Nicotinic Acetylcholine Receptor Density in Cognitively Intact Subjects at an Early Stage of Parkinson’s Disease

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.

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

“…Results of animal model studies also indicated that increased striatal glutamatergic activity is implicated in the development and maintenance of LIDs 31, 32. Recent studies showed that nAChR agonists (e.g., nicotine) attenuate LIDs, especially when striatal dopamine transmission is relatively intact 10, 33. This effect is believed to occur through desensitization of nAChRs, with a consequent decline in nAChR‐mediated function,34 and release of glutamate from cortical and thalamic afferent 35, 36.…”

“…SPECT scans were performed 240 min after an intravenous single bolus injection of 187.3 ± 7.2 MBq of 123 I‐5‐IA 9, 10. These data were compared with a group of 12 healthy subjects (HC) age‐ (63.9 ± 11.7 years) and gender‐matched (5 males) 11, 12.…”

“…Each image was then delineated employing a whole brain VOI set with 67 predefined regions on the Automated Anatomical Labeling brain atlas 16. Average regional binding values were used to calculate regional estimates of the non‐displaceable binding potential (BP) for caudate nucleus and putamen, using as a reference the average global brain (for BP 5‐IA )10, 17 and the average occipital lobe binding value (for BP FP‐CIT ) 13. Similarly, the standardized uptake value ratio (SUVR FDG ) was calculated for each subject as the ratio of mean count per voxel of basal ganglia VOIs to mean count per voxel of the global 18 F‐FDG brain uptake.…”

Imaging in Parkinson's Disease

“…SPECT studies using [ 123 I]-5IA showed in early cognitively normal PD patients significantly higher nAChR density 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 but not contralateral to the clinically most affected side (Isaias et al, 2014). Advanced PD patients without dementia showed a widespread nAChR decrease, ranging between 10% and 25%, in cortical and subcortical areas (Fujita et al, 2006;Lorenz et al, 2014;Oishi et al, 2007), and a significant correlation was found between cognitive dysfunction and cortical nAChR uptakes (Lorenz et al, 2014).…”

“…Two selective SPECT radioligands, [ 123 I]-QNB and [ 123 I]-5IA, have been used to assess postsynaptic cholinergic system availability of M1 mAChR and α4β2 nAChR, respectively (Colloby et al, 2005;Fujita et al, 2006;Isaias et al, 2014;Lorenz et al, 2014;Oishi et al, 2007). SPECT studies using [ 123 I]-5IA showed in early cognitively normal PD patients significantly higher nAChR density 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.…”