Alternative application of Tau protein in Creutzfeldt-Jakob disease diagnosis: Improvement for weakly positive 14-3-3 protein in the laboratory

Hyeon, Jae Wook; Kim, Su Yeon; Lee, Jeongmin; Park, Jun-Sun; Hwang, Kyu Jam; Lee, Sol Moe; An, Seong Soo A.; Lee, Myung Koo; Ju, Young Ran

doi:10.1038/srep15283

Cited by 15 publications

(16 citation statements)

References 32 publications

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“…While the combined use of 14-3-3, tau, and the p-tau/tau ratio improved the specificity of diagnosis for undefined 14-3-3 measurements (weak positive/traces) [24], our data suggest that tau and/or p-tau/tau measurements are sufficient to correctly differentiate between sCJD and non-CJD cases with almost full accuracy. Taking into account that both biomarkers are usually routinely analyzed in clinical dementia centers, the present data support the use of the p-tau/tau ratio in the sCJD clinical diagnostic routine as the first discriminatory assay with high sensitivity, which could be further validated with the RT-QuIC test [17], a new highly specific diagnostic platform not yet fully implemented in all diagnostic centers.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid Biomarker-Based Diagnosis of Sporadic Creutzfeldt-Jakob Disease: A Validation Study for Previously Established Cutoffs

Llorens

Karch

Golanska

et al. 2017

Dement Geriatr Cogn Disord

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Background: Several biomarkers have been proposed to discriminate sporadic Creutzfeldt-Jakob disease (sCJD) from other dementias and control cases. However, their clinical accuracy depends on the PRNP codon 129 genotype, leaving it unclear how well established markers behave in untested conditions. Methods: We analyzed 14-3-3, tau, p-tau levels, and the p-tau/tau ratio in a population sample collected from Polish hospitals including nondementia, dementia, and definite sCJD cases and validated their parameters according to previously established cutoffs. Additionally, the correlation between biomarkers and disease duration as well as the influence of the PRNP129 polymorphism are reported. Results: The tau levels and p-tau/tau ratios differed considerably between sCJD and clinically characterized non-CJD cases (p < 0.001). p-tau was only elevated in sCJD when compared to cases without dementia (p < 0.05). Tau and the p-tau/tau ratio showed a sensitivity of 95 and 100%, respectively, in detecting sCJD cases. A negative correlation between tau levels and disease duration, but not the timing of lumbar puncture was observed. Conclusion: The present findings confirmed the value of the p-tau/tau ratio as a robust sCJD biomarker and suggest a role for tau as prognostic marker.

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Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid Biomarker-Based Diagnosis of Sporadic Creutzfeldt-Jakob Disease: A Validation Study for Previously Established Cutoffs

Llorens

Karch

Golanska

et al. 2017

Dement Geriatr Cogn Disord

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“…The level of Ab 1-42 , p-tau protein and BACE-1 in mice brain tissue was detected using the ELISA kit performed according to the operating instructions. [32,33] Experimental protocol for primary cortical neuron culture…”

Section: Experimental Protocol For Behaviour Experimentsmentioning

confidence: 99%

Melatonin ameliorates Aβ1-42-induced Alzheimer's cognitive deficits in mouse model

Gong

Hua

Zang

et al. 2017

Journal of Pharmacy and Pharmacology

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Objectives The objective of this study was to evaluate whether melatonin could ameliorate cognitive function in Ab 1-42 -induced mouse model and its underlying mechanisms. Methods Series behaviour tests were performed to demonstrate the amelioration of cognitive function of the Alzheimer's disease (AD) mice induced by Ab 1-42 . Additionally, enzyme-linked immunosorbent assay was applied to detect the expression of Ab 1-42 , BACE1 and p-tau protein in the brain of the AD mice. JC-1 was performed to investigate the role in alleviating mitochondrial damage by melatonin in vitro. Western blot was used to detect the expression of melatonin on apoptosis-related factors caspase-3 and Bcl-2, as well as the expressions of GSK-3b and PP2A to further determine the mechanisms of melatonin on the expression of p-tau protein.Key findings Melatonin significantly ameliorated the cognitive function and mitochondrial damage in AD mice, reduced the expression levels of GSK-3b, caspase-3, Ab 1-42 , BACE1, p-tau protein and increased the expressions of PP2A and Bcl-2. Conclusion From the overall results, we concluded that melatonin alleviated the mitochondrial damage effectively and decreased the expressions of the p-tau and some key proteins of apoptosis, leading to the improvement of cognitive function of the mice induced by Ab 1-42 .

