{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T17:25:11Z","timestamp":1783445111330,"version":"3.54.6"},"reference-count":61,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:00:00Z","timestamp":1772409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) and associated synucleinopathies are preceded by a prolonged prodromal phase during which neurodegenerative processes evolve years before the onset of motor or cognitive symptoms. Identifying biologically specific and accessible biomarkers during this window is critical for early diagnosis, risk stratification, and the development of disease-modifying therapies. Increasing evidence supports the skin as a key peripheral tissue involved in synucleinopathy, offering a minimally invasive source for in vivo detection of pathological \u03b1-synuclein. This review summarizes current evidence on skin-derived biomarkers across the prodromal continuum of PD, with particular emphasis on skin biopsy-based detection of phosphorylated \u03b1-synuclein and \u03b1-synuclein seed amplification assays (SAAs). Findings in high-risk prodromal phenotypes, including idiopathic REM sleep behavior disorder (iRBD) and pure autonomic failure (PAF), are critically reviewed. Emerging data suggest that cutaneous \u03b1-synuclein pathology may precede nigrostriatal dopaminergic degeneration and may predict phenoconversion to overt synucleinopathies. Important knowledge gaps are highlighted, including the lack of data in other prodromal phenotypes such as hyposmia. Overall, skin-based biomarkers appear to represent promising, scalable tools for biological diagnosis, prognostication, and enrichment of prodromal PD cohorts in clinical trials.<\/jats:p>","DOI":"10.3390\/biom16030376","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T16:06:59Z","timestamp":1772467619000},"page":"376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Skin-Based \u03b1-Synuclein Deposits Detection Across the Prodromal Continuum of Synucleinopathies: Updated Evidence and Perspectives"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9255-9351","authenticated-orcid":false,"given":"Seyed-Mohammad","family":"Fereshtehnejad","sequence":"first","affiliation":[{"name":"Pacific Parkinson\u2019s Research Centre (PPRC), Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada"},{"name":"Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada"},{"name":"Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 171 77 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/S0140-6736(23)01419-8","article-title":"The epidemiology of Parkinson\u2019s disease","volume":"403","author":"Darweesh","year":"2024","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e095610","DOI":"10.1136\/bmjopen-2024-095610","article-title":"Global burden of Parkinson\u2019s disease from 1990 to 2021: A population-based study","volume":"15","author":"Li","year":"2025","journal-title":"BMJ Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e080952","DOI":"10.1136\/bmj-2024-080952","article-title":"Projections for prevalence of Parkinson\u2019s disease and its driving factors in 195 countries and territories to 2050: Modelling study of Global Burden of Disease Study 2021","volume":"388","author":"Su","year":"2025","journal-title":"BMJ"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1007\/s11910-017-0738-x","article-title":"Subtypes of Parkinson\u2019s Disease: What Do They Tell Us About Disease Progression?","volume":"17","author":"Fereshtehnejad","year":"2017","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e214108","DOI":"10.1212\/WNL.0000000000214108","article-title":"Evolution of Motor and Nonmotor Characteristics in an Idiopathic\/Isolated REM Sleep Behavior Disorder Cohort","volume":"105","author":"Delva","year":"2025","journal-title":"Neurology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1093\/brain\/awz111","article-title":"Evolution of prodromal Parkinson\u2019s disease and dementia with Lewy bodies: A prospective study","volume":"142","author":"Fereshtehnejad","year":"2019","journal-title":"Brain"},{"key":"ref_7","first-page":"681","article-title":"The Concept of Prodromal Parkinson\u2019s Disease","volume":"5","author":"Mahlknecht","year":"2015","journal-title":"J. Park. Dis."},{"key":"ref_8","first-page":"S345","article-title":"Combining Biomarkers with Genetics In Prodromal\/Earliest Phase Parkinson\u2019s Disease","volume":"14","author":"Seibler","year":"2024","journal-title":"J. Park. Dis."},{"key":"ref_9","first-page":"S353","article-title":"Imaging Biomarkers in Prodromal and Earliest Phases of Parkinson\u2019s Disease","volume":"14","author":"Theis","year":"2024","journal-title":"J. Park. