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Diagnostic value of α-synuclein seeding amplification assays in α-synucleinopathies: A systematic review and meta-analysis

  • Author Footnotes
    1 These authors contributed equally to this study.
    Dallah Yoo
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Department of Neurology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Republic of Korea
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  • Author Footnotes
    1 These authors contributed equally to this study.
    Ji-In Bang
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Department of Nuclear Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Gyeonggi-do, Republic of Korea
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  • Choonghyun Ahn
    Affiliations
    Department of Orthopedic Surgery, University of Tokyo Hospital, Tokyo, Japan
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  • Victoria Nyawira Nyaga
    Affiliations
    Unit of Cancer Epidemiology - Belgian Cancer Centre, Sciensano, Juliette Wytsmanstraat 14, 1050, Brussels, Belgium
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  • Young-Eun Kim
    Affiliations
    Department of Neurology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea
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  • Min Ju Kang
    Affiliations
    Department of Neurology, Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Republic of Korea
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  • Tae-Beom Ahn
    Correspondence
    Corresponding author. Department of Neurology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
    Affiliations
    Department of Neurology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Republic of Korea
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  • Author Footnotes
    1 These authors contributed equally to this study.

      Abstract

      Introduction

      Alpha-synuclein(αSyn) aggregates are definite pathological hallmarks of α-synucleinopathies. Seeding amplification assays (SAAs) have been developed to detect trace amounts of αSyn oligomers in vivo.. Herein, we assessed the diagnostic accuracy of the αSyn-SAAs across biospecimens, diagnostic references, methods, and subtypes.

      Methods

      A systematic literature search yielded 36 eligible studies for a meta-analysis of the sensitivity and specificity of αSyn-SAAs in patients with α-synucleinopathies(n = 2722) and controls(n = 2278). Pooled sensitivities and specificities with 95% confidence intervals (CIs) were calculated using bivariate random-effects models and a meta-regression analysis was performed.

      Results

      The summary sensitivity and specificity of αSyn-SAAs positivity for the diagnosis of α-synucleinopathies were 0.88(95% CIs = 0.84–0.91) and 0.95(0.93–0.97), respectively. Two covariates (biospecimen and diagnostic reference) were significant in fitting the meta-regression model (likelihood-ratio test for sensitivity and specificity, p < 0.01, p = 0.01, respectively). Skin αSyn-SAAs exhibited the highest sensitivity 0.92(0.87–0.95), which was not different from that of cerebrospinal fluid (CSF)(0.90(0.86–0.93), p = 0.39). Olfactory mucosa αSyn-SAAs exhibited a lower sensitivity 0.64(0.49–0.76) than those of the other two specimens(p = 0.02, 0.01, compared to CSF and skin, respectively). Application of pathological diagnostic standards were associated with a higher specificity of αSyn-SAAs compared to clinical diagnosis (p < 0.01). The diagnostic sensitivity and specificity of CSF αSyn-SAAs were 0.91(0.87–0.94) and 0.96(0.93–0.98) for Lewy body disease, 0.90(0.79–0.95) and 0.96(0.90–0.98) for prodromal α-synucleinopathies, and 0.63(0.24–0.90) and 0.97(0.93–0.99) for multiple system atrophy.

      Conclusions

      αSyn-SAAs are promising in vivo detectors of abnormal αSyn aggregates and may aid the early diagnosis of α-synucleinopathies.

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