Nicotinicα₄β₂acetylcholine receptors and cognitive function in Parkinson's disease

Abstract

Background -Idiopathic Parkinson's disease (IPD) is characterized by the clinical motor symptoms of hypokinesia, rigidity, and tremor. Apart from these motor symptoms, cognitive deficits often occur in IPD. The positive effect of cholinesterase inhibitors on cognitive deficits in IPD and findings of earlier molecular imaging studies suggest that the cholinergic system plays an important role in the origin of cognitive decline in IPD. Methods -Twenty-five nondemented patients with IPD underwent a 5-[123 I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) SPECT to visualize a 4 b 2 nicotinic acetylcholine receptors (nAchR) and cognitive testing with the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) battery to identify domains of cognitive dysfunction. Results -In the CERAD, the IPD patients exhibited deficits in nonverbal memory, attention, psychomotor velocity, visuoconstructive ability, and executive functions. After Bonferroni correction for multiple comparisons, we found significant correlations between performance of the CERAD subtests Boston Naming Test (a specific test for visual perception and for detection of word-finding difficulties) and Word List Intrusions (a specific test for learning capacity and memory for language information) vs binding of a 4 b 2 nAchR in cortical (the right superior parietal lobule) and subcortical areas (the left thalamus, the left posterior subcortical region, and the right posterior subcortical region). Conclusions -These significant correlations between the results of the CERAD subtests and the cerebral a 4 b 2 nAchR density, as assessed by 5-I-A-85380 SPECT, indicate that cerebral cholinergic pathways are relevant to cognitive processing in IPD.

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

“…In this study, 25 non-demented PD patients underwent a 5-[123I]iodo-3-[2( S )-2-azetidinylmethoxy]pyridine (5-I-A-85380) SPECT to visualize α4β2 nAChRs and cognitive testing with the CERAD (Consortium to Establish a Registry for Alzheimer’s Disease) battery to identify domains of cognitive dysfunction. 113 Results showed significant correlations between performance of the CERAD subtests Boston Naming Test (a specific test for visual perception and for detection of word-finding difficulties) and Word List Intrusions (a specific test for learning capacity and memory for language information) with the density of α4β2 nAChRs at the right superior parietal lobe cortex and the left thalamus, and left and right posterior subcortical regions.…”

“…113 Previous studies have revealed reduced binding to these receptors in PD brains, and some preliminary findings suggest that the density of these receptors might correlate with cognitive impairments. In this study, 25 non-demented PD patients underwent a 5-[123I]iodo-3-[2( S )-2-azetidinylmethoxy]pyridine (5-I-A-85380) SPECT to visualize α4β2 nAChRs and cognitive testing with the CERAD (Consortium to Establish a Registry for Alzheimer’s Disease) battery to identify domains of cognitive dysfunction.…”

Biomarkers for dementia and mild cognitive impairment in Parkinson's disease

“…216,217 Compared with controls, cholinergic deficits were evident in the midbrain, pons, and cerebellum in 1 study of PD-MCI patients, 218 but not in another that included more patients. 198 In addition, lower cortical cholinergic activity has been associated with worse global cognition 219,220 and language 221 and with working memory impairment in PDD and PDND patients. 217 PET studies indicate that assessing the cholinergic state might be useful as a biomarker of dementia in PD.…”

Imaging in Parkinson's Disease

“…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.…”