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Memory decline in elderly with cerebral small vessel disease explained by temporal interactions between white matter
Esther M C van Leijsen1, Jonathan Tay2, Ingeborg W M van Uden1
1Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Donders Center for Medical Neuroscience, Radboud University Medical Centre, Nijmegen, The Netherlands.
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.
Insights
White matter hyperintensities (WMH) and hippocampal atrophy interact to explain memory decline in older adults with small vessel disease (SVD). Hippocampal atrophy does not mediate the effect of WMH on memory loss, indicating varied causes of cognitive decline in SVD.
Area of Science:
- Neuroscience
- Gerontology
- Radiology
Background:
- White matter hyperintensities (WMH) are key markers of cerebral small vessel disease (SVD) and are linked to cognitive decline.
- However, WMH alone do not fully explain the memory decline observed in individuals with SVD.
- The indirect effects of WMH on memory, potentially through remote structures like the hippocampus, require investigation.
Purpose of the Study:
- To investigate the temporal interactions between WMH, hippocampal atrophy, and memory decline in older adults with SVD.
- To assess the mediating role of hippocampal atrophy in the association between WMH and memory decline (working memory and episodic memory).
Main Methods:
- Longitudinal study of 503 participants with SVD from the RUNDMC cohort, with neuroimaging and cognitive assessments over 8.7 years.
- Semi-automated assessment of WMH volumes and FreeSurfer-based calculation of hippocampal volumes (HV).
- Application of linear mixed effects models and causal mediation analyses to evaluate interaction and mediation effects.
Main Results:
- The interaction between WMH and hippocampal volumes significantly explained memory decline in both working memory (WM) and episodic memory (EM).
- Model fit improved significantly with the inclusion of the WMH*HV interaction term for both WM and EM.
- Mediation analyses revealed that while baseline WMH and hippocampal atrophy independently related to EM decline, hippocampal atrophy did not mediate the effect of WMH on EM decline.
Conclusions:
- Memory decline in elderly individuals with SVD is best explained by the interaction between WMH and hippocampal volumes.
- The relationship between WMH and memory decline is not causally mediated by hippocampal atrophy.
- Memory decline in aging with SVD is likely a heterogeneous condition influenced by multiple, distinct pathologies.
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