Memory decline in elderly with cerebral small vessel disease explained by temporal interactions between white matter hyperintensities and hippocampal atrophy

Abstract

White matter hyperintensities (WMH) constitute the visible spectrum of cerebral small vessel disease (SVD) markers and are associated with cognitive decline, although they do not fully account for memory decline observed in individuals with SVD. We hypothesize that WMH might exert their effect on memory decline indirectly by affecting remote brain structures such as the hippocampus. We investigated the temporal interactions between WMH, hippocampal atrophy and memory decline in older adults with SVD. Five hundred and three participants of the RUNDMC study underwent neuroimaging and cognitive assessments up to 3 times over 8.7 years. We assessed WMH volumes semi‐automatically and calculated hippocampal volumes (HV) using FreeSurfer. We used linear mixed effects models and causal mediation analyses to assess both interaction and mediation effects of hippocampal atrophy in the associations between WMH and memory decline, separately for working memory (WM) and episodic memory (EM). Linear mixed effect models revealed that the interaction between WMH and hippocampal volumes explained memory decline (WM: β = .067; 95%CI[.024–0.111]; p < .01; EM: β = .061; 95%CI[.025–.098]; p < .01), with better model fit when the WMH*HV interaction term was added to the model, for both WM (likelihood ratio test, χ2[1] = 9.3, p < .01) and for EM (likelihood ratio test, χ2[1] = 10.7, p < .01). Mediation models showed that both baseline WMH volume (β = −.170; p = .001) and hippocampal atrophy (β = 0.126; p = .009) were independently related to EM decline, but the effect of baseline WMH on EM decline was not mediated by hippocampal atrophy (p value indirect effect: 0.572). Memory decline in elderly with SVD was best explained by the interaction of WMH and hippocampal volumes. The relationship between WMH and memory was not causally mediated by hippocampal atrophy, suggesting that memory decline during aging is a heterogeneous condition in which different pathologies contribute to the memory decline observed in elderly with SVD.

Serum Neurofilament Light Chain Is Associated with Incident Lacunes in Progressive Cerebral Small Vessel Disease

“…2,[21][22][23][24] A recent study from our cohort showed that memory decline in elderly with SVD is best explained by the interaction of white matter damage and hip-pocampal volume, suggesting that memory decline observed in subjects with SVD is heterogeneous process. 11 However, in our study we did not identify serum NfL to be an independent marker of cognitive decline. Therefore, further studies in independent cohorts are needed to further address role of NfL as a potential predictor of future cognitive deterioration.…”

“…Dementia case finding was described previously. 11 In short, dementia was diagnosed after examination at the Radboud Alzheimer Center or by expert panel consensus diagnosis. Age and education were considered for interpretation, next to interference with daily living, confirmed by family/caregivers.…”

Apathy, but not depression, predicts all-cause dementia in cerebral small vessel disease

“…This would be consistent with initial executive deficits that are followed by declining episodic memory, which may be a cognitive phenotype of SVD patients that develop vascular or mixed dementia. 32 34 …”

White Matter Hyperintensity Burden Is Associated With Hippocampal Subfield Volume in Stroke

“…In support of this hypothesis, longitudinal analysis of 503 nondemented subjects with small-vessel disease, as part of the RUN DMC study, demonstrated that the interaction term of WMH and hippocampal atrophy significantly improved model accuracy for both working and episodic memory (35). Moreover, increased WMH burden was associated with decline in episodic memory and this association was not causally mediated by hippocampal atrophy in mediation analysis (35).…”