Assessing the Global Impact of Brain Small Vessel Disease on Cognition: The Multi-Ethnic Study of Atherosclerosis - PubMed (original) (raw)

Tanweer Rashid 1, Christina Dintica 3, Mitzi Gonzales 2 4, Hangfan Liu 1 5, Jeffrey B Ware 6, Thomas R Austin 7 8, Paul N Jensen 8 9, Alison E Fohner 7, Jordan E Tanley 10, Jingzhong Ding 10, José A Luchsinger 11, Bonnie Sachs 12, Ilya M Nasrallah 6 13, R Nick Bryan 6, Kathleen M Hayden 14, David Wolk 15 16, Katya Rascovsky 16, Christos Davatzikos 6 13, William T Longstreth Jr 7 17, Kristine Yaffe 3, Sudha Seshadri 1 2, Susan R Heckbert 7 8, Timothy Hughes 10, Mohamad Habes 1 2 13

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Assessing the Global Impact of Brain Small Vessel Disease on Cognition: The Multi-Ethnic Study of Atherosclerosis

Sokratis Charisis et al. Alzheimers Dement. 2025 Jun.

Abstract

Introduction: We aimed to examine the global impact of brain small vessel disease (SVD) on cognitive performance.

Methods: In 892 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), we derived perivascular spaces (PVS), white matter hyperintensities (WMH), microbleeds (MB), and white matter fractional anisotropy (FA) and trace (TR). Cognitive function was assessed with a comprehensive neuropsychological battery.

Results: A composite SVD measure was constructed as a linear combination of basal ganglia PVS, thalamus PVS, periventricular WMH, subcortical WMH, and white matter FA and TR, and exhibited associations with worse global and domain-specific cognitive performance. Additionally, SVD mediated the effect of age and cardiovascular disease risk on global cognitive function, both directly and through smaller gray matter (GM) volume.

Discussion: Integrating multiple individual SVD endophenotypes may more accurately reflect the neurobiology of SVD and capture its global impact on cognition. SVD mediates the effects of age and cardiovascular disease risk on cognition through both atrophy-related and non-atrophy-related pathways.

Highlights: Associations between individual magnetic resonance imaging (MRI) markers of brain small vessel disease and cognitive outcomes might not fully capture the global impact of small vessel disease on cognition. We modeled small vessel disease as a latent construct, integrating multiple MRI endophenotypes in strategic brain regions. The small vessel disease construct was associated with worse global and domain-specific cognitive performance. The small vessel disease construct exhibited mediating effects in the relationships of aging and cardiovascular disease risk with cognition through pathways that both involve and are independent of brain atrophy. Integrating information from multiple relevant imaging endophenotypes could open new avenues in small vessel disease research, broadening our understanding of its risk factors and clinical correlates.

Keywords: Framingham risk score; aging; atrophy; attention; cardiovascular disease risk; cerebral small vessel disease; cognition; cognitive performance; deep learning; delayed memory; diffusion tensor imaging; enlarged perivascular spaces; executive function; factor analysis; fractional anisotropy; global cognition; gray matter volume; immediate memory; language; latent variable; magnetic resonance imaging; mediation; microbleeds; phonemic fluency; processing speed; semantic fluency; structural equation modeling; trace; visuospatial functioning; white matter hyperintensities.

© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

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Conflict of interest statement

The authors report no disclosures relevant to the present manuscript. Author disclosures are available in the supporting information.

Figures

FIGURE 1

FIGURE 1

Path diagram of the conceptual model for the effect of age on cognition. In the measurement model, small vessel disease (SVD) is hypothesized as the underlying, or latent, cause of perivascular spaces (PVS) in the basal ganglia and thalamus, white matter hyperintensities (WMH) in periventricular and subcortical locations, and mean white matter (WM) fractional anisotropy and trace. In the structural model, SVD and gray matter (GM) volume are hypothesized as mediators of the effect of age on cognition. Arrow values in the measurement model represent standardized loadings (or residual covariances for double‐headed arrows), and in the structural model, comparative fit index standardized regression coefficients. Asterisks indicate statistically significant parameter estimates at p <0.01 (*) and p <0.001 (**). For calculation of the indirect effect via SVD, both the pathways Age→SVD→Cognition and Age→SVD→GMvolume→Cognition were considered.

FIGURE 2

FIGURE 2

Path diagram of the conceptual model for the effect of cardiovascular disease risk on cognition. In the measurement model, small vessel disease (SVD) is hypothesized as the underlying, or latent, cause of perivascular spaces (PVS) in the basal ganglia and thalamus, white matter hyperintensities (WMH) in periventricular and subcortical locations, and mean white matter (WM) fractional anisotropy and trace. In the structural model, SVD and gray matter (GM) volume are hypothesized as mediators of the effect of Framingham cardiovascular disease Risk Score (FRS) on cognition. Arrow values in the measurement model represent standardized loadings (or residual covariances for double‐headed arrows), and in the structural model, standardized regression coefficients. Asterisks indicate statistically significant parameter estimates at p < 0.01 (*) and p < 0.001 (**). For calculation of the indirect effect via SVD, both the pathways FRS→SVD→Cognition and FRS→SVD→GMvolume→Cognition were considered.

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