Deficits in cholinergic neurotransmission and their clinical correlates in Parkinson’s disease

Santiago Perez-Lloret,Francisco J Barrantes

doi:10.1038/npjparkd.2016.1

Abstract

In view of its ability to explain the most frequent motor symptoms of Parkinson’s Disease (PD), degeneration of dopaminergic neurons has been considered one of the disease’s main pathophysiological features. Several studies have shown that neurodegeneration also affects noradrenergic, serotoninergic, cholinergic and other monoaminergic neuronal populations. In this work, the characteristics of cholinergic deficits in PD and their clinical correlates are reviewed. Important neurophysiological processes at the root of several motor and cognitive functions remit to cholinergic neurotransmission at the synaptic, pathway, and circuital levels. The bulk of evidence highlights the link between cholinergic alterations and PD motor symptoms, gait dysfunction, levodopa-induced dyskinesias, cognitive deterioration, psychosis, sleep abnormalities, autonomic dysfunction, and altered olfactory function. The pathophysiology of these symptoms is related to alteration of the cholinergic tone in the striatum and/or to degeneration of cholinergic nuclei, most importantly the nucleus basalis magnocellularis and the pedunculopontine nucleus. Several results suggest the clinical usefulness of antimuscarinic drugs for treating PD motor symptoms and of inhibitors of the enzyme acetylcholinesterase for the treatment of dementia. Data also suggest that these inhibitors and pedunculopontine nucleus deep-brain stimulation might also be effective in preventing falls. Finally, several drugs acting on nicotinic receptors have proved efficacious for treating levodopa-induced dyskinesias and cognitive impairment and as neuroprotective agents in PD animal models. Results in human patients are still lacking.

Highlights

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting about 1 person out of every 1,000 in their fifth decade and 19 out of every 1,000 in their eighth decade or older.[1]Its principal epiphenomenological clinical symptoms are abnormal involuntary movements, bradykinesia, rigidity, and tremor.Patients frequently display non-motor symptoms, including cognitive impairment, mood disorders, sleep alterations, dysautonomia, and hallucinations, among others.[2]Histopathological changes are mainly, but not exclusively, characterized by the progressive loss of the nigrostriatal dopaminergic pathway and of the source dopaminergic neurons in the substantia nigra pars compacta, which explain the most typical motor symptoms.[3]
There is robust evidence indicating the important role of nAChRs in the genesis of Levodopa-induced dyskinesias (LIDs)
Results showed that the Cholinergic Pathways Hyperintensities Scale (CHIPS) score was correlated with MMSE, SOB scores of the Clinical Dementia Rating, and verbal and visuospatial memory domains in demented patients

Summary

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting about 1 person out of every 1,000 in their fifth decade and 19 out of every 1,000 in their eighth decade or older.[1]Its principal epiphenomenological clinical symptoms are abnormal involuntary movements, bradykinesia, rigidity, and tremor.Patients frequently display non-motor symptoms, including cognitive impairment, mood disorders, sleep alterations, dysautonomia, and hallucinations, among others.[2]Histopathological changes are mainly, but not exclusively, characterized by the progressive loss of the nigrostriatal dopaminergic pathway and of the source dopaminergic neurons in the substantia nigra pars compacta, which explain the most typical motor symptoms.[3]. Levodopa-induced dyskinesias (LIDs) are choreoathetosic hyperkinetic movements that complicate motor treatment with dopaminergic drugs in PD and have profound effects on the quality of life.[62] Their physiopathology is complex and involves changes in neurotransmitters and gene expression,[63] groups These results reinforce the notion that PPN might including cholinergic abnormalities. ChAT activity, a measure of the presence of cholinergic terminals in a given brain region, was reduced in the hippocamintense research in diseases affecting cognitive functions, pus of PD with dementia compared to non-demented patients especially the subclass of ligands termed positive allosteric and controls. Several pieces of evidence coming from studies on different parkinsonian animal models indicate that nicotine exposure improves dopaminergic markers and function in the lesioned striatum, the brain region predominantly affected in PD.[145] These effects have been linked to the activation of nAChRs.[146]

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