Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients

Abstract

The clinical diagnosis of sporadic CreutzfeldtJakob disease (sCJD) is difficult, and reliable markers are highly desired. In this work we assess the value of several cerebrospinal fluid (CSF) markers for sCJD diagnosis. Within the framework of the Portuguese Epidemiological Surveillance Program for Human Prion Diseases, CSF samples from 71 patients with clinically suspected sCJD, 30 definite sCJD and 41 non-CJD patients, were analysed for the presence of 14-3-3 protein. CSF levels of tau (t-tau), and phosphorylated tau (p-tau181), S-100b and b amyloid (Ab42) proteins were determined. The influence of clinical and genetic characteristics on CSF markers sensitivity was also evaluated. Protein 14-3-3 was detected in 29/30 sCJD patients and 9/41 non-CJD patients. Extremely elevated t-tau and S-100b protein levels were found in sCJD patients, while p-tau181 levels were only slightly elevated and Ab42 showed no differences compared to controls. 14-3-3 was the most sensitive parameter (97%), but its specificity was low (78%); sensitivity/specificity for other proteins were: S-100b-93/93%, t-tau-93/95%, with maximum accuracy being obtained by a combination of tests (14-3-3 combined with either t-tau or S-100b, or combining S-100b with t-tau/Ab42 or p-tau/t-tau ratios). The sensitivity of 14-3-3, as well as of p-tau181/t-tau ratio, was decreased in younger patients with long disease duration, with the PrP-2 isotype and MV genotype. Both 14-3-3, t-tau and S-100b are sensitive markers for sCJD, but 14-3-3 specificity seems to be lower in this special clinical setting of rapidly progressing dementias. We propose that in cases with a 14-3-3 weak positive result, or in young patients with long disease duration, a second CSF marker would be valuable for the diagnosis of sCJD.

CSF Tau proteins reduce misdiagnosis of sporadic Creutzfeldt–Jakob disease suspected cases with inconclusive 14-3-3 result

“…CSF t-Tau reaches extremely high levels in sCJD, probably reflecting the extent of the neurodegenerative process, and its clinical utility has been previously reported by us [14] and others [11,12,22,23], with sensitivity ranging from 87 to 94 % and specificities of 90-100 %. Interestingly, recently published studies have suggested t-Tau as the single best marker for sCJD [24,25], particularly in early stage sCJD [26], with increased specificity compared to 14-3-3 [19,27].…”

“…Immunodetection of protein 14-3-3 in CSF was originally demonstrated to have a high sensitivity and specificity for sCJD [8,9]. International collaborative studies [10], as well as single center studies [11][12][13][14], have shown that in the appropriate clinical circumstances, a positive 14-3-3 protein detection correlates with clinical diagnosis in 85-94 % of cases. However, this view has been challenged by findings of poor specificity [15,16], and low sensitivity in autopsy-proven sCJD cases [17].…”

“…However, this view has been challenged by findings of poor specificity [15,16], and low sensitivity in autopsy-proven sCJD cases [17]. In addition, it has been shown that the sensitivity of 14-3-3 test is also influenced by disease duration [10,12,13] and by the prion molecular sub-type, with a decrease in sensitivity for PrP-type 2 and PRNP codon 129 heterozygotes [10,13,14,18].…”

“…However, the ratio between p-Tau and t-Tau levels (p-Tau/t-Tau) has shown to improve discrimination between AD or other RPDs and sCJD, with lower levels in favour of the latter [14,24,29,30]. Only limited information is available on p-Tau/t-Tau ratio optimal cutoff levels and its comparative value in relation to 14-3-3 or t-Tau alone [31].…”

Subtype Specific CSF Biomarkers in Sporadic Creutzfeldt-Jakob Disease

“…Most widely used surrogate protein markers are brain derived CSF proteins (14-3-3, t-PrP, total (t)-tau and t-tau/phosphorylated (p)-tau ratio) with different level of specificity and sensitivity for differential diagnosis of CJD from other rapidly progressive dementias [8,18,20,[39][40][41][42][43]. While many studies have analysed utility of these biomarkers for differential diagnosis, only few studies have particularly analysed the effect of the disease-subtypes on the specificity and sensitivity of the biomarkers [23,24,44].…”