Intersite variability of CSF Alzheimer's disease biomarkers in clinical setting.

BACKGROUND: The assessment of total tau, phosphorylated tau (pTau-181) and amyloid beta (Aß 1-42) concentrations in the cerebrospinal fluid (CSF) of subjects has been validated for the diagnosis of Alzheimer's disease (AD). Although these measurements have shown some variability, little is known about their intersite variability in clinical settings. METHODS: A total of 880 subjects (AD, n = 515; non-AD, n = 365) from three French memory centers were included. Receiver-operating characteristic analyses were performed to computerized area under curves (AUCs) and optimal thresholds for each biomarker in the three centers. A test-retest study was performed in a group of 32 CSF samples by repeated blind analysis of the three biomarkers using the same immunoassay batches in the three centers. RESULTS: In the three centers, tau (AUC, 0.82-0.88) and pTau-181 (AUC, 0.83-0.89) outperformed Aß 1-42 (AUC, 0.70 -0.73) to discriminate subjects with AD from those without AD. An intersite variation of mean levels and cutoffs was observed for the three biomarkers. This variation was higher for Aß 1-42 (range of cutoff, 368-582 pg/mL) than for tau (range of cutoff, 289-353 pg/mL). In a test-retest study, the mean interlaboratory coefficients of variation were 12.2% for Aß 1-42, 11.3% for tau, and 11.5% for pTau-181. CONCLUSION: Intercenter variability of CSF biomarkers has been confirmed in a multisite cohort of subjects and can be improved in clinical settings. Efforts on harmonization of procedures should be encouraged to optimize the accuracy of CSF biomarkers in AD.

Decreased sAßPPß, Aß38, and Aß40 cerebrospinal fluid levels in frontotemporal dementia.

To improve the etiological diagnosis of neurodegenerative dementias like Alzheimer's disease (AD) or frontotemporal dementia (FTD), we evaluated the value of individual and combined measurements of the following relevant cerebrospinal fluid (CSF) biomarkers: Tau, 181p-Tau, Aß38, Aß40, Aß42, sAßPPα, and sAßPPß. This study conducted in two centers included patients with FTD (n = 34), AD (n = 52), as well as a control group of persons without dementia (CTRL, n = 42). Identical clinical criteria and pre-analytical conditions were used while CSF biomarkers were measured using commercial single and multiplex quantitative immunoassays. Thorough statistical analyses, including ROC curves, logistic regressions, and decision trees, were performed. We validated in AD the specific increase of p-Tau levels and the decrease of Aß42 levels, two biological hallmarks of this disease. Tau concentrations were highest in AD and intermediate in FTD when compared to CTRL. The most interesting results were obtained by focusing on amyloid biomarkers as we found out in FTD a significant decrease of sAßPPß, Aß38, and Aß40 levels. Aß38 in particular was the most useful biomarker to differentiate FTD subjects from the CTRL population. Combining p-Tau and Aß38 led us to correctly classifying FTD patients with sensitivity at 85% and specificity at 82%. Significant changes in amyloid biomarkers, particularly for Aß38, are therefore seen in FTD. This could be quite useful for diagnosis purposes and it might provide additional evidence on the interrelationship between Tau and AßPP biology which understanding is essential to progress towards optimal therapeutic and diagnostic approaches of dementia.

Correlations between soluble α/ß forms of amyloid precursor protein and Aß38, 40, and 42 in human cerebrospinal fluid.

Cerebrospinal fluid (CSF) biomarkers are now widely used for diagnosis of Alzheimer disease (AD) in atypical clinical forms, for differential and early diagnosis, or for stratification of patients in clinical trials. Among these biomarkers, different forms of amyloid peptides (Aß) produced by the cleavage of a transmembrane precursor protein called APP (amyloid precursor protein) have a major role. Aß peptides exist in different length the most common ones having 40 (Aß40), 42 (Aß42), or 38 (Aß38) amino acids in length. APP processing by gamma-secretase releases also an amino-terminal secreted fragment called sAßPP-beta while an alternative nonamyloidogenic cleavage of APP, through an alpha-secretase, liberates another fragment called sAßPP-alpha. To decipher the molecular and pathological mechanisms leading to the production and the detection of these entities is essential for the comprehension and the prevention of AD. In this report, we present the results of the multiplex measurement of CSF Aß38, Aß40, Aß42, sAßPP-alpha, and sAßPP-beta in 60 patients mostly with dementia eventually segregated between neurochemical dementia diagnostic (NDD) positive and negative groups. The NDD classification was based on our routine Tau, P-tau(181), and Aß(42) cutoff values. We confirmed previous findings regarding the correlation between sAßPP-alpha and sAßPP-beta, as well as the potential interest of these new biomarkers. We also studied the correlation between sAßPPs and Aß peptides, as well as between Aß peptides themselves. We observed a strong correlation between Aß38 and sAßPP-beta which suggested that the production of this peptide was in direct relation with ß secretase activities. We also reported a strong correlation between Aß38 and Aß40, while Aß42 was correlated to these fragments only in nonpathological situations. These results enlighten the complex relationships between these molecular markers in both physiological and pathological situations. Our results are important for the further use of these analytes for AD diagnosis as well as for validating the cell biological hypotheses of APP processing and Aß fragment production.