Objective: This study aims to evaluate the effect of levodopa on cerebello-thalamo-cortical (CTC) gamma-aminobutyric acid (GABA) and glutamate in patients with Parkinson’s disease (PD) using J-difference edited magnetic resonance spectroscopy (MRS) in order to ascertain if levodopa normalizes any alterations, and explore the influence of GABA and glutamate on motor symptoms.

Background: Dopaminergic deficit in PD leads to altered excitatory and inhibitory drives within the basal ganglia, thalamo-cortical and cerebellar networks. Levodopa is the main therapeutic modality in PD, however, the reported modulatory effects on GABA and glutamate in regions within the CTC, and the role of pathological alterations on motor symptom severity are variable [1,2,3].

Method: Thirty subjects with PD, and 15 healthy controls (HC) were evaluated [Table-1]. Clinical and imaging assessments were performed in OFF and ON states, i.e. post 200/50mg levodopa/carbidopa.  Disease severity was measured using the MDS-UPDRS Part III, and the side with higher severity was noted. Single voxel J-difference edited MRS data was acquired using MEGA-semiLASER from the cerebellum (dentate), thalamus and motor cortex (MC) of hemispheres corresponding to the more affected side in PD, and randomized hemispheres in HC. Data was processed using MRspa [4] which incorporates LCModel for quantification. Absolute GABA+ (GABA+macromolecule) and Glx (Glutamate+Glutamine) were estimated and utilized for comparison between OFF, ON states and HC data, and correlations between obtained values and tremor severity measures.

Results: Definite patterns of variations of GABA+ and Glx levels were observed between the OFF and ON state and HC, with a significantly higher Glx in the OFF state compared to HC [Figure-1]. Although most differences were not significant, it is evident that levodopa induces changes in GABA+ and Glx levels bringing them closer to HC. OFF state rigidity scores directly correlated with MC OFF state GABA+ levels, and percentage improvement in total tremor and action tremor scores were inversely related to OFF state cerebellar Glx levels [Figure-2].

Conclusion: The dopaminergic effect of levodopa leads to a normalization of GABA+ and Glx levels in the ON state. Furthermore, GABA+ and Glx levels influence rigidity and tremor, with the observed post-levodopa normalization probably contributing to ON state improvement in motor symptoms.

Table-1

Figure-1

Figure-2

References: [1] van Nuland AJ, den Ouden HE, Zach H, Dirkx MF, van Asten JJ, Scheenen TW, Toni I, Cools R, Helmich RC. GABAergic changes in the thalamocortical circuit in Parkinson’s disease. Human Brain Mapping. 2020 Mar;41(4):1017-29.
[2] Trujillo P, Song AK, Hay KR, Aumann M, Yan Y, Kang H, Donahue MJ, Claassen DO. Dopamine-induced changes to thalamic GABA concentration in impulsive Parkinson disease patients. npj Parkinson’s Disease. 2022 Apr 5;8(1):37.
[3] Song Y, Gong T, Xiang Y, Mikkelsen M, Wang G, Edden RA. Single-dose L-dopa increases upper brainstem GABA in Parkinson’s disease: A preliminary study. Journal of the Neurological Sciences. 2021 Mar 15;422:117309.
[4] Deelchand D. MRspa: Magnetic Resonance signal processing and analysis. Available at: https://www.cmrr.umn.edu/downloads/mrspa/.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/levodopa-mediated-normalization-of-cerebello-thalamo-cortical-gaba-and-glutamate-in-parkinsons-disease/