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 Aβ42 levels

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

Research output: Contribution to journalArticle

40 Citations (Scopus)

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-β (Aβ) 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 Aβ42 CSF levels, with 38% of cases having significantly decreased protein levels in the absence of Aβ 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 Aβ42 as markers of brain tauopathy and β-amyloidosis.

Original languageEnglish
Pages (from-to)559-578
JournalActa Neuropathologica
Volume133
Issue number4
DOIs
Publication statusPublished - 2017

Fingerprint

Creutzfeldt-Jakob Syndrome
Prions
Cerebrospinal Fluid
Biomarkers
Tauopathies
Brain
14-3-3 Proteins
Amyloidosis
Nervous System Diseases
Amyloid
Proteins
Differential Diagnosis
Sensitivity and Specificity

Keywords

  • Alzheimer’s disease
  • Amyloid-beta
  • Biomarkers
  • Human prions
  • Protease-sensitive prionopathy
  • RT-QuIC
  • Tauopathy

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

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 Aβ42 levels. / Lattanzio, Francesca; Abu Rumeileh, Samir; Franceschini, Alessia; Kai, Hideaki; Amore, Giulia; Poggiolini, Ilaria; Rossi, Marcello; Baiardi, Simone; Mcguire, Lynne I.; Ladogana, Anna; Pocchiari, Maurizio; Green, Alison; Capellari, Sabina; Parchi, Piero.

In: Acta Neuropathologica, Vol. 133, No. 4, 2017, p. 559-578.

Research output: Contribution to journalArticle

Lattanzio, Francesca ; Abu Rumeileh, Samir ; Franceschini, Alessia ; Kai, Hideaki ; Amore, Giulia ; Poggiolini, Ilaria ; Rossi, Marcello ; Baiardi, Simone ; Mcguire, Lynne I. ; Ladogana, Anna ; Pocchiari, Maurizio ; Green, Alison ; Capellari, Sabina ; Parchi, Piero. / 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 Aβ42 levels. In: Acta Neuropathologica. 2017 ; Vol. 133, No. 4. pp. 559-578.
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T1 - Prion-specific and surrogate CSF biomarkers in Creutzfeldt-Jakob disease

T2 - diagnostic accuracy in relation to molecular subtypes and analysis of neuropathological correlates of p-tau and Aβ42 levels

AU - Lattanzio, Francesca

AU - Abu Rumeileh, Samir

AU - Franceschini, Alessia

AU - Kai, Hideaki

AU - Amore, Giulia

AU - Poggiolini, Ilaria

AU - Rossi, Marcello

AU - Baiardi, Simone

AU - Mcguire, Lynne I.

AU - Ladogana, Anna

AU - Pocchiari, Maurizio

AU - Green, Alison

AU - Capellari, Sabina

AU - Parchi, Piero

N1 - Ricercatori distaccati presso IRCCS a seguito Convenzione esclusiva con Università di Bologna (Capellari Sabina, Parchi Piero)

PY - 2017

Y1 - 2017

N2 - 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-β (Aβ) 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 Aβ42 CSF levels, with 38% of cases having significantly decreased protein levels in the absence of Aβ 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 Aβ42 as markers of brain tauopathy and β-amyloidosis.

AB - 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-β (Aβ) 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 Aβ42 CSF levels, with 38% of cases having significantly decreased protein levels in the absence of Aβ 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 Aβ42 as markers of brain tauopathy and β-amyloidosis.

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KW - Amyloid-beta

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KW - Human prions

KW - Protease-sensitive prionopathy

KW - RT-QuIC

KW - Tauopathy

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