WO2015067915A1 - Biomarqueurs pour lésion cérébrale traumatique - Google Patents

Biomarqueurs pour lésion cérébrale traumatique Download PDF

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WO2015067915A1
WO2015067915A1 PCT/GB2014/000445 GB2014000445W WO2015067915A1 WO 2015067915 A1 WO2015067915 A1 WO 2015067915A1 GB 2014000445 W GB2014000445 W GB 2014000445W WO 2015067915 A1 WO2015067915 A1 WO 2015067915A1
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tbi
biomarker
map2
pnf
injury
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PCT/GB2014/000445
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English (en)
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Alun CARTER
Gareth David Griffiths
Stuart HARRISSON
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The Secretary Of State For Defence
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2871—Cerebrovascular disorders, e.g. stroke, cerebral infarct, cerebral haemorrhage, transient ischemic event

Definitions

  • the present invention relates to a subset of brain biomarkers for determining Traumatic Brain Injury (TBI), a method for screening a biological sample from a subject to determine whether the subject is suffering from traumatic brain injury, and an assay and kit for determining whether a subject is suffering from TBI.
  • TBI Traumatic Brain Injury
  • the brain is the major organ of the nervous system of all vertebrates and most invertebrates, acting to control a complex network of cell types and organs that coordinate motor output in response to sensory input.
  • the brain is the main sensory processor of the central nervous system (CNS), directing electrochemical signal impulses via the spinal cord to effector cells, such as muscles and glands, to generate a physiological response to a given environmental stimulus.
  • CNS central nervous system
  • effector cells such as muscles and glands
  • Communication between the CNS and effector cells is achieved via the peripheral nervous system (PNS), which comprises a network of nerves capable of conducting electrochemical signals.
  • Neurons are one of the primary cell types found in the brain, whilst collections of tightly bundled neurons and associated connective tissue make up the structure of nerves of the nervous system.
  • Neurons comprise an organelle-containing cell body and two types of extending fibres: dendrites, which conduct electrochemical signals towards the cell body; and axons, which conduct electrochemical signals away from the cell body to synaptic terminals.
  • dendrites which conduct electrochemical signals towards the cell body
  • axons which conduct electrochemical signals away from the cell body to synaptic terminals.
  • Axon are enclosed in an insulting layer of Schwann cells termed the myelin sheath and typically terminate at synaptic terminals which in turn communicate with other neurons or target cells via neurotransmitters released by the synapse.
  • the brain is protected by a layered structure in the form of bone, membrane and fluid which acts to minimise any possible damage.
  • the brain is encased in an outer layer of bone termed the skull or cranium, which provides protection against impact.
  • the dura mater, arachnoid membrane and pia mater three membranous layers termed the dura mater, arachnoid membrane and pia mater, known collectively as the meninges, provide a further lining for the brain.
  • the dura mater is situated as the outermost membranous layer, whilst the pia mater directly encloses the brain.
  • the arachnoid membrane is situated between the dura mater and pia mater. Further cushioning and immunological protection for the brain is provided by cerebrospinal fluid (CSF), a clear liquid found within the subarachnoid space between the arachnoid mater and pia mater.
  • CSF cerebrospinal fluid
  • a specialised network of closely-located capillaries termed the blood-brain barrier acts to ensure only certain molecules are able to pass into the brain.
  • Intracranial injury also known as TBI
  • TBI Intracranial injury
  • TBI is defined by the Demographics and Clinical Assessment Working Group of the International and Interagency Initiative towards Common Data Elements for Research on TBI and Psychological Health as 'an alteration in brain function, or other evidence of brain pathology, caused by an external force'.
  • TBI injury There is a prevalence of TBI injury to males of 3:1 , with violence associated with between 7-10% of TBI in civilian practice. Trauma is the leading cause of mortality in the under-35 ages group in England and Wales, with head injury said to account for half of trauma deaths. In Europe, the annual aggregate incidence of hospitalised and fatal TBI has been estimated at approximately 235 per 100,000 people, whilst in the USA there were 403/100,000 Emergency Department visits for TBI per annum and
