Roadmap and standard operating procedures for biobanking and discovery of neurochemical markers in ALS

Department of Neurology, University of Ulm, Oberer Eselsberg 34, Ulm, Germany.
Amyotrophic Lateral Sclerosis (Impact Factor: 2.37). 01/2012; 13(1):1-10. DOI: 10.3109/17482968.2011.627589
Source: PubMed


Despite major advances in deciphering the neuropathological hallmarks of amyotrophic lateral sclerosis (ALS), validated neurochemical biomarkers for monitoring disease activity, earlier diagnosis, defining prognosis and unlocking key pathophysiological pathways are lacking. Although several candidate biomarkers exist, translation into clinical application is hindered by small sample numbers, especially longitudinal, for independent verification. This review considers the potential routes to the discovery of neurochemical markers in ALS, and provides a consensus statement on standard operating procedures that will facilitate multicenter collaboration, validation and ultimately clinical translation.

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    • "de biomarqueurs est le manque de spécificité, inhérent à l'hétérogénéité de l'expression de la maladie et à la méthodologie des études [18]. La taille critique des cohortes, notamment pour des études impliquant "
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    ABSTRACT: Numerous biomarkers studies in ALS used targeted and non-targeted approaches, to help for the diagnosis, the prognosis or to identify new pathophysiological ways. The emerging approaches such as "omics" studies are very promising, but the practical and technical limits do not enable their optimization. Even if some biomarkers such as cystatin C or glutamate are highlighted in ALS, to date, no biomarker is currently used in routine practice. Diffusion-based neuroimaging has emerged as a tool to identify the involvement of the central neuron, but a recent meta-analysis shows a poor sensitivity and specificity. Spinal cord imaging has the advantage of simultaneoulsy investigating both the corticospinal tract and the peripheral motor neurons in the anterior horns of the spinal cord. Its interest to provide biomarkers in ALS is illustrated by recent studies that used a multiparametric approach. The limits of biomarkers studies are principally based on small cohorts, involving a control population who does not allow to assess specificity. The discrepancies between the biomarkers identified in the different studies are based on a strong heterogeneity of the disease and a lack of standardization of the research methodology, including the step of the validation of these molecules in independent cohorts. The perspectives in biomarker research in ALS imply the combination of analytical methods, human abilities and harmonization of the strategies.
    La Presse Médicale 04/2014; 43(5). DOI:10.1016/j.lpm.2014.12.014 · 1.08 Impact Factor
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    • "However, none of these biomarkers have been validated in larger independent studies. Although CSF biomarkers show promise the invasive nature of CSF sampling is problematic for ALS patients and especially healthy controls [2]. Therefore searches in other bio-fluids such as urine should not be dismissed and could added to potential panels in large studies. "
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    ABSTRACT: Objective biomarkers for amyotrophic lateral sclerosis would facilitate the discovery of new treatments. The common neurotrophin receptor p75 is up regulated and the extracellular domain cleaved from injured neurons and peripheral glia in amyotrophic lateral sclerosis. We have tested the hypothesis that urinary levels of extracellular neurotrophin receptor p75 serve as a biomarker for both human motor amyotrophic lateral sclerosis and the SOD1(G93A) mouse model of the disease. The extracellular domain of neurotrophin receptor p75 was identified in the urine of amyotrophic lateral sclerosis patients by an immuno-precipitation/western blot procedure and confirmed by mass spectrometry. An ELISA was established to measure urinary extracellular neurotrophin receptor p75. The mean value for urinary extracellular neurotrophin receptor p75 from 28 amyotrophic lateral sclerosis patients measured by ELISA was 7.9±0.5 ng/mg creatinine and this was significantly higher (p<0.001) than 12 controls (2.6±0.2 ng/mg creatinine) and 19 patients with other neurological disease (Parkinson's disease and Multiple Sclerosis; 4.1±0.2 ng/mg creatinine). Pilot data of disease progression rates in 14 MND patients indicates that p75NTR(ECD) levels were significantly higher (p = 0.0041) in 7 rapidly progressing patients as compared to 7 with slowly progressing disease. Extracellular neurotrophin receptor p75 was also readily detected in SOD1(G93A) mice by immuno-precipitation/western blot before the onset of clinical symptoms. These findings indicate a significant relation between urinary extracellular neurotrophin receptor p75 levels and disease progression and suggests that it may be a useful marker of disease activity and progression in amyotrophic lateral sclerosis.
    PLoS ONE 01/2014; 9(1):e87398. DOI:10.1371/journal.pone.0087398 · 3.23 Impact Factor
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    • "This protocol addresses the preanalytical steps of CSF collection: lumbar puncture, transportation to the laboratory, processing and storage, and as such provides very practical guidelines for biobanking. The protocol has been the template for several other protocols, i.e. one adapted for ALS biomarker studies [12] and one for Alzheimer biomarker evaluation [21]. Furthermore, an updated version has been published for the BIOMARKAPD consortium, which is a joint programming EU-project aimed at standardizing of as many of the procedures of biomarker evaluation for Alzheimer's and Parkinson's disease as possible. "
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    ABSTRACT: Cerebrospinal fluid (CSF) reflects pathophysiological aspects of neurological diseases, where neuroprotective strategies and biomarkers are urgently needed. Therefore, biobanking is very relevant for biomarker discovery and evaluation in these neurological diseases. Important and unique features of CSF biobanking is intensive collaboration in international networks and the tight application of standardized protocols. The current adoption of standardized protocols for CSF and blood collection as presented in this review enables biomarker studies in large cohorts of patients and controls. Another topic of this review is the selection of control groups, which influences the outcome of biomarker investigations. Control groups in CSF biobanks mainly consist of different disease controls. This is in part due to the fact that lumbar punctures are mostly performed for clinical indications and rarely for research purposes only, as it is a relatively invasive procedure. Moreover, there is a lack of homogenous criteria and definition of control groups. We therefore propose uniform consensus definitions for such control groups in biomarker research, i.e. Healthy controls (HC), Spinal anaesthesia subjects (SAS), Symptomatic controls (SC), Inflammatory Neurological Disease Controls (CINDC), Peripheral Inflammatory Neurological Disease Controls (PINDC) and Non-inflammatory Neurological Disease Controls (NINDC). Another important aspect of CSF biobanking, is quality control. Systematic studies to address effects of pre-analytical and storage variation on a broad range of CSF proteins are needed. In conclusion, biomarker research in neurodegenerative diseases has entered a new era due to the collaborative and multicenter efforts of many groups. The streamlining of biobanking procedures, including quality control, and the selection of optimal control groups for investigating biomarkers is an important improvement to perform high quality biomarker studies.
    Clinical biochemistry 01/2014; 47(4-5). DOI:10.1016/j.clinbiochem.2013.12.024 · 2.28 Impact Factor
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