Disruptions of the diffusion tensor image analysis along the perivascular space index and dynamic functional connectivity across the Alzheimer's disease spectrum: Implications for cognitive impairment

BackgroundAcross the Alzheimer's disease spectrum (ADS), spanning subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia, the interplay between alterations in diffusion tensor imaging (DTI) analysis along the perivascular space (ALPS), brain functional connectivity, and cognitive impairment (CI) remains poorly understood.ObjectiveTo evaluate DTI-ALPS index and brain network across clinical stages of ADS and assess whether brain network disruptions mediates the association between DTI-ALPS index and CI.MethodsA total of 188 ADS patients and 77 healthy controls (HC) were recruited. The DTI-ALPS index, dynamic functional connectivity (dFC) and network topology were estimated from MRI. Group differences were assessed using analysis of covariance. Mediation analyses examined whether disruptions in dFC or topology mediated the association between the DTI-ALPS index and CI.ResultsCompared with HC, SCD patients showed significantly reduced ALPS index in the left hemisphere, whereas MCI and AD patients showed significantly reduced ALPS index in both hemispheres. While topology showed no significant differences across ADS, dFC analysis revealed stage-specific alterations, with abnormalities in higher-order cognitive systems in the early stage and in primary processing systems in later stages. Mediation analysis indicated that dFC disruption, but not topology abnormalities, mediated the association between reduced DTI-ALPS index and CI in ADS patients.ConclusionsDecreased DTI-ALPS index and abnormalities in higher-order cognitive systems emerged as early as the SCD stage and exhibited stage-dependent differences across disease severity. Importantly, dFC disruption mediated the association between reduced DTI-ALPS index and CI, suggesting a potential underlying pathological mechanism.