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1001\/jama.2024.0792","article-title":"Skin Biopsy Detection of Phosphorylated alpha-Synuclein in Patients With Synucleinopathies","volume":"331","author":"Gibbons","year":"2024","journal-title":"JAMA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1212\/WNL.0b013e3182825127","article-title":"Skin sympathetic fiber alpha-synuclein deposits: A potential biomarker for pure autonomic failure","volume":"80","author":"Donadio","year":"2013","journal-title":"Neurology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1002\/mds.28636","article-title":"Onset of Skin, Gut, and Genitourinary Prodromal Parkinson\u2019s Disease: A Study of 1.5 Million Veterans","volume":"36","author":"Scott","year":"2021","journal-title":"Mov. Disord."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/s41582-021-00486-9","article-title":"Prodromal Parkinson disease subtypes-key to understanding heterogeneity","volume":"17","author":"Berg","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.smrv.2018.09.008","article-title":"The risk of neurodegeneration in REM sleep behavior disorder: A systematic review and meta-analysis of longitudinal studies","volume":"43","author":"Galbiati","year":"2019","journal-title":"Sleep Med. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/alz.13386","article-title":"Prodromal dementia with Lewy bodies in REM sleep behavior disorder: A multicenter study","volume":"20","author":"Joza","year":"2024","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.parkreldis.2020.11.017","article-title":"Parkinson\u2019s disease and skin","volume":"82","author":"Niemann","year":"2021","journal-title":"Park. Relat. Disord."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1159\/000512189","article-title":"A Review of the Current Evidence Connecting Seborrheic Dermatitis and Parkinson\u2019s Disease and the Potential Role of Oral Cannabinoids","volume":"237","author":"Rietcheck","year":"2021","journal-title":"Dermatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/s41531-025-00928-x","article-title":"Linking Parkinson\u2019s disease and melanoma: The impact of copper-driven cuproptosis and related mechanisms","volume":"11","author":"Wang","year":"2025","journal-title":"NPJ Park. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1111\/ene.13939","article-title":"Abnormal alpha-synuclein deposits in skin nerves: Intra- and inter-laboratory reproducibility","volume":"26","author":"Donadio","year":"2019","journal-title":"Eur. J. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00401-025-02973-5","article-title":"Biochemical signatures of skin alpha-synuclein in synucleinopathies revealed by RT-QuIC assay end-product analysis","volume":"151","author":"Gerasimenko","year":"2026","journal-title":"Acta Neuropathol."},{"key":"ref_21","first-page":"e47179","article-title":"Skin Biopsy as a Diagnostic Tool for Synucleinopathies","volume":"15","author":"Waqar","year":"2023","journal-title":"Cureus"},{"key":"ref_22","unstructured":"Zuber, T.J. (2002). Punch biopsy of the skin. Am. Fam. Physician, 65."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Isaacson, J.R., Freeman, R., and Gibbons, C.H. (2024). Clinical utility of synuclein skin biopsy in the diagnosis and evaluation of synucleinopathies. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1510796"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Liu, X., Yang, J., Yuan, Y., He, Q., Gao, Y., Jiang, C., Li, L., and Xu, Y. (2020). Optimization of the Detection Method for Phosphorylated alpha-Synuclein in Parkinson Disease by Skin Biopsy. Front. Neurol., 11.","DOI":"10.3389\/fneur.2020.569446"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/S1474-4422(25)00194-2","article-title":"alpha-synuclein biomarker assays: Bridging research and patient care","volume":"24","author":"Lodge","year":"2025","journal-title":"Lancet Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1093\/jnen\/nlaf036","article-title":"Evaluation of 6 monoclonal antibodies against Ser129-phosphorylated alpha-synuclein: Critical role of proteinase K antigen retrieval and superior sensitivity of the D1R1R clone in human skin biopsies","volume":"84","author":"Delprete","year":"2025","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e2513","DOI":"10.1212\/WNL.0000000000011935","article-title":"In Vivo Diagnosis of Synucleinopathies: A Comparative Study of Skin Biopsy and RT-QuIC","volume":"96","author":"Donadio","year":"2021","journal-title":"Neurology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1001\/jamaneurol.2020.3311","article-title":"Skin alpha-Synuclein Aggregation Seeding Activity as a Novel Biomarker for Parkinson Disease","volume":"78","author":"Wang","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s40035-024-00449-2","article-title":"\u03b1-Synuclein seeding amplification assays for diagnosing synucleinopathies: An innovative tool in clinical implementation","volume":"13","author":"Kuang","year":"2024","journal-title":"Transl. Neurodegener."