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“…In Llorens et al [50], p-Tau/t-Tau ratio discriminating power was higher in the differential diagnosis of sCJD when compared with other dementias than Tau alone. In our study, the combination of t-Tau with p-Tau in the p-Tau/t-Tau ratio did not improve diagnostic accuracy in relation to t-Tau alone, but resulted in a similar improvement in specificity and overall accuracy in relation to Tau ratio improved the specificity of diagnosis compared with the use of the 14-3-3 protein assay alone (47 % for 14-3-3 alone; 86 % for 14-3-3 combined with t-Tau; and 91 % for 14-3-3 combined with the p-Tau/t-Tau ratio) [31]. However, in the same study, very few patients had autopsyproven diagnosis, in contrast with our study, in which all sCJD patients had neuropathological confirmation.…”

Section: Discussionmentioning

confidence: 84%

“…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]. Along with the introduction of these alternative CSF markers in laboratories worldwide, questions about the sensitivity, specificity, and added value of these assays, although recognised as extremely useful, have been raising.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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Cerebrospinal fluid (CSF) 14-3-3 protein supports sporadic Creutzfeldt-Jakob (sCJD) diagnosis, but often leads to weak-positive results and lacks standardization. In this study, we explored the added diagnostic value of Total Tau (t-Tau) and phosphorylated Tau (p-Tau) in sCJD diagnosis, particularly in the cases with inconclusive 14-3-3 result. 95 definite sCJD and 287 patients without prion disease (non-CJD) were included in this study. CSF samples were collected in routine clinical diagnosis and analysed for 14-3-3 detection by Western blot (WB). CSF t-Tau and p-Tau were quantified by commercial ELISA kits and PRNP and APOE genotyping assessed by PCR-RFLP. In a regression analysis of the whole cohort, 14-3-3 protein revealed an overall accuracy of 82 % (sensitivity = 96.7 %; specificity = 75.6 %) for sCJD. Regarding 14-3-3 clear positive results, we observed no added value either of t-Tau alone or p-Tau/t-Tau ratio in the model. On the other hand, considering 14-3-3 weakpositive cases, t-Tau protein increased the overall accuracy of 14-3-3 alone from 91 to 94 % and specificity from 74 to 93 % (p \ 0.05), with no sensitivity improvement. However, inclusion of p-Tau/t-Tau ratio did not significantly improve the first model (p = 0.0595). Globally, t-Tau protein allowed a further discrimination of 65 % within 14-3-3 inconclusive results. Furthermore, PRNP MV genotype showed a trend to decrease 14-3-3 sensitivity (p = 0.051), but such effect was not seen on t-Tau protein.In light of these results, we suggest that t-Tau protein assay is of significant importance as a second marker in identifying 14-3-3 false-positive results among sCJD probable cases.

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Alternative application of Tau protein in Creutzfeldt-Jakob disease diagnosis: Improvement for weakly positive 14-3-3 protein in the laboratory

Cited by 15 publications

References 32 publications

Cerebrospinal Fluid Biomarker-Based Diagnosis of Sporadic Creutzfeldt-Jakob Disease: A Validation Study for Previously Established Cutoffs

Cerebrospinal Fluid Biomarker-Based Diagnosis of Sporadic Creutzfeldt-Jakob Disease: A Validation Study for Previously Established Cutoffs

Melatonin ameliorates Aβ1-42-induced Alzheimer's cognitive deficits in mouse model

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

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