Cerebellar and cerebral contributions to dual physical-cognitive impairment in middle-aged and older adults: Potential biomarkers and therapeutic targets for healthy aging

Dual physical and cognitive decline, or physio-cognitive decline syndrome (PCDS), significantly increases disability, dementia, and mortality risks in older adults. To elucidate the neurobiological mechanisms underlying PCDS, we used an innovative, cerebellum-centered, data-driven approach to establish structural covariance networks (SCNs) and identify specific cerebellar SCNs associated with simultaneous physical and cognitive impairments. This analysis was based on MRI data from 1193 adults aged ≥50 and older (mean age ± SD: 62.8 ± 8.7 years) in the I-Lan Longitudinal Aging Study. Through non-negative matrix factorization analysis, we identified seven cerebellar SCNs, among which SCN-2, predominantly located in the posterior lobe (63% in lobule VI, 10% in Crus I), showed significant association with dual-domain impairment (ρ = 0.083 for physical domain and ρ = 0.154 for cognitive domain, p < 0.007 by Bonferroni-correction). Voxel-wise mediation analyses, adjusted for age, sex, education, and intracranial volume, revealed that specific cerebral regions, including bilateral thalamus, left frontal orbital cortex, left amygdala/hippocampus, right hippocampus, right occipital fusiform gyrus, and right temporal pole, significantly mediated the relationship between SCN-2 and dual impairments. Our findings establish SCN-2 and its mediated cerebral regions as potential biomarkers for understanding and treating PCDS, suggesting that preserving cerebellar SCNs integrity could be crucial for developing targeted interventions in healthy aging strategies.