Altered Cholinergic Innervation in De Novo Parkinson's Disease with and Without Cognitive Impairment

Abstract

Background Altered cholinergic innervation plays a putative role in cognitive impairment in Parkinson's disease (PD) at least in advanced stages. Identification of the relationship between cognitive impairment and cholinergic innervation early in the disease will provide better insight into disease prognosis and possible early intervention. Objective The aim was to assess regional cholinergic innervation status in de novo patients with PD, with and without cognitive impairment. Methods Fifty‐seven newly diagnosed, treatment‐naive, PD patients (32 men, mean age 64.6 ± 8.2 years) and 10 healthy controls (5 men, mean age 54.6 ± 6.0 years) were included. All participants underwent cholinergic [18F]fluoroethoxybenzovesamicol positron emission tomography and detailed neuropsychological assessment. PD patients were classified as either cognitively normal (PD‐NC) or mild cognitive impairment (PD‐MCI). Whole brain voxel‐based group comparisons were performed. Results Results show bidirectional cholinergic innervation changes in PD. Both PD‐NC and PD‐MCI groups showed significant cortical cholinergic denervation compared to controls (P < 0.05, false discovery rate corrected), primarily in the posterior cortical regions. Higher‐than‐normal binding was most prominent in PD‐NC in both cortical and subcortical regions, including the cerebellum, cingulate cortex, putamen, gyrus rectus, hippocampus, and amygdala. Conclusion Altered cholinergic innervation is already present in de novo patients with PD. Posterior cortical cholinergic losses were present in all patients independent of cognitive status. Higher‐than‐normal binding in cerebellar, frontal, and subcortical regions in cognitively intact patients may reflect compensatory cholinergic upregulation in early‐stage PD. Limited or failing cholinergic upregulation may play an important role in early, clinically evident cognitive impairment in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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“…In general, these outcomes survived control for age and disease duration in a pattern that largely depended on the strength of the zero‐order correlations. Prior VAChT FEOBV brain PET imaging studies have shown evidence of early vulnerability of occipital and parietal cortices in PD 19, 20 . This observation is consistent with (cross‐sectional) findings of a suggested posterior‐to‐anterior cortical denervation gradient from PD to PD with dementia in VAChT SPECT and AChE PET studies 28, 29 .…”

“…The purpose of the current study, therefore, was to examine the topographic relationship between degeneration in sub‐regions of the cBF and regional [ 18 F]‐FEOBV binding in nondemented people with PD. Since in vivo VAChT binding studies have shown early vulnerability of posterior cortical regions in PD, 19, 20 we expected to observe strong correlations between posterior cortical VAChT binding and regional volume loss (especially Ch4ai) compared to anterior cortical regions.…”

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“…Therefore, it is expected that multimodal imaging using nuclear and MR imaging allows to further disentangle the complex interplay between neurodegenerative [ 206 ] and compensatory plasticity [ 207 ], as recently exemplified for the serotonergic [ 26 , 88 ] and cholinergic [ 107 , 208 ] systems. This process will be facilitated by hybrid PET/MR scanners [ 209 ], dual-phase PET, new radiotracers, pharmacological challenges, and biased agonism providing functional selectivity [ 210 ], in addition to technological efforts to reduce scan time and radiation hazard.…”

“…Notably, no tracer is currently available to image the neurotransmitter synthesis by the choline acetyltransferase. Most interestingly, van der Zee et al demonstrated that PD patients without cognitive impairment had higher-than-normal binding in cerebellar, frontal, and subcortical regions possibly reflecting early compensatory cholinergic upregulation [ 107 ], although all patients had lower 18F-FEOBV in the posterior cortical region. In addition, patients with RBD exhibited increased 18F-FEOBV uptake in brainstem nuclei involved in muscle atonia, deep cerebellar nuclei, as well as in limbic territories of the thalamus, anterior cingulate, and orbitofrontal cortex [ 108 ].…”

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“…What's more, the highest density of cholinergic markers is existed in the striatum of the brain, and there is a cholinergic pathway between the striatum and the posterior cortex, including the OLF 33 . Some molecular imaging studies found that compensatory cholinergic upregulation is already present in early PD with and without cognitive impairment, mainly distributed in the posterior cortical regions 33,34 . However, cholinergic activity is decreasing in PD patients with cognitive impairment as the disease progresses 35,36 .…”