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Find video protocols related to scientific articles indexed in Pubmed.
Guidelines for uniform reporting of body fluid biomarker studies in neurologic disorders.
Neurology
PUBLISHED: 08-22-2014
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The aim of these guidelines is to make the process of reporting body fluid biomarker studies in neurologic disorders more uniform and transparent, in line with existing standards for reporting research in other biomedical areas. Although biomarkers have been around for decades, there are concerns over the high attrition rate of promising candidate biomarkers at later phases of development.
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Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 07-11-2014
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To investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS).
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Serum neurofilament light chain is a biomarker of human spinal cord injury severity and outcome.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 06-18-2014
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Neurofilaments (Nf) are major structural proteins that occur exclusively in neurons. In spinal cord injury (SCI), the severity of disease is quantified by clinical measures that have limited sensitivity and reliability, and no blood-based biomarker has been established to further stratify the degree of injury. We aimed to examine a serum-based NfL immunoassay as predictor of the clinical outcome in SCI.
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Unraveling natalizumab effects on deregulated miR-17 expression in CD4+ T cells of patients with relapsing-remitting multiple sclerosis.
J Immunol Res
PUBLISHED: 03-28-2014
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MicroRNAs (miRNAs) are a family of noncoding RNAs that play critical roles in the posttranscriptional regulation of gene expression. Accumulating evidence supports their involvement in the pathogenesis of multiple sclerosis (MS). Here, we compare miR-17 expressions in CD4+ T cells from relapsing-remitting (RR) MS patients treated with natalizumab versus untreated patients. miR-17 was downregulated under natalizumab treatment and upregulated during relapse, therefore supporting a possible role of miR-17 in MS immunopathogenesis. Downregulation of miR-17 was associated with upregulation of PTEN, BIM, E2F1, and p21 target genes. In vitro miR-17 inhibition was associated with upregulation of the same targets and resulted in impaired CD4+ T cell activation and proliferation. We further describe deregulated TGFBR2 expression in untreated patients versus healthy volunteers (HVs) and confirm in vitro the link between miR-17 and TGFBR2 expressions. These findings support an effect of natalizumab on expression of specific miRNA and subsequent expression of genes involved in proliferation and control of the cell cycle.
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Cholestenoic acids regulate motor neuron survival via liver X receptors.
J. Clin. Invest.
PUBLISHED: 03-17-2014
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Cholestenoic acids are formed as intermediates in metabolism of cholesterol to bile acids, and the biosynthetic enzymes that generate cholestenoic acids are expressed in the mammalian CNS. Here, we evaluated the cholestenoic acid profile of mammalian cerebrospinal fluid (CSF) and determined that specific cholestenoic acids activate the liver X receptors (LXRs), enhance islet-1 expression in zebrafish, and increase the number of oculomotor neurons in the developing mouse in vitro and in vivo. While 3?,7?-dihydroxycholest-5-en-26-oic acid (3?,7?-diHCA) promoted motor neuron survival in an LXR-dependent manner, 3?-hydroxy-7-oxocholest-5-en-26-oic acid (3?H,7O-CA) promoted maturation of precursors into islet-1+ cells. Unlike 3?,7?-diHCA and 3?H,7O-CA, 3?-hydroxycholest-5-en-26-oic acid (3?-HCA) caused motor neuron cell loss in mice. Mutations in CYP7B1 or CYP27A1, which encode enzymes involved in cholestenoic acid metabolism, result in different neurological diseases, hereditary spastic paresis type 5 (SPG5) and cerebrotendinous xanthomatosis (CTX), respectively. SPG5 is characterized by spastic paresis, and similar symptoms may occur in CTX. Analysis of CSF and plasma from patients with SPG5 revealed an excess of the toxic LXR ligand, 3?-HCA, while patients with CTX and SPG5 exhibited low levels of the survival-promoting LXR ligand 3?,7?-diHCA. Moreover, 3?,7?-diHCA prevented the loss of motor neurons induced by 3?-HCA in the developing mouse midbrain in vivo.Our results indicate that specific cholestenoic acids selectively work on motor neurons, via LXR, to regulate the balance between survival and death.
