Cholinergic Upregulation in Dorsomedial Thalamus prior to Conversion to Freezing of Gait in Parkinson’s Disease

Abstract

Background and Aim: The mechanisms underlying Freezing of Gait (FOG) in Parkinson’s Disease (PD) are poorly understood, making it a challenging symptom to treat. Previous work identified morphological alterations in the Thalamus and Caudate nuclei as predictive of conversion to FOG, however the neurochemical changes involved in these adaptations were unexplored. In this study, we used [¹⁸F]fluoroethoxybenzovesamicol (FEOBV) radiotracer PET imaging to investigate the cholinergic activity in the Dorsomedial Thalamus and Head of the Caudate in relationship to the onset of FOG in PD. Methods: Eighty-two participants (11 Healthy Controls, 71 PD – 51 Non-Freezers & 20 Freezers) underwent FEOBV PET and structural MR imaging as well as behavioral assessments at the University Hospital, Ann Arbor, MI. These participants were re-tested two years later and conversion to FOG was determined. Standardized uptake value maps for FEOBV were generated and high resolution T1-weighted scans underwent Voxel-Based Morphometry, implemented in FSL’s (Oxford, UK) tool FIRST. Previously identified masks of the Dorsomedial Thalamus and Caudate Head were used to extract mean FEOBV and local shape values bilaterally which were analyzed in IBM SPSSS version 23 (Armonk, NY). Results: Six out of the fifty-one (11.7%) Non-Freezers converted to FOG during the study (CONV). Baseline analysis revealed that CONV tended to show higher FEOBV values across groups in the right Dorsomedial Thalamus (Group effect: F3,75 = 2.268, P = 0.087), particularly with respect to the baseline Freezers (post-hoc Tukey P=0.068). Interestingly, FEOBV values in the Dorsomedial Thalamus were positively associated with local shape values (Right: r = 0.448, P < 0.001; Left: r = 0.25, P = 0.026) while in the Caudate head they showed an inverse relationship (Right: r = -0.207, P = 0.067; Left: r = -0.229, P = 0.043). Behavioral analyses showed that at baseline, Thalamus FEOBV values were associated with better performance on multiple cognitive tests [MMSE, MOCA and Parkinson’s Disease Cognitive Rating Scale (r – 0.3 – 0.4, Ps < 0.012)], while change in Right Thalamus FEOBV values over two years were related to greater improvements in Parkinson’s Disease Cognitive Rating Scale (r = 0.31, P = 0.039). Conclusions: This study provides a link between cholinergic neuronal activity and subcortical morphological adaptations as well as converging evidence implicating the Dorsomedial Thalamus as an important player in conversion to FOG. The compensatory upregulation seen in the cholinergic neurons in the Dorsomedial Thalamus prior to the onset of FOG seems to be positive and, subject to further investigation, may provide an interesting target for clinical studies.status: publishe