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s44328-024-00023-w","article-title":"A same day alpha-synuclein RT-QuIC seed amplification assay for synucleinopathy biospecimens","volume":"2","author":"Parveen","year":"2025","journal-title":"NPJ Biosens."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.tibtech.2024.01.007","article-title":"alpha-Synuclein seed amplification technology for Parkinson\u2019s disease and related synucleinopathies","volume":"42","author":"Soto","year":"2024","journal-title":"Trends Biotechnol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Rissardo, J.P., and Fornari Caprara, A.L. (2025). Alpha-Synuclein Seed Amplification Assays in Parkinson\u2019s Disease: A Systematic Review and Network Meta-Analysis. Clin. Pract., 15.","DOI":"10.3390\/clinpract15060107"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1007\/s00415-025-12978-5","article-title":"Skin alpha-synuclein assays in diagnosing Parkinson\u2019s disease: A systematic review and meta-analysis","volume":"272","author":"Zhao","year":"2025","journal-title":"J. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3949","DOI":"10.1111\/ene.16041","article-title":"Comparison of biospecimens for alpha-synuclein seed amplification assays in Parkinson\u2019s disease: A systematic review and network meta-analysis","volume":"30","author":"Zheng","year":"2023","journal-title":"Eur. J. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/S1474-4422(25)00085-7","article-title":"Biological effects of pathologies in Lewy body diseases: Why timing matters","volume":"24","author":"Matar","year":"2025","journal-title":"Lancet Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1002\/mds.28592","article-title":"Longitudinal Changes in Isolated Rapid Eye Movement Sleep Behavior Disorder-Related Metabolic Pattern Expression","volume":"36","author":"Kim","year":"2021","journal-title":"Mov. Disord."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1093\/brain\/awz030","article-title":"Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: A multicentre study","volume":"142","author":"Postuma","year":"2019","journal-title":"Brain"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"105832","DOI":"10.1016\/j.parkreldis.2023.105832","article-title":"Peripheral alpha-synuclein isoforms are potential biomarkers for diagnosis and prognosis of isolated REM sleep behavior disorder","volume":"115","author":"Arnaldo","year":"2023","journal-title":"Park. Relat. Disord."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/S1474-4422(13)70056-5","article-title":"Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: An observational cohort study","volume":"12","author":"Iranzo","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1212\/WNL.0000000000200878","article-title":"alpha-Synuclein Seed Amplification Assays for Diagnosing Synucleinopathies: The Way Forward","volume":"99","author":"Bellomo","year":"2022","journal-title":"Neurology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S1474-4422(20)30449-X","article-title":"Detection of alpha-synuclein in CSF by RT-QuIC in patients with isolated rapid-eye-movement sleep behaviour disorder: A longitudinal observational study","volume":"20","author":"Iranzo","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e14204","DOI":"10.1111\/jsr.14204","article-title":"Alpha-synuclein pathology in isolated rapid eye movement sleep behaviour disorder: A meta-analysis","volume":"33","author":"Iftikhar","year":"2024","journal-title":"J. Sleep Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e1944","DOI":"10.1212\/WNL.0000000000207147","article-title":"Misfolded alpha-Synuclein Assessment in the Skin and CSF by RT-QuIC in Isolated REM Sleep Behavior Disorder","volume":"100","author":"Iranzo","year":"2023","journal-title":"Neurology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s00401-017-1684-z","article-title":"Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson\u2019s disease","volume":"133","author":"Doppler","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/S1474-4422(21)00176-9","article-title":"Biomarkers of conversion to alpha-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder","volume":"20","author":"Miglis","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.parkreldis.2021.04.007","article-title":"Consistent skin alpha-synuclein positivity in REM sleep behavior disorder\u2014A two center two-to-four-year follow-up study","volume":"86","author":"Doppler","year":"2021","journal-title":"Park. Relat. Disord."