Background Cortical cerebral microinfarcts (CMIs) are a small vessel disease (SVD) biomarker underlying cognitive impairment and dementia. However, it is unknown whether CMIs are associated with neuropsychiatric disturbances, and whether its effects are independent of conventional SVD markers. Aims We investigated the associations of CMI burden with incidence and progression of neuropsychiatric subsyndromes (NPS) in a memory clinic cohort of elderly in Singapore. Methods In this prospective cohort, 496 subjects underwent detailed neuropsychological and clinical assessments, 3T brain MRI, and Neuropsychiatric Inventory assessment at baseline and 2 years later. Cortical CMIs and other SVD markers, including white matter hyperintensities, lacunes, and microbleeds, were graded according to established criteria. NPS were clustered into subsyndromes of Hyperactivity, Psychosis, Affective, and Apathy following prior findings. Functional decline was determined using the Clinical Dementia Rating (CDR) scale. Results The presence of multiple CMIs (â¥2) was associated with higher NPS-total (β=4.19, 95% CI=2.81-5.58, p<0.001), particularly Hyperactivity (β=2.01, 95% CI=1.30-2.71, p<0.01) and Apathy (β=1.42, 95% CI=0.65-2.18, p<0.01) at baseline. Between baseline and year-2, multiple CMIs were associated with accelerated progression in NPS-total (β=0.29, 95% CI=0.06-0.53, p=0.015), driven by Hyperactivity (β=0.45, 95% CI=0.17-0.72, p<0.01). Subjects with multiple CMIs also had a faster functional decline, as measured with the CDR-sum-of-boxes scores, when accompanied with NPS-total progression (β=0.31, 95% CI=0.11-0.51, p<0.01), or Hyperactivity (β=0.34, 95% CI=0.13-0.56, p<0.01). Conclusion Cortical CMIs are associated with incidence and progression of geriatric neurobehavioral disturbances, independent of conventional SVD markers. The impact of incident CMIs on neurocognitive and neuropsychiatric trajectories warrants further investigations.