Threshold Effects, Cognitive Decline, and Longitudinal Changes in White Matter Hyperintensity Volume

Changes in ischemic white matter hyperintensity (WMH) volume on magnetic resonance imaging over time are associated with cognitive decline. We investigated whether changes in WMH volume over time exhibit threshold effects of normalized WMH volume on declining cognitive performance and whether these effects on cognition differ between deep WMHs (DWMHs) and periventricular WMHs (PVWMHs).

We followed 339 participants longitudinally from GeneSTAR (Genetic Study of Atherosclerosis Risk) with brain magnetic resonance imaging and neuropsychological testing at baseline (2009-2013) and at 13-year follow-up (2023 to present; 62% female, and 33% Black; mean baseline age, 49.7±9.6 years). WMHs were classified as PVWMH (within 2 mm of ventricles) or DWMH. Two-segment linear spline regression models using adjusted mixed linear regression identified test-specific thresholds longitudinally beyond which cognitive decline accelerated. Cognitive scores from both timepoints were treated as repeated measures, with WMH included as a time-varying predictor.

Declines in motor function and processing speed accelerated beyond thresholds of changing PVWMH and DWMH volumes. For Grooved Pegboard tests, changes in volume were associated with minimal effects below a threshold of changing volume (log-transformed ratio of lesion volume to intracranial volume for PVWMH from -9.42 to -9.29 and DWMH from -11.8 to -11.7). Substantial declines in cognitive performance were observed above thresholds of increases in volume (slope differences: PVWMH: 14.5-15.1 seconds per log-unit; P<0.001; and DWMH: 9.54-10.9; P<0.001). The digit symbol substitution test demonstrated paradoxical positive associations below changing volume thresholds (PVWMH: β=6.68; P=0.001; and DWMH: β=6.98; P<0.001), reversing to decline above thresholds of increase in volume for PVWMH (Δβ=-11.2; P<0.001) and DWMH (Δβ=-9.77; P<0.001).

Changes in WMH volume exhibit nonlinear threshold effects on changes in cognitive performance over time and differ by anatomic region. Minimal cognitive impact occurred below thresholds, with accelerated declines above. PVWMHs demonstrate larger effects on declining cognitive function than DWMH, particularly for motor and processing speed functions, and progress at a faster rate.