{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T06:11:46Z","timestamp":1776147106288,"version":"3.50.1"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Parkinson\u2019s disease (PD) is a neurodegenerative condition with progressive phosphorylated alpha-synuclein (P-SYN) deposition. Skin biopsies are a sensitive and specific source of tissue to detect intra-axonal P-SYN in patients with PD. Further, isolated REM sleep behavior disorder (iRBD) is a prodromal condition with a high risk of phenoconversion to PD. The objective of the Synuclein-Quantification (Syn-Q) study is to quantify cutaneous P-SYN across a range of PD severity and in iRBD and measure changes in P-SYN over time.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>After consent, participants with iRBD and PD across Hoehn and Yahr stages 1, 2, 3 will complete neurological and cognitive evaluation, motor and olfactory assessments, orthostatic vitals, and questionnaires. Skin biopsies (3\u202fmm diameter and 3\u20134\u202fmm depth) will be taken from distal leg 10\u202fcm above the lateral malleolus, distal thigh 10\u202fcm above the lateral knee, and posterior cervical region 3\u202fcm lateral to the C-7 spinous process with quantitation of cutaneous intra-axonal P-SYN. Participants will return for follow-up visits to repeat study procedures at 6, 12, and 18\u202fmonths following the baseline visit. This study is funded by the Michael J. Fox Foundation and is registered on Clinicaltrial.org (NCT06621602).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Expected results<\/jats:title>\n                    <jats:p>We anticipate that patients with more severe stages of PD will have higher levels of quantitative P-SYN. We also predict that increases in P-SYN over time will be associated with worsening disease severity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>In patients with PD, the detection and quantification of P-SYN is a critical step to supporting clinical trials that seek to alter the natural history of disease. Skin biopsies offer a more accessible, repeatable and quantifiable approach to monitoring phosphorylated alpha-synuclein compared to cerebrospinal fluid. This study will define the longitudinal rates of P-SYN change in patients with PD from prodromal to advanced disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/clinicaltrials.gov\/study\/NCT06621602<\/jats:ext-link>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1823991","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T05:36:10Z","timestamp":1776144970000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The Syn-Q study: detection of cutaneous phosphorylated alpha-synuclein in Parkinson\u2019s disease progression: a trial protocol"],"prefix":"10.3389","volume":"17","author":[{"given":"Jourdan H.","family":"Parent","sequence":"first","affiliation":[{"name":"CND Life Sciences","place":["Scottsdale, AZ, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Todd","family":"Levine","sequence":"additional","affiliation":[{"name":"CND Life Sciences","place":["Scottsdale, AZ, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roy","family":"Freeman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School","place":["Boston, MA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher H.","family":"Gibbons","sequence":"additional","affiliation":[{"name":"CND Life Sciences","place":["Scottsdale, AZ, United States"]},{"name":"Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School","place":["Boston, MA, United 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2021","volume":"16","author":"Luo","year":"2024","journal-title":"Front Aging Neurosci"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"5405","DOI":"10.3390\/ijms26115405","article-title":"Alpha-synuclein pathology in synucleinopathies: mechanisms, biomarkers, and therapeutic challenges","volume":"26","author":"Arias-Carrion","year":"2025","journal-title":"Int J Mol Sci"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1111\/j.1440-1789.2007.00803.x","article-title":"The Lewy body in Parkinson's disease: molecules implicated in the formation and degradation of alpha-synuclein aggregates","volume":"27","author":"Wakabayashi","year":"2007","journal-title":"Neuropathology"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1016\/S1474-4422(21)00061-2","article-title":"Progress towards therapies for disease modification in Parkinson's disease","volume":"20","author":"Vijiaratnam","year":"2021","journal-title":"Lancet Neurol"},{"key":"ref7","doi-asserted-by":"publisher","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":"ref8","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1038\/s41596-022-00787-3","article-title":"Seed amplification assay for the detection of pathologic alpha-synuclein aggregates in cerebrospinal fluid","volume":"18","author":"Concha-Marambio","year":"2023","journal-title":"Nat Protoc"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1001\/jama.2024.0792","article-title":"Skin biopsy detection of phosphorylated alpha-synuclein in patients with 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