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

Article type: Research Article

Authors: Lench, Daniel H.^a | Keith, Kathryn^b | Wilson, Sandra^a | Padgett, Lucas^a | Benitez, Andreana^{a; d} | Ramakrishnan, Viswanathan^b | Jensen, Jens H.^{c; d} | Bonilha, Leonardo^a | Revuelta, Gonzalo J.^{a; e; *}

Affiliations: [a] Department of Neurology, Medical University of South Carlina, Charleston, SC, USA | [b] Department of Public Health Sciences, Medical University of South Carlina, Charleston, SC, USA | [c] Department of Neuroscience, Medical University of South Carlina, Charleston, SC, USA | [d] Center for Biomedical Imaging, Medical University of South Carlina, Charleston, SC, USA | [e] Ralph H. Johnson VA Medical Center, Charleston, SC, USA

Correspondence: [*] Correspondence to: Gonzalo J. Revuelta, DO, 208-B Rutledge Ave, Charleston, SC 29403, USA. Tel.: +1 843 792 7262; E-mail: [email protected].

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.

Keywords: Freezing, Parkinson’s disease, connectivity, neuroimaging, gait, dopamine, tractography, L-DOPA

DOI: 10.3233/JPD-213062

Journal: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1241-1250, 2022