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PubMed | Copenhagen University, Masaryk University, University of Perugia, Khalifa University and 6 more.
Type: Journal Article | Journal: Biomarkers in medicine | Year: 2015

The discovery of -synuclein (-syn) as a major component of Lewy bodies, neuropathological hallmark of Parkinsons disease (PD), dementia with Lewy bodies and of glial inclusions in multiple system atrophy initiated the investigation of -syn as a biomarker in cerebrospinal fluid (CSF). Due to the involvement of the periphery in PD the quantification of -syn in peripheral fluids such as serum, plasma and saliva has been investigated as well. We review how the development of multiple assays for the quantification of -syn has yielded novel insights into the variety of -syn species present in the different fluids; the optimal preanalytical conditions required for robust quantification and the potential clinical value of -syn as biomarker. We also suggest future approaches to use of CSF -syn in neurodegenerative diseases.


Andreasson U.,Gothenburg University | Vanmechelen E.,ADx NeuroSciences | Shaw L.M.,University of Pennsylvania | Zetterberg H.,Gothenburg University | And 3 more authors.
Biomarkers in Medicine | Year: 2012

In general, a biomarker has multiple uses such as a diagnostic tool and a method to monitor therapy. The quality of a biomarker depends on how big the difference is between, for example, patients and healthy controls, but also on the capacity of the method used to measure it (the uncertainty in the method should be much less than the difference between the groups). A good biomarker should also be specific towards a disease, allowing for differentiation between clinically related syndromes. In addition, it is of importance that the stability of the methods used is high enough to establish cut-off levels both in individual laboratories and on a global scale. In the field of Alzheimers disease, there are currently three cerebrospinal fluid markers that have been verified in multiple studies and the analytical aspects of measuring them will be discussed. © 2012 Future Medicine Ltd.


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.


PubMed | ADx NeuroSciences, Hasselt University and International Drug Development Institute IDDI
Type: Journal Article | Journal: Journal of Alzheimer's disease : JAD | Year: 2015

Current technologies quantifying cerebrospinal fluid biomarkers to identify subjects with Alzheimers 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 biomarkers 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 A1-42 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.


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.


PubMed | Euroimmun Medizinische Labordiagnostika, Lund University, ADx NeuroSciences and IDDI
Type: Journal Article | Journal: Journal of Alzheimer's disease : JAD | Year: 2016

Reduced cerebrospinal fluid (CSF) concentration of amyloid-1-42 (A1-42) reflects the presence of amyloidopathy in brains of subjects with Alzheimers disease (AD).To qualify the use of A1-42/A1-40 for improvement of standard operating procedures (SOP) for measurement of CSF A with a focus on CSF collection, storage, and analysis.Euroimmun ELISAs for CSF A isoforms were used to set up a SOP with respect to recipient properties (low binding, polypropylene), volume of tubes, freeze/thaw cycles, addition of detergents (Triton X-100, Tween-20) in collection or storage tubes or during CSF analysis. Data were analyzed with linear repeated measures and mixed effects models.Optimization of CSF analysis included a pre-wash of recipients (e.g., tubes, 96-well plates) before sample analysis. Using the A1-42/A1-40 ratio, in contrast to A1-42, eliminated effects of tube type, additional freeze/thaw cycles, or effect of CSF volumes for polypropylene storage tubes. Low binding tubes reduced the loss of A when aliquoting CSF or in function of additional freeze/thaw cycles. Addition of detergent in CSF collection tubes resulted in an almost complete absence of variation in function of collection procedures, but affected the concentration of A isoforms in the immunoassay.The ratio of A1-42/A1-40 is a more robust biomarker than A1-42 toward (pre-) analytical interfering factors. Further, low binding recipients and addition of detergent in collection tubes are able to remove effects of SOP-related confounding factors. Integration of the A1-42/A1-40 ratio and low-binding tubes into guidance criteria may speed up worldwide standardization of CSF biomarker analysis.


