Synergistic effect between cortical cerebral microinfarcts and brain atrophy on cognitive decline.

Cortical cerebral microinfarcts are associated with brain atrophy in cross-sectional studies, while further investigation using longitudinal datasets is warranted. Moreover, little is known about their combined impact on cognition. This study aims to establish the association between cortical cerebral microinfarcts and brain volume loss over time and to explore whether they synergistically contribute to cognitive decline. 475 patients, aged 72.7±7.9 years, were enrolled from a memory clinic cohort, who underwent neuroimaging and neuropsychological assessments at least twice over five years. Cortical cerebral microinfarcts and other cerebrovascular disease were assessed on 3-Tesla MRI. Brain volumes were calculated semi-automatically using FreeSurfer. Cognitive function was assessed using a neuropsychological test battery including six domains. Linear mixed-effect models were utilized to examine the association between cortical cerebral microinfarcts and brain volume loss and their interaction on cognitive decline. Estimated marginal means were derived to plot global cognitive trajectories. Cortical cerebral microinfarcts were associated with greater decrease over two years in total brain volume (β = -1.94 [-3.07, -0.82] at year 2, P-interaction with time < 0.001), gray matter volume (β = -1.00 [-1.69, -0.30] at year 2, P-interaction = 0.002), and white matter volume (β = -0.95 [-1.54, -0.35] at year 2, P-interaction < 0.001). Brain volume loss was more pronounced in patients with multiple microinfarcts. Patients with high brain volume loss and cortical cerebral microinfarcts, particularly multiple microinfarcts, exhibited significantly lower global cognitive scores (Single microinfarct: β = -1.83 [-2.68, -0.97] at year 5, P-interaction with time < 0.001; Multiple microinfarcts: β = -3.13 [-4.21, -2.05] at year 5, P-interaction < 0.001). The synergistic effects were more significant in the domains of executive function, memory, language, and visuospatial function. Global cognitive trajectories revealed greater cognitive decline in patients with high brain volume loss and single or multiple microinfarcts, with the latter showing the steepest slope. This study established a longitudinal association between cortical cerebral microinfarcts and brain atrophy progression, with higher microinfarct burden associated with more pronounced brain volume loss. Furthermore, cortical cerebral microinfarcts and brain atrophy showed synergistic effects on cognitive decline. These findings highlight the importance of investigating the role of mixed pathologies in the development of cognitive impairment and dementia in future research.