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MiR-126: a novel route for natalizumab action?
Mult. Scler.
PUBLISHED: 03-05-2014
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MicroRNAs (miRNAs) have emerged as a family of post-transcriptional regulators of gene expression that mediate diverse aspects of immunity. MiRNA dysregulation has been found in multiple sclerosis (MS), reflecting the growing need to identify disease-specific miRNA expression signatures. Our previous low-density array studies reveal differential miR-126 expression in the CD4(+)T cells of untreated relapsing-remitting MS (RRMS) patients. Here, we investigated miR-126 expression in natalizumab-treated patients.
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Neurofilament light antibodies in serum reflect response to natalizumab treatment in multiple sclerosis.
Mult. Scler.
PUBLISHED: 02-10-2014
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Increased levels of antibodies to neurofilament light protein (NF-L) in biological fluids have been found to reflect neuroinflammatory responses and neurodegeneration in multiple sclerosis (MS).
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The refinement of genetic predictors of multiple sclerosis.
PLoS ONE
PUBLISHED: 01-01-2014
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A recent genome wide association study (GWAS) demonstrated that more than 100 genetic variants influence the risk of multiple sclerosis (MS). We investigated what proportion of the general population can be considered at high genetic risk of MS, whether genetic information can be used to predict disease development and how the recently found genetic associations have influenced these estimates. We used summary statistics from GWAS in MS to estimate the distribution of risk within a large simulated general population. We profiled MS associated loci in 70 MS patients and 79 healthy controls (HC) and assessed their position within the distribution of risk in the simulated population. The predictive performance of a weighted genetic risk score (wGRS) on disease status was investigated using receiver operating characteristic statistics. When all known variants were considered, 40.8% of the general population was predicted to be at reduced risk, 49% at average, 6.9% at elevated and 3.3% at high risk of MS. Fifty percent of MS patients were at either reduced or average risk of disease. However, they showed a significantly higher wGRS than HC (median 13.47 vs 12.46, p?=?4.08×10(-10)). The predictive performance of the model including all currently known MS associations (area under the curve?=?79.7%, 95%CI?=?72.4%-87.0%) was higher than that of models considering previously known associations. Despite this, considering the relatively low prevalence of MS, the positive predictive value was below 1%. The increasing number of known associated genetic variants is improving our ability to predict the development of MS. This is still unlikely to be clinically useful but a more complete understanding of the complexity underlying MS aetiology and the inclusion of environmental risk factors will aid future attempts of disease prediction.
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Hypovitaminosis-D and EBV: no interdependence between two MS risk factors in a healthy young UK autumn cohort.
Mult. Scler.
PUBLISHED: 11-05-2013
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Late Epstein-Barr virus infection and hypovitaminosis-D as environmental risk factors in the pathogenesis of multiple sclerosis are gaining great interest. We, therefore, tested for in-vivo interdependence between Epstein-Barr-virus (EBV)-status and 25-hydroxyvitamin D3 (25(OH)D3) -level in healthy young individuals from a United Kingdom (UK) autumn cohort. EBV-load was measured by quantitative polymerase chain reaction and 25(OH)D3 levels by isotope-dilution liquid chromatography-tandem mass spectrometry. This young, healthy UK autumn cohort showed surprisingly low levels of 25(OH)D3 (mean value: 40.5 nmol/L ± 5.02). Furthermore, we found that low 25(OH)D3 levels did not impact on EBV load and anti-EBV nuclear antigen-1 (EBNA-1) titers. However, we observed a correlation between EBV load and EBNA-1 titers. These observations should be of value in the study of the potential relationship between hypovitaminosis-D and EBV-status in the pathophysiology of multiple sclerosis.
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DNase hypersensitive sites and association with multiple sclerosis.
Hum. Mol. Genet.
