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.

[P3–382]: NEURAL EVIDENCE FOR DEFECTIVE TOP‐DOWN CONTROL OF VISUAL PROCESSING IN PARKINSON's AND ALZHEIMER's DISEASE

“…Our results are consistent with other fMRI studies demonstrating decreased activation/connectivity within frontoparietal attention and executive control networks in amnestic AD-MCI as compared to HC (Neufang et al, 2011;Rombouts et al, 2002;Saykin et al, 2004;Sorg et al, 2007), and in PD-MCI as compared to PD-NC (Amboni et al, 2015;Baggio et al, 2015;Gratwicke et al, 2015), and with cognitive studies demonstrating impaired top-down control of visual attention in PD (Tommasi et al, 2015) and in AD-MCI (Redel et al, 2012). While impaired attention, working memory capacity and executive function in PD-MCI have been mostly linked to fronto-striatal and mesocortical dopamine network deficits (Gratwicke et al, 2015;Cools et al, 2008), dementia in both AD and PD has been related to cholinergic network dysfunction (Ballinger et al, 2016;Bohnen et al, 2015Bohnen et al, , 2003Francis et al, 1999;Hilker et al, 2005;Perez-Lloret and Barrantes, 2016). Of note, cholinergic afferents are relatively enriched in frontal cortices (Petrou et al, 2014) and prefrontal projections to the nucleus basalis of Meynert may modulate cholinergic inputs to sensory cortices and thus represent another component of the top-down frontoparietal attention network (Gratwicke et al, 2015) (in addition to direct projections from frontoparietal cortices to extrastriate visual areas).…”

Piribedil for the Treatment of Motor and Non-motor Symptoms of Parkinson Disease

“…The authors proposed that the mechanism explaining this effect may involve the release of acetylcholine in the basal forebrain, induced by the blockade of the alpha2-adrenoreceptors. Indeed, attentional deficits in PD are known to be related to cholinergic degeneration in these regions [44,45].…”

Donepezil for Lewy Body Constipation: A Six-Month Follow-up

“…Because Lewy pathology impairs cholinergic function [13][14][15][16][17], cholinergic agonists like cholinesterase inhibitors (AChEIs) are prescribed to NCDLB and PD patients with the intention of mitigating cholinergic impairment. Data were also reviewed demonstrating that (e) among AChEIs, Donepezil has performed well [18][19][20][21][22]; (f) a Cochrane database systematic review found that Donepezil produced consistent reduction in neurocognitive symptoms in patients with PD and NCDLB, without exacerbation of Parkinsonian features or other side effects [23]; (g) Donepezil has reduced constipation in nongeriatric affective patients [24]; and (h) Donepezil increased cholinergically mediated bowel contractions as much as 477% in patients suffering from severe intestinal dysmotility [25].…”