  • TBI Although the rate of TBI is reducing in the young, the global incidence of TBI is increasing. Possible reasons for this include increased global use of motor vehicles, and the increasingly elderly nature of the general population suffering head injuries as a result of falls. In recent times, there has been renewed focus of the effect of TBI as a result of deployed military personnel sustaining head trauma as a consequence of exposure to explosive blasts. Indeed, it has been suggested that mild TBI is a novel signature injury for British and American troops deployed to Iraq and Afghanistan. In general, four types of blast injury have been described in relation to deployed
  • primary blast injuries relating to the over-pressure, also termed shock wave
  • secondary blast injury relating to primary and secondary fragments
  • tertiary blast injuries relating to the blast wind, also termed dynamic over-pressure
  • quaternary blast injuries relating to other injury mechanism
  • GSC Glasgow Coma Scale
  • CT Computerised Tomography
  • MRI Magnetic Resonance Imaging
  • EEG Electroencephalogram
  • ICP Intra-Cranial Pressure
  • a possible solution to determining TBI is to screen a biological sample, such as CSF or blood, for biomarkers indicative of TBI.
  • the term 'biomarker' as used herein is a biological characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathological processes or responses to a therapeutic intervention.
  • Biomarkers can be physical or biochemical measurements which can be used as a validated substitute for a clinical endpoint. Examples of biomarkers include certain cell types, proteins (for example enzymes, hormones, antibodies), gene products, genes or molecules that may indicate normal or abnormal biological processes or states.
  • Clinical screening for biomarkers may offer advantages that include earlier diagnosis of disease severity, allowing better prognostication and prediction of outcomes, and enable monitoring of on-going pathological processes and therapeutic interventions. Examples of biomarkers already used in other pathologies include Troponin-I after myocardial infarction or Prostate Specific Antigen in prostate cancer.
  • Biomarkers of TBI could potentially offer a high sensitivity and specificity for brain injury, if suitable biomarkers could be identified and assessed. Certain biomarkers may only be released after irreversible destruction of brain tissue, which could provide a good measure of TBI. Furthermore, biomarkers could allow for: better initial assessment of both mild and severe head injury in isolated head and polytrauma patients; monitoring of disease progression; and success of therapy (Neumar, R.W. (2002) Rule out TBI? Serum markers for traumatic brain injury. Ann Emerg Med, 39, 342-343;
  • biomarker of head injury Many attempts have been made to find a biomarker of head injury.
  • potential biomarkers such as Creatine Kinase, Glial Fibrillary Acidic Protein, Lactate Dehydrogenase, Myelin Basic Protein and S100 protein have all been studied to varying degrees of success (Ingebrigtsen, T. & Romner, B. (2002) Biochemical serum markers of traumatic brain injury. J Trauma, 52, 798-808; Kochanek, P.M. et al. (2008)
  • Phosphorylated Neurofilament-H has been identified as a biomarker of TBI (Zurek er a/. (201 1 ) Hyperphosphorylated neurofilament NF-H as a predictor of mortality after brain injury in children. Brain Injury, 25, 221 -226; Anderson er a/. (2008) The Phosphorylated Axonal Form of the Neurofilament Subunit NF-H (pNF- H) as a Blood Biomarker of Traumatic Brain Injury.
  • MAP2 Microtubule Associated Protein 2
  • PCT/US99/29023 ⁇ method for detecting neuronal cell damage by quantification of MAP-2 levels in biological fluids' A single ideal biomarker is, however, unlikely to exist as each head injury has a unique pattern with several different pathological pathways often acting at the same time.
  • the present invention thus aims to address the problem of identifying a small subset of brain biomarkers for determining traumatic brain injury, and more specifically a small subset of brain biomarkers capable of providing a reliable prognosis for instances of TBI.
  • a method for screening a biological sample from a subject to determine whether the subject is suffering from TBI comprising the steps of measuring the concentration of an axonal-associated neuronal biomarker and a dendritic-associated neuronal biomarker; and comparing the concentration of each biomarker with a respective control threshold concentration; wherein a concentration higher than its respective control threshold concentration is indicative of TBI.
