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Identification of a novel biomarker candidate, a 4.8-kDa peptide fragment from a neurosecretory protein VGF precursor, by proteomic analysis of cerebrospinal fluid from children with acute encephalopathy using SELDI-TOF-MS
Takeshi Asano, Shinya Koizumi, Atsushi Takagi, Takayuki Hatori, Kentaroh Kuwabara, Osamu Fujino, Yoshitaka Fukunaga
BMC Neurology , 2011, DOI: 10.1186/1471-2377-11-101
Abstract: For detection of biomarkers, CSF samples were obtained from 13 children with acute encephalopathy and 42 children with febrile seizure. Mass spectral data were generated by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) technology, which is currently applied in many fields of biological and medical sciences. Diagnosis was made by at least two pediatric neurologists based on the clinical findings and routine examinations. All specimens were collected for diagnostic tests and the remaining portion of the specimens were used for the SELDI-TOF MS investigations.In experiment 1, CSF from patients with febrile seizures (n = 28), patients with encephalopathy (n = 8) (including influenza encephalopathy (n = 3), encephalopathy due to rotavirus (n = 1), human herpes virus 6 (n = 1)) were used for the SELDI analysis. In experiment 2, SELDI analysis was performed on CSF from a second set of febrile seizure patients (n = 14) and encephalopathy patients (n = 5). We found that the peak with an m/z of 4810 contributed the most to the separation of the two groups. After purification and identification of the 4.8-kDa protein, a 4.8-kDa proteolytic peptide fragment from the neurosecretory protein VGF precursor (VGF4.8) was identified as a novel biomarker for encephalopathy.Expression of VGF4.8 has been reported to be decreased in pathologically degenerative changes such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and encephalopathy. Thus, the VGF4.8 peptide might be a novel marker for degenerative brain conditions.Acute encephalopathy is characterized by sudden onset of high fever, lethargy, convulsions, and loss of consciousness, with poor prognoses associated with virus infections including causative viruses such as the influenza virus and other etiologies [1-3]. Given that encephalopathy leads to rapid deterioration and a poor prognosis, early intervention is essential in order to prevent progre
Consensus Guidelines for CSF and Blood Biobanking for CNS Biomarker Studies  [PDF]
Charlotte E. Teunissen,Hayrettin Tumani,Jeffrey L. Bennett,Frode S. Berven,Lou Brundin,Manuel Comabella,Diego Franciotta,Jette L. Federiksen,John O. Fleming,Roberto Furlan,Rogier Q. Hintzen,Steve G. Hughes,Connie R. Jimenez,Michael H. Johnson,Joep Killestein,Eva Krasulova,Jens Kuhle,Maria-Chiara Magnone,Axel Petzold,Cecilia Rajda,Konrad Rejdak,Hollie K. Schmidt,Vincent van Pesch,Emmanuelle Waubant,Christian Wolf,Florian Deisenhammer,Gavin Giovannoni,Bernhard Hemmer
Multiple Sclerosis International , 2011, DOI: 10.1155/2011/246412
Abstract: 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. 1. Introduction: The Need for Collaborative Biobanking and Biomarker Studies NMO can be diagnosed based on a blood-derived biomarker, that is antibodies against aquaporin-4, a channel protein present on astrocytes, extensively discussed in other contributions in this special issue. The presence of antibodies against aquaporin-4 has been proven as one of the most successful results of biomarker studies, and is supportive for the idea that central nervous system (CNS) abnormalities are reflected in changes in body fluids. It also proofs the autoimmune component of this disorder and of pathologies that are related to the NMO spectrum disorders, such as longitudinally extensive transverse myelitis. Determination of serum anti-aquaporin-4 antibody levels is a mainstay in the diagnosis of NMO, but the discovery of such disease-specific antibodies is relatively recent [1], and, therefore, further studies in body fluids are warranted. One case report suggested that NMO-immunoglobulin G (IgG), the NMO-associated antibodies that are reactive to cerebellar tissue [1], can be absent in serum, but present in CSF [2]. However, another study on a relative large cohort of patients showed that testing CSF does not increase diagnostic sensitivity [3]. Another recently identified candidate biomarker for NMO is
Cystatin C: A Candidate Biomarker for Amyotrophic Lateral Sclerosis  [PDF]
