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.
Highlights
Human prion diseases, known as transmissible spongiform encephalopathies (TSE), are rapidly progressive neurodegenerative disorders caused by prion protein misfolding [57]
We aimed to investigate the utility of several cerebrospinal fluid (CSF) biomarkers (14-3-3, t-tau, p-tau, Aβ42 and rec-PrP seeded conversion by Real-time quaking-induced prion conversion (RT-QuIC)) in the differential diagnosis of Creutzfeldt-Jakob disease (CJD) from other neurological disorders, in a large non-selected clinical population suspected to be affected by a prion disease
When the analysis was limited to the definite sporadic Creutzfeldt-Jakob disease (sCJD) and the “definite” non-CJD groups the sensitivity did not change significantly (83.3%), whereas the specificity dropped to 62.7% (Table 1)
Summary
Known as transmissible spongiform encephalopathies (TSE), are rapidly progressive neurodegenerative disorders caused by prion protein misfolding [57]. Current diagnostic criteria for sCJD [80] were mainly developed for epidemiological purposes and do not take into account the extent of clinical heterogeneity shown by sCJD patients. This is a major cause of the difficulties in the clinical diagnosis and differentiation of prion diseases against other neurological disorders. The number and variety of clinical symptoms (especially at onset), the rate of disease progression, and the underlying regional brain pathology vary significantly among sCJD subtypes; this affects the relative accuracy of the proposed diagnostic criteria
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