  • the term 'biological sample' in relation to the present invention refers to a sample suitable for screening to determine whether the subject is suffering from TBI and includes, but not exclusively, CSF, blood or samples derived thereof (for example whole blood, plasma, serum, cell-free serum, cell-free plasma), tissues, cells, saliva, transpired secretion, urine, faeces, stomach fluid, digestive fluid, nasal fluid, cytosolic fluid or other biological tissue or fluid .sample recognised in the art.
  • the term 'subject' in relation to the present invention includes, but not exclusively, any person or other animal that; in particular, is in need or thought to be in need of being assessed to determine whether said person or other animal is suffering from TBI.
  • the Applicant has identified that neuronal damage to axons and dendrites are key elements to TBI, and that in some cases damage to one type of fibre may be more apparent than the other. Potentially one type of fibre may be affected independent of the other.
  • This characteristic has been exemplified by screening a biological sample for the presence and/or elevated concentration of an axonal-associated neuronal biomarker (pNF-H) and a dendritic-associated neuronal biomarker (MAP2), compared with respective control threshold concentrations for each biomarker.
  • pNF-H axonal-associated neuronal biomarker
  • MAP2 dendritic-associated neuronal biomarker
  • Screening a biological sample which has already been obtained from a subject, potentially circumvents the need for expensive techniques such as radiological-based methods (for example CT, MRI) for screening, wherein the nature of such complex or expensive techniques often allows only a minimum number of investigations to be performed, thus gaining only a limited snapshot of the clinical picture.
  • Screening of a biological sample offers a simpler means to determine whether a subject may be suffering from TBI, and monitoring changes in at least two categories of brain biomarker allows the evolution of the TBI to be followed.
  • the method provides a simple means for determining whether a subject is suffering from TBI. Given the many varied circumstances in which a subject can succumb to TBI, as well as the many potential biomarkers associated with the nervous system, this present invention has shown that a method comprising a simple combination of a minimum of two biomarkers from different cellular locations (i.e. axons and dendrites) is capable of indicating TBI in a biological sample from a subject. Evaluating biomarkers from at least two different locations within the brain allows a more global assessment of TBI to be conducted.
  • a higher concentration of either or both of an axonal-associated neuronal biomarker and a dendritic-associated neuronal biomarker, relative to the respective control threshold concentration for each biomarker, is indicative of TBI.
  • a method for screening a biological sample from a subject to determine whether the subject is suffering from TBI comprising the steps of measuring the concentration of two biomarkers consisting of an axonal-associated neuronal biomarker and a dendritic-associated neuronal biomarker; and comparing the concentration of two biomarkers consisting of an axonal-associated neuronal biomarker and a dendritic-associated neuronal biomarker; and comparing the concentration of two biomarkers consisting of an axonal-associated neuronal biomarker and a dendritic-associated neuronal biomarker; and comparing the concentration of two biomarkers consisting of an axonal-associated neuronal biomarker and a dendritic-associated neuronal biomarker; and comparing the concentration of two biomarkers consisting of an axonal-associated neuronal biomarker and a dendritic-associated neuronal biomarker; and comparing the concentration of two biomarkers consisting of an axonal
  • This embodiment of the present invention is advantageous as it offers a further simplified method for screening a biological sample from a subject to determine whether the subject is suffering from TBI.
  • the axonal-associated neuronal biomarker is phosphorylated Neurofilament-H (pNF-H) and the dendritic- associated neuronal biomarker is Microtubule Associated Protein 2 (MAP2).
  • pNF-H is the largest of three neurofilament subunits that comprise the neuronal cyctoskeleton which assists the structural integrity of the axon.
  • the molecular weight of mammalian pNF-H is approximately 120 kDa.
  • MAP2 is located in dendrites of neurons and is considered to play a role in the assembly of microtubules, via the cross-linking with intermediate filaments, to lead to the production of the cytoskeleton, which in turn provides the scaffolding network that assists intracellular function and cell division.
