Neurodegeneration of the Globus Pallidus Internus as a Neural Correlate to Dopa-Response in Freezing of Gait

Abstract

Background: Background: Parkinson’s disease (PD) patients who develop freezing of gait (FOG) have reduced mobility and independence. While some patients experience improvement in their FOG symptoms with dopaminergic therapies, a subset of patients have little to no response. To date, it is unknown what changes in brain structure underlie dopa-response and whether this can be measured using neuroimaging approaches. Objective: We tested the hypothesis that structural integrity of brain regions (subthalamic nucleus and globus pallidus internus, GPi) which link basal ganglia to the mesencephalic locomotor region (MLR), a region involved in automatic gait, would be associated with FOG response to dopaminergic therapy. Methods: In this observational study, thirty-six participants with PD and definite FOG were recruited to undergo diffusion kurtosis imaging (DKI) and multiple assessments of dopa responsiveness (UPDRS scores, gait times ON versus OFF medication). Results: The right GPi in participants with dopa-unresponsive FOG showed reduced fractional anisotropy, mean kurtosis (MK), and increased radial diffusivity relative to those with dopa-responsive FOG. Furthermore, using probabilistic tractography, we observed reduced MK and increased mean diffusivity along the right GPi-MLR tract in dopa-unresponsive FOG. MK in the right GPi was associated with a subjective dopa-response for FOG (r = –0.360, df = 30, p = 0.043) but not overall motor dopa-response. Conclusion: These results support structural integrity of the GPi as a correlate to dopa-response in FOG. Additionally, this study suggests DKI metrics may be a sensitive biomarker for clinical studies targeting dopaminergic circuitry and improvements in FOG behavior.

Freezing of gait in Parkinson’s disease is associated with the microstructural and functional changes of globus pallidus internus

“…Notably, the current study showed alterations mainly in the right hemisphere of PD-FOG patients, which is consistent with a growing body of literature demonstrating that the right hemisphere appears to be selectively affected in FOG ( Fling et al, 2013 ; Peterson et al, 2014 ; Bharti et al, 2020 ; Lv et al, 2021 ; Song et al, 2021 ; Lench et al, 2022 ). The laterality of imaging abnormalities in PD-FOG patients is likely related to the fact that the right hemisphere plays a strong role in visuospatial function in right-handed subjects ( Joseph, 1988 ).…”

“…Previous study also observed higher MD and RD values in the globus pallidus in PD patients of the postural instability and gait difficulties (PIGD) subtype compared to controls, and the MD value in the globus pallidus showed a positive correlation with motor severity in the PIGD group ( Nagae et al, 2016 ), in consistency with our finding. Recently, Lench et al (2022) using diffusion kurtosis imaging approach observed that PD patients with dopa-resistant FOG had higher RD value for the right GPi compared to those with dopa-responsive FOG, further supporting the link between GPi microstructure change and FOG in PD. In conclusion, the MD and RD changes in the right GPi may contribute to FOG in PD and may serve as an imaging biomarker of PD-FOG.…”

Quantitative Susceptibility Mapping Changes Relate to Gait Issues in Parkinson’s Disease

“…Recent studies have showed that diffusion changes in the globus pallidus are associated with FOG. 39,40 Within the landscape of susceptibility MRI studies in PD investigating the relationship between susceptibility and gait, our study aligns with another study demonstrating susceptibility changes in the putamen and globus pallidus. 10 Our study complements these susceptibility and diffusion MRI studies by showing that susceptibility changes in the globus pallidus are also implicated in FOG.…”

“…Recent studies have showed that diffusion changes in the globus pallidus are associated with FOG. 39,40…”