Abstract
We investigated in vivo brain nicotinic acetylcholine receptor (nAChR) distribution in cognitively intact subjects with Parkinson’s disease (PD) at an early stage of the disease. Fourteen patients and 13 healthy subjects were imaged with single photon emission computed tomography and the radiotracer 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine ([123I]5IA). Patients were selected according to several criteria, including short duration of motor signs (<7 years) and normal scores at an extensive neuropsychological evaluation. In PD patients, nAChR density was significantly higher in the putamen, the insular cortex and the supplementary motor area and lower in the caudate nucleus, the orbitofrontal cortex, and the middle temporal gyrus. Disease duration positively correlated with nAChR density in the putamen ipsilateral (ρ = 0.56, p < 0.05) but not contralateral (ρ = 0.49, p = 0.07) to the clinically most affected hemibody. We observed, for the first time in vivo, higher nAChR density in brain regions of the motor and limbic basal ganglia circuits of subjects with PD. Our findings support the notion of an up-regulated cholinergic activity at the striatal and possibly cortical level in cognitively intact PD patients at an early stage of disease.
Highlights
At an early motor stage, Parkinson’s disease (PD) is predominantly characterized by a progressive loss of the nigrostriatal dopaminergic neurons leading to a severe state of dopamine depletion
We investigated by means of 5-[123I]iodo3-[2(S)-2-azetidinylmethoxy]pyridine ([123I]5IA), a specific α4β2 nicotinic acetylcholine receptor (nAChR) ligand, and single photon emission computed tomography (SPECT) ([123I]5IA-SPECT) a group of PD patients selected for a short disease duration, the capability to be withdrawn from all dopaminergic medications for 3 days, and normal scores from extensive neuropsychological evaluation
Despite the long history of the dopamine-ACh balance hypothesis, we are just beginning to understand why and how dopamine depletion triggers a profound deterioration of basal ganglia circuit dynamics, such as over-activation of cholinergic system activity leading to motor and cognitive disturbances
Summary
At an early motor stage, Parkinson’s disease (PD) is predominantly characterized by a progressive loss of the nigrostriatal dopaminergic neurons leading to a severe state of dopamine depletion. The two primary sources of acetylcholine (ACh) in the brain include local interneurons that are interspersed among their cellular targets and projection neurons that innervate distal areas. ACh signals through two classes of receptors localized both pre- and postsynaptically: metabotropic muscarinic acetylcholine receptors (mAChRs) and ionotropic nicotinergic acetylcholine receptors (nAChRs). Presynaptic mAChRs (M2, M4) act as inhibitory autoreceptors on the cholinergic terminals, with M4 predominant in striatum. The actual mechanism of action in PD is not known, clinically available anti-cholinergics (e.g., trihexyphenidyl, benztropine, etc.) act mainly as competitive antagonists of mAChRs (Brocks, 1999). Presynaptic nAChRs induce release of a number of neurotransmitters, including dopamine. Postsynaptic nAChRs depolarize neurons, increase their firing rate, and can contribute to long-term potentiation (reviewed in Picciotto et al, 2012)
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