Diagnostic performance of CSF biomarkers in a well-characterized Australian cohort of sporadic Creutzfeldt-Jakob disease

Abstract

The most frequently utilized biomarkers to support a pre-mortem clinical diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD) include concentrations of the 14-3-3 and total tau (T-tau) proteins, as well as the application of protein amplification techniques, such as the real time quaking-induced conversion (RT-QuIC) assay, in cerebrospinal fluid (CSF). Utilizing CSF from a cohort of neuropathologically confirmed (definite) sCJD (n = 50) and non-CJD controls (n = 48), we established the optimal cutpoints for the fully automated Roche Elecsys® immunoassay for T-tau and the CircuLexTM 14-3-3 Gamma ELISA and compared these to T-tau protein measured using a commercially available assay (INNOTEST hTAU Ag) and 14-3-3 protein detection by western immunoblot (WB). These CSF specimens were also assessed for presence of misfolded prion protein using the RT-QuIC assay. T-tau showed similar diagnostic performance irrespective of the assay utilized, with ~90% sensitivity and specificity. The 14-3-3 protein detection by western blot (WB) has 87.5% sensitivity and 66.7% specificity. The 14-3-3 ELISA demonstrated 81.3% sensitivity and 84.4% specificity. RT-QuIC was the single best performing assay, with a sensitivity of 92.7% and 100% specificity. Our study indicates that a combination of all three CSF biomarkers increases sensitivity and offers the best chance of case detection pre-mortem. Only a single sCJD case in our cohort was negative across the three biomarkers, emphasizing the value of autopsy brain examination on all suspected CJD cases to ensure maximal case ascertainment.

Alzheimer's disease biomarker utilization at first referral enhances differential diagnostic precision with simultaneous exclusion of Creutzfeldt‐Jakob disease

“…The ability of t‐tau and the t‐tau/p‐tau ratio to distinguish CJD from non‐CJD, which consists of both neurological and non‐neurological conditions (Table SA.1), was assessed. Both t‐tau and the t‐tau/p‐tau ratio achieved an AUC of over 90, with the t‐tau/p‐tau ratio being marginally superior to t‐tau alone, which performed similarly to a previous report 5 . Moreover, the discriminatory power of t‐tau and the t‐tau/p‐tau ratio in differentiating CJD from AD was confirmed.…”

“…In the NfL sub‐cohort comprising both CJD and non‐CJD subjects, both CSF NfL and t‐tau concentrations and the t‐tau/p‐tau ratio were increased significantly in subjects with CJD compared to the non‐CJD sub‐cohort, reinforcing the utility of these biomarkers for assisting the diagnosis of CJD, which has been explored previously. 5 , 14 , 45 , 46 For subjects with CJD excluded, CSF t‐tau concentrations were increased significantly in those with biomarker profiles consistent with AD (A+T+) compared to other profiles, suggesting those with A+T+ biomarker profiles may harbor more extensive neuronal damage compared to those with A+T‐ or A– biomarker profiles. On the other hand, CSF NfL did not differentiate between the three non‐CJD sub‐cohorts, although utility in distinguishing rapidly progressive, including neurodegenerative disorders as a group and from primary psychiatric disorders, has been demonstrated previously.…”

“…Creutzfeldt‐Jakob disease (CJD) is prototypical of a rapidly progressive dementia and a most concerning differential diagnosis due to inexorable decline, lack of disease‐modifying treatment, and potential transmissibility 2 . A clinical diagnosis of CJD is assisted by laboratory investigations such as estimation of cerebrospinal fluid (CSF) 14‐3‐3 and total tau (t‐tau) protein levels, as well as the real‐time quaking‐induced conversion (RT‐QuIC) assay to detect misfolded prion protein seeding activity 3–6 . The 14‐3‐3 and t‐tau proteins are non‐specific markers of neuronal degeneration, and although the specificity of the RT‐QuIC assay is excellent, sensitivity is reduced in some sporadic and genetic CJD subtypes, often those with more atypical clinical presentations 7 .…”

“… 2 A clinical diagnosis of CJD is assisted by laboratory investigations such as estimation of cerebrospinal fluid (CSF) 14‐3‐3 and total tau (t‐tau) protein levels, as well as the real‐time quaking‐induced conversion (RT‐QuIC) assay to detect misfolded prion protein seeding activity. 3 , 4 , 5 , 6 The 14‐3‐3 and t‐tau proteins are non‐specific markers of neuronal degeneration, and although the specificity of the RT‐QuIC assay is excellent, sensitivity is reduced in some sporadic and genetic CJD subtypes, often those with more atypical clinical presentations. 7 In addition, the differential diagnosis of CJD can be challenging due to non‐specific presenting symptoms, which may overlap other neurodegenerative disorders, as well as primarily non‐neurodegenerative disorders such as encephalitis, vascular dementia, and psychiatric disorders.…”

Molecular Biomarkers of Neurodegenerative Disorders: A Practical Guide to Their Appropriate Use and Interpretation in Clinical Practice

“…CJD was first described in 1920 by Hans Creutzfeldt and later in 1921 and 1923 by Alfons Jakob. According to the mode of transmission, CJD is classified into three forms: sporadic (sCJD), which is the most common, accounting for 85-90% of cases; genetic, accounting for 15% of cases, due to autosomal-dominant mutations in the prion protein gene (PRNP); and acquired, accounting for less than 1% of cases resulting from prion transmission by an external source, such as the human exposure to bovine spongiform encephalopathy (BSE) during the late 1980s and early 1990s [66].…”