Longitudinal Changes of White Matter Hyperintensities in Sporadic Small Vessel Disease: A Systematic Review and Meta-analysis

Abstract

Background and objectives: White matter hyperintensities (WMHs) are frequent imaging features of small vessel disease (SVD) and related to poor clinical outcomes. WMH progression over time is well described, but regression was also noted recently, although the frequency and associated factors are unknown. This systematic review and meta-analysis aims to assess longitudinal intraindividual WMH volume changes in sporadic SVD.

Methods: We searched EMBASE and MEDLINE for articles up to 28 January 2022 on WMH volume changes using MRI on ≥2 time points in adults with sporadic SVD. We classified populations (healthy/community-dwelling, stroke, cognitive, other vascular risk factors, and depression) based on study characteristics. We performed random-effects meta-analyses with Knapp-Hartung adjustment to determine mean WMH volume change (change in milliliters, percentage of intracranial volume [%ICV], or milliliters per year), 95% CI, and prediction intervals (PIs, limits of increase and decrease) using unadjusted data. Risk of bias assessment tool for nonrandomized studies was used to assess risk of bias. We followed Preferred Reporting in Systematic Review and Meta-Analysis guidelines.

Results: Forty-one articles, 12,284 participants, met the inclusion criteria. Thirteen articles had low risk of bias across all domains. Mean WMH volume increased over time by 1.74 mL (95% CI 1.23-2.26; PI -1.24 to 4.73 mL; 27 articles, N = 7,411, mean time interval 2.7 years, SD = 1.65); 0.25 %ICV (95% CI 0.14-0.36; PI -0.06 to 0.56; 6 articles, N = 1,071, mean time interval 3.5 years, SD = 1.54); or 0.58 mL/y (95% CI 0.35-0.81; PI -0.26 to 1.41; 8 articles, N = 3,802). In addition, 13 articles specifically mentioned and/or provided data on WMH regression, which occurred in asymptomatic, stroke, and cognitive disorders related to SVD.

Discussion: Net mean WMH volume increases over time mask wide-ranging change (e.g., mean increase of 1.75 mL ranging from 1.25 mL decrease to 4.75 mL increase), with regression documented explicitly in up to one-third of participants. More knowledge on underlying mechanisms, associated factors, and clinical correlates is needed, as WMH regression could be an important intervention target.

Figure 1. Flowchart of Study Selection

WMH = white matter hyperintensity.

Figure 2. Random-Effects Meta-analysis of Raw Mean WMH Volume Change in Milliliters Over Median of 2 Years, Range 0.25–8.1 Years

Squares represent means and bars the 95% CI. AD = Alzheimer disease; CAA = cerebral amyloid angiopathy; DLB = Lewy body dementia; DM = diabetes mellitus; healthy/CD = healthy/community-dwelling; MDD = major depressive disorder; MRAW = raw means; PDD = Parkinson disease dementia; SVD = small vessel disease; VRF = vascular risk factor; WMH = white matter hyperintensity.

Figure 3. Random-Effects Meta-analysis of Mean WMH Volume Change as %ICV Over Median of 3 Years, Range 1.9–6.7 Years

Squares represent means and bars the 95% CI. DM2 = diabetes mellitus type 2; healthy/CD = healthy/community-dwelling; MRAW = raw means; VRF = vascular risk factorWMH = white matter hyperintensity.

Figure 4. Random-Effects Meta-analysis of Mean WMH Volume in Milliliters Per Year

Squares represent means and bars the 95% CI. AD = Alzheimer disease; CAA = cerebral amyloid angiopathy; healthy/CD = healthy/community-dwelling; MCI = mild cognitive impairment; MRAW = raw means; NC = normal control; VRF = vascular risk factor; WMH = white matter hyperintensity.

Figure 5. Bubble Plot of Mean WMH Change (Milliliters), in Individual Studies, Related to Time Between Scans (Years)

Points in the plot are scaled by sample size, and the color of points refers to the population group. Healthy/CD = healthy/community-dwelling; VRF = vascular risk factor; WMH = white matter hyperintensity.

Figure 6. Bubble Plot of Mean WMH Change (%ICV), in Individual Studies, Related to Time Between Scans (Years)

Points in plot are scaled by sample size, and the color of points refers to the population group. %ICV = percentage of intracranial volume; healthy/CD = healthy/community-dwelling; VRF = vascular risk factor; WMH = white matter hyperintensity.

Figure 7. Bubble Plot of Mean WMH Change (Milliliters) Related to Age at Baseline (Years)

Points in plot are scaled by sample size, and the color of points refers to the population group. Healthy/CD = healthy/community-dwelling; VRF = vascular risk factor; WMH = white matter hyperintensity.