Connections across regional glymphatic clearance, neural activity and amyloid-β deposition in cortex

Neural activity inevitably produces waste, which promotes neurodegeneration with topographic features. The glymphatic system is important for waste clearance. However, the spatial characteristics of glymphatic clearance across cortex, the pattern it coupled with neural activity, and whether those mismatch regions overlap with known amyloid-prone cortical regions in human remain unexplored. Here, by intrathecal administration of gadolinium-based contrast agents, glymphatic influx and clearance patterns across cortex in 96 participants are depicted via Glymphatic MRI. Analyses integrating public post-mortem transcriptomic profiles from Allen Human Brain Atlas indirectly indicate that, genes related with excitatory and inhibitory neurons, and pathways engaging in synaptic function were spatially enriched in regions with faster glymphatic clearance. Fractional amplitude of low frequency fluctuation was calculated from resting-state fMRI to represent neural activity. At the regional level, based on a subgroup with rs-fMRI (N = 15), regional glymphatic clearance was positively coupled with spontaneous neural activity. The mismatch index, reflecting decoupling between spontaneous neural activity and glymphatic clearance function, showed positive spatial associations with an external group-average 11C-PiB SUVR map. Together, this study for the first time demonstrates that neural activity is associated with glymphatic dynamics from transcriptional to physiological level. The mismatch magnitude between these two processes may potentiate regional vulnerability to proteopathy and subsequent neurodegeneration in cortex.