WO2018228935A1 - Améliorations apportées au diagnostic d'un accident vasculaire cérébral - Google Patents

Améliorations apportées au diagnostic d'un accident vasculaire cérébral Download PDF

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Publication number
WO2018228935A1
WO2018228935A1 PCT/EP2018/065142 EP2018065142W WO2018228935A1 WO 2018228935 A1 WO2018228935 A1 WO 2018228935A1 EP 2018065142 W EP2018065142 W EP 2018065142W WO 2018228935 A1 WO2018228935 A1 WO 2018228935A1
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Prior art keywords
stroke
mimic
tia
patient
reference value
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PCT/EP2018/065142
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English (en)
Inventor
Ivan McConnell
Ciaran RICHARDSON
Peter Fitzgerald
Paul Innocenzi
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Randox Laboratories Ltd
Randox Teoranta
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Priority to EP18729430.1A priority Critical patent/EP3639036A1/fr
Publication of WO2018228935A1 publication Critical patent/WO2018228935A1/fr

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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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/54—Interleukins [IL]
    • G01N2333/5412—IL-6
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/715—Assays involving receptors, cell surface antigens or cell surface determinants for cytokines; for lymphokines; for interferons
    • G01N2333/7151—Assays involving receptors, cell surface antigens or cell surface determinants for cytokines; for lymphokines; for interferons for tumor necrosis factor [TNF]; for lymphotoxin [LT]
    • 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

  • Stroke is the third leading cause of death worldwide and can be defined as the rapidly developing loss of brain function(s) due to interruption in the blood supply to the brain. According to the World Health Organization, 15 million people per year suffer stroke worldwide, with 5 million dying and a further 5 million being permanently disabled. High blood pressure is estimated to be a contributing factor in 12.7 million of these 15 million stroke cases. In the UK, approximately 150,000 people have a stroke each year and stroke accounts for around 53,000 deaths per year. Stroke costs the economy an estimated £8 billion per year in England alone and stroke patients occupy approximately 20 per cent of all acute hospital beds and 25 per cent of long term beds.
  • Ischaemic stroke occurs when blood supply to the brain is decreased, resulting in brain damage.
  • An ischemic stroke occurs when a blood vessel becomes blocked, usually via a blood clot. This clot may form locally at an atherosclerotic plaque (thrombotic stroke) or alternatively may occur due to a travelling particle or debris that has originated from elsewhere in the bloodstream (embolic stroke);
  • Transient ischaemic attack is a 'mini stroke' that occurs when blood supply to the brain is temporarily decreased.
  • a TIA is diagnosed if symptoms are quickly resolved (within 24 hours with the individual returning to normal health); and iii) Haemorrhagic stroke (HS) occurs when blood accumulates within the skull vault, usually when a weakened blood vessel ruptures.
  • Haemorrhagic stroke can be classified into two major subtypes, namely intracerebral (within the brain tissue) and subarachnoid (around the surface of the brain and under its protective layer). IS and TIA account for approximately 85% of all stroke cases and HS accounts for 15%. To minimise neurological damage following stroke it is crucial that stroke patients are rapidly and accurately diagnosed, so that appropriate treatment can be administered.
  • thrombolytic therapy such as tissue plasminogen activator (TPA) can be administered.
  • TPA tissue plasminogen activator
  • TIA tissue plasminogen activator
  • blood thinners such as warfarin and aspirin are prescribed in such cases.
  • CT computerised tomography
  • a CT scan has good sensitivity for identifying HS patients (approximately 90% sensitivity) but poor sensitivity for identifying IