The diagnostic efficiency of biomarkers in sporadic Creutzfeldt-Jakob disease compared to Alzheimer's disease.
ABSTRACT Laboratory markers have a prominent place among the diagnostic criteria for sporadic Creutzfeldt-Jakob disease (sCJD). Here we investigate the capability of protein 14-3-3, total-tau (t-tau), threonin-181-phosphorylated tau (p-tau), and neuron-specific enolase (NSE) in cerebrospinal fluid (CSF) together with the prion protein gene genotype to discriminate patients with sCJD (n=21) from neurological controls (n=164) and Alzheimer's disease (AD) patients (n=49). Low p-tau/t-tau ratio was the best single marker for sCJD with 90% specificity against neurological controls at 86% sensitivity whilst NSE was the least accurate with 79% sensitivity at 90% specificity. Many of the sCJD patients had extremely elevated t-tau values but normal values of the AD-marker p-tau. Protein 14-3-3 was very sensitive (95%) although the specificity was relatively low (75%). A combination of elevated t-tau concentration with the presence of 14-3-3 protein in CSF gave the best test specificity of 96% at 84% sensitivity. We conclude that the combination of more than one CSF marker for neurodegeneration can improve the diagnostic test accuracy for sCJD against neurological controls including patients with other dementias.
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ABSTRACT: BACKGROUND: Accuracy of serum neuron-specific enolase (NSE) measurement is paramount, particularly in the context of neurological outcome prognostication. However, NSE measurements are compromised by even slight hemolysis, as it is abundant in red blood cells (RBCs). We derived and validated an individualized hemolysis correction equation in an attempt to reduce the current rejection rate of 14% at our institution. METHODS: Intracellular NSE was measured in RBC lysates to determine concentration variability. A correction equation was derived, accounting for both RBC-derived NSE false-elevation and hemoglobin-derived signal quenching. The performance of this individualized correction was evaluated in intentionally hemolyzed samples and accuracy was compared to a generalized correction. RESULTS: Significant inter-individual variability of RBC NSE was observed, with an almost two-fold range (15.7-28.5 ng NSE/mg Hb, p<0.001); intra-individual variability was insignificant. The individualized hemolysis correction equation derived: NSEcorr=NSEmeas-(Hbserum)(NSERBCs/Hb)+0.0844(Hbserum)+1.1 corrected 95% of the intentionally hemolyzed samples to within ±5ng/ml of corresponding baseline NSE concentrations, compared to 74% using a generalized formula. CONCLUSIONS: The individualized hemolysis correction provides increased accuracy in the estimation of true serum NSE concentrations for hemolyzed samples, compared to a generalized approach, by accounting for inter-individual RBC NSE variability. Incorporating this correction should reduce sample rejection rates and overall health care costs.Clinica chimica acta; international journal of clinical chemistry 06/2013; · 2.54 Impact Factor
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ABSTRACT: To compare the respective efficiency of CSF tau (quantitative) and CSF 14-3-3 protein (qualitative) in the diagnosis of prion disease. We made measurements on 420 live subjects, who subsequently underwent a postmortem neuropathology examination, including protein chemistry, immunohistochemistry, and histology. We performed tau by ELISA. We detected 14-3-3 protein by Western blot. Both assays were optimized for maximum efficiency (accuracy). We found tau and 14-3-3 proteins to be closely correlated, but tau had a significantly better ability to predict disease status than 14-3-3 protein. Also, tau distinguished disease status at least as well as when both assays' results are combined in a variety of ways. Importantly, the area under the receiver operating characteristic curve for tau (0.82) was significantly larger than that for 14-3-3 protein (0.68) (p < 0.001). Diagnostic test statistics are provided for the study subjects with 58.3% prevalence, and for a more typical, nonselected, 7.5% prevalence as received by our center. In this study, tau is superior to 14-3-3 protein as a marker in the diagnosis of Creutzfeldt-Jakob disease, and is as efficient singly compared to a variety of combinations with 14-3-3 protein. This is the first study of this magnitude to examine prion disease diagnostic tests in a carefully characterized patient population with detailed statistical evaluation.Neurology 07/2012; 79(6):547-52. · 8.25 Impact Factor
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ABSTRACT: Cerebral spinal fluid (CSF) Aβ42, tau and p181tau are widely accepted biomarkers of Alzheimer's disease (AD). Numerous studies show that CSF tau and p181tau levels are elevated in mild-to-moderate AD compared to age-matched controls. In addition, these increases might predict preclinical AD in cognitively normal elderly. Despite their importance as biomarkers, the molecular nature of CSF tau and ptau is not known. In the current study, reverse-phase high performance liquid chromatography was used to enrich and concentrate tau prior to western-blot analysis. Multiple N-terminal and mid-domain fragments of tau were detected in pooled CSF with apparent sizes ranging from <20 kDa to ~40 kDa. The pattern of tau fragments in AD and control samples were similar. In contrast, full-length tau and C-terminal-containing fragments were not detected. To quantify levels, five tau ELISAs and three ptau ELISAs were developed to detect different overlapping regions of the protein. The discriminatory potential of each assay was determined using 20 AD and 20 age-matched control CSF samples. Of the tau ELISAs, the two assays specific for tau containing N-terminal sequences, amino acids 9-198 (numbering based on tau 441) and 9-163, exhibited the most significant differences between AD and control samples. In contrast, CSF tau was not detected with an ELISA specific for a more C-terminal region (amino acids 159-335). Significant discrimination was also observed with ptau assays measuring amino acids 159-p181 and 159-p231. Interestingly, the discriminatory potential of p181 was reduced when measured in the context of tau species containing amino acids 9-p181. Taken together, these results demonstrate that tau in CSF occurs as a series of fragments and that discrimination of AD from control is dependent on the subset of tau species measured. These assays provide novel tools to investigate CSF tau and ptau as biomarkers for other neurodegenerative diseases.PLoS ONE 01/2013; 8(10):e76523. · 3.73 Impact Factor