Altered Cortical Cholinergic Network in Parkinson's Disease at Different Stage: A Resting-State fMRI Study.

Wenshuang Sheng,Minming Zhang,Cheng Zhou,Yunjun Yang,Xiaojun Guan,Jiali Pu,Tao Guo,Baorong Zhang,Xiaojun Xu,Ting Gao,Jingjing Wu

doi:10.3389/fnagi.2021.723948

Abstract

The cholinergic system is critical in Parkinson’s disease (PD) pathology, which accounts for various clinical symptoms in PD patients. The substantia innominata (SI) provides the main source of cortical cholinergic innervation. Previous studies revealed cholinergic-related dysfunction in PD pathology at early stage. Since PD is a progressive disorder, alterations of cholinergic system function along with the PD progression have yet to be elucidated. Seventy-nine PD patients, including thirty-five early-stage PD patients (PD-E) and forty-four middle-to-late stage PD patients (PD-M), and sixty-four healthy controls (HC) underwent brain magnetic resonance imaging and clinical assessments. We employed seed-based resting-state functional connectivity analysis to explore the cholinergic-related functional alterations. Correlation analysis was used to investigate the relationship between altered functional connectivity and the severity of motor symptoms in PD patients. Results showed that both PD-E and PD-M groups exhibited decreased functional connectivity between left SI and left frontal inferior opercularis areas and increased functional connectivity between left SI and left cingulum middle area as well as right primary motor and sensory areas when comparing with HC. At advanced stages of PD, functional connectivity in the right primary motor and sensory areas was further increased. These altered functional connectivity were also significantly correlated with the Unified Parkinson’s Disease Rating Scale motor scores. In conclusion, this study illustrated that altered cholinergic function plays an important role in the motor disruptions in PD patients both in early stage as well as during the progression of the disease.

Highlights

Parkinson’s disease (PD), a chronic and progressive movement disorder, has been recognized as a heterogeneous syndrome (Zhang et al, 2005; Reich and Savitt, 2019)
Functional connectivity in the right primary motor and sensory areas continued to increase in PD-M group when compared with PD-E group
These results indicated that even in the early stages of PD, cortical cholinergic denervation has occurred in left frontal inferior opercularis areas, and cholinergic hyperactivity has occurred in the left cingulum middle area and right primary motor and sensory areas

Summary

Introduction

Parkinson’s disease (PD), a chronic and progressive movement disorder, has been recognized as a heterogeneous syndrome (Zhang et al, 2005; Reich and Savitt, 2019). A positron emission tomography (PET) study of cerebral acetylcholinesterase demonstrated that cholinergic dysfunction occurs in the early course of PD (Hughes et al, 1992; Latt et al, 2009). Given that PD is a progressive disorder, patients at advanced stages seem to have a significantly faster disease progression (Zhao et al, 2010) and show a high incidence of balance dysfunction (Latt et al, 2009). These heterogeneous clinical symptoms indicate that the degenerative mechanisms of the cholinergic system may be different during PD progression, which have yet to be elucidated

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