PUBLISHED: 10-02-2013
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Genome-wide association studies (GWASs) have shown that approximately 60 genetic variants influence the risk of developing multiple sclerosis (MS). Our aim was to identify the cell types in which these variants are active. We used available data on MS-associated single nucleotide polymorphisms (SNPs) and deoxyribonuclease I hypersensitive sites (DHSs) from 112 different cell types. Genomic intervals were tested for overlap using the Genomic Hyperbrowser. The expression profile of the genes located nearby MS-associated SNPs was assessed using the software GRAIL (Gene Relationships Across Implicated Loci). Genomic regions associated with MS were significantly enriched for a number of immune DHSs and in particular T helper (Th) 1, Th17, CD8+ cytotoxic T cells, CD19+ B cells and CD56+ natural killer (NK) cells (enrichment = 2.34, 2.19, 2.27, 2.05 and 1.95, respectively; P < 0.0001 for all of them). Similar results were obtained when genomic regions with suggestive association with MS and additional immune-mediated traits were investigated. Several new candidate MS-associated genes located within regions of suggestive association were identified by GRAIL (CARD11, FCRL2, CHST12, SYK, TCF7, SOCS1, NFKBIZ and NPAS1). Genetic data indicate that Th1, Th17, cytotoxic T, B and NK cells play a prominent role in the etiology of MS. Regions with confirmed and suggestive association have a similar immunological profile, indicating that many SNPs truly influencing the risk of MS actually fail to reach genome-wide significance. Finally, similar cell types are involved in the etiology of other immune-mediated diseases.
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Immune reactivity to neurofilament proteins in the clinical staging of amyotrophic lateral sclerosis.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 09-27-2013
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Neurofilament (NF) proteins detection in biological fluids as a by-product of axonal loss is technically challenging and to date relies mostly on cerebrospinal fluid (CSF) measurements. Plasma antibodies against NF proteins and particularly to their soluble light chain (NF-L) could be a more practical surrogate marker for disease staging in amyotrophic lateral sclerosis (ALS), an invariably fatal and clinically heterogeneous neuromuscular disorder.
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The relationship between total and regional corpus callosum atrophy, cognitive impairment and fatigue in multiple sclerosis patients.
Mult. Scler.
PUBLISHED: 08-19-2013
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The objective of this paper is to investigate the relationship between total and regional corpus callosum (CC) atrophy, neuropsychological test performance and fatigue in multiple sclerosis (MS) patients.
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Lesion-to-ventricle distance and other risk factors for the persistence of newly formed black holes in relapsing-remitting multiple sclerosis.
Mult. Scler.
PUBLISHED: 07-11-2013
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Progenitor cells from the subventricular zone (SVZ) of the lateral ventricles are assumed to contribute to remyelination and resolution of black holes (BHs) in multiple sclerosis (MS). This process may depend on the distance between the lesion and the SVZ.
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Natalizumab therapy for multiple sclerosis.
Semin Neurol
PUBLISHED: 05-25-2013
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Natalizumab is a monoclonal therapeutic antibody that inhibits migration of lymphocytes into the central nervous system (CNS) by blocking integrins. Several clinical trials have shown an excellent efficacy in the treatment of relapsing remitting multiple sclerosis. This efficacy is also underlined by postmarketing data of patients with a more aggressive disease compared with the clinical trials. Certain patients might even improve during natalizumab treatment. These positive effects have to be balanced against potential adverse events. In this respect, allergic reactions, hematologic abnormalities, melanoma, lymphoma, infections, and most importantly, progressive multifocal leukoencephalopathy (PML) are discussed. A special emphasis is put on the risk stratification algorithm for PML and approaches for PML treatment. Further, patient and disease characteristics are discussed that might prompt the start or cessation of natalizumab. Finally, data on how to continue after stopping natalizumab are summarized.
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T-cell response against varicella-zoster virus in fingolimod-treated MS patients.
Neurology
PUBLISHED: 05-22-2013
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To study the immune response against varicella-zoster virus (VZV) in patients with multiple sclerosis before and during fingolimod therapy.
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The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis.
Mult. Scler.
