# Contribution of Cerebellar Glutamatergic and GABAergic Systems in Premotor and Early Stages of Parkinson’s Disease

## TL;DR

This study explores how cerebellar neurotransmitter systems change in early Parkinson’s disease and REM sleep behavior disorder, suggesting potential new biomarkers and treatment targets.

## Contribution

The study identifies early cerebellar E/I ratio changes in Parkinson’s disease and links GABAergic activity to neuropsychiatric symptoms in REM sleep behavior disorder.

## Key findings

- De novo PD patients showed a hyperexcitability shift in cerebellar E/I ratio without clinical or cognitive correlations.
- iRBD individuals exhibited an inverse relationship between increased GABAergic activity and neuropsychiatric symptoms.
- Cerebellar GABA MRS is proposed as a potential biomarker for early Parkinson’s disease.

## Abstract

Parkinson’s disease (PD) is a multisystem disorder, with early changes extending beyond basal ganglia circuitries and involving non-dopaminergic pathways, including cerebellar networks. Whether cerebellar dysfunction reflects a compensatory mechanism or an intrinsic hallmark of disease progression remains unresolved. In this cross-sectional study, we examined how cerebellar γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx) systems, as well as their excitatory/inhibitory (E/I) balance, are modulated along the disease course. As to ascertain how these mechanisms contribute to motor and non-motor features in the premotor and early stages of PD, 18 individuals with isolated REM sleep behavior disorder (iRBD), 20 de novo, drug-naïve PD (dnPD), and 18 matched healthy controls underwent clinical, cognitive, and neuropsychiatric assessments alongside cerebellar magnetic resonance spectroscopy (MRS, MEGA-PRESS, 3T). While cerebellar neurotransmitter levels did not differ significantly across groups, dnPD patients exhibited a shift toward hyperexcitability in the E/I ratio, without correlation to clinical or cognitive measures. In contrast, in iRBD, an inverse relationship between heightened GABAergic activity and neuropsychiatric symptoms emerged. These findings suggest an early, dynamic cerebellar involvement, potentially reflecting compensatory modulation of altered basal ganglia output. Our results support cerebellar GABA MRS as a promising biomarker and open perspectives for targeting non-dopaminergic pathways in PD.