PubMed | University of Tübingen, EUROIMMUN Medizinische Labordiagnostika AG and ADx NeuroSciences
Type: Journal Article | Journal: Alzheimer's research & therapy | Year: 2016

Mild parkinsonian signs (MPS) are common in older people and are associated with an increased risk of different neurodegenerative diseases. This study prospectively evaluates the longitudinal course of cognitive performance in older individuals with MPS.From the TREND study, 480 individuals neurologically healthy at baseline, aged between 50 and 80years, with complete follow-up data for three assessments within a mean of 43.8months, were included in this analysis. Participants underwent a detailed cognitive test battery, evaluation of prodromal markers for neurodegenerative diseases and history of vascular diseases at each study visit. In addition, plasma levels of amyloid-beta (A)In 52 (11%) of the 480 participants, MPS could be detected at baseline. These individuals had cognitive deficits significantly more often compared with controls at each time point and their cognitive performance showed a steeper decline during follow-up. In addition, their levels of plasma AThis longitudinal study shows that MPS are associated with cognitive decline and decrease in plasma A


PubMed | ADx NeuroSciences and University of Antwerp
Type: Journal Article | Journal: Journal of Alzheimer's disease : JAD | Year: 2016

Intra- and inter-laboratory variability of cerebrospinal fluid (CSF) biomarker analyses remains an important issue. We investigated the clinical-diagnostic impact of CSF biomarker concentration shifts in mild cognitive impairment (MCI) and autopsy-confirmed Alzheimers disease (AD) dementia patients. MCI patients (n=85), autopsy-confirmed AD dementia patients (n=72), and cognitively healthy controls (n=100) were included in this prospective, longitudinal study. AD dementia patients were followed up until death, and controls were included from 1992 until 2003. In-house validated cutoff values of biomarkers were applied: A1-42 <638.5 pg/mL, T-tau>296.5 pg/mL, P-tau(181P) >56.5 pg/mL. Both increments and decrements (from 5% to 40% ) were added to the true (=observed) CSF biomarker values, imitating the anticipated differences in biomarker concentrations. Within certain limits, the clinical diagnostic performance of AD CSF biomarkers remains largely unchanged and clinical diagnostic accuracy deviated less than 8.2% from the reference when concentration shifts ranging between -20% and +20% were added to one of the three CSF biomarkers in MCI and autopsy-confirmed AD patients. Notwithstanding the fact that (pre- and post-)analytical parameters can affect the clinical classification, the present exploratory study provides evidence that for a specific context of use, the impact on clinical accuracy of biomarker concentration shifts might be lower than originally expected. In conclusion, induced shifts of 20% in only one of the three biomarkers has limited impact on the clinical accuracy of AD CSF biomarkers in MCI and autopsy-confirmed AD patients when using the IWG-2 criteria.


PubMed | ADx NeuroSciences, University College London, Gothenburg University and University of Antwerp
Type: Journal Article | Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association | Year: 2015

Biomarkers monitoring synaptic degeneration/loss would be valuable for Alzheimers disease (AD) diagnosis. Postsynaptic protein neurogranin may be a promising cerebrospinal fluid (CSF) biomarker but has not yet been evaluated as a plasma biomarker.Using an in-house designed prototype enzyme-linked immunosorbent assay (ELISA) targeting neurogranin C-terminally, we studied neurogranin in paired CSF/plasma samples of controls (n = 29) versus patients experiencing MCI, or dementia, due to AD (in total n = 59).CSF neurogranin was increased in AD and positively correlated with CSF tau, whereas there was a negative relationship between CSF neurogranin (and tau) and CSF A1-42/A1-40. No differences were detected in plasma neurogranin between controls and AD. Also, there was no correlation between CSF and plasma neurogranin, excluding confounding effects of the latter.This study strengthens the potential of neurogranin as an AD CSF biomarker, which now needs validation in larger studies. As tools, straightforward immunoassays can be used, as demonstrated by the described ELISA.

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