Synuclein-One Study: Skin Biopsy Detection of Phosphorylated α-Synuclein for Diagnosis of Synucleinopathies

Gibbons, Christopher H.; Freeman, Roy; Bellaire, Bailey; Adler, Charles H.; Moore, Dan H.; Levine, Todd

doi:10.2217/bmm-2021-0646

Cited by 21 publications

(15 citation statements)

References 61 publications

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“…The study design and methods have been previously published. 9 In brief, this was a blinded, multicenter, crosssectional study conducted from February 2021 through March 2023 to evaluate the detection of P-SYN by skin biopsy in individuals with PD, DLB, MSA, and PAF and control individuals without synucleinopathy. The study was approved by a central institutional review board (Sterling: 8385).…”

Section: Methodsmentioning

confidence: 99%

“…The study included adults aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on consensus criteria as previously published. [9][10][11][12] Control participants were adults aged 40 to 99 years with no history of clinical examination findings or symptoms suggestive of synucleinopathy (including hyposmia, constipation, rapid-eyemovement [REM] sleep behavior disorder, mild cognitive impairment, or dementia) or other neurodegenerative diseases. Controls were recruited through all study sites via local advertisements and at routine visits with local primary care physicians.…”

Section: Inclusion Criteriamentioning

confidence: 99%

“…Controls were recruited through all study sites via local advertisements and at routine visits with local primary care physicians. Exclusion criteria for all participants were published previously 9 and include risks associated with performing a biopsy and diseases that could mimic symptoms of a synucleinopathy.…”

Section: Inclusion Criteriamentioning

confidence: 99%

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

Gibbons,

Levine,

Adler

et al. 2024

JAMA

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Inclusion Criteriamentioning

confidence: 99%

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

Gibbons,

Levine,

Adler

et al. 2024

JAMA

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“…The Project Team felt that these two targets should be pursued in tandem, in the hope With respect to the adaptation of seeding assays for alternative biosamples: The current RT-QuIC situation has further drawbacks -at present, the procedure involves obtaining CSF as part of the diagnostic evaluation. However, there is a very recent report of success analyzing serum 23 and skin biopsy assays being integrated into LBD research studies, 31 and we are optimistic about these sorts of assays becoming more widely available. The hope is that, in the next 5 years, assays will be developed that are quicker, bloodbased, and quantitative -whether upgraded seeding assays or other ultrasensitive, protein-conformation-sensitive assays, such as soluble oligomer binding assay (SOBA).…”

Section: 22mentioning

confidence: 99%

Lewy body dementia: Overcoming barriers and identifying solutions

Agarwal,

Backler,

Bayram

et al. 2024

Alzheimer's & Dementia

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Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public‐health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public‐domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor.Highlights A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field.

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“…The detection of phosphorylated alpha-synuclein in cholinergic and adrenergic nerve fibers in the skin is a sentinel discovery in the search for an understanding of the pathophysiology of sympathetic neurodegeneration and holds promise as a potentially useful biomarker to diagnose Parkinson disease and multiple system atrophy ( 21 – 25 ).…”

Section: Looking Forwardmentioning

confidence: 99%