THE CASE FOR CHOLINESTERASE INHIBITION TO MODIFY NEURODEGENERATIVE DISEASES THROUGH THE INTRAMURAL PERIARTERIAL DRAINAGE OF THE CNS (IPAD)

Background Cholinesterase inhibition has been the most successful treatment in neurodegenerative dementias to date. Usually considered to be limited to symptomatic improvement, retrospective data and recent studies suggest disease modifying effects as evidenced by pathologic, imaging and clinical data. The mechanism is unknown, as much of CNS acetylcholine is released extrasynaptically with unclarified activity. We hypothesize that acetylcholine may act by facilitating the clearance of pathologic metabolic by-products through the intramural peri-arterial drainage system (IPAD). Methods A review of the existing animal and human laboratory data regarding the disease modifying effects of cholinesterase inhibition is presented and correlated with emerging clinical and epidemiological data to support or refute this hypothesis. Results Animal and human histopathologic studies have demonstrated that destruction of basal forebrain cholinergic neurons results in accumulation of fibrillar amyloid and functional impairment. Moreover, the IPAD system in mice appears to be impaired by selective chemical cholinergic denervation. Human Studies show that cholinesterase inhibition results in functional improvements in a dose dependent manner, including postponing the need for institutionalization in Alzheimer’s Disease. A human case series demonstrated a reduced cognitive decline in Dementia with Lewy Bodies with higher than usually tolerated doses of cholinesterase inhibitors. Inhibition of muscarinic receptors can identify humans with reduced cholinergic reserve, and correlate with amyloid accumulation. Finally, chronic exposure to muscarinic antagonists may increase risk for developing dementia. Conclusions A fundamental role for acetylcholine in the pathophysiology of neurodegenerative diseases is supported by experimental studies in animals and humans. It is further supported by recent human therapeutic trials and experimental studies in the preclinical stage of AD. Case series and epidemiological data support an association between cholinergic manipulations (in either direction) with the incidence and clinical course of neurodegenerative diseases. The data show strength of association, consistency across species and specificity to the cholinergic system. There is a temporal association between interventions and outcomes as well as dose-response relationships. These findings are all consistent with an emerging mechanistic understanding of CNS protein clearance. Experimental confirmation of the role of acetylcholine in IPAD function is indicated.