Meghan E. Wilson,Imene Boumaza,David Lacomis,Robert Bowser
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015133
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurologic disease characterized by progressive motor neuron degeneration. Clinical disease management is hindered by both a lengthy diagnostic process and the absence of effective treatments. Reliable panels of diagnostic, surrogate, and prognostic biomarkers are needed to accelerate disease diagnosis and expedite drug development. The cysteine protease inhibitor cystatin C has recently gained interest as a candidate diagnostic biomarker for ALS, but further studies are required to fully characterize its biomarker utility. We used quantitative enzyme-linked immunosorbent assay (ELISA) to assess initial and longitudinal cerebrospinal fluid (CSF) and plasma cystatin C levels in 104 ALS patients and controls. Cystatin C levels in ALS patients were significantly elevated in plasma and reduced in CSF compared to healthy controls, but did not differ significantly from neurologic disease controls. In addition, the direction of longitudinal change in CSF cystatin C levels correlated to the rate of ALS disease progression, and initial CSF cystatin C levels were predictive of patient survival, suggesting that cystatin C may function as a surrogate marker of disease progression and survival. These data verify prior results for reduced cystatin C levels in the CSF of ALS patients, identify increased cystatin C levels in the plasma of ALS patients, and reveal correlations between CSF cystatin C levels to both ALS disease progression and patient survival.
-Synuclein as CSF and Blood Biomarker of Dementia with Lewy Bodies  [PDF]
Kensaku Kasuga,Masatoyo Nishizawa,Takeshi Ikeuchi
International Journal of Alzheimer's Disease , 2012, DOI: 10.1155/2012/437025
Abstract: Dementia with Lewy bodies (DLB) is a common subtype of dementia in the elderly. DLB is neuropathologically characterized by the presence of Lewy bodies and Lewy neurites, both of which are composed of α-synuclein. Although α-synuclein was initially considered to be an exclusively intracellular protein, it has been found to be secreted into biological fluids. α-Synuclein in biological fluids such as cerebrospinal fluid (CSF) and blood has been discussed as a potential biomarker of DLB and α-synuclein-related disorders, because α-synuclein is characteristically accumulated in the brain of patients with these disorders. The α-synuclein level in CSF has been examined by several investigators, and the majority of studies have shown a reduction in CSF α-synuclein level in DLB and α-synuclein-related disorders. Discrepant findings of studies of plasma α-synuclein level in patients with DLB have been reported. Because the level of α-synuclein stored in red blood cells is considerably high, blood contamination and haemolysis during sample collection and processing should be considered as a confounding factor for quantification of α-synuclein. Here, the recent progress in the studies of α-synuclein as a biomarker of DLB and their potential clinical applications are reviewed. 1. Introduction Dementia with Lewy bodies (DLB) is a common subtype of dementia and is reported to be the second most common neurodegenerative dementia after Alzheimer’s disease (AD) in the elderly in several studies [1–3]. DLB is a progressive cognitive disorder characterized by fluctuating cognitive impairment, visual hallucination, and parkinsonism [4]. Diagnosis of DLB in patients with such characteristic clinical features would not be difficult by taking medical history and careful neurological examinations. However, it could be laborious to make an accurate diagnosis of DLB when patients have a substantial degree of concomitant AD pathology, which affects the clinical symptoms with lower rates of visual hallucinations and parkinsonism [5, 6]. Accurate clinical diagnosis of DLB is important because patients may benefit from cholinesterase inhibitors, which improve cognitive function and neuropsychiatric symptoms of DLB [7]. Furthermore, it should be noted that DLB patients are particularly sensitive to neuroleptic drugs [4, 8]. Recent intensive research has given hope for disease-modifying therapeutics for DLB to become a reality. The evaluation of such therapies largely depends on reliable diagnostic and prognostic biomarkers for early detection and monitoring of the stage of DLB.