PUBLISHED: 05-22-2013
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Observational studies have shown an association between lower vitamin D levels and higher risk of relapse among people with multiple sclerosis (MS). This has raised interest in potential clinical benefits of vitamin D supplementation in the management of MS. The objectives were to examine the effect of vitamin D based interventions on the relative risk of relapse in MS. Any randomised controlled trial assessing the effect on the relative risk of relapse of any formulation or dose of vitamin D, in participants with MS, was eligible. The inverse variance with random effects model in Review Manager 5.1 was used to calculate the odds ratio of relapses in high dose vitamin D treated patients vs. controls. Five studies were published as of September 2012, yielding a total of 129 high-dose vitamin D-treated patients and 125 controls. We found no significant association between high-dose vitamin D treatment and risk of MS relapse (OR 0.98, 95% CI 0.45-2.16). In conclusion, although no significant association between high-dose vitamin D treatment and risk of MS relapses was found, the studies were limited by several methodological limitations. Further larger, more prolonged studies are merited.
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Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis.
Mult. Scler.
PUBLISHED: 05-21-2013
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The choice of appropriate control group(s) is critical in cerebrospinal fluid (CSF) biomarker research in multiple sclerosis (MS). There is a lack of definitions and nomenclature of different control groups and a rationalized application of different control groups. We here propose consensus definitions and nomenclature for the following groups: healthy controls (HCs), spinal anesthesia subjects (SASs), inflammatory neurological disease controls (INDCs), peripheral inflammatory neurological disease controls (PINDCs), non-inflammatory neurological controls (NINDCs), symptomatic controls (SCs). Furthermore, we discuss the application of these control groups in specific study designs, such as for diagnostic biomarker studies, prognostic biomarker studies and therapeutic response studies. Application of these uniform definitions will lead to better comparability of biomarker studies and optimal use of available resources. This will lead to improved quality of CSF biomarker research in MS and related disorders.
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A comparative study of CSF neurofilament light and heavy chain protein in MS.
Mult. Scler.
PUBLISHED: 03-25-2013
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There is a lack of reliable biomarkers of axonal degeneration. Neurofilaments are promising candidates to fulfil this task. We compared two highly sensitive assays to measure two subunits of the neurofilament protein (neurofilament light (NfL) and neurofilament heavy chain (NfH)).
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Increased neurofilament light chain blood levels in neurodegenerative neurological diseases.
PLoS ONE
PUBLISHED: 01-01-2013
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Neuronal damage is the morphological substrate of persisting neurological disability. Neurofilaments (Nf) are cytoskeletal proteins of neurons and their release into cerebrospinal fluid has shown encouraging results as a biomarker for neurodegeneration. This study aimed to validate the quantification of the Nf light chain (NfL) in blood samples, as a biofluid source easily accessible for longitudinal studies.
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Screening for balance disorders in mildly affected multiple sclerosis patients.
J. Neurol.
PUBLISHED: 10-17-2011
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Multiple sclerosis (MS) patients often complain about balance problems when Rombergs test and tandem gait are normal. The aim of the study was to determine if measures of trunk sway taken during a battery of stance and gait tasks could be used to detect subclinical balance disorders. We recorded trunk angular sway in the pitch and roll directions from 20 MS patients (EDSS 1.4 ± 0.5) and 20 age- and gender-matched healthy controls (HCs), during 12 stance and gait tasks. We filmed 22 subjects simultaneously. Two neurologists assessed the videos, deciding whether task performance was pathological. Sway measures were significantly different between patients and HCs in eight out of 12 balance tasks. The most significant differences between MS patients and HCs were pitch angle range standing on one leg with eyes open on a firm surface (mean 3.13° vs. 2.09°, p = 0.005), and on a foam support surface (mean 6.24° vs. 2.96°, p = 0.006), pitch velocity range walking 8 m with eyes closed (mean 75.5 vs. 50.2°/s, p < 0.001) and pitch velocity range walking 3 m on heels (mean 85.37 vs. 60.9°/s, p = 0.002). Multivariate analysis revealed a model with three tasks which detected balance disorders in 84% of the MS patients and 90% of the HCs correctly. The neurologists achieved accuracies of 30% for the MS patients and 82% for the HCs. Using trunk sway measures during stance and gait tasks is a sensitive screening method for balance problems in MS patients, and is more accurate than assessment by trained neurologists.
