Neural substrates of cognitive frailty as a high-risk factor for dementia compared with mild cognitive impairment: A multimodal magnetic resonance imaging study

Cognitive frailty (CF) is recognized as a high-risk state for dementia, defined by the coexistence of physical frailty (PF) and mild cognitive impairment (MCI). While both PF and MCI increase vulnerability to dementia, CF confers an even higher risk than either condition alone. However, the neural substrates distinguishing CF from MCI remain unclear. The objective of this study is to elucidate the neural differences between CF and MCI using multimodal MRI analyses.

We investigated the neural substrates of community-dwelling older adults with CF (n = 61) and MCI (n = 108) by performing between-group comparisons of multimodal MRI measures to comprehensively examine the underlying neural mechanisms. Whole-brain analyses were conducted to assess gray matter (GM) volume, white matter hyperintensities (WMHs), and both structural and resting-state functional connectivity. Age, sex, vascular risk factors, and intracranial volume were included as covariates.

The CF group exhibited significantly greater GM atrophy than the MCI group in widespread brain regions, including the temporal lobe, fusiform gyrus, cerebellum, cuneus, precuneus, precentral and postcentral gyri, and caudate nucleus. In contrast, no significant differences were observed between groups in WMH volume or count, structural connectivity, or resting-state functional connectivity.

These findings suggest that widespread GM atrophy may be more evident in CF than in MCI, whereas no clear differences were observed in WMHs or structural or functional connectivity. This study provides new evidence on the neural basis of CF and highlights the utility of multimodal MRI in elucidating the neural substrates of frailty states.