A Novel 3D Semi‐Automated Full Quantification Technique for Detection of Intraneural Phospho‐α‐Synuclein in Skin Biopsies
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2026
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| author | Sophia Lonczewski Verian Bader Louisa Ortmann Louisa Basner Markus Stücker Ralf Gold Raphael Scherbaum Eun Hae Kwon Konstanze F. Winklhofer Lars Tönges |
| author_facet | Sophia Lonczewski Verian Bader Louisa Ortmann Louisa Basner Markus Stücker Ralf Gold Raphael Scherbaum Eun Hae Kwon Konstanze F. Winklhofer Lars Tönges Sophia Lonczewski Verian Bader Louisa Ortmann Louisa Basner Markus Stücker Ralf Gold Raphael Scherbaum Eun Hae Kwon Konstanze F. Winklhofer Lars Tönges |
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| contents | A Novel 3D Semi‐Automated Full Quantification Technique for Detection of Intraneural Phospho‐α‐Synuclein in Skin Biopsies Sophia Lonczewski Verian Bader Louisa Ortmann Louisa Basner Markus Stücker Ralf Gold Raphael Scherbaum Eun Hae Kwon Konstanze F. Winklhofer Lars Tönges European Journal of Neurology ABSTRACT Background Parkinson'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. Methods In 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. Results Our 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. Conclusions This 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. 10.1111/ene.70525 http://creativecommons.org/licenses/by-nc/4.0/ |
| doi_str_mv | 10.1111/ene.70525 |
| format | Artículo Open Access |
| id | wiley_oa_10_1111_ene_70525 |
| institution | Wiley Open Access |
| license_str_mv | http://creativecommons.org/licenses/by-nc/4.0/ |
| publishDate | 2026 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | A Novel 3D Semi‐Automated Full Quantification Technique for Detection of Intraneural Phospho‐α‐Synuclein in Skin Biopsies Sophia Lonczewski Verian Bader Louisa Ortmann Louisa Basner Markus Stücker Ralf Gold Raphael Scherbaum Eun Hae Kwon Konstanze F. Winklhofer Lars Tönges European Journal of Neurology A Novel 3D Semi‐Automated Full Quantification Technique for Detection of Intraneural Phospho‐α‐Synuclein in Skin Biopsies Sophia Lonczewski Verian Bader Louisa Ortmann Louisa Basner Markus Stücker Ralf Gold Raphael Scherbaum Eun Hae Kwon Konstanze F. Winklhofer Lars Tönges European Journal of Neurology ABSTRACT Background Parkinson'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. Methods In 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. Results Our 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. Conclusions This 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. 10.1111/ene.70525 http://creativecommons.org/licenses/by-nc/4.0/ |
| title | A Novel 3D Semi‐Automated Full Quantification Technique for Detection of Intraneural Phospho‐α‐Synuclein in Skin Biopsies |
| topic | European Journal of Neurology |
| url | https://onlinelibrary.wiley.com/doi/10.1111/ene.70525 |