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Pathology of immune reconstitution inflammatory syndrome in multiple sclerosis with natalizumab-associated progressive multifocal leukoencephalopathy.
Acta Neuropathol.
PUBLISHED: 09-17-2011
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Natalizumab is an approved medication for highly active multiple sclerosis (MS). Progressive multifocal leukoencephalopathy (PML) may occur as a severe side effect of this drug. Here, we describe pathological and radiological characteristics of immune reconstitution inflammatory syndrome (IRIS), which occurs in natalizumab-associated PML after the cessation of therapy, and we differentiate it from ongoing PML. Brain biopsy tissue and MRI scans from five MS patients with natalizumab-associated PML were analyzed and their histology compared with non-MS PML. Histology showed an extensive CD8-dominated T cell infiltrate and numerous macrophages within lesions, and in nondemyelinated white and grey matter, in four out of five cases. Few or no virally infected cells were found. This was indicative of IRIS as known from HIV patients with PML. Outstandingly high numbers of plasma cells were present as compared to non-MS PML and typical MS lesions. MRI was compatible with IRIS, revealing enlarging lesions with a band-like or speckled contrast enhancement either at the lesion edge or within lesions. Only the fifth patient showed typical PML pathology, with low inflammation and high numbers of virally infected cells. This patient showed a similar interval between drug withdrawal and biopsy (3.5 months) to the rest of the cohort (range 2.5-4 months). MRI could not differentiate between PML-associated IRIS and ongoing PML. We describe in detail the histopathology of IRIS in natalizumab-associated PML. PML-IRIS, ongoing PML infection, and MS exacerbation may be impossible to discern clinically alone. MRI may provide some clues for distinguishing different pathologies that can be differentiated histologically. In our individual cases, biopsy helped to clarify diagnoses in natalizumab-associated PML.
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What makes a prognostic biomarker in CNS diseases: strategies for targeted biomarker discovery? Part 2: chronic progressive and relapsing disease.
Expert Opin Med Diagn
PUBLISHED: 06-15-2011
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Introduction: Compared with acute neurological conditions, biomarker discovery in chronic progressive and relapsing neurodegenerative diseases may be more difficult. First, the degenerative process may be so slow that the biomarker discovered is released only in small quantities making it a fishing exercise with very little to catch. Second, it may be difficult to differentiate acute new damage, relevant to prognostic estimates, from already existing background damage. A potential advantage in chronic conditions is that there may be sufficient time for the disease to leave a specific signature on the biomarker by the means of post-translational modifications. Areas covered: In this review, the authors cover chronic and relapsing neurological diseases including multiple sclerosis, neuromyelitis optica, motor neuron disease and a number of neurodegenerative dementias and movement disorders. In these entities, prognostic estimates depend, at least in part, on an accurate differential diagnosis. Therefore, the authors have given particular attention to the added value of biomarkers that can be used in a laboratory setting to support differential diagnosis. Each biomarker was given a class IV rating to demonstrate their prognostic value. Expert opinion: There has been substantial progress in validating and integrating biomarkers in the diagnostic workup of patients with multiple sclerosis and dementia. New data suggest that prognostic accuracy may be improved in motor neuron disease using protein biomarkers for neurodegeneration. Hypothesis-driven biomarker discovery, which focuses on post-translational modifications such as phosphorylation, aggregate formation or changes in protein stoichiometry, may open new avenues for successful biomarker discovery in chronic and relapsing conditions.
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Soluble beta-amyloid precursor protein is related to disease progression in amyotrophic lateral sclerosis.
PLoS ONE
PUBLISHED: 06-13-2011
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Biomarkers of disease progression in amyotrophic lateral sclerosis (ALS) could support the identification of beneficial drugs in clinical trials. We aimed to test whether soluble fragments of beta-amyloid precursor protein (sAPP? and sAPPß) correlated with clinical subtypes of ALS and were of prognostic value.
