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Expert Rev Neurother. 2019 Oct 12:1-13. doi: 10.1080/14737175.2020.1676152. [Epub ahead of print]

Therapeutic approaches to cholinergic deficiency in Lewy body diseases.

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Department of Neurology, University of Virginia School of Medicine , Charlottesville , VA , USA.
Department of Neurology, Virginia Commonwealth University School of Medicine , Richmond , VA , USA.
Department of Neurosurgery, Virginia Commonwealth University School of Medicine , Richmond , VA , USA.
The Southeast Parkinson's Disease Research, Education, and Care Center, Hunter Holmes McGuire Veteran Affairs Medical Center , Richmond , VA , USA.


Introduction: Cortical cholinergic denervation resulting from degeneration of the nucleus basalis of Meynert (NBM) is a primary contributor to cognitive impairment and neuropsychiatric symptoms in the Lewy body diseases Parkinson's disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB). Considering the morbidity associated with cognitive impairment and neuropsychiatric symptoms in these diseases, it is important to investigate all potential therapies to improve these symptoms. Areas covered: The authors review the current landscape of pharmacological and surgical therapies for mitigating the cortical cholinergic deficiency in PD, PDD, and DLB. Expert opinion: The cholinesterase inhibitors rivastigmine, donepezil, and galantamine are currently the primary pharmacological treatments available to improve cognition and associated neuropsychiatric symptoms in Lewy body diseases. Other possible pharmacological strategies include increasing acetylcholine release with 5-HT4 agonists or directly stimulating cholinergic receptors with muscarinic and nicotinic agonists. The side effect profile of muscarinic agonists is a deterrent to their future study, but 5-HT4 and nicotinic agonists deserve further investigation. Targeting the basal forebrain with either deep brain stimulation (DBS)- or cell-based therapies is another strategy to mitigate cortical cholinergic deficiency. Before NBM DBS studies continue, it will be important to resolve issues related to targeting, stimulation pattern, and duration.


Lewy body disease; Parkinson’s disease; acetylcholine; attention; basal forebrain; cholinesterase inhibitors; cognition; deep brain stimulation; nicotinic agonist; nucleus basalis of meynert

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