Topography of regional cerebral GABA-A receptor availability in Parkinson disease fallers and freezers

Introduction: Falls and freezing of gait are the most debilitating motor impairments in Parkinson’s disease (PD) that do not respond well to dopaminergic drugs. This suggests the involvement of other neurotransmitter systems. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter found in sensorimotor and other circuits. The role that GABA plays in mobility disturbances in PD is not well understood. The objective of this study was to examine the association between a history of falls and freezing of gait with regional GABA-A receptor availability using [¹¹C]-flumazenil in patients with PD.

Methods: 27 PD subjects (7F/20M; age 68.9±6.3, disease duration 8.3±5.7, motor MDS-UPDRS scores 44.0±14.3) underwent brain [¹¹C]-flumazenil and MR imaging. Distribution volume ratios (DVR) were computed using Logan plot analysis with ventral pons reference region. Participants were separated into "fallers" (n =12) vs "non-fallers" (n=15) through analysis of a self-reported questionnaire where participants indicated the number of falls that they experienced over the last 6 months. Participants were separated into "freezers" (n=5) vs "non freezers" (n=22) by analyzing a sub-section of part 3 of the MDS-UPDRS examination. Voxel-based group-comparison t-tests were performed using SPM12.

Results: Analyses of fallers showed reduced GABA_A binding in the cerebellum, vermis, inferior temporal lobe, cerebellar peduncles, and calcarine cortex (P<0.05; figure 1). Analyses of freezers showed reduced GABA_A binding in the cerebellum, middle and inferior temporal lobe, putamen, fusiform gyrus, vermis, caudate nucleus, and parahippocampal regions (exploratory P<0.05; figure 2).

Conclusions: The voxel-based analysis revealed greater reductions of GABA_A binding in the cerebellum, inferior temporal lobe and calcarine cortex in fallers when compared to non-fallers. Our findings may augur GABA-A inverse agonist treatment approaches to treat falls in PD. Although more extensive brain regions were identified in freezers, findings did not reach statistical significance likely due to the sample size of freezers in this study. Future larger studies for freezers are needed.

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