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What makes a prognostic biomarker in CNS diseases: strategies for targeted biomarker discovery? Part 1: acute and monophasic diseases.
Expert Opin Med Diagn
PUBLISHED: 05-27-2011
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Introduction: Biomarker discovery studies are sometimes referred to as fishing exercises as the excitement of discovering a potentially important new biomarker is offset by the likelihood of finding something that is barely useful. For biomarkers to increase their prognostic value, biomarkers need to improve the current prognostic accuracy. In this regard, one potential advantage in biomarker discovery for acute neurological disease is that damage-related release of biomarkers can be timed, allowing for targeted sample collection. Areas covered: In this article, the authors focus on the accuracy of prognosis for the following acute and monophasic neurological diseases: Guillain-Barré syndrome, stroke, traumatic brain injury and subarachnoid hemorrhage. For each condition, the prognostic accuracy, based on clinical information, is compared with the potential gain using biomarker data. Expert opinion: Lessons have been learned from discovery studies on prognostic protein biomarkers in all of the diseases mentioned. The data provided allow the prognostic value of future biomarkers to be increased through the definition of criteria that future biomarkers must surpass. A class IV rating was given for the value of each biomarker. Two distinct but targeted strategies may be useful for future biomarker discovery in acute conditions: strategies focused on biomarker discovery from acutely damaged tissue (e.g., laser capture microdissection); and strategies focused at eloquent time points (e.g., based on selecting high-likelihood samples that are positive for already established biomarkers). Validation studies, both analytically and clinically, are a key requirement for the success of future biomarker discovery.
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Consensus Guidelines for CSF and Blood Biobanking for CNS Biomarker Studies.
Mult Scler Int
PUBLISHED: 04-05-2011
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There is a long history of research into body fluid biomarkers in neurodegenerative and neuroinflammatory diseases. However, only a few biomarkers in cerebrospinal fluid (CSF) are being used in clinical practice. Anti-aquaporin-4 antibodies in serum are currently useful for the diagnosis of neuromyelitis optica (NMO), but we could expect novel CSF biomarkers that help define prognosis and response to treatment for this disease. One of the most critical factors in biomarker research is the inadequate powering of studies performed by single centers. Collaboration between investigators is needed to establish large biobanks of well-defined samples. A key issue in collaboration is to establish standardized protocols for biobanking to ensure that the statistical power gained by increasing the numbers of CSF samples is not compromised by pre-analytical factors. Here, consensus guidelines for CSF collection and biobanking are presented, based on the guidelines that have been published by the BioMS-eu network for CSF biomarker research. We focussed on CSF collection procedures, pre-analytical factors and high quality clinical and paraclinical information. Importantly, the biobanking protocols are applicable for CSF biobanks for research targeting any neurological disease.
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Placental ?-microglobulin-1 to detect uncertain rupture of membranes in a European cohort of pregnancies.
Arch. Gynecol. Obstet.
PUBLISHED: 03-15-2011
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We evaluated the performance of the placental alpha-microglobulin-1 immunoassay (AmniSure(®), AT) in cervicovaginal secretions in patients with uncertain rupture of membranes (ROM) and investigated the influence of the examiners experience.
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Antigen-specific adaptive immune responses in fingolimod-treated multiple sclerosis patients.
Ann. Neurol.
PUBLISHED: 03-10-2011
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T cells exit secondary lymphoid organs along a sphingosine1-phosphate (S1P) gradient and, accordingly, are reduced in blood upon fingolimod-mediated S1P-receptor (S1PR)-blockade. Serving as a model of adaptive immunity, we characterized cellular and humoral immune responses to influenza vaccine in fingolimod-treated patients with multiple sclerosis (MS) and in untreated healthy controls. Although the mode of action of fingolimod might predict reduced immunity, vaccine-triggered T cells accumulated normally in blood despite efficient S1PR-blockade. Concentrations of anti-influenza A/B immunoglobulin (Ig)M and IgG also increased similarly in both groups. These results indicate that fingolimod-treated individuals can mount vaccine-specific adaptive immune responses comparable to healthy controls.
