Oscillating Hypercapnia Induces Neural Abundant Protein Efflux and Potential Depletion in Health and Chronic Traumatic Brain Injury

Abstract Emerging preclinical and clinical evidence suggests that low frequency hemodynamic oscillations drive CSF flow, which in turn mediates glymphatic clearance. The current study investigated whether CO2-induced low frequency hemodynamic oscillations during magnetic resonance imaging would increase clearance of proteins (glial fibrillary acidic protein, neurofilament light chain, ptau217 and brain-derived tau) from brain to blood, and temporarily improve cognitive performance in individuals with chronic traumatic brain injury (TBI) and age/sex-matched healthy controls. Results indicated that cerebrovascular reactivity, normalized CSF volume, and predicted brain age significantly differed between chronic TBI and controls, while bulk CSF flow differed only at trend levels. Multiple protein concentrations were significantly increased at ∼45 minutes post-hypercapnia, decreased at ∼90 minutes, and returned to pre-hypercapnia levels by ∼150 minutes. Protein efflux was more strongly associated with total CSF volume and total white matter volume rather than cerebrovascular reactivity or bulk CSF flow. Both groups exhibited reduced cognitive interference post-hypercapnia, and hypercapnia associated symptoms quickly returned to baseline levels. In conclusion, hypercapnia temporarily increases clearance of multiple neural abundant proteins into blood, and this effect is moderated by atrophy. Current results suggest that hypercapnia may therapeutically combat pathological protein aggregation post-trauma, and prophylactically during normal aging. Competing Interest Statement Dr. Meier receives in-kind research support from Abbott Laboratories and has received compensation as a member of the Clinical and Scientific Advisory Board for Quadrant Biosciences Inc. Dr. Mannix receives research support from Abbott Laboratories by a grant to her institution. No other competing financial interests exist.