Cutaneous Phosphorylated Alpha-Synuclein in Lewy Body Dementia

Christopher H Gibbons¹, Todd Levine^{2

3}, Charles H Adler⁴, Bailey Bellaire³, Ningshan Wang¹, Pinky Agarwal⁵, Georgina M Aldridge⁶, Alexandru Barboi⁷, Daniel Claassen⁸, Virgilio G H Evidente⁹, Douglas Galasko¹⁰, Alejandra Gonzalez-Duarte¹¹, Ramon Gil¹², Mark Gudesblatt¹³, Stuart H Isaacson¹⁴, Horacio Kaufmann¹¹, Pravin Khemani¹⁵, Rajeev Kumar¹⁶, Guillaume Lamotte¹⁷, Andy J Liu¹⁸, Nikolaus R McFarland¹⁹, Mitchell G Miglis²⁰, Adam Reynolds²¹, Gregory A Sahagian²², Marie-Helene Saint-Hilaire²³, Julie B Schwartzbard²⁴, Wolfgang Singer²⁵, Michael J Soileau²⁶, Steven Vernino²⁷, Patricio Millar Vernetti¹¹, Oleg Yerstein²⁸, Roy Freeman¹

Affiliations

¹ Department of Neurology Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
² Honorhealth Neurology, Scottsdale, Arizona, USA.
³ CND Life Sciences, Scottsdale, Arizona, USA.
⁴ Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
⁵ Booth Gardner Parkinson's Center, Evergreen Health, Kirkland, Washington, USA.
⁶ Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
⁷ Department of Neurology, Northshore University Health System, Evanston, Illinois, USA.
⁸ Department of Neurology, Vanderbilt, Nashville, Tennessee, USA.
⁹ Movement Disorder Center of Arizona, Scottsdale, Arizona, USA.
¹⁰ Department of Neurology, University of California, San Diego, La Jolla, California, USA.
¹¹ Department of Neurology, New York University Grossman School of Medicine, New York, New York, USA.
¹² Parkinson's Disease Treatment Center of Southwest Florida, Port Charlotte, Florida, USA.
¹³ Department of Neurology, New York University Grossman Long Island School of Medicine, Mineola, New York, USA.
¹⁴ Parkinson's Disease and Movement Disorders Center of Boca Raton, Boca Raton, Florida, USA.
¹⁵ Department of Neurology, Swedish Medical Center, Seattle, Washington, USA.
¹⁶ Rocky Mountain Movement Disorders Center, Englewood, Colorado, USA.
¹⁷ Department of Neurology, University of Utah, Salt Lake City, Utah, USA.
¹⁸ Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA.
¹⁹ Department of Neurology, University of Florida Health Center, Gainesville, Florida, USA.
²⁰ Department of Neurology, Stanford University Medical Center, Stanford, California, USA.
²¹ Tuscan Center for Neurosciences, Tucson, Arizona, USA.
²² The Neurology Center of Southern California, San Diego, California, USA.
²³ Department of Neurology, Boston Medical Center, Boston, Massachusetts, USA.
²⁴ Aventura Associates, Miami, Florida, USA.
²⁵ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
²⁶ Texas Movement Disorder Specialists, Georgetown, Texas, USA.
²⁷ Department of Neurology, University of Texas Southwestern, Dallas, Texas, USA.
²⁸ Department of Neurology, Lahey Hospital and Medical Center, Burlington, Massachusetts, USA.

PMID: 41449577
DOI: 10.1002/acn3.70291

Free article

Cutaneous Phosphorylated Alpha-Synuclein in Lewy Body Dementia

Christopher H Gibbons et al. Ann Clin Transl Neurol. 2025.

Free article

. 2025 Dec 25.

doi: 10.1002/acn3.70291. Online ahead of print.

