Increases in periventricular WMH volume were associated with significant cognitive decline across multiple tests over 13 years, more so than deep WMH.
Are increases in white matter hyperintensity volumes associated with cognitive decline over 13 years in family members of patients with early-onset coronary artery disease?
Increases in periventricular white matter hyperintensities are strongly associated with long-term cognitive decline, serving as a potential sensitive marker in individuals with a family history of early-onset CAD.
Introduction: White matter hyperintensities (WMH) are a common imaging finding in cerebral small vessel disease and can be associated with cognitive impairment. We investigated whether increases in periventricular WMH (PVWMH) and deep WMH (DWMH) volume would be associated with changes in performance on cognitive testing. Hypothesis: We hypothesized that a greater accumulation of WMH, especially PVWMH, would be associated with lower cognitive scores. Methods: 308 participants from GeneSTAR, family members of patients with early-onset coronary artery disease, underwent MRI and cognitive testing at baseline and again 13 years later. WMH volumes were normalized to intracranial volume, log-transformed, and standardized (z-scores). Linear mixed-effects models used to estimate the timepoint × WMH interaction for cognitive outcomes included: Mini-Mental State Examination (MMSE); Digit Span Forward, Backward, Total; Delayed Word Recall 1, Short, Long; Digit Symbol Substitution Test; Word Fluency; Grooved Pegboard Test (GPT) Dominant Time; and GPT Non-Dominant Hand Time. The models were adjusted for age, sex, race, education, BMI, and systolic blood pressure. Results: In the mixed-effects models, the interaction between timepoint and WMH volume showed that PVWMH demonstrated stronger and more consistent associations with cognitive performance than DWMH. Significant PVWMH interactions were found for Digit Span Backward (β = –0.378, p = 0.041), Digit Span Forward (β = –0.351, p = 0.031), Digit Span Total (β = –0.681, p = 0.016), GPT Dominant Time (β = 16.914, p < 0.001), Digit Symbol Substitution Test: Correct (β = –2.177, p < 0.001), Delayed Word Recall 1 (β = –0.379, p = 0.034), Delayed Word Recall Long (β = –0.314, p = 0.038), MMSE (β = –0.908, p = 0.002), GPT Non-Dominant Time (β = 14.018, p < 0.001), and Word Fluency (β = –2.289, p < 0.001). In comparison, DWMH interactions were generally smaller in magnitude and often non-significant, with significance observed primarily for GPT Dominant Time (β = 13.455, p < 0.001), Digit Symbol Substitution Test: Correct (β = –1.868, p < 0.001), GPT Non-Dominant Time (β = 11.287, p < 0.001), and Word Fluency (β = –1.494, p = 0.002). (Figure 1) Conclusions: Over a 13-year follow-up, increases in PWMH were linked to declines across a wider range of cognitive tests and demonstrated stronger associations than DWMH. These findings suggest that PVWMH may serve as a more sensitive marker of long-term cognitive decline.
Sasannia et al. (2026) studied this question. Increases in periventricular WMH volume were associated with significant cognitive decline across multiple tests over 13 years, more so than deep WMH.