  • Mammalian MAP2 exists as different isoforms which can be grouped, for example, according to molecular weight: high molecular weight MAP2 includes MAP2A (280 KDA) and MAP2B (270 kDa); and low molecular weight MAP2 includes MAP2C (70 kDA) and MAP2D (75 kDa).
  • the term 'MAP2' in relation to the present invention refers to at least one MAP2 isoform from MAP2 isoforms that include MAP2A, MAP2B, MAP2C and MAP2D:
  • This embodiment of the present invention is advantageous as the combination of pNF-H and MAP2 has been shown to be particularly effective at indicating TBI.
  • a higher concentration of either or both pNF-H and MAP2, relative to the respective control threshold concentration for each biomarker. is indicative of TBI.
  • the Applicant has shown herein that although there can be a lack of correlation between elevated concentrations of pNF-H and MAP2, relative to respective control thresholds, which the Applicant attributes to different cellular locations of the brain being affected, the combination of both biomarkers can capture the majority of cases of TBI with a high predictive accuracy.
  • the biological sample may be blood (or derived thereof) or CSF.
  • Blood and especially CSF are excellent sources of biomarkers that are indicative of brain activity, or damage to the brain.
  • Blood or samples derived thereof include, but not exclusively, whole blood, plasma, serum, cell-free serum or cell-free plasma.
  • the pNF-H control threshold concentration may be 327.4 ng/ml and the MAP2 control threshold
  • concentration may be 0.08 pg/ml.
  • This embodiment of the present invention is advantageous in that it provides a quantitative control threshold for pNF-H and MAP2 in CSF.
  • a CSF sample with a pNF-H concentration higher than 327.4 ng ml and/or a MAP2 concentration higher than 0.08 pg/ml would indicate TBI.
  • the pNF-H control threshold concentration may be 253.6 ng/ml and the MAP2 control threshold concentration may be 318.1 pg/ml.
  • This embodiment is advantageous in that it provides a quantitative control threshold for pNF-H and MAP2 in blood or samples derived thereof.
  • a blood sample or sample derived thereof with a pNF-H concentration higher than 253.6 ng/ml and/or a MAP2 concentration higher than 318.1 pg/ml would indicate TBI.
  • an assay for determining whether a subject is suffering from TBI comprising recognition elements specific for an axonal-associated neuronal biomarker and a dendritic-associated neuronal biomarker.
  • the term 'assay' in relation to the present invention refers to a qualitative or quantitative investigation, in particular for determining the presence or concentration of an axonal- associated neuronal biomarker and a dendritic-associated neuronal biomarker in a biological sample taken from a subject to determine whether the subject is suffering from TBI.
  • assays include, but not exclusively, assays well known to those skilled in the art, for example radio-labelled assays, electrochemical assays, surface plasmon resonance (SPR) assays, mass spectrometry assays and immunoassays.
  • 'mass spectrometry' assays includes, but not exclusively, immunoaffinity Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) assays and peptide Multiple Reaction Monitoring (MRM) on protein or immune-enriched proteins or samples that have undergone immune-adsorption-based depletion.
  • LC-MS/MS immunoaffinity Liquid Chromatography-Mass Spectrometry/Mass Spectrometry
  • MRM Multiple Reaction Monitoring
  • immunoassay includes, but not exclusively, Western blotting, Enzyme-Linked Immunosorbant Assays (ELISAs), lateral flow devices, flow cytometry and
  • recognition elements in relation to the present invention refers to an assay component capable of binding or interacting with a specific target analyte.
  • Recognition elements include, but not exclusively, such elements known to those skilled in the art, for example proteins, polypeptides, peptides, antibodies (such as monoclonal or polyclonal antibodies), enzymes, small molecules, deoxyribose nucleic acid (DNA) or ribonucleic acid (RNA) polynucleotides, synthetic polymers, cells or tissue.
  • the term 'specific target analyte' in relation to the present invention includes, but not exclusively, an axonal-associated neuronal biomarker and a dendritic-associated neuronal biomarker.
  • the axonal-associated neuronal biomarker biomarker is pNF-H and the dendritic-associated neuronal biomarker is MAP2.
  • the recognition elements comprise a reporter element.
  • reporter element' in relation to the present invention refers to an assay component that provides a detectable signal representing a binding or interaction event between a recognition element and a specific target analyte.
  • Reporter elements include, but not exclusively, such elements known to those skilled in the art, for example chromogens, fluorophores, contrast agents, bioluminescent molecules, adsorptive molecules, reflective molecules and radioactive isotopes.
