{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T10:54:59Z","timestamp":1783335299199,"version":"3.54.6"},"reference-count":82,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","award":["PNRR-MAD-2022-12375706"],"award-info":[{"award-number":["PNRR-MAD-2022-12375706"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Parkinson\u2019s 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 \u03b3-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-na\u00efve 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.<\/jats:p>","DOI":"10.3390\/ijms262110754","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T13:19:29Z","timestamp":1762348769000},"page":"10754","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Contribution of Cerebellar Glutamatergic and GABAergic Systems in Premotor and Early Stages of Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3272-1094","authenticated-orcid":false,"given":"Clelia","family":"Pellicano","sequence":"first","affiliation":[{"name":"Neuropsychiatry Laboratory, Clinical Neuroscience and Neurorehabilitation Department, IRCCS Santa Lucia Foundation, Via Ardeatina 306, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8428-7376","authenticated-orcid":false,"given":"Daniela","family":"Vecchio","sequence":"additional","affiliation":[{"name":"Neuropsychiatry Laboratory, Clinical Neuroscience and Neurorehabilitation Department, IRCCS Santa Lucia Foundation, Via Ardeatina 306, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Giove","sequence":"additional","affiliation":[{"name":"Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Via Ardeatina 306, 00179 Rome, Italy"},{"name":"Centro Ricerche Enrico Fermi, Via Panisperna 89a, 00184 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1602-2397","authenticated-orcid":false,"given":"Lucia","family":"Macchiusi","sequence":"additional","affiliation":[{"name":"Neuropsychiatry Laboratory, Clinical Neuroscience and Neurorehabilitation Department, IRCCS Santa Lucia Foundation, Via Ardeatina 306, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Clemenzi","sequence":"additional","affiliation":[{"name":"Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Via Ardeatina 306, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Marzi","sequence":"additional","affiliation":[{"name":"Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Via Ardeatina 306, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 4, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Cirillo","sequence":"additional","affiliation":[{"name":"Neurology Unit, University Hospital of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Maio","sequence":"additional","affiliation":[{"name":"Neurology Unit, University Hospital of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Liguori","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 4, 00133 Rome, Italy"},{"name":"Neurology Unit, University Hospital of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Piras","sequence":"additional","affiliation":[{"name":"Neuropsychiatry Laboratory, Clinical Neuroscience and Neurorehabilitation Department, IRCCS Santa Lucia Foundation, Via Ardeatina 306, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9546-7038","authenticated-orcid":false,"given":"Federica","family":"Piras","sequence":"additional","affiliation":[{"name":"Neuropsychiatry Laboratory, Clinical Neuroscience and Neurorehabilitation Department, IRCCS Santa Lucia Foundation, Via Ardeatina 306, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s11065-010-9143-9","article-title":"The Cerebellum and Basal Ganglia Are Interconnected","volume":"20","author":"Bostan","year":"2010","journal-title":"Neuropsychol. 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