Prion-specific and surrogate CSF biomarkers in Creutzfeldt-Jakob disease: diagnostic accuracy in relation to molecular subtypes and analysis of neuropathological correlates of p-tau and A beta 42 levels

Francesca Lattanzio, Samir Abu-Rumeileh, Alessia Franceschini, Hideaki Kai, Giulia Amore, Ilaria Poggiolini, Marcello Rossi, Simone Baiardi, Lynne McGuire, Anna Ladogana, Maurizio Pocchiari, Alison Green, Sabina Capellari, Piero Parchi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The differential diagnosis of Creutzfeldt-Jakob disease (CJD) from other, sometimes treatable, neurological disorders is challenging, owing to the wide phenotypic heterogeneity of the disease. Real-time quaking-induced prion conversion (RT-QuIC) is a novel ultrasensitive in vitro assay, which, at variance with surrogate neurodegenerative biomarker assays, specifically targets the pathological prion protein (PrPSc). In the studies conducted to date in CJD, cerebrospinal fluid (CSF) RT-QuIC showed good diagnostic sensitivity (82-96%) and virtually full specificity. In the present study, we investigated the diagnostic value of both prion RT-QuIC and surrogate protein markers in a large patient population with suspected CJD and then evaluated the influence on CSF findings of the CJD type, and the associated amyloid-alpha (A beta) and tau neuropathology. RT-QuIC showed an overall diagnostic sensitivity of 82.1% and a specificity of 99.4%. However, sensitivity was lower in CJD types linked to abnormal prion protein (PrPSc) type 2 (VV2, MV2K and MM2C) than in typical CJD (MM1). Among surrogate proteins markers (14-3-3, total (t)-tau, and t-tau/phosphorylated (p)-tau ratio) t-tau performed best in terms of both specificity and sensitivity for all sCJD types. Sporadic CJD VV2 and MV2K types demonstrated higher CSF levels of p-tau when compared to other sCJD types and this positively correlated with the amount of tiny tau deposits in brain areas showing spongiform change. CJD patients showed moderately reduced median A beta 42 CSF levels, with 38% of cases having significantly decreased protein levels in the absence of A beta brain deposits. Our results: (1) support the use of both RT-QuIC and t-tau assays as first line laboratory investigations for the clinical diagnosis of CJD; (2) demonstrate a secondary tauopathy in CJD subtypes VV2 and MV2K, correlating with increased p-tau levels in the CSF and (3) provide novel insight into the issue of the accuracy of CSF p-tau and A beta 42 as markers of brain tauopathy and beta-amyloidosis.

Original languageEnglish
Pages (from-to)559-578
Number of pages20
JournalActa Neuropathologica
Volume133
Issue number4
Early online date15 Feb 2017
DOIs
Publication statusE-pub ahead of print - 15 Feb 2017

Keywords

  • Human prions
  • Biomarkers
  • RT-QuIC
  • Amyloid-beta
  • Tauopathy
  • Alzheimer's disease
  • Protease-sensitive prionopathy
  • QUAKING-INDUCED CONVERSION
  • PROTEASE-SENSITIVE PRIONOPATHY
  • RAPIDLY PROGRESSIVE DEMENTIA
  • STRAUSSLER-SCHEINKER DISEASE
  • CEREBROSPINAL-FLUID
  • ALZHEIMERS-DISEASE
  • NEUROFIBRILLARY PATHOLOGY
  • DIFFERENTIAL-DIAGNOSIS
  • PHOSPHORYLATED TAU
  • MARKERS

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