Cerebral aqueduct CSF dynamics by diffusion tensor imaging and its association with glymphatic function and cognitive decline in Alzheimer’s spectrum

Cerebrospinal fluid (CSF) plays a critical role in maintaining brain homeostasis through the clearance of neurotoxic metabolites, yet the relationship between CSF dynamics and cognitive dysfunction remains unclear. This study examined the diffusion metrics of CSF water molecules in the cerebral aqueduct and their association with cognitive impairment and Alzheimer’s disease (AD) pathology, aiming to establish a non-invasive neuroimaging marker of CSF dynamics. A total of 226 participants from the Ruijin Neurobank cohort were included, consisted of cognitively normal individuals, mild cognitive impairment, and AD. Diffusion tensor imaging (DTI) was used to derive fractional anisotropy (FA), mean diffusivity (MD), and the DTI-ALPS index within the aqueduct. Amyloid-β and tau deposition were quantified using 18F-Florbetapir and 18F-MK-6240 PET-MR, and cognitive performance was evaluated by the Mini-Mental State Examination and Auditory Verbal Learning Test. Significant group differences were observed in aqueductal FA metrics, which correlated with amyloid and tau accumulation, cortical thinning, and impaired memory performance. FA and Mes-FA were also associated with the DTI-ALPS index, suggesting a link between CSF dynamics and glymphatic function. Mediation analyses indicated that glymphatic dysfunction mediated the relationship between altered CSF flow and cognitive decline. These findings suggest that impaired CSF dynamics within the cerebral aqueduct may contribute to cognitive deterioration independently of amyloid and tau pathology and highlight DTI-based assessment of CSF flow as a promising translational biomarker for neurodegenerative cognitive disorders.