Circulating Progenitor Cells, Regenerative Capacity and Cognition: Evidence From 2 Community-Based Cohorts

Impaired endogenous vascular regenerative capacity, reflected by reduced circulating progenitor cell (CPC) counts, has been linked to age-related diseases, particularly adverse cardiovascular outcomes. Lower CPC counts have also been associated with accelerated age-related cognitive decline in otherwise healthy individuals, but their relationships with cognitive impairment and neuroimaging markers of vascular brain injury and neurodegeneration remain unclear. We investigated cross-sectional associations between CPC subsets, cognitive performance, and neuroimaging phenotypes, hypothesizing that lower CPC levels would be associated with worse cognition and adverse brain markers.

In 283 community-dwelling participants (mean age, 65 years; 59% female, 39% Black) enrolled in the Brain Stress, Hypertension, and Aging Research Program, cognitive assessments (including Montreal Cognitive Assessment), brain magnetic resonance imaging-derived white matter hyperintensity volumes, and whole-brain cortical thickness were measured. Flow cytometry was used to enumerate CPCs as CD45^med mononuclear cells expressing CD34 with coexpression of either CD133, chemokine CXCR4 (CXC motif receptor 4), or VEGFR2⁺ (vascular endothelial growth factor receptor-2). Linear regression models were adjusted for demographic and vascular risk factors.

In fully adjusted models, lower CD34⁺/CD133⁺ CPC levels were associated with worse global cognition (Montreal Cognitive Assessment: β=0.59; P=0.01), lower mean cortical thickness (β=0.01; P=0.01), and greater white matter hyperintensity burden (β=-0.15; P=0.01). Similarly, lower CD34⁺ and lower CD34⁺/CXCR4⁺ CPC levels were significantly associated with greater white matter hyperintensity volume (CD34⁺: β=-0.27, P<0.01; CD34⁺/CXCR4+: β=-0.14, P=0.03). CD34⁺/VEGFR2⁺ CPC levels were associated with Montreal Cognitive Assessment (β=0.37, P<0.01) and Boston Naming Test performance (β=0.01, P=0.03), but not with neuroimaging phenotypes.

Reduced regenerative capacity was associated with worse global cognitive performance and markers of vascular brain injury, including greater white matter hyperintensity burden and cortical thinning. These findings should be validated in longitudinal studies to clarify temporality and potential causality.