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 behaviour 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.

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.

Background: Cenobamate (CNB) is an anti-seizure medication (ASM) approved for the treatment of drug-resistant focal epilepsy in adults. Notwithstanding significant proof of efficacy, real-world pharmacokinetics (PK) data are lacking, particularly regarding sex-based variations and the effect of concomitant ASMs. This exploratory study aimed to investigate the PK profile of CNB in responder adults with drug-resistant focal epilepsy and assess potential relationship with concomitant ASMs and clinical variables. Methods: We enrolled 17 patients receiving add-on CNB. The concentration-to-dose ratio (C/D), incremental slope (ΔC/ΔD), and dose-to-concentration AUC were calculated. Enrolled individuals were stratified into three exposure clusters (low, medium, and high). Univariate ANOVA was used to explore associations between PK parameters, clinical variables and concomitant ASMs. Results: Sex appeared to be associated with AUC cluster classification (p = 0.026), showing females predominating in the high-exposure group. A nonlinear dose-concentration relationship emerged from the ΔC/ΔD analysis, showing steeper slopes at low doses (12.5–50 mg), great variability at higher doses (100–200 mg), and a negative slope in some individuals. Higher CNB concentrations were observed in patients co-treated with lacosamide, while concomitant topiramate was associated with lower exposure. Carbamazepine and valproate showed non-significant trends consistent with their known enzyme-inducing and inhibiting properties. Conclusions: PK of CNB appears highly variable and seems to be influenced by sex and concomitant ASMs. These findings highlight the importance of therapeutic drug monitoring and individualized titration strategies to optimize efficacy and safety in clinical practice. These results should be regarded as exploratory and hypothesis-generating due to the small and monocentric sample size and need to be confirmed in larger, multicenter cohorts.