The Synuclein-One Study: Skin Biopsy Detection of Phosphorylated alpha-synuclein for Diagnosis of the Synucleinopathies

Congratulations Dr. Nikolaus McFarland, on the publication of “The Synuclein-One Study: Skin Biopsy Detection of Phosphorylated alpha-synuclein for Diagnosis of the Synucleinopathies.”  This research was published in the April 26th edition of Neuorology.



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.