Therapeutic approaches to cholinergic deficiency in Lewy body diseases

ABSTRACT

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.

KEYWORDS:

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

Article highlights

• Cholinergic basal forebrain degeneration is a core feature of all Lewy body diseases and contributes to cognitive impairment and neuropsychiatric symptoms.

• The cholinesterase inhibitors rivastigmine, donepezil, and galantamine are the pharmacological treatments currently available to improve cognition in Lewy body diseases.

• Other pharmacological strategies to reverse the effects of cholinergic deficiency in Lewy body diseases may also be helpful for enhancing cognition.

• Other potential pharmacological strategies include 5-HT₄ agonists to increase acetylcholine release or muscarinic and nicotinic agonists to directly stimulate cholinergic receptors.

• Deep brain stimulation- or cell-based therapies targeting the cholinergic basal forebrain are potential other strategies for mitigating cortical cholinergic deficiency.

Declaration of interest

MJ Barrett was site primary investigator for clinical trials funded by National Institutes of Health, Azevan, Axovant, Merck, Eisai, Biogen, and Acadia. LJ Cloud received funding from the Michael J. Fox Foundation to investigate RQ-00000010 for gastroparesis and constipation in Parkinson’s disease. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Neurotoxin Exposure Treatment Parkinson’s Research Program under Award No. [W81XWH-16-1-0768].