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

Weiguanliu Zhang; Christina D Orrú; Aaron Foutz; Mingxuan Ding; Jue Yuan; Syed Zahid Ali Shah; Jing Zhang; Keisi Kotobelli; Maria Gerasimenko; Tricia Gilliland; Wei Chen; Michelle Tang; Mark Cohen; Jiri Safar; Bin Xu; Dao-Jun Hong; Li Cui; Andrew G Hughson; Lawrence B Schonberger; Curtis Tatsuoka; Shu G Chen; Justin J Greenlee; Zerui Wang; Brian S Appleby; Byron Caughey; Wen-Quan Zou

doi:10.1007/s00401-023-02661-2

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

Acta Neuropathol. 2024 Jan 17;147(1):17. doi: 10.1007/s00401-023-02661-2.

Authors

Weiguanliu Zhang^#^{1

2}, Christina D Orrú^#³, Aaron Foutz^#¹, Mingxuan Ding^#^{1

2}, Jue Yuan¹, Syed Zahid Ali Shah¹, Jing Zhang⁴, Keisi Kotobelli⁵, Maria Gerasimenko¹, Tricia Gilliland¹, Wei Chen⁵, Michelle Tang¹, Mark Cohen¹, Jiri Safar¹, Bin Xu⁶, Dao-Jun Hong⁷, Li Cui², Andrew G Hughson³, Lawrence B Schonberger⁸, Curtis Tatsuoka⁹, Shu G Chen^{1

10}, Justin J Greenlee¹¹, Zerui Wang¹, Brian S Appleby^{1

5

12}, Byron Caughey¹³, Wen-Quan Zou^{14

15

16

17}

Affiliations

¹ Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
² Department of Neurology, The First Hospital of Jilin University, Changchun, 130021, Jilin Province, China.
³ Laboratory of Persistent Viral Diseases, NIH/NIAID Rocky Mountain Laboratories, 903 S 4 St., Hamilton, MT, 59840, USA.
⁴ Department of Population and Quantitative Health Science, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
⁵ National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
⁶ Department of Pharmaceutical Sciences, North Carolina Central University, Durham, NC, 27707, USA.
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.
⁸ Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA, 30329, USA.
⁹ Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15232, USA.
¹⁰ Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
¹¹ Virus and Prion Research Unit, National Animal Disease Center, USDA, Agricultural Research Service, 1920 Dayton Avenue, Ames, IA, 50010, USA.
¹² Department of Neurology, University Hospitals Cleveland Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
¹³ Laboratory of Persistent Viral Diseases, NIH/NIAID Rocky Mountain Laboratories, 903 S 4 St., Hamilton, MT, 59840, USA. bcaughey@niaid.nih.gov.
¹⁴ Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA. wenquanzou@ncu.edu.cn.
¹⁵ National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA. wenquanzou@ncu.edu.cn.
¹⁶ 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. wenquanzou@ncu.edu.cn.
¹⁷ Department of Neurology, University Hospitals Cleveland Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA. wenquanzou@ncu.edu.cn.

^# Contributed equally.

PMID: 38231266
DOI: 10.1007/s00401-023-02661-2

Abstract

Definitive diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) relies on the examination of brain tissues for the pathological prion protein (PrP^Sc). Our previous study revealed that PrP^Sc-seeding activity (PrP^Sc-SA) is detectable in skin of sCJD patients by an ultrasensitive PrP^Sc seed amplification assay (PrP^Sc-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 PrP^Sc-SA by RT-QuIC assay. The results were compared with demographic information, clinical manifestations, cerebrospinal fluid (CSF) PrP^Sc-SA, other laboratory tests, subtypes of prion diseases defined by the methionine (M) or valine (V) polymorphism at residue 129 of PrP, PrP^Sc 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 PrP^Sc-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 PrP^Sc-SA as a biomarker for the detection of prion diseases, which is influenced by the PrP^Sc types, PRNP 129 polymorphisms, dermatome sampled, and disease duration.

Keywords: Biomarker; Prion; Protein misfolding cyclic amplification (PMCA); Real-time quaking-induced conversion (RT-QuIC); Seeding activity; Skin.

MeSH terms

Biomarkers
Creutzfeldt-Jakob Syndrome* / diagnosis
Creutzfeldt-Jakob Syndrome* / genetics
Humans
Prion Diseases* / diagnosis
Prion Diseases* / genetics
Prions* / genetics

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

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