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

Abstract

ImportanceFinding 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.ObjectiveTo evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF.Design, Setting, and ParticipantsThis 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.ExposureSkin biopsy for detection of phosphorylated α-synuclein.Main OutcomesRates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy.ResultsOf 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 RelevanceIn 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.

Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies—Reply

“…In Reply We appreciate the letter by Dr Tu and colleagues about our article on skin biopsy detection of phosphorylated α-synuclein (P-SYN) . We agree that P-SYN deposition within the skin is variable, and that a single skin biopsy may not be sufficient in all patients.…”

“…We also agree with the need to ensure unbiased handling of missing data and a rigorous approach to study design. In this study, all outcomes (primary, secondary, and exploratory) were prespecified and previously published . The reclassification of patients who did not meet defined entry criteria into a secondary analysis cohort was an integral feature of our study design.…”

Substantia(l) Impacts of Contact Sport Play and Parkinsonism

“…It remains unclear whether specific features of parkinsonism may help differentiate RHI- or CTE-related parkinsonism from other more common causes of parkinsonism. Since we do not yet have CTE-specific diagnostic biomarkers, this may represent an additional context of use for emerging diagnostic α-synuclein biomarkers showing promise for detecting LB neuropathology during life …”

Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies

“…To the Editor We have some concerns about a recent study about phosphorylated α-synuclein as a diagnostic biomarker for synucleinopathies.…”