A Novel 3D Semi-Automated Full Quantification Technique for Detection of Intraneural Phospho-α-Synuclein in Skin Biopsies.
A Novel 3D Semi-Automated Full Quantification Technique for Detection of Intraneural Phospho-α-Synuclein in Skin Biopsies.
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Bochum, DE · Author affiliation
Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University, Bochum, Germany.Location evidence
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Original abstract
BackgroundParkinson's disease (PD) and multiple system atrophy (MSA) are synucleinopathies marked by α-synuclein aggregation, while progressive supranuclear palsy (PSP) is a tauopathy. Clinical overlap between these diseases complicates diagnosis. Detection of intraneural S129 phospho-α-synuclein (pαSyn) via immunofluorescence staining (IF) in skin biopsies shows diagnostic promise. However, prior studies rarely addressed differentiation between synucleinopathies and tauopathies and lacked assessment of varying pαSyn burden-particularly relevant for this aim.MethodsIn this cross-sectional study, we analyzed skin biopsies from 29 PD, 5 MSA, and 4 PSP patients. Samples obtained at C7 and Th12 were double-immunostained with pαSyn and PGP9.5, a pan-axonal neurite marker.ResultsOur novel method digitizes biopsy sections semi-automatically and performs computer-assisted 3D signal reconstruction. The resulting full volumetric quantification of intraneural pαSyn load enables burden-dependent test results based on ROC-derived cut-offs. Applied as a differential diagnostic test, it showed excellent discrimination of synucleinopathies from tauopathies, achieving AUCs of 0.912 (C7) and 0.934 (Th12), with 88.2% sensitivity and 100% specificity. Intraneural pαSyn load was significantly higher in PD and MSA compared to PSP (C7 p = 0.004; Th12 p = 0.002), with no difference between PD and MSA.ConclusionsThis novel technique refines IF by increasing objectivity and allowing gradual pαSyn-burden assessment, offering potential as a confirmatory differential biomarker. Validation in larger, neuropathologically confirmed cohorts of these preliminary small-group results is warranted to fully evaluate the diagnostic and prognostic potential.