Blood and CSF Biomarker Dynamics in Multiple Sclerosis: Implications for Data Interpretation  [PDF]
M. J. Eikelenboom,B. M. J. Uitdehaag,A. Petzold
Multiple Sclerosis International , 2011, DOI: 10.1155/2011/823176
Abstract: Background. Disability in multiple sclerosis (MS) is related to neuroaxonal degeneration. A reliable blood biomarker for neuroaxonal degeneration is needed. Objectives. To explore the relationship between cerebrospinal fluid (CSF) and serum concentrations of a protein biomarker for neuroaxonal degeneration, the neurofilaments heavy chain (NfH). Methods. An exploratory cross-sectional ( ) and longitudinal ( ) study on cerebrospinal fluid (CSF) and serum NfH phosphoform levels in patients with MS. The expanded disability status scale (EDSS), CSF, and serum levels of NfH-SMI34 and NfH-SMI35 were quantified at baseline. Disability progression was assessed at 3-year followup. Results. At baseline, patients with primary progressive MS (PPMS, EDSS 6) and secondary progressive MS (SPMS, EDSS 6) were more disabled compared to patients with relapsing remitting MS (RRMS, EDSS 2, ). Serum and CSF NfH phosphoform levels were not correlated. Baseline serum levels of the NfH-SMI34 were significantly ( ) higher in patients with PPMS (2.05?ng/mL) compared to SPMS (0.03?ng/mL) and RRMS (1.56?ng/mL). In SPMS higher serum than CSF NfH-SMI34 levels predicted disability progression from baseline ( 2, ). In RRMS higher CSF than serum NfH-SMI35 levels predicted disability progression ( 2, ). Conclusion. Serum and CSF NfH-SMI34 and NfH-SMI35 levels did not correlate with each other in MS. The quantitative relationship of CSF and serum NfH levels suggests that neuroaxonal degeneration of the central nervous system is the likely cause for disability progression in RRMS. In more severely disabled patients with PP/SPMS, subtle pathology of the peripheral nervous system cannot be excluded as an alternative source for blood NfH levels. Therefore, the interpretation of blood protein biomarker data in diseases of the central nervous system (CNS) should consider the possibility that pathology of the peripheral nervous system (PNS) may influence the results. 1. Introduction In multiple sclerosis, irreversible disability progression is anatomically associated with neuroaxonal degeneration [1–3]. Using cerebral microdialysis, it was shown that as a result of neuroaxonal degeneration, protein biomarkers were released into the extracellular fluid (ECF) [4, 5]. Once released into the ECF of the brain, these brain-specific proteins diffuse into the cerebrospinal fluid (CSF) [6]. A protein biomarker specific for neuroaxonal degeneration are neurofilaments [7, 8]. Of the various neurofilament proteins (Nf), the light (NfL) and heavy (NfH) chains were successfully quantified from the CSF and
Candidate List of yoUr Biomarker (CLUB): A Web-based Platform to Aid Cancer Biomarker Research
Bernett T.K. Lee,Lailing Liew,Jiahao Lim,Jonathan K.L. Tan
Biomarker Insights , 2008,
Abstract: CLUB (“Candidate List of yoUr Biomarkers”) is a freely available, web-based resource designed to support Cancer biomarker research. It is targeted to provide a comprehensive list of candidate biomarkers for various cancers that have been reported by the research community. CLUB provides tools for comparison of marker candidates from different experimental platforms, with the ability to filter, search, query and explore, molecular interaction networks associated with cancer biomarkers from the published literature and from data uploaded by the community. This complex and ambitious project is implemented in phases. As a first step, we have compiled from the literature an initial set of differentially expressed human candidate cancer biomarkers. Each candidate is annotated with information from publicly available databases such as Gene Ontology, Swiss-Prot database, National Center for Biotechnology Information’s reference sequences, Biomolecular Interaction Network Database and IntAct interaction. The user has the option to maintain private lists of biomarker candidates or share and export these for use by the community. Furthermore, users may customize and combine commonly used sets of selection procedures and apply them as a stored workflow using selected candidate lists. To enable an assessment by the user before taking a candidate biomarker to the experimental validation stage, the platform contains the functionality to identify pathways associated with cancer risk, staging, prognosis, outcome in cancer and other clinically associated phenotypes. The system is available at http://club.bii.a-star.edu.sg.