Authors

Affiliations

¹ Department of Neurology Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
² Honorhealth Neurology, Scottsdale, Arizona, USA.
³ CND Life Sciences, Scottsdale, Arizona, USA.
⁴ Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
⁵ Booth Gardner Parkinson's Center, Evergreen Health, Kirkland, Washington, USA.
⁶ Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
⁷ Department of Neurology, Northshore University Health System, Evanston, Illinois, USA.
⁸ Department of Neurology, Vanderbilt, Nashville, Tennessee, USA.
⁹ Movement Disorder Center of Arizona, Scottsdale, Arizona, USA.
¹⁰ Department of Neurology, University of California, San Diego, La Jolla, California, USA.
¹¹ Department of Neurology, New York University Grossman School of Medicine, New York, New York, USA.
¹² Parkinson's Disease Treatment Center of Southwest Florida, Port Charlotte, Florida, USA.
¹³ Department of Neurology, New York University Grossman Long Island School of Medicine, Mineola, New York, USA.
¹⁴ Parkinson's Disease and Movement Disorders Center of Boca Raton, Boca Raton, Florida, USA.
¹⁵ Department of Neurology, Swedish Medical Center, Seattle, Washington, USA.
¹⁶ Rocky Mountain Movement Disorders Center, Englewood, Colorado, USA.
¹⁷ Department of Neurology, University of Utah, Salt Lake City, Utah, USA.
¹⁸ Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA.
¹⁹ Department of Neurology, University of Florida Health Center, Gainesville, Florida, USA.
²⁰ Department of Neurology, Stanford University Medical Center, Stanford, California, USA.
²¹ Tuscan Center for Neurosciences, Tucson, Arizona, USA.
²² The Neurology Center of Southern California, San Diego, California, USA.
²³ Department of Neurology, Boston Medical Center, Boston, Massachusetts, USA.
²⁴ Aventura Associates, Miami, Florida, USA.
²⁵ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
²⁶ Texas Movement Disorder Specialists, Georgetown, Texas, USA.
²⁷ Department of Neurology, University of Texas Southwestern, Dallas, Texas, USA.
²⁸ Department of Neurology, Lahey Hospital and Medical Center, Burlington, Massachusetts, USA.

PMID: 41449577
DOI: 10.1002/acn3.70291

Abstract

Objective: To determine the test performance of cutaneous phosphorylated alpha-synuclein (P-SYN) in dementia with Lewy bodies (DLB), individuals with reduced Montreal Cognitive Assessment (MoCA) and healthy controls.

Methods: This is the first subgroup analysis of the Synuclein-One study, a prospective, blinded study evaluating P-SYN detection from skin biopsies in 218 subjects with a referral diagnosis of control (N = 151) and DLB (N = 67). All subjects completed detailed examinations, questionnaires, and had skin biopsies for detection of P-SYN. DLB patients were included if meeting the 4th DLB consensus probable criteria. Control subjects, aged 40-99, had no history, examination findings, or symptoms suggestive of a synucleinopathy or neurodegenerative disease. An expert review panel, blinded to pathological data, determined the final diagnosis. Controls with reduced MoCA (MoCA < 26, N = 26) at screening were analyzed separately.

Results: After expert panel review, only 50/67 patients met consensus criteria for DLB, 26/151 controls had a reduced MoCA, and 120/151 controls had a normal MoCA. The proportions of subjects with cutaneous P-SYN detected by skin biopsy were 96.0% (48 of 50) of the DLB group, 31% (8 of 26) of the controls with reduced MoCA, and 3.3% (4 of 120) of the controls with normal MoCA.

Interpretation: In this prospective, blinded, cross-sectional study, a high proportion of subjects meeting clinical consensus criteria for DLB had P-SYN detected in skin biopsies. Almost 1/3 of subjects with reduced MoCA testing also had P-SYN detected. These results support a role for skin biopsy detection of P-SYN in patients with DLB.

Trial registration: NCT04700722.

Keywords: dementia with Lewy bodies; mild cognitive impairment; skin biopsy; synucleinopathy.

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References

1. J. R. Isaacson, R. Freeman, and C. H. Gibbons, “Clinical Utility of Synuclein Skin Biopsy in the Diagnosis and Evaluation of Synucleinopathies,” Frontiers in Neurology 15 (2024): 1510796.
1. V. Donadio, K. Doppler, A. Incensi, et al., “Abnormal Alpha‐Synuclein Deposits in Skin Nerves: Intra‐ and Inter‐Laboratory Reproducibility,” European Journal of Neurology: The Official Journal of the European Federation of Neurological Societies 26, no. 10 (2019): 1245–1251.
1. V. Donadio, A. Incensi, G. Rizzo, et al., “A New Potential Biomarker for Dementia With Lewy Bodies: Skin Nerve Alpha‐Synuclein Deposits,” Neurology 89, no. 4 (2017): 318–326.
1. V. Donadio, A. Incensi, V. Leta, et al., “Skin Nerve Alpha‐Synuclein Deposits: A Biomarker for Idiopathic Parkinson Disease,” Neurology 82, no. 15 (2014): 1362–1369.
1. C. H. Gibbons, T. Levine, C. Adler, et al., “Skin Biopsy Detection of Phosphorylated Alpha‐Synuclein in Patients With Synucleinopathies,” Journal of the American Medical Association 331, no. 15 (2024): 1298–1306.

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Cutaneous Phosphorylated Alpha-Synuclein in Lewy Body Dementia

Affiliations

Cutaneous Phosphorylated Alpha-Synuclein in Lewy Body Dementia

Authors

Affiliations

Abstract

References

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous