Cholinergic activity and levodopa‐induced dyskinesia: a multitracer molecular imaging study

Abstract

ObjectiveTo investigate the association between levodopa‐induced dyskinesias and striatal cholinergic activity in patients with Parkinson's disease.MethodsThis study included 13 Parkinson's disease patients with peak‐of‐dose levodopa‐induced dyskinesias, 12 nondyskinetic patients, and 12 healthy controls. Participants underwent 5‐[123I]iodo‐3‐[2(S)‐2‐azetidinylmethoxy]pyridine single‐photon emission computed tomography, a marker of nicotinic acetylcholine receptors, [123I]N‐ω‐fluoropropyl‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)nortropane single‐photon emission computed tomography, to measure dopamine reuptake transporter density and 2‐[18F]fluoro‐2‐deoxyglucose positron emission tomography to assess regional cerebral metabolic activity. Striatal binding potentials, uptake values at basal ganglia structures, and correlations with clinical variables were analyzed.ResultsDensity of nicotinic acetylcholine receptors in the caudate nucleus of dyskinetic subjects was similar to that of healthy controls and significantly higher to that of nondyskinetic patients, in particular, contralaterally to the clinically most affected side.InterpretationOur findings support the hypothesis that the expression of dyskinesia may be related to cholinergic neuronal excitability in a dopaminergic‐depleted striatum. Cholinergic signaling would play a role in maintaining striatal dopaminergic responsiveness, possibly defining disease phenotype and progression.

Cholinergic control of striatal neurons to modulate L‐dopa‐induced dyskinesias

“…Collectively, all the above pre‐clinical studies strongly indicate that striatal nAChR signaling influences LIDs expression. In agreement with this, a recent imaging study also found that LIDs expression is related to cholinergic neuron excitability and density of nAChRs in PD patients (Brumberg et al ., ).…”

“…Although clinical evidence linking the nicotinic cholinergic system to the pathological changes leading to LIDs are only emerging (Brumberg et al ., ), preclinical evidence for their involvement stems from multiple seminal studies showing that nicotine and nAChR drugs reduce LIDs by up to 60% in several parkinsonian animal models (Bordia et al ., , ; Huang et al ., ,b; Quik et al ., ; Zhang et al ., , ). Since nicotine can lead to sensitized behaviors (Gregorio et al ., ), the question that next arises is whether nicotinic drugs can also lead to such secondary changes in dyskinetic animals; our studies show no such sensitization or tolerance to long‐term use of nicotine or nAChR targeted drugs on locomotor behavior (Quik et al ., ; Bordia et al ., ; Huang et al ., ,b; Quik et al ., ; Bordia et al ., ; Zhang et al ., ).…”

Effects of Parkinson's disease on molar bite force, electromyographic activity and muscle thickness of the masseter, temporal and sternocleidomastoid muscles: A case‐control study

“…Levodopa is the drug most commonly used to control Parkinson's disease and improve muscle control and cognitive response of patients; however, it may have adverse side effects 40. Levodopa is transformed into dopamine by enzymes present in various organs of the body 41. Owing to the peripheral effects of dopamine, adverse responses such as the onset of postural hypotension may occur 42.…”

MRI of Motor and Nonmotor Therapy‐Induced Complications in Parkinson's Disease

“…PD patients with LIDs showed increased dopamine release after the administration of levodopa compared with PD patients with stable response to levodopa and reduction in radioligand levels in the putamen correlating with worse deficits, suggesting that LIDs may be related to fluctuating dopamine levels . Another study, by means of 5‐[ 123 I]iodo‐3‐[2(S)‐2‐azetidinylmethoxy]pyridine single photon emission tomography (SPECT), a marker of nicotinic acetylcholine receptors, showed that density of nicotinic acetylcholine receptors in the caudate nucleus of dyskinetic subjects is higher than that of nondyskinetic patients, supporting the hypothesis that LIDs may be related to intrastriatal cholinergic neuronal excitability in dopaminergic‐depleted striatum . These findings could be the indirect explanation for the results obtained in fMRI studies, demonstrating the presence of abnormal connectivity involving the striatocortical networks in association with LIDs …”