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Evidence for acute neurotoxicity after chemotherapy.
Ann. Neurol.
PUBLISHED: 07-17-2010
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Chronic neurotoxicity is a recognized long-term complication following chemotherapy in a range of diseases. Neurotoxicity adversely affects patients quality of life. The objective of this study is to examine whether there is evidence of acute neurotoxicity.
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CSF-tau and CSF-Abeta(1-42) in posterior cortical atrophy.
Dement Geriatr Cogn Disord
PUBLISHED: 04-29-2010
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Our purpose was to measure Abeta(1-42), T-tau and P-tau(181) in the cerebrospinal fluid (CSF) of patients with posterior cortical atrophy (PCA), a presenile dementia likely to represent a variant of Alzheimers disease (AD).
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Altered expression of miR-17-5p in CD4+ lymphocytes of relapsing-remitting multiple sclerosis patients.
Eur. J. Immunol.
PUBLISHED: 02-12-2010
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MicroRNA (miRNA) are a class of post-transcriptional regulators of gene expression targeting mRNA for translational repression and/or degradation. We analyzed the expression of 365 miRNA in lymphocytes in relapsing-remitting MS patients, and show the first evidence for distinct miRNA expression profiles in CD4(+), CD8(+) and B cells in MS when compared with those in healthy volunteers. MiR-17-5p, which is involved in autoimmunity, was up-regulated in CD4(+) cells from MS patients. This was correlated with alterations in the expression of potential target genes of miR-17-5p, i.e. phosphatase and tensin homology and phosphatidyl-inositol-3-kinase regulatory subunit 1, which were down-regulated upon stimulation of CD4(+) cells with anti-CD3/CD28 in vitro. Functional experiments with a synthetic inhibitor of miR-17 supported the link between miRNA expression and the altered target gene expression. Moreover, we found distinct responses of deregulated miRNA to stimulation, i.e. miR-17-5p and miR-193a were strongly up-regulated, in contrast to the down-regulation of miR-497, miR-1 and miR-126. Other deregulated miRNA did not respond to the stimulation probably due to other, non-T-cell activation related, mechanisms in their mode of action. Our findings support the role of miRNA-dependent regulatory mechanisms in the immunopathogenesis of MS.
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A highly sensitive electrochemiluminescence immunoassay for the neurofilament heavy chain protein.
J. Neuroimmunol.
PUBLISHED: 01-05-2010
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The loss of neurological function is closely related to axonal damage. Neurofilament subunits are concentrated in neurons and axons and have emerged as promising biomarkers for neurodegeneration. Electrochemiluminescence (ECL) based assays are known to be of superior sensitivity and require less sample volume than conventional ELISAs.
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Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis.
J. Immunol.
PUBLISHED: 08-17-2009
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Multiple sclerosis (MS) typically manifests in early to mid adulthood, but there is increasing recognition of pediatric-onset MS, aided by improvements in imaging techniques. The immunological mechanisms of disease are largely unexplored in pediatric-onset MS, in part because studies have historically focused on adult-onset disease. We investigated autoantibodies to myelin surface Ags in a large cohort of pediatric MS cases by flow cytometric labeling of transfectants that expressed different myelin proteins. Although Abs to native myelin oligodendrocyte glycoprotein (MOG) were uncommon among adult-onset patients, a subset of pediatric patients had serum Abs that brightly labeled the MOG transfectant. Abs to two other myelin surface Ags were largely absent. Affinity purification of MOG Abs as well as competition of binding with soluble MOG documented their binding specificity. Such affinity purified Abs labeled myelin and glial cells in human CNS white matter as well as myelinated axons in gray matter. The prevalence of such autoantibodies was highest among patients with a very early onset of MS: 38.7% of patients less than 10 years of age at disease onset had MOG Abs, compared with 14.7% of patients in the 10- to 18-year age group. B cell autoimmunity to this myelin surface Ag is therefore most common in patients with a very early onset of MS.
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Neurofilament ELISA validation.
