Cholinergic basal forebrain deficit impairs BOLD-CSF coupling and glymphatic flux

Motivation: What regulates the glymphatic system and why it is impaired in aging and dementia are largely unknown. Global BOLD (gBOLD) signal anticorrelates with CSF inflow and is modulated by basal forebrain cholinergic activity. Could it be the regulator? Goal(s): To determine the role of basal forebrain cholinergic neurons in regulating gBOLD-CSF coupling and glymphatic function. Approach: PET-MRI in non-demented aged subjects to measure cholinergic activity and gBOLD-CSF coupling. Validate by cholinergic lesion in mice with intracisternal Gd contrast injection. Results: gBOLD-CSF coupling correlated with cortical cholinergic activity. Cholinergic lesion abolished BOLD-CSF coupling. Regional BOLD-CSF coupling correlated with tissue glymphatic influx. Impact: As cholinergic neurodegeneration is an early feature of Alzheimer's disease, the cholinergic pathway could be a new diagnostic and treatment target for improving glymphatic function in aging and dementia.