Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies, 2024, Gibbons et al

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

Authors
Christopher H. Gibbons, MD, MMSc1; Todd Levine, MD2,3; Charles Adler, MD, PhD4; Bailey Bellaire, BS3; Ningshan Wang, PhD1; Jade Stohl, BA3; Pinky Agarwal, MD5; Georgina M. Aldridge, MD, PhD6; Alexandru Barboi, MD7; Virgilio G. H. Evidente, MD8; Douglas Galasko, MD9; Michael D. Geschwind, MD, PhD10; Alejandra Gonzalez-Duarte, MD11; Ramon Gil, MD12; Mark Gudesblatt, MD13; Stuart H. Isaacson, MD14; Horacio Kaufmann, MD11; Pravin Khemani, MD15; Rajeev Kumar, MD16; Guillaume Lamotte, MD, MMSc17; Andy J. Liu, MD, MS18; Nikolaus R. McFarland, MD, PhD19; Mitchell Miglis, MD20; Adam Reynolds, MD21; Gregory A. Sahagian, MD22; Marie-Helene Saint-Hillaire, MD, PhD23; Julie B. Schwartzbard, MD24; Wolfgang Singer, MD, PhD25; Michael J. Soileau, MD26; Steven Vernino, MD, PhD27; Oleg Yerstein, MD28; Roy Freeman, MD1
Author Affiliations
  • 1Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
  • 2HonorHealth Neurology, Scottsdale, Arizona
  • 3CND Life Sciences, Scottsdale, Arizona
  • 4Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, Arizona
  • 5Evergreen Health, Kirkland, Washington
  • 6Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City
  • 7Department of Neurology, Northshore University Health System, Glenview, Illinois
  • 8Movement Disorder Center of Arizona, Scottsdale
  • 9Department of Neurology, University of California, San Diego
  • 10Department of Neurology, University of California, San Franscisco
  • 11Department of Neurology, New York University Grossman School of Medicine, New York
  • 12Parkinson’s Disease Treatment Center of Southwest Florida, Port Charlotte
  • 13Department of Neurology, New York University Grossman Long Island School of Medicine, New York
  • 14Parkinson’s Disease and Movement Disorders Center of Boca Raton, Boca Raton, Florida
  • 15Department of Neurology, Swedish Medical Center, Seattle, Washington
  • 16Rocky Mountain Movement Disorders Center, Englewood, Colorado
  • 17Department of Neurology, University of Utah, Salt Lake City
  • 18Department of Neurology, Duke University School of Medicine, Durham, North Carolina
  • 19Department of Neurology, University of Florida Health Center, Gainesville
  • 20Department of Neurology, Stanford University Medical Center, Palo Alto, California
  • 21Center for Neurosciences, Tuscan, Arizona
  • 22The Neurology Center of Southern California, Carlsbad
  • 23Department of Neurology, Boston Medical Center, Boston, Massachusetts
  • 24Aventura Associates, Aventura, Florida
  • 25Department of Neurology, Mayo Clinic Rochester, Rochester, New York
  • 26Texas Movement Disorder Specialists, Georgetown
  • 27Department of Neurology, The University of Texas Southwestern Medical Center, Dallas
  • 28Department of Neurology, Lahey Clinic, Burlington, Massachusetts
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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.

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.
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Link (JAMA)
 
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"Follow up studies are in the works.

Both NIH RECOVER and CND Life Sciences will be investigating the prevalence of the #Parkinsons biomarker in #LongCovid via skin biopsy."

"This will be an excellent complement to the post-COVID RT-QuIC (another PD biomarker) study coming out of Innsbruck."

"Each of which will offer direct insight into whether COVID-19 can trigger the proteinopathy responsible for Parkinsons and related diseases."

"Synucleinopathy is currently a plausible explanation for long covid, which would make it akin to prodromal PD or incidental Lewy body disease. We'll have to see what comes out of these studies though."
 
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