{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T23:27:27Z","timestamp":1772666847521,"version":"3.50.1"},"reference-count":399,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione Italiana Fegato\u2014Onlus (Italian Liver Foundation-NPO)","award":["P20GM103418"],"award-info":[{"award-number":["P20GM103418"]}]},{"name":"Manajemen Talenta, the National Research and Innovation Agency of Indonesia","award":["P20GM103418"],"award-info":[{"award-number":["P20GM103418"]}]},{"name":"NIH","award":["P20GM103418"],"award-info":[{"award-number":["P20GM103418"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is the second most common neurodegenerative disorder in the world. PD is characterized by motor and non-motor symptoms, but the diagnosis primarily relies on the clinical assessment of postural and movement abnormalities, supported by imaging and genetic testing. It is widely accepted that the disease process begins decades before the onset of overt symptoms. Emerging evidence suggests that neuroinflammation plays a central role in the pathogenesis of PD, particularly during the pre-clinical phase. Activated microglia, increased levels of pro-inflammatory cytokines, and persistent oxidative stress have all been associated with the gradual loss of dopaminergic neurons. Although earlier detection and diagnosis remain elusive, achieving these goals is crucial for advancing prevention and disease-modifying strategies. Clinical studies are ongoing. To fill the gap, research models that recapitulate the chronic disease progression of PD are crucial to test preventive and disease-modifying strategies. This review briefly summarizes clinical knowledge on PD as a starting point for improving research models. Furthermore, we will critically evaluate how the existing models have been utilized and highlight opportunities to overcome their limitations and enhance the translational relevance to clinical application.<\/jats:p>","DOI":"10.3390\/ijms26146881","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T14:13:43Z","timestamp":1752761623000},"page":"6881","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Understanding the Pre-Clinical Stages of Parkinson\u2019s Disease: Where Are We in Clinical and Research Settings?"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3678-8331","authenticated-orcid":false,"given":"Camilla","family":"Dalla Verde","sequence":"first","affiliation":[{"name":"Liver Brain Unit \u201cRita Moretti\u201d, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy"},{"name":"Department of Life Sciences, University of Trieste, 34139 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sri","family":"Jayanti","sequence":"additional","affiliation":[{"name":"Eijkman Research Centre for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Korri","family":"El Khobar","sequence":"additional","affiliation":[{"name":"Eijkman Research Centre for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4667-4057","authenticated-orcid":false,"given":"John A.","family":"Stanford","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of Kansas School of Medicine, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6596-7595","authenticated-orcid":false,"given":"Claudio","family":"Tiribelli","sequence":"additional","affiliation":[{"name":"Liver Brain Unit \u201cRita Moretti\u201d, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9403-3564","authenticated-orcid":false,"given":"Silvia","family":"Gazzin","sequence":"additional","affiliation":[{"name":"Liver Brain Unit \u201cRita Moretti\u201d, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Dommershuijsen, L.J., Boon, A.J.W., and Ikram, M.K. (2021). Probing the Pre-diagnostic Phase of Parkinson\u2019s Disease in Population-Based Studies. Front. 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