J. Immunol. Methods
PUBLISHED: 05-03-2009
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Neurofilament proteins (Nf) are highly specific biomarkers for neuronal death and axonal degeneration. As these markers become more widely used, an inter-laboratory validation study is required to identify assay criteria for high quality performance.
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A modern approach to CSF analysis: pathophysiology, clinical application, proof of concept and laboratory reporting.
Clin Neurol Neurosurg
PUBLISHED: 01-30-2009
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The CNS immune response often leads to characteristic interrelated biochemical changes in cerebrospinal fluid. Multiple analytes, i.e. cell count, cell differential, evaluation of barrier function and intrathecal IgG, IgA and IgM synthesis should be included in basic diagnostic workup. We describe the scientific background, laboratory investigations and characteristic patterns found with basic CSF analysis, based on the recommendations of the German cerebrospinal fluid society. The concept is substantiated by retrospectively analyzing data of 4026 paired CSF/serum samples. 53% of our samples presented with at least one or several combined abnormal findings. An intrathecal IgG, IgA or IgM immunoglobulin response (37%, n=1481) and a blood-CSF barrier dysfunction (37%; n=1473) were most frequent; followed by an elevated leukocyte cell count (25%; n=992). The immunoglobulin response showed an intrathecal production of IgG in 49% (n=731/1481), which was only detectable in isoelectric focusing in 27% (n=200/731). Intrathecal IgM (n=389) and IgA (n=361) synthesis presented with nearly equal frequency of 25% in samples with intrathecal immunoglobulin response. The immunoglobulin pattern showed a solitary one class reaction of IgG, IgA or IgM in 67%, a combined two class reaction of IgG/IgA, IgG/IgM or IgA/IgM synthesis in 16% and a combined three-class reaction of IgG, IgA and IgM in 17%. This approach generates valuable but numerous complex and interrelated biochemical data. We therefore developed a knowledge-based system combined with visual oriented laboratory output to transfer the information more effectively. This often uncovers typical patterns specific for distinct neurological diseases, is well accepted by our medical community documented by a 37% increase in external ordering.
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Balance control in multiple sclerosis: correlations of trunk sway during stance and gait tests with disease severity.
Gait Posture
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To investigate which measures of trunk sway taken during stance and gait tasks are best correlated with Expanded Disability Status Scale (EDSS) scores of multiple sclerosis (MS) patients.
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Neurofilament heavy chain and heat shock protein 70 as markers of seizure-related brain injury.
Epilepsia
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? Status epilepticus (SE) has deleterious effects on brain tissue, but whether brief recurrent seizures may also damage neurons represents a matter of controversy. Therefore, it remains a central area of epilepsy research to identify individuals at risk where disease progression can be potentially prevented. Biomarkers may serve as tools for such identification. Thus the present study aimed at analyzing the levels of heat shock protein 70 (HSP-70, also designated as HSPA1A) and neurofilament heavy chain protein (NfH(SMI35) ) in cerebrospinal fluid (CSF) of patients with seizures of different severity.
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Biomarkers of dementia: comparison of electrochemiluminescence results and reference ranges with conventional ELISA.
Methods
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We compared the performance of the Meso Scale Diagnostics electrochemiluminescence (MSD) multiplex assay for t-tau and p-tau(231), originally developed for measurement of brain cell extract and tissue cultures, with the established standard method, the Innogenetics ELISA for total and p-tau(181). The methods were also clinically evaluated with 120 samples from our mono center population. The established Innogenetics ELISA procedures have been well optimized to measure patient samples in the normal and pathological range. Compared to the MSD they were superior in the limit of detection for total as well as p-tau. The obtained reference values for our normal controls were in the upper third of the published studies. Innogenetics tau, Innogenetics p-tau(181) and MSD t-tau differentiated the Alzheimers (n=44) and minimal impairment group (MCI, n=39) from normal controls (n=37), but the MCI group was not statistically different from the normal controls. The MSD multiplex assay measured t-tau adequately but p-tau(231) could not differentiate normal from pathological results in CSF due to the high limit of detection. Both procedures however, have to be further standardized and complemented by adequate internal and external quality control schemes to qualify for routine analysis in a medical laboratory.
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