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Del Campo M.,VU University Amsterdam | Mollenhauer B.,Paracelsus Medical University | Bertolotto A.,Neurologia 2 CRESM Centro Riferimento Regionale Sclerosi Multipla Azienda Ospedaliera | Engelborghs S.,University of Antwerp | And 16 more authors.
Biomarkers in Medicine | Year: 2012

Early diagnosis of neurodegenerative disorders such as Alzheimers (AD) or Parkinsons disease (PD) is needed to slow down or halt the disease at the earliest stage. Cerebrospinal fluid (CSF) biomarkers can be a good tool for early diagnosis. However, their use in clinical practice is challenging due to the high variability found between centers in the concentrations of both AD CSF biomarkers (A42, total tau and phosphorylated tau) and PD CSF biomarker (α-synuclein). Such a variability has been partially attributed to different preanalytical procedures between laboratories, thus highlighting the need to establish standardized operating procedures. Here, we merge two previous consensus guidelines for preanalytical confounding factors in order to achieve one exhaustive guideline updated with new evidence for A42, total tau and phosphorylated tau, and α-synuclein. The proposed standardized operating procedures are applicable not only to novel CSF biomarkers in AD and PD, but also to biomarkers for other neurodegenerative disorders. © 2012 Future Medicine Ltd.

Garcia Barrado L.,Hasselt University | Coart E.,International Drug Development Institute IDDI | Vanderstichele H.M.J.,ADx Neurosciences | Burzykowski T.,Hasselt University | Burzykowski T.,International Drug Development Institute IDDI
Journal of Alzheimer's Disease | Year: 2015

Current technologies quantifying cerebrospinal fluid biomarkers to identify subjects with Alzheimer's disease pathology report different concentrations in function of technology and suffer from between-laboratory variability. Hence, lab-and technology-specific cut-off values are required. It is common practice to establish cut-off values on small datasets and, in the absence of well-characterized samples, to transfer the cut-offs to another assay format using 'side-by-side' testing of samples with both assays. We evaluated the uncertainty in cut-off estimation and the performance of two methods of cut-off transfer by using two clinical datasets and simulated data. The cut-off for the new assay was transferred by applying the commonly-used linear regression approach and a new Bayesian method, which consists of using prior information about the current assay for estimation of the biomarker's distributions for the new assay. Simulations show that cut-offs established with current sample sizes are insufficiently precise and also show the effect of increasing sample sizes on the cut-offs' precision. The Bayesian method results in unbiased and less variable cut-offs with substantially narrower 95 confidence intervals compared to the linear-regression transfer. For the BIODEM datasets, the transferred cut-offs for INNO-BIA Aβ1-42 are 167.5 pg/mL (95 credible interval [156.1, 178.0] and 172.8 pg/mL (95 CI [147.6, 179.6]) with Bayesian and linear regression methods, respectively. For the EUROIMMUN assay, the estimated cut-offs are 402.8 pg/mL (95 credible interval [348.0, 473.9]) and 364.4 pg/mL (95 CI [269.7, 426.8]). Sample sizes and statistical methods used to establish and transfer cut-off values have to be carefully considered to guarantee optimal diagnostic performance of biomarkers. © 2016-IOS Press and the authors.

Kang J.-H.,University of Pennsylvania | Kang J.-H.,Inha University | Vanderstichele H.,ADx Neurosciences | Trojanowski J.Q.,University of Pennsylvania | Shaw L.M.,University of Pennsylvania
Methods | Year: 2012

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. © 2012 Elsevier Inc.

Marklund N.,Uppsala University | Marklund N.,Uppsala University Hospital | Farrokhnia N.,Uppsala University | Hanell A.,Uppsala University | And 6 more authors.
Journal of Neurotrauma | Year: 2014

Epidemiological evidence links severe or repeated traumatic brain injury (TBI) to the development of Alzheimer's disease (AD). Accumulation of amyloid precursor protein (APP) occurs with high frequency after TBI, particularly in injured axons, and APP may be cleaved to amyloid-β (Aβ) peptides playing key pathophysiological roles in AD. We used cerebral microdialysis (MD) to test the hypothesis that interstitial Aβ levels are altered following TBI and are related to the injury type, cerebral energy metabolism, age of the patient, and level of consciousness. In the present report, we evaluated 10 mechanically ventilated patients (7 male, 3 female, ages 18-76 years) with a severe TBI, who had intracranial pressure and MD monitoring. Each MD sample was analyzed for hourly routine energy metabolic biomarkers (MD-lactate, MD-pyruvate, MD-glucose, and MD-lactate/pyruvate ratio), cellular distress biomarkers (MD-glutamate, MD-glycerol), and MD-urea. The remaining MD samples were analyzed for Aβ1-40 (Aβ40; n=765 samples) and Aβ1-42 (Aβ42; n=765 samples) in pooled 2 h fractions up to 14 days post-injury, using the Luminex xMAP technique, allowing detection with high temporal resolution of the key Aβ peptides Aβ40 and Aβ42. Data are presented using medians and 25th and 75th percentiles. Both Aβ40 and Aβ42 were consistently higher in patients with predominately diffuse axonal injury compared with patients with focal TBI at days 1-6 post-injury, Aβ42 being significantly increased at 113-116 h post-injury (p<0.05). The Aβ levels did not correlate with the interstitial energy metabolic situation, age of the patient, or the level of consciousness. These results support that interstitial generation of potentially toxic Aβ species may occur following human TBI, particularly related to axonal injury. © Copyright 2014, Mary Ann Liebert, Inc. 2014.

Vanderstichele H.,ADx Neurosciences | Kodadek T.,Scripps Research Institute
Alzheimer's Research and Therapy | Year: 2014

In the field of Alzheimer's disease, the development of novel biomarker assays is critically needed to improve the early diagnosis of the disease, to estimate the risk of developing the disease, to predict the rate of cognitive decline, and to monitor the response or effectiveness of a therapy. The molecular mechanisms of the disease are becoming more evident. This basic knowledge has yet to be translated into novel biomarker tools with a clinical value for general use by the community. There is therefore high interest in evaluating new technological approaches beside the classical immunoassay approach. The present paper discusses the hypothesis that there might be an adaptive immune response, unique to Alzheimer's disease, which can be visualized by the presence in body fluids of antibodies against specific analytes. Current technologies to identify such antibodies are reviewed. In addition, the major challenges to transfer discovery results of the novel antibody-based biomarker assays to a clinically relevant test will be discussed. © 2014 Vanderstichele and Kodadek; licensee BioMed Central Ltd.

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