  • the recognition elements comprise aptamers.
  • aptamer' in relation to the present invention refers to a nucleic acid or peptide ligand capable of binding or interacting with specific target analyte.
  • aptamer includes, but not exclusively, such elements known to those skilled in the art, for example DNA, modified DNA, single strand DNA, modified DNA, RNA, modified RNA and peptide aptamers.
  • kits for determining whether a subject is suffering from TBI comprising one or more reagent solutions comprising recognition elements specific for an axonal-associated neuronal biomarker and a dendritic-associated neuronal biomarker.
  • 'kit' in relation to the present invention refers to a laboratory-ready or fieldable qualitative or quantitative investigation, in particular for determining the presence or concentration of an axonal-associated neuronal biomarker and a dendritic-associated neuronal biomarker in a biological sample taken from a subject to determine whether the subject is suffering from TBI.
  • the axonal-associated neuronal biomarker is pNF- H and the dendritic-associated neuronal biomarker is MAP2.
  • the recognition elements comprise a reporter element.
  • the recognition elements comprise aptamers.
  • FIG. 1 is a graph showing the results for pNF-H and MAP2 concentrations in CSF from brain injury and control patients
  • FIG. 2 is a graph showing the results for pNF-H and MAP2 concentration in blood plasma from brain injury and control patients.
  • the study was designed to focus on a comparison of patients with severe brain injury (study group) compared to those with no head injury (control group).
  • the study group consisted of patients who had suffered a severe head injury requiring admission to an Intensive Care Unit, assessed on the Glasgow Coma Scale (GCS) as being ⁇ 8 or those who were felt likely to deteriorate to a GCS ⁇ 8 with evidence of injury on imaging, and were subsequently managed within the first 72 hours of injury on the Neurolntensive Care Unit. Patients had to need to have insertion of an External GCS ⁇ 8 or those who were felt likely to deteriorate to a GCS ⁇ 8 with evidence of injury on imaging, and were subsequently managed within the first 72 hours of injury on the Neurolntensive Care Unit. Patients had to need to have insertion of an External
  • ETD Ventricular Drain
  • the control group patients were initially those patients admitted for pituitary surgery and having a lumbar drain (LD) inserted as part of their routine care. Patients with pituitary tumours were chosen as their pathology does not involve neurological tissue and therefore was felt to be less likely to provide a false positive result (as opposed to patients with other neurological conditions requiring lumbar drain or lumbar puncture, for example Normal Pressure Hydrocephalus or Idiopathic Intra-cranial Hypertension, where there is a theoretical risk of ongoing neurological injury which may provide a false negative result).
  • the control group was then further broadened to include those patients admitted for repair of CSF leak, requiring LD insertion, who had no recent (defined as within six months) history of head injury or meningitis. The change was necessary as after opening recruitment to the trial, the number of suitable candidates was only one in the first eight months.
  • Each blood sample was 5 ml drawn into a citrated blood vacutainer tube. In control cases only a single sample was taken, whereas for head injury patients up to four samples could be taken. It was therefore envisaged a maximum blood volume taken in a 72 hour period would be 20 ml, which would have no detectable physiological effect on the head injury patient. Control CSF samples were taken from material which would normally be discarded as part of clinical investigations. The volume of CSF was limited to 2 ml per sample in head injury patients, with a maximum volume of 8 ml over 48 hours. This would be taken from expected EVD drainage.
  • patients with brain injury have elevated concentrations of either pNF-H or MAP2, or both biomarkers, in CSF which is indicative of either axonal damage (pNF-H) and/or dendritic damage (MAP2).
  • pNF-H axonal damage
  • MAP2 dendritic damage
  • FIG. 1 and 2 suggest that different cellular locations of the brain can be affected to different extents by TBI, for example axonal damage may result independent of neuronal damage, as is illustrated by the results for expression of pNF-H (elevated by axonal damage) and MAP2 (elevated by dendritic damage).
  • pNF-H elevated by axonal damage
  • MAP2 elevated by dendritic damage
  • Control threshold concentrations in CSF and plasma samples were determined by taking the upper 95% Confidence Index of the negative control values.

