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Multicenter Study
. 2024 Apr 16;331(15):1298-1306.
doi: 10.1001/jama.2024.0792.

Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies

Christopher H Gibbons  1 , Todd Levine  2   3 , Charles Adler  4 , Bailey Bellaire  3 , Ningshan Wang  1 , Jade Stohl  3 , Pinky Agarwal  5 , Georgina M Aldridge  6 , Alexandru Barboi  7 , Virgilio G H Evidente  8 , Douglas Galasko  9 , Michael D Geschwind  10 , Alejandra Gonzalez-Duarte  11 , Ramon Gil  12 , Mark Gudesblatt  13 , Stuart H Isaacson  14 , Horacio Kaufmann  11 , Pravin Khemani  15 , Rajeev Kumar  16 , Guillaume Lamotte  17 , Andy J Liu  18 , Nikolaus R McFarland  19 , Mitchell Miglis  20 , Adam Reynolds  21 , Gregory A Sahagian  22 , Marie-Helene Saint-Hillaire  23 , Julie B Schwartzbard  24 , Wolfgang Singer  25 , Michael J Soileau  26 , Steven Vernino  27 , Oleg Yerstein  28 , Roy Freeman  1
Affiliations
Multicenter Study

Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies

Christopher H Gibbons et al. JAMA. .

Abstract

Importance: Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies.

Objective: To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF.

Design, setting, and participants: This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis.

Exposure: Skin biopsy for detection of phosphorylated α-synuclein.

Main outcomes: Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy.

Results: Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected.

Conclusions and relevance: In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Gibbons reported receiving grants from the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) during the conduct of the study and having stock options in CND Life Sciences outside the submitted work. Dr Levine reported having a patent for detection of cutaneous alpha synuclein pending. Dr Evidente reported receiving grants from Alexza, NeuroStim, Jazz Pharmaceuticals, Cerevance, Theravance, Ipsen, Neurocrine, Pharma2B, Revance, AbbVie, Acadia, and Neuraly and personal fees from Ipsen, Neurocrine, Teva, Revance, AbbVie, Amneal, and Medtronic outside the submitted work. Dr Galasko reported receiving a grant from Amprion, Inc to the University of California San Diego outside the submitted work. Dr Geschwind reported receiving personal fees for consulting from Gerson Lehrman Group, Reata Pharmaceuticals, Inc, MedConnect Pro LLC, and Clarion Consulting outside the submitted work. Dr Gudesblatt reported receiving study funding from the South Shore Neurologic Associates during the conduct of the study. Dr Isaacson reported receiving personal fees from CND Life Sciences outside the submitted work. Dr Kaufmann reported receiving grants from Bigen MA Inc; Vaxxinity Inc; the NINDS, NIH; the Familial Dysautonomia Foundation, and the HSAN IV Foundation during the conduct of the study and receiving personal fees for consulting from Takeda Pharmaceutical Company Ltd, Ono Pharma UK Ltd, Theravance Biopharma US Inc, and Parexel; receiving royalties from UpToDate; and being Editor in Chief of Clinical Autonomic Research outside the submitted work. Dr Khemani reported receiving speaker honoraria from Amneal, receiving personal fees for consulting from Boston Scientific and Cala Health, and serving on the advisory board for Ipsen and Reata outside the submitted work. Dr Kumar reported owning stock in CenExel outside the submitted work. Dr McFarland reported participating on a trial steering committee for ONO Pharmaceutical Co during the conduct of the study. Dr Miglis reported receiving personal fees from 2nd.MD, InfiniteMD, and Jazz Pharmaceuticals; royalties from Elsevier; and grants from the NIH, Embr Wave, Argenx, and Dysautonomia International outside the submitted work. Dr Sahagian reported receiving personal fees from UCB Pharma, Argenx, Alexion, and Biogen outside the submitted work. Dr Soileau reported receiving grants from CND Life Sciences to the institution during the conduct of the study and receiving personal fees from AbbVie, Abbott, Amneal, Merz Therapeutics, Medtronic, Neurocrine, Supernus, Cerevel Therapeutics, Jazz Pharmaceuticals, Praxis Precision Medicine, Scion, Teva, and Kyowa Kiran and grants from the Huntington's Disease Society of America outside the submitted work. Dr Freeman reported receiving grants from the NINDS, NIH during the conduct of the study and having stock options in CND Life Sciences outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Participant Flow Diagram
REM indicates rapid-eye-movement. aUpdated diagnoses based on expert review are shown. bOriginal diagnoses and reasons for exclusion are shown.
See this image and copyright information in PMC

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