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

Changes in Ischemic White matter hyperintensities volume (WMH) on MRI over time are associated with cognitive decline. We investigated whether changes in WMH volume over time exhibit WMH-normalized volume threshold effects on declining cognitive performance and whether these effects on cognition differ between deep white matter hyperintensities (DWMH) and periventricular white matter hyperintensities (PVWMH).

We followed 339 participants longitudinally from GeneSTAR with brain MRI and neuropsychological testing at baseline and at 13-years (62% female, and 33% Black, mean baseline age 49.7±9.6). WMH were classified as PVWMH (within 2mm 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 -9.42 to -9.29; and DWMH -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). 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. PVWMH demonstrate larger effects on declining cognitive function than DWMH, particularly for motor and processing speed functions and progresses at a faster rate.