miR-21 in the Extracellular Vesicles (EVs) of Cerebrospinal Fluid (CSF): A Platform for Glioblastoma Biomarker Development  [PDF]
Johnny C. Akers, Valya Ramakrishnan, Ryan Kim, Johan Skog, Ichiro Nakano, Sandeep Pingle, Juliya Kalinina, Wei Hua, Santosh Kesari, Ying Mao, Xandra O. Breakefield, Fred H. Hochberg, Erwin G. Van Meir, Bob S. Carter, Clark C. Chen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078115
Abstract: Glioblastoma cells secrete extra-cellular vesicles (EVs) containing microRNAs (miRNAs). Analysis of these EV miRNAs in the bio-fluids of afflicted patients represents a potential platform for biomarker development. However, the analytic algorithm for quantitative assessment of EV miRNA remains under-developed. Here, we demonstrate that the reference transcripts commonly used for quantitative PCR (including GAPDH, 18S rRNA, and hsa-miR-103) were unreliable for assessing EV miRNA. In this context, we quantitated EV miRNA in absolute terms and normalized this value to the input EV number. Using this method, we examined the abundance of miR-21, a highly over-expressed miRNA in glioblastomas, in EVs. In a panel of glioblastoma cell lines, the cellular levels of miR-21 correlated with EV miR-21 levels (p<0.05), suggesting that glioblastoma cells actively secrete EVs containing miR-21. Consistent with this hypothesis, the CSF EV miR-21 levels of glioblastoma patients (n=13) were, on average, ten-fold higher than levels in EVs isolated from the CSF of non-oncologic patients (n=13, p<0.001). Notably, none of the glioblastoma CSF harbored EV miR-21 level below 0.25 copies per EV in this cohort. Using this cut-off value, we were able to prospectively distinguish CSF derived from glioblastoma and non-oncologic patients in an independent cohort of twenty-nine patients (Sensitivity=87%; Specificity=93%; AUC=0.91, p<0.01). Our results suggest that CSF EV miRNA analysis of miR-21 may serve as a platform for glioblastoma biomarker development.
Altered Prion Protein Expression Pattern in CSF as a Biomarker for Creutzfeldt-Jakob Disease  [PDF]
Mauricio Torres, Luis Cartier, José Manuel Matamala, Nancy Hernández, Ute Woehlbier, Claudio Hetz
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036159
Abstract: Creutzfeldt-Jakob disease (CJD) is the most frequent human Prion-related disorder (PrD). The detection of 14-3-3 protein in the cerebrospinal fluid (CSF) is used as a molecular diagnostic criterion for patients clinically compatible with CJD. However, there is a pressing need for the identification of new reliable disease biomarkers. The pathological mechanisms leading to accumulation of 14-3-3 protein in CSF are not fully understood, however neuronal loss followed by cell lysis is assumed to cause the increase in 14-3-3 levels, which also occurs in conditions such as brain ischemia. Here we investigated the relation between the levels of 14-3-3 protein, Lactate dehydrogenase (LDH) activity and expression of the prion protein (PrP) in CSF of sporadic and familial CJD cases. Unexpectedly, we found normal levels of LDH activity in CJD cases with moderate levels of 14-3-3 protein. Increased LDH activity was only observed in a percentage of the CSF samples that also exhibited high 14-3-3 levels. Analysis of the PrP expression pattern in CSF revealed a reduction in PrP levels in all CJD cases, as well as marked changes in its glycosylation pattern. PrP present in CSF of CJD cases was sensitive to proteases. The alterations in PrP expression observed in CJD cases were not detected in other pathologies affecting the nervous system, including cases of dementia and tropical spastic paraparesis/HTLV-1 associated myelopathy (HAM/TSP). Time course analysis in several CJD patients revealed that 14-3-3 levels in CSF are dynamic and show a high degree of variability during the end stage of the disease. Post-mortem analysis of brain tissue also indicated that 14-3-3 protein is upregulated in neuronal cells, suggesting that its expression is modulated during the course of the disease. These results suggest that a combined analysis of 14-3-3 and PrP expression pattern in CSF is a reliable biomarker to confirm the clinical diagnosis of CJD patients and follow disease progression.