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.1002\/acn3.50833","article-title":"Biomarkers for REM sleep behavior disorder in idiopathic and narcoleptic patients","volume":"6","author":"Antelmi","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1212\/WNL.0000000000003989","article-title":"Skin nerve phosphorylated alpha-synuclein deposits in idiopathic REM sleep behavior disorder","volume":"88","author":"Antelmi","year":"2017","journal-title":"Neurology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1002\/mds.28399","article-title":"Immunohistochemical Detection of Synuclein Pathology in Skin in Idiopathic Rapid Eye Movement Sleep Behavior Disorder and Parkinsonism","volume":"36","author":"Tsao","year":"2021","journal-title":"Mov. Disord."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"zsab172","DOI":"10.1093\/sleep\/zsab172","article-title":"Cutaneous alpha-synuclein is correlated with autonomic impairment in isolated rapid eye movement sleep behavior disorder","volume":"44","author":"Miglis","year":"2021","journal-title":"Sleep"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1002\/mds.29340","article-title":"Dermal Real-Time Quaking-Induced Conversion Is a Sensitive Marker to Confirm Isolated Rapid Eye Movement Sleep Behavior Disorder as an Early alpha-Synucleinopathy","volume":"38","author":"Kuzkina","year":"2023","journal-title":"Mov. Disord."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/s41531-023-00473-5","article-title":"A comparative blind study between skin biopsy and seed amplification assay to disclose pathological alpha-synuclein in RBD","volume":"9","author":"Liguori","year":"2023","journal-title":"NPJ Park. Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1002\/ana.24567","article-title":"Skin nerve misfolded alpha-synuclein in pure autonomic failure and Parkinson disease","volume":"79","author":"Donadio","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"14246","DOI":"10.1038\/s41598-018-32588-8","article-title":"Skin alpha-synuclein deposits differ in clinical variants of synucleinopathy: An in vivo study","volume":"8","author":"Donadio","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.parkreldis.2020.10.016","article-title":"Comparison of 123I-MIBG scintigraphy and phosphorylated alpha-synuclein skin deposits in synucleinopathies","volume":"81","author":"Giannoccaro","year":"2020","journal-title":"Park. Relat. Disord."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2440","DOI":"10.1093\/brain\/awae033","article-title":"Phenoconversion in pure autonomic failure: A multicentre prospective longitudinal cohort study","volume":"147","author":"Palma","year":"2024","journal-title":"Brain"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1002\/ana.24877","article-title":"Natural history of pure autonomic failure: A United States prospective cohort","volume":"81","author":"Kaufmann","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1007\/s10286-021-00829-y","article-title":"Different phenoconversion pathways in pure autonomic failure with versus without Lewy bodies","volume":"31","author":"Goldstein","year":"2021","journal-title":"Clin. Auton. Res."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Liu, M., Wen, T., Luo, H., Yang, T., Kong, Y., Jin, Y., Li, L., Yuan, Y., Liu, X., and Yuan, J. (2025). Distinct cutaneous alpha-synuclein signatures in body-first and brain-first Parkinson\u2019s disease subtypes. Brain, awaf395.","DOI":"10.1093\/brain\/awaf395"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Donadio, V., Incensi, A., Rizzo, G., Furia, A., Bonvenga, S., Olivola, E., Piatti, M., Ventruto, F., Vacchiano, V., and Delprete, C. (2025). Skin intraneural phosphorylated alpha-synuclein is a highly specific biomarker for early Parkinson\u2019s disease. Brain, awaf313.","DOI":"10.1093\/brain\/awaf313"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/S1474-4422(21)00030-2","article-title":"Challenges in the diagnosis of Parkinson\u2019s disease","volume":"20","author":"Tolosa","year":"2021","journal-title":"Lancet Neurol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/3\/376\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T16:39:03Z","timestamp":1772469543000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/3\/376"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,2]]},"references-count":61,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["biom16030376"],"URL":"https:\/\/doi.org\/10.3390\/biom16030376","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,2]]}}}