Association of glymphatic function with 40-Hz neural oscillations, systemic metabolic markers, and cognitive...

Aging-related cognitive decline is frequently concomitant with systemic metabolic dysregulation. However, the mechanisms linking age-related cognitive decline to systemic metabolic dysregulation remain poorly defined. We collected magnetic resonance imaging (MRI), electroencephalogram (EEG), and serum markers from 193 individuals (135 young adults [94 males] and 58 older adults [29 males]) in a multimodal dataset. Glymphatic system (GS) metrics were assessed indirectly using diffusion tensor image analysis along the perivascular space (DTI-ALPS) index and blood-oxygen-level-dependent cerebrospinal fluid (BOLD-CSF) coupling. EEG data were used to evaluate 40-Hz neural oscillatory dynamics. Partial correlation analyses and moderation analyses were performed to identify relationships among age, GS metrics, serum markers, cognitive performance, and 40-Hz oscillatory dynamics. The MRI metrics of GS activity declined with age in healthy adults. The power of 40-Hz neural oscillations across the whole brain showed a negative correlation with global BOLD-CSF coupling, similar correlations were also observed between regional 40-Hz power and corresponding regional BOLD-CSF coupling in the anterior, middle, and posterior regions of the brain. The MRI metrics of GS activity significantly associated with several serum markers and moderated the relationship between serum markers and cognitive performance. The results established an integrated neurophysiological framework of aging, metabolic dysregulation, gamma oscillation deficits, GS metrics decline, and cognitive decline. These findings emphasize the critical importance of maintaining normal GS function and preserving 40-Hz oscillatory activity in the current landscape of therapeutics targeting age-related cognitive deterioration.