Phospho-tau/total tau ratio in cerebrospinal fluid discriminates Creutzfeldt–Jakob disease from other dementias

Abstract

Early clinical symptoms of sporadic Creutzfeldt-Jakob disease (CJD) may overlap with other neurodegenerative diseases like Alzheimer's disease (AD) and frontotemporal degeneration (FTD). On entering an era in which pharmaceutical treatment of CJD occurs, reliable diagnostic markers like immunodetection of 14-3-3 proteins in the cerebrospinal fluid (CSF) are required. However, false negative results in autopsy-proven, sporadic CJD cases, as well as false positive results in several other disorders including AD and FTD showing high CSF tau protein levels, limit the potential of this marker. Due to neuronal lysis the cytosolic fraction of total tau containing phosphorylated and non-phosphorylated isoforms is partially liberated into the CSF. Since hyperphosphorylation of tau may specifically occur in neurodegenerative diseases associated with neurofibrillary changes, we hypothesized that the phospho-tau (P-tau)/total tau ratio in CSF may be a useful marker to discriminate CJD from other neurodegenerative disorders. The P-tau/total tau ratio discriminated patients with CJD from all other neurodegenerative disorders including patients with AD and FTD without any overlap. Although the results have to be confirmed in a larger sample, the preliminary data suggest that simultaneous measurement of total tau and P-tau in CSF may be useful to identify patients with CJD.

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

“…The extremely high levels of t-tau that we found in sCJD patients are in accordance with other studies [5,14,22,28,32,38,39], with sensitivity (87-94%) and specificity (90-100%) figures similar to ours. In fact, t-tau has been suggested to be the most sensitive marker in early stage sCJD [33].…”

“…Furthermore, associating ttau with p-tau (p-tau/t-tau ratio) improved the sensitivity of the t-tau test alone (from 90% to 93%), but not its specificity (95%). This is in line with previous studies, reporting comparable sensitivity (78-100%) and specificity (93-100%) [2,5,28,32]. The increase in CSF S-100b levels observed in sCJD patients has been previously reported, but the absolute values are difficult to compare as different methodologies have been employed [14,30,31].…”

“…Unlike what happens in Alzheimer's disease (AD), hyperphosphorylation of tau and formation of neurofibrillary tangles (NFTs) do not occur in sCJD. As so the ratio between phosphorylated tau (p-tau) and t-tau levels (p-tau/ t-tau) was shown to improve discrimination between AD and sCJD, with lower levels in favour of the latter [5,28,32]. Reduced Ab42 CSF levels have also been reported in sCJD patients, as in AD, but mostly overlapping [17,38,39].…”

Dissociation between CSF total tau and tau protein phosphorylated at threonine 231 in Creutzfeldt–Jakob disease

“…In a recent study, the ratio of tau protein phosphorylated at threonine 181 and t-tau had been suggested as a useful measurement to identify patients with CJD [16]. In agreement with that study, we found that the p-tau/t-tau ratio was lowest in the CJD group compared to the other groups studied.…”

“…Measurement of CSF p-tau 181 , however, did not improve diagnostic power between CJD and AD compared to measurement of t-tau [20]. Another study showed an overlap of CSF p-tau 181 concentrations between AD and CJD patients and suggested the p-tau 181 /t-tau ratio as a potential biomarker to differentiate CJD from AD [16].…”