Objective: To examine the cerebral topography of GABA_A Receptor Expression in Parkinson’s Disease (PD) Fallers and Freezers.

Background: Episodic mobility disturbances, like falls and freezing of gait, are debilitating mobility impairments in PD. Limited responses to dopaminergic therapy suggest a role of non-dopaminergic mechanisms. Gamma-aminobutyric acid (GABA) plays a key role in striatal output to the brainstem and thalamus, and its alterations may contribute to episodic mobility disturbances in PD.

Method: Twenty-seven PD participants (M20/F7) underwent clinical assessments, motor testing, and brain [¹¹C]-Flumazenilimaging. The MDS-UPDRS was used to assess freezing in the DA medication ‘off’ state. Fall status was defined by historical falls in the last 12 months.  SPM12 whole brain voxel-based group comparisons (fallers vs. non-fallers; freezers vs. non-freezers) were performed.

Results: The mean age of the participants was 68.93 (SD=6.34). Participants had an average Hoehn Yar stage of 2.70 (SD= 0.44) and an average disease duration of 8.32 years (SD=5.71 years) and mean MDS-UPDRS scores (M=44.04,SD=14.26). There 12 fallers and 5 freezers. Two of the participants experienced both freezing and falling.

Analyses of fallers showed reductions in GABA_A receptor binding in the bilateral middle cerebellar peduncles, right more than left superior cerebellar peduncles, nodulus, superior vermis, brainstem pedunculopontine nucleus (PPN), and the right visual cortex (P<0.05). Analyses of freezers showed more extensive reductions in GABA_A receptor binding in the cerebellum, middle and inferior temporal lobe, putamen, fusiform gyrus, vermis, caudate nucleus, andparahippocampal regions (uncorrected).

Conclusion: The reduction in GABA_A receptor binding in the vermis, cerebellar peduncles and  PPN in fallers indicates a prominent role in gait dysfunction and postural instability in PD. Although exploratory in nature due to the small number of freezers, the more extensive binding reductions in the freezers suggest more extensive GABAergic changes in multi-system cerebello-thalamostriatal-cortical circuitry compared to fallers. Findings may augur novel GABAergic therapeutic approaches to treat falls and freezing of gait in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cerebral-topography-of-11c-flumazenil-gabaa-receptor-expression-in-parkinsons-disease-fallers-and-freezers/