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  • Title: Simultaneous analysis of cerebrospinal fluid biomarkers using microsphere-based xMAP multiplex technology for early detection of Alzheimer's disease.
    Author: Kang JH, Vanderstichele H, Trojanowski JQ, Shaw LM.
    Journal: Methods; 2012 Apr; 56(4):484-93. PubMed ID: 22503777.
    Abstract:
    The xMAP-Luminex multiplex platform for measurement of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers using Innogenetics AlzBio3 immunoassay reagents that are for research use only has been shown to be an effective tool for early detection of an AD-like biomarker signature based on concentrations of CSF Aβ(1-42), t-tau and p-tau(181). Among the several advantages of the xMAP-Luminex platform for AD CSF biomarkers are: a wide dynamic range of ready-to-use calibrators, time savings for the simultaneous analyses of three biomarkers in one analytical run, reduction of human error, potential of reduced cost of reagents, and a modest reduction of sample volume as compared to conventional enzyme-linked immunosorbant assay (ELISA) methodology. Recent clinical studies support the use of CSF Aβ(1-42), t-tau and p-tau(181) measurement using the xMAP-Luminex platform for the early detection of AD pathology in cognitively normal individuals, and for prediction of progression to AD dementia in subjects with mild cognitive impairment (MCI). Studies that have shown the prediction of risk for progression to AD dementia by MCI patients provide the basis for the use of CSF Aβ(1-42), t-tau and p-tau(181) testing to assign risk for progression in patients enrolled in therapeutic trials. Furthermore emerging study data suggest that these pathologic changes occur in cognitively normal subjects 20 or more years before the onset of clinically detectable memory changes thus providing an objective measurement for use in the assessment of treatment effects in primary treatment trials. However, numerous previous ELISA and Luminex-based multiplex studies reported a wide range of absolute values of CSF Aβ(1-42), t-tau and p-tau(181) indicative of substantial inter-laboratory variability as well as varying degrees of intra-laboratory imprecision. In order to address these issues a recent inter-laboratory investigation that included a common set of CSF pool aliquots from controls as well as AD patients over a range of normal and pathological Aβ(1-42), t-tau and p-tau(181) values as well as agreed-on standard operating procedures (SOPs) assessed the reproducibility of the multiplex methodology and Innogenetics AlzBio3 immunoassay reagents. This study showed within-center precision values of 5% to a little more than 10% and good inter-laboratory %CV values (10-20%). There are several likely factors influencing the variability of CSF Aβ(1-42), t-tau and p-tau(181) measurements. In this review, we describe the pre-analytical, analytical and post-analytical sources of variability including sources inherent to kits, and describe procedures to decrease the variability. A CSF AD biomarker Quality Control program has been established and funded by the Alzheimer Association, and global efforts are underway to further define optimal pre-analytical SOPs and best practices for the methodologies available or in development including plans for production of a standard reference material that could provide for a common standard against which manufacturers of immunoassay kits would assign calibration standard values.
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