Cerebrospinal fluid markers in Creutzfeldt-Jakob disease

<p>Abstract</p> <p>Background</p> <p>The objective was to assess the utility of total tau protein (tTau), the ratio of (tTau)/181 phosphorylated tau protein (P-Tau) and 14-3-3 protein, as diagnostic markers in cerebrospinal fluid (CSF) for Creutzfeldt-Jakob disease (CJD).</p> <p>Methods</p> <p>CSF samples received from Norwegian hospitals between August 2005 and August 2007 were retrospectively selected from consecutive patients with tTau values > 1200 ng/L (n = 38). The samples from patients clinically diagnosed with CJD (n = 12) were compared to those from patients with other degenerative neurological diseases: Alzheimer's/vascular dementia (AD/VaD, n = 21), other neurological diseases (OND, n = 5). Total Tau, P-Tau, and β-Amyloid (Aβ₄₂) were measured with commercial kits. Additionally, 14-3-3 protein was measured semi-quantitatively by immunoblot.</p> <p>Results</p> <p>The minimum cut-off limits for diagnosis of CJD were chosen from the test results. For tTau the lower limit was fixed at 3000 ng/L, for the tTau/P-Tau ratio it was 60, and for 14-3-3 protein it was 0.75 arbitrary units. For tTau and tTau/P-Tau ratio, all but three CJD patients had levels above the minimum, whereas almost all of the other patients were below. For the 14-3-3 protein, two CJD patients were below the minimum and five were above. Only one of the other patients was higher than the limit. The sensitivities, specificities and diagnostic efficiencies were: tTau 75%, 92%, and 87%; tTau/P-Tau 75%, 96%, and 89%; and 14-3-3 protein 80%, 96%, and 91%.</p> <p>Conclusion</p> <p>The results suggest that 14-3-3 protein may be the better marker for CJD, tTau/P-Tau ratio and tTau are also efficient markers, but showed slightly inferior diagnostic properties in this study, with tTau/P-Tau marginally better than tTau.</p

Perinatal Asphyxia May Influence the Level of Beta-Amyloid (1-42) in Cerebrospinal Fluid: An Experimental Study on Newborn Pigs

<div><p>Objective</p><p>Total tau (T-tau), phosphorylated tau (p-Tau) and Beta-Amyloid 1–42 (AB42) in Cerebrospinal Fluid (CSF) are useful biomarkers in neurodegenerative diseases. The aim of the study was to investigate the role of these and other CSF biomarkers (T-tau, p-Tau, AB42, S100B and NSE), during hypoxia-reoxygenation in a newborn pig model.</p><p>Design</p><p>Thirty newborn pigs were included in a study of moderate or severe hypoxia. The moderate hypoxia group (n = 12) was exposed to global hypoxia (8% O₂) until Base excess (BE) reached -15 mmol/l. The pigs in the group exposed to severe hypoxia (n = 12) received 8% O₂ until BE reached -20 mmol/l or mean Blood Pressure fell below 20 mm Hg, The control group (n = 6) was kept at room air. For all treatments, the CSF was collected at 9.5 hours after the intervention.</p><p>Results</p><p>The level of AB42 in CSF was significantly lower in the pigs exposed to severe hypoxia compared with the control group, 922(SD +/-445)pg/ml versus. 1290(SD +/-143) pg/ml (p<0.05), respectively. Further, a non-significant reduction of AB42 was observed in the group exposed to moderate hypoxia T-tau and p-Tau revealed no significant differences between the intervention groups and the control group, however a significantly higher level of S100B was seen in the CSF of pigs receiving hypoxia in comparison to the level in the control group. Further on, there was a moderate negative correlation between the levels of AB42 and S100B in CSF, as well as a moderate negative correlation between Lactate in blood at end of hypoxia and AB42 in CSF.</p><p>Interpretation</p><p>This is the first study to our knowledge that demonstrated a significant drop in AB42 in CSF after neonatal hypoxia. Whether or not this has an etiological basis for adult neurodegenerative disorders needs to be studied with additional experiments and epidemiological studies. AB42 and S100B are significantly changed in neonatal pigs subjected to hypoxia compared to controls and thus may be valuable biomarkers of perinatal asphyxia.</p></div

BE, pH, PaCO2, Lactate and Glucose at 5 different time points after hypoxia.

<p>BE, pH, PaCO2, Lactate and Glucose at 5 different time points after hypoxia.</p

Physiological parameters in the animals of the different groups at start.

<p>Physiological parameters in the animals of the different groups at start.</p

S100B in CSF and serum.

<p>(A) shows the Log-values of S100B in CSF for both intervention groups and the Control group, Log-S100B was significantly higher in the group exposed to hypoxia than in the control group, 1.0 (SD +/-0.3) pg/ml vs. 1.4 (SD +/-0.4) pg/ml, p<0.05. Mean difference was 0.4 (95% CI: 0.2–0.9). (B) depicts the Delta-Value from End of Hypoxia to End of experiment, p = 0.05. There was no difference between the group exposed to moderate vs. severe hypoxia regarding the levels of S100B, neither in CSF nor in blood, therefore we decided to combine both hypoxia groups into one intervention group.</p

Correlation between NSE and S100B in CSF.

<p>Fig 5 describes the correlation between the logarithmic values of NSE and S100B in CSF. It was a high correlation between logNSE and logS100B measured in CSF at the end of the experiment, R = 0.86, p<0.001. The values are depicted as log-values because there was a relatively wide range in the concentration of NSE and S100B.</p

Mean values of the concentrations of AB42 with standard deviations (SD).

<p>AB42 was significantly lower in the group exposed to severe hypoxia * compared with the control group, 922 (SD +/-445) pg/ml vs. 1290 (SD +/-143) pg/ml, p<0.05. Mean difference was 368 (95% CI: 61–675). The concentration of AB42 in the group exposed to moderate asphyxia was 1059 (SD+/-75) pg/mg, p = 0.07, when compared with the control group.</p

Study design.

<p>Twelve pigs were included in each experimental group and six pigs in the control group. The pigs in the first experimental group were exposed to global hypoxia (8% O2 in Nitrogen) until Base Excess (BE) reached -15 mmol/l (moderate hypoxia). The animals in the second experimental group (severe hypoxia) were exposed to 8% O2 until BE reached -20 mmol/l and/ or mean blood pressure fell below 20 mmHg. Thereafter the pigs were reoxygenated with air for 9.5 hours. CSF was collected 9.5 hours after end of hypoxia.</p

Multicenter immunoassay validation of cerebrospinal fluid neurofilament light: A biomarker for neurodegeneration

Aim: Neurofilament light (NfL) chain, a putative cerebrospinal fluid biomarker, can support neurodegenerative disease diagnosis and indicate disease severity and prognosis. Universal validation protocols when used to measure biomarkers can reduce pre and analytical laboratory variation, thus increasing end-user confidence in the consistency of validation data across sites. Methodology: Here, a commercially available NfL ELISA (UmanDiagnostics, Umeå, Sweden) was validated in a multicentered setting using comprehensive newly developed standard operating procedures. Results: The data showed good assay sensitivity and intra and interassay precision. Interlaboratory precision was, however, suboptimal. Conclusion: The UmanDiagnostics assay is suitable for the quantification of NfL in human cerebrospinal fluid. However, sources of interlaboratory variation in the data require further investigation