Cholinergic basal forebrain atrophy in Parkinson's disease with freezing of gait

Abstract

Background: Mounting research support that cholinergic dysfunction plays a prominent role in freezing of gait (FOG), which commonly occurs in Parkinson's disease (PD). Basal forebrain (BF), especially the cholinergic nuclei 4 (Ch4), provides the primary source of the brain cholinergic input. However, whether the degeneration of BF and its innervated cortex contribute to the pathogenesis of FOG is unknown. Objective: To explore the role of structural alterations of BF and its innervated cortical brain regions in the pathogenesis of PD patients with freezing. Methods: Magnetic resonance imaging assessments and neurological assessments were performed on 20 PD patients with FOG (PD-FOG), 20 without FOG (PD-NFOG), and 21 healthy participants. Subregion volumes of the BF were compared among groups. Local gyrification index (LGI) was computed to reveal the cortical alternations. Relationships among subregional BF volumes, LGI, and the severity of FOG were evaluated by multiple linear regression. Results: Our study discovered that, compared to PD-NFOG, PD-FOG exhibited significant Ch4 atrophy (p = 4.6 9 10 À5 ), accompanied by decreased LGI values in the left entorhinal cortex (p = 3.00 9 10 À5 ) and parahippocampal gyrus (p = 2.90 9 10 À5 ). Based on the regression analysis, Ch4 volume was negatively associated with FOG severity in PD-FOG group (b = À12.224, T = À2.556, p = 0.031). Interpretation: Our results imply that Ch4 degeneration and microstructural disorganization of its innervated cortical brain regions may play important roles in PD-FOG.

Cholinergic nucleus degeneration and its association with gait impairment in Parkinson’s disease

“…Previous animal and in vivo studies have confirmed the significant role of cBF in attention and gait impairments in PD patients [ 38 ]. Neuroimaging studies have also demonstrated a notable correlation between cBF degeneration in PD patients and gait impairments, with attentional deficits playing a mediating role [ 4 , 11 , 14 , 39 ]. While previous research has predominantly focused on the PPN regarding cholinergic modulation of gait, clinical studies have shown that DBS targeting the PPN for dopaminergic-resistant gait and balance disturbances did not yield effective symptom improvement over a 2-month period [ 40 ].…”

“…Recent neuroimaging studies have provided compelling evidence supporting the role of cBF in contributing to gait dysfunction in PD. Specifically, a magnetic resonance imaging (MRI) study has identified significant atrophy in the Ch4 region in PD patients with concurrent freezing of gait (FOG), and the severity of Ch4 atrophy has been found to positively correlate with the severity of FOG [ 11 ]. Positron emission tomography-computed tomography (PET-CT) study has further demonstrated a connection between the postural control and the right hemisphere cholinergic network [ 12 ].…”