The Synuclein-One Study: Skin Biopsy Detection of Phosphorylated alpha-synuclein for Diagnosis of the Synucleinopathies
Christopher Gibbons1, Bailey Bellaire2, Ningshan Wang3, Roy Freeman4, Charles Adler5, Mitchell Miglis6, Stuart Isaacson7, Virgilio Gerald Evidente8, Michael Soileau9, Mark Gudesblatt10, Guillaume Lamotte11, Rajeev Kumar12, Melita Petrossian13, Maria Alejandra Gonzalez Duarte14, Pravin Khemani15, Marie-Helene Saint-Hilaire16, Nikolaus McFarland17, Hemant Pandey18, Oleg Yerstein19, Alexandru Barboi20, Andrew Liu21, Todd Levine22
1Beth Israel Deaconess Medical Center, 2CND Life Sciences, 3BIDMC, 4Beth Israel Deaconess Hosp, 5Mayo Clinic Arizona, 6Stanford University Medical Center, 7Parkinson’s Disease and Movement Disorders Center of Boca Raton, 8Movement Disorders Center of Arizona, 9Texas Movement Disorder Specialists, PLLC, 10South Shore Neurologic Associates, 11University of Utah, 12Rocky Mountain Movement Disorders Center, 13Pacific Movement Disorders Center, 14NYU, 15Swedish Neuroscience Institute, 16Boston University School of Medicine, 17University of Florida, 18Brain and Spine Center, 19Lahey Hospital & Medical Center, 20NorthShore University, 21Duke Health, 22Honor Health
Objective:
To describe the sensitivity, specificity, accuracy and precision of skin biopsy to detect the presence of phosphorylated alpha-synuclein in patients with synucleinopathies.
Background:
The Synuclein-One study is an ongoing NIH-funded 30-site multicenter trial of ~400 patients with synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and pure autonomic failure (PAF). Enrollment will close in December 2022, with final data analysis 2/1/2022.
Design/Methods:
After signing informed consent, all subjects will complete detailed neurologic examinations (MDS-UPDRS, Hoehn and Yahr scale), detailed disease history review, cognitive evaluation (MOCA), orthostatic vital signs, RBD questionnaire, orthostatic hypotension questionnaire, MSA red flags and Parkinson’s Disease Questionnaire-39. All subjects will complete skin biopsies at the distal leg, distal thigh and proximal thigh. All clinical material will be reviewed by a blinded expert consensus panel to confirm the referring diagnosis or move to an ‘indeterminate’ category. Skin biopsies will be processed at 2 independent laboratories. Phosphorylated alpha-synuclein deposition will be quantified by 2 readers, blinded to referring diagnosis and results of the other reader.
Results:
Final un-blinded results will be presented at the AAN 2023 annual meeting with a focus on sensitivity, specificity, accuracy and precision. In addition, synucleinopathy subgroup analysis will be performed to define unique pathological characteristics of disease (PD, MSA, DLB or PAF).
Conclusions:
The need for a validated, well-characterized, simple, reproducible marker of synuclein pathology has never been greater. The number of individuals with neurodegenerative diseases continues to grow and misdiagnosis within and among synuclein and non-synuclein pathologies continues to occur, resulting in incorrect medication choices, iatrogenic complications, poor prognostication and patient frustration. The Synuclein-One study is the largest investigation of cutaneous phosphorylated alpha-synuclein detection across all four synucleinopathies and will advance the field of neuro-diagnostic testing in neurodegenerative disease.