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Abstract

La présente invention concerne une méthode, un dosage et un kit pour déterminer si un sujet souffre d'une Lésion Cérébrale Traumatique (LCT), au moyen de biomarqueurs indicatifs de TBI.
PCT/GB2014/000445 2013-11-05 2014-11-05 Biomarqueurs pour lésion cérébrale traumatique WO2015067915A1 (fr)

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Citations (3)

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WO2005106038A2 (fr) * 2004-04-15 2005-11-10 University Of Florida Research Foundation, Inc. Neuro-proteines utilisees comme biomarqueurs pour deceler une lesion du systeme nerveux et d'autres troubles neurologiques
US9929023B2 (en) 2015-11-19 2018-03-27 Samsung Electronics Co., Ltd. Method of manufacturing semiconductor device

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Publication number Priority date Publication date Assignee Title
WO2000034336A1 (fr) * 1998-12-09 2000-06-15 Zemlan Frank P Procede de detection de lesions de cellules nerveuses par quantification des niveaux de map-2 dans des fluides biologiques
WO2005106038A2 (fr) * 2004-04-15 2005-11-10 University Of Florida Research Foundation, Inc. Neuro-proteines utilisees comme biomarqueurs pour deceler une lesion du systeme nerveux et d'autres troubles neurologiques
US9929023B2 (en) 2015-11-19 2018-03-27 Samsung Electronics Co., Ltd. Method of manufacturing semiconductor device

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Title
ANDERSON ET AL.: "The Phosphorylated Axonal Form of the Neurofilament Subunit NF-H (pNF-H) as a Blood Biomarker of Traumatic Brain Injury", JOURNAL OF NEUROTRAUMA, vol. 25, 2008, pages 1079 - 1085
INGEBRIGTSEN, T.; ROMNER, B.: "Biochemical serum markers of traumatic brain injury", J TRAUMA, vol. 52, 2002, pages 798 - 808
KEVIN J. ANDERSON ET AL: "The Phosphorylated Axonal Form of the Neurofilament Subunit NF-H (pNF-H) as a Blood Biomarker of Traumatic Brain Injury", JOURNAL OF NEUROTRAUMA, vol. 25, no. 9, 1 September 2008 (2008-09-01), pages 1079 - 1085, XP055162462, ISSN: 0897-7151, DOI: 10.1089/neu.2007.0488 *
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ZUREK ET AL.: "Hyperphosphorylated neurofilament NF-H as a predictor of mortality after brain injury in children", BRAIN INJURY, vol. 25, 2011, pages 221 - 226

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