Fibrinogen is not elevated in the cerebrospinal fluid of patients with multiple sclerosis
Rainer Ehling, Franziska Di Pauli, Peter Lackner, Bettina Kuenz, Wolfram Santner, Andreas Lutterotti, Claudia Gneiss, Harald Hegen, Michael Schocke, Florian Deisenhammer, Thomas Berger, Markus Reindl
Fluids and Barriers of the CNS , 2011, DOI: 10.1186/2045-8118-8-25
Abstract: We analyzed CSF and plasma fibrinogen levels together with routine parameters in patients with multiple sclerosis (MS), acute inflammatory diseases of the CNS (bacterial and viral meningoencephalitis, BM and VM) and PNS (Guillain-Barré syndrome; GBS), as well as in non-inflammatory neurological controls (OND) in a total of 103 patients. Additionally, MS patients underwent cerebral MRI scans at time of lumbar puncture.CSF and plasma fibrinogen levels were significantly lower in patients with MS and OND patients as compared to patients with BM, VM and GBS. There was a close correlation between fibrinogen levels and albumin quotient (rho = 0.769, p < 0.001) which strongly suggests passive transfer of fibrinogen through the blood-CSF-barrier during acute inflammation. Hence, in MS, the prototype of chronic neuroinflammation, CSF fibrinogen levels were not elevated and could not be correlated to clinical and neuroradiological outcome parameters.Although previous work has shown clear evidence of the involvement of fibrinogen in MS pathogenesis, this is not accompanied by increased fibrinogen in the CSF compartment.Fibrinogen is a soluble 340 kDa dimeric glycoprotein that is synthesized in the liver, secreted into the plasma and able to signal via a number of receptors expressed on cells of the hematopoietic, immune and nervous systems [1,2]. Apart from its pivotal role in thrombogenesis, inflammation, immune responses and atherogenesis, it is also a prominent acute-phase reactant. Transiently elevated plasma fibrinogen levels have been described in acute infectious diseases, in acute stroke and myocardial infarction; chronically raised plasma fibrinogen levels have been associated with an increased risk for cardiovascular diseases [3]. Whilst the significance of plasma fibrinogen is well established, the determination of fibrinogen in cerebrospinal fluid (CSF) has so far been restricted to descriptions of elevated fibrinogen degradation products in the CSF of patients wit
Fibrinogen metabolic responses to trauma
Wenjun Martini
Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine , 2009, DOI: 10.1186/1757-7241-17-2
Abstract: Coagulation complications are significant contributors to morbidity and mortality in trauma patients [1,2]. Mortality in patients with severe injuries and coagulopathy is found to be four times greater than in patients with injuries alone [3]. Trauma-related coagulopathy is associated with hypoperfusion due to tissue injury and blood loss, hemodilution from resuscitation with crystalloid and/or colloid solutions, progressive hypothermia and the development of acidosis. Since the recognition of the lethal triad of hypothermia, acidosis, and coagulopathy over a decade ago [1,2], a great deal of effort has been made to elucidate possible mechanisms contributing to trauma related coagulopathy as well as to search for effective treatments [4-7]. Recent data suggest that fibrinogen availability may play an important role in the survival of patients. The purpose of this article is to review recent findings that have been made concerning clotting protein fibrinogen metabolism and availability following trauma-related events, including hemorrhage, resuscitation, hypothermia and acidosis.As the precursor of clot formation, fibrinogen plays an important role in coagulation function. Fibrinogen deficiency is associated with uncontrolled bleeding and compromised survival [8-12]. Thus, regulation of fibrinogen availability is critical to survival in trauma patients.As an acute phase protein, fibrinogen is synthesized in the liver and released into the circulation. It is catabolized through normal protein degradation, the coagulation process, and other unknown pathways. At any moment, fibrinogen availability is delineated by the dynamic balance of synthesis and breakdown. Mathematically, fibrinogen availability can be expressed as:Where [fibrinogen] is the initial fibrinogen concentration (mg/dL); synthesis is the amount of fibrinogen (mg) produced in a unit of time (hour); and breakdown rate is the amount of fibrinogen (mg) consumed in a unit of time (hour).The importance of init
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