speed and executive functioning (Trail Making Test [TMT] A and B, and the B/A ratio with ratio ≥3 reflecting executive dysfunction), and the Letter Digit Substitution Test. We measured WMH volumes at baseline and 1 year and categorized net WMH volume change into quintiles: Q1 (most regression), Q3 (stable), and Q5 (most progression). We applied repeated-measures linear mixed models to analyze longitudinal WMH and cognitive changes, adjusting for age, sex, premorbid intelligence, stroke severity, disability, white matter structural integrity, and baseline WMH volume.

Results: One hundred ninety-eight of 229 participants had WMH volumes available at both time-points. At baseline, the mean age was 67.5 years (SD = 10.9), with 33% female. Mean net WMH volume change per quintile was Q1 -1.79 mL (SD = 1.54), Q2 -0.27 mL (0.20), Q3 0.35 mL (0.18), Q4 1.43 mL (0.48), and Q5 5.31 mL (3.07). MoCA deteriorated the most in participants with most WMH progression (Q5) (estimated β -0.428 [95% CI -0.750 to -0.106]), compared with stable WMH (Q3), with no clear deterioration in those with most WMH regression (Q1). TMT B/A ratio improved in participants with most WMH regression (Q1; -0.385 [-0.758 to -0.012]).

Discussion: WMH regression was associated with preserved global cognition and improved executive function, compared with stable WMH, while WMH progression was associated with global cognitive decline. Cognitive benefits of WMH regression suggest that WMH-affected tissue can recover, may explain variance in cognitive outcomes, offer an important intervention target, and should be assessed in other populations and longer follow-up times.

Figure 1. Consort Diagram

COVID-19 = coronavirus disease 2019; WMH = white matter hyperintensity.

Figure 2. Predictors of Change in MoCA (Left) and LDST (Right) Over 1 Year; Linear Mixed Model

Estimates (standardized β) left of line: worsening MoCA or LDST scores; to the right: improving MoCA or LDST scores; higher MoCA and LDST scores reflect better performance. Q3 functions as reference. ICV = intracranial volume; LDST = Letter Digit Substitution Test; mRS = modified Rankin score; NART = National Adult Reading Test at baseline; NIHSS = NIH Stroke Scale; PSMD = peak width of skeletonized mean diffusivity; Q = quintile of WMH change; Q1 = most WMH regression; Q5 = most WMH progression; WMH = white matter hyperintensity.

Figure 3. Predictors of Change in TMT-A (Top Left), TMT-B (Top Right), and TMT B/A Ratio (Bottom Left) Over 1 Year; Linear Mixed Model

Estimates (standardized β) left of line: decreasing times or B/A ratio; to the right: increasing times or B/A ratio. Longer times or higher B/A ratio indicates poorer performance. Q3 functions as reference. ICV = intracranial volume; mRS = modified Rankin score; NART = National Adult Reading Test at baseline; NIHSS = NIH Stroke Scale; PSMD = peak width of skeletonized mean diffusivity; Q = quintile of WMH change; Q1 = most WMH regression; Q5 = most WMH progression; TMT = Trail Making Test; WMH = white matter hyperintensity.