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Large-scale validation of skin prion seeding activity as a biomarker for diagnosis of prion diseases

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Abstract

Definitive diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD) relies on the examination of brain tissues for the pathological prion protein (PrPSc). Our previous study revealed that PrPSc-seeding activity (PrPSc-SA) is detectable in skin of sCJD patients by an ultrasensitive PrPSc seed amplification assay (PrPSc-SAA) known as real-time quaking-induced conversion (RT-QuIC). A total of 875 skin samples were collected from 2 cohorts (1 and 2) at autopsy from 2–3 body areas of 339 cases with neuropathologically confirmed prion diseases and non-sCJD controls. The skin samples were analyzed for PrPSc-SA by RT-QuIC assay. The results were compared with demographic information, clinical manifestations, cerebrospinal fluid (CSF) PrPSc-SA, other laboratory tests, subtypes of prion diseases defined by the methionine (M) or valine (V) polymorphism at residue 129 of PrP, PrPSc types (#1 or #2), and gene mutations in deceased patients. RT-QuIC assays of the cohort #1 by two independent laboratories gave 87.3% or 91.3% sensitivity and 94.7% or 100% specificity, respectively. The cohort #2 showed sensitivity of 89.4% and specificity of 95.5%. RT-QuIC of CSF available from 212 cases gave 89.7% sensitivity and 94.1% specificity. The sensitivity of skin RT-QuIC was subtype dependent, being highest in sCJDVV1-2 subtype, followed by VV2, MV1-2, MV1, MV2, MM1, MM1-2, MM2, and VV1. The skin area next to the ear gave highest sensitivity, followed by lower back and apex of the head. Although no difference in brain PrPSc-SA was detected between the cases with false negative and true positive skin RT-QuIC results, the disease duration was significantly longer with the false negatives [12.0 ± 13.3 (months, SD) vs. 6.5 ± 6.4, p < 0.001]. Our study validates skin PrPSc-SA as a biomarker for the detection of prion diseases, which is influenced by the PrPSc types, PRNP 129 polymorphisms, dermatome sampled, and disease duration.

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All materials used in this study will be made available subject to a materials transfer agreement.

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Acknowledgements

We thank all donors and their families for their tissue and CSF donations, and the physicians for their support.

Funding

This study was supported by the CJD Foundation, National Institutes of Health (NIH) NS109532, NS096626, the BAND grant jointly funded by the Alzheimer’s Association, Alzheimer’s Research UK, Michael J. Fox Foundation for Parkinson’s Research, and Weston Brain Institute, and USDA to W.Q.Z., NS112010 to W.Q.Z., Z.W., and S.G.C., NS118760 to S.G.C. and the Intramural Research Program of the NIAID, NIH and gifts from Mary Hilderman Smith, Zoë Smith Jaye, and Jenny Smith Unruh in memory of Jeffrey Smith to B.C., as well as CDC grant to B.S.A.

Author information

Author notes

  1. Shu G. Chen

    Present address: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

  2. Weiguanliu Zhang, Christina D. Orrú, Aaron Foutz, and Mingxuan Ding contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Weiguanliu Zhang, Aaron Foutz, Mingxuan Ding, Jue Yuan, Syed Zahid Ali Shah, Maria Gerasimenko, Tricia Gilliland, Michelle Tang, Mark Cohen, Jiri Safar, Shu G. Chen, Zerui Wang, Brian S. Appleby & Wen-Quan Zou

  2. Department of Neurology, The First Hospital of Jilin University, Changchun, 130021, Jilin Province, China

    Weiguanliu Zhang, Mingxuan Ding & Li Cui

  3. Laboratory of Persistent Viral Diseases, NIH/NIAID Rocky Mountain Laboratories, 903 S 4 St., Hamilton, MT, 59840, USA

    Christina D. Orrú, Andrew G. Hughson & Byron Caughey

  4. Department of Population and Quantitative Health Science, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Jing Zhang

  5. National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Keisi Kotobelli, Wei Chen, Brian S. Appleby & Wen-Quan Zou

  6. Department of Pharmaceutical Sciences, North Carolina Central University, Durham, NC, 27707, USA

    Bin Xu

  7. Institute of Neurology and Department of Neurology, Jiangxi Academy of Clinical Medical Sciences, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi Province, China

    Dao-Jun Hong & Wen-Quan Zou

  8. Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA, 30329, USA

    Lawrence B. Schonberger

  9. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15232, USA

    Curtis Tatsuoka

  10. Virus and Prion Research Unit, National Animal Disease Center, USDA, Agricultural Research Service, 1920 Dayton Avenue, Ames, IA, 50010, USA

    Justin J. Greenlee

  11. Department of Neurology, University Hospitals Cleveland Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Brian S. Appleby & Wen-Quan Zou

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  1. Weiguanliu Zhang
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Contributions

W.Q.Z. conceived and designed the study. W.Z., C.D.O., A.F., J.Y., M.D., B.C., and W.Q.Z. developed, performed, and interpreted RT-QuIC analysis of the skin samples. J.Y., S.Z.A.S., and W.Q.Z developed, performed, and interpreted the western blotting analyses of RT-QuIC end products of the skin samples. J.Z. and C.T. did McNemar’s tests for data comparisons. S.G.C. provided skin autopsy samples and demographic data of part of non-CJD cases originated from outside of NPDPSC. K.K. and B.S.A. provided clinical data and CSF RT-QuIC results. B.X. provided recombinant protein controls. W.Z., C.D.O., A.F., M.D., Z.W., B.C., and W.Q.Z. wrote the first version of the paper. All authors critically reviewed, revised, and approved the final version of the manuscript.

Corresponding authors

Correspondence to Byron Caughey or Wen-Quan Zou.

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Competing interest disclosure

BC has US Patent 8,216,788 and European Patent EP 2554996 pertaining to RT-QuIC testing. All other authors declare that they have no competing interests.

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The sponsors provided financial support for the research but were not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Zhang, W., Orrú, C.D., Foutz, A. et al. Large-scale validation of skin prion seeding activity as a biomarker for diagnosis of prion diseases. Acta Neuropathol 147, 17 (2024). https://doi.org/10.1007/s00401-023-02661-2

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