{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T14:45:19Z","timestamp":1785681919983,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,30]]},"group-title":"Neurology","reference-count":64,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"funder":[{"name":"Fresco Post-Doctoral Clinical Fellowship"},{"name":"Fondazione Regionale per la Ricerca Biomedica (Regione Lombardia),","award":["3433068 LINKING PARK"],"award-info":[{"award-number":["3433068 LINKING PARK"]}]},{"name":"NIH","award":["NS133742"],"award-info":[{"award-number":["NS133742"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The heterogenous clinical and pathophysiological presentation of idiopathic Parkinson\u2019s Disease (iPD) suggests the existence of underlying distinct biological subtypes. A better definition of PD subtypes is crucial for the development of target disease modifier approaches. Using data from the Parkinson\u2019s Precision Medicine Initiative (PPMI) cohort, we aimed to identify distinct biological subtypes of iPD through data-driven cluster analysis leveraging currently available biomarker data.<\/jats:p>\n                <jats:p>\n                  We included n=225\n                  <jats:italic>de novo<\/jats:italic>\n                  iPD subjects. Individuals with known genetic forms of PD were excluded. A total of 22 biomarkers reflecting different biological pathways (neurodegeneration, proteinopathy, neuroinflammation, mitochondrial impairment, and lipid metabolism\/autophagy-lysosomal dysfunction) and measured in cerebrospinal fluid (CSF), whole blood, serum, plasma, or urine were selected. Hierarchical clustering was performed using ward.D2 method and Gower dissimilarity. Clinical-demographic characteristics of the identified clusters were compared at baseline and 5-year follow-up.\n                <\/jats:p>\n                <jats:p>We identified three clusters: Cluster I (\u201cMitochondrial-Predominant\u201d subtype); Cluster II (\u201cCryptic\u201d subtype); Cluster III (\u201cMixed Pathology\u201d subtype). The \u201cMitochondrial-Predominant\u201d and \u201cMixed Pathology\u201d subtypes showed higher levels of CSF mitochondrial DNA deletions and ND1 compared to the \u201cCryptic\u201d subtype. The \u201cMixed Pathology\u201d subtype was also characterized by higher levels of serum NfL, CSF p-tau, CSF GFAP, CSF YKL-40, and lower levels of plasma total ceramide, glucosylceramide, and sphingomyelin compared to the other subtypes. In the \u201cCryptic\u201d subtype no clear dominant biological profile was detected. Clinically, subjects belonging to the \u201cMixed Pathology\u201d subtype were older and predominantly male. No differences in 5-year clinical progression were found between clusters.<\/jats:p>\n                <jats:p>While most of the previous research has performed a biological characterization of the clinical subtypes of PD, with our work we propose a biology-driven clustering in a large cohort if subjects with iPD. We identified three biological subtypes. The \u201cMitochondrial-Predominant\u201d subtype was characterized by alterations exclusively of biomarkers reflecting mitochondrial dysfunction. The \u201cMixed Pathology\u201d subtype, in contrast, was characterized by biomarker alterations across all explored pathological pathways. Finally, the \u201cCryptic\u201d subtype included subjects whose biomarker signature did not indicate predominant alterations in any of the explored pathways. The clusters did not differ in terms of baseline clinical-demographic characteristics, except for age and sex. No difference in mid-term clinical progression was observed between subtypes.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Abstract Figure<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"26359072v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.28.26359072","type":"posted-content","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T19:05:16Z","timestamp":1785438316000},"source":"Crossref","is-referenced-by-count":0,"title":["Data-Driven Biological Subtypes of Parkinson\u2019s Disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8196-3914","authenticated-orcid":false,"given":"Piergiorgio","family":"Grillo","sequence":"first","affiliation":[{"name":"The Marlene and Paolo Fresco Institute for Parkinson\u2019s and Movement Disorders, Department of Neurology, NYU Langone Health, NY, United States"},{"name":"IRCCS Mondino Foundation, Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1718-5414","authenticated-orcid":false,"given":"Chan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Population Health, NYU Langone Health, NY, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8432-594X","authenticated-orcid":false,"given":"Antonio","family":"Pisani","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, Pavia, Italy"},{"name":"Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5970-6839","authenticated-orcid":false,"given":"Un Jung","family":"Kang","sequence":"additional","affiliation":[{"name":"The Marlene and Paolo Fresco Institute for Parkinson\u2019s and Movement Disorders, Department of Neurology, NYU Langone Health, NY, United States"},{"name":"Department of Neuroscience, Institute for Translational Neuroscience, Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9255-9351","authenticated-orcid":false,"given":"Seyed-Mohammad","family":"Fereshtehnejad","sequence":"additional","affiliation":[{"name":"Pacific Parkinson\u2019s Research Centre (PPRC), Djavad Mowafaghian Centre for Brain Health (DMCBH), University of British Columbia, Vancouver, BC, Canada"},{"name":"Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada"},{"name":"Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 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