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

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.

Figure 1

Cholinergic neurons and networks in the rodent CNS. bas, nucleus basalis; BLA, basolateral amygdala; DR, dorsal raphe; EC, entorhinal cortex; hdb, horizontal diagonal band nucleus; Icj, islands of Cajella; IPN, interpeduncular nucleus; LC; locus ceruleus; ldt, laterodorsal tegmental nucleus; LH, lateral hypothalamus; ms, medial septal nucleus; PPN, pedunculopontine nucleus; si, substantia innominata; SN, substantia nigra; vdb, vertical diagonal band nucleus. Reprinted from Woolf and Butcher, Cholinergic systems mediate action from movement to higher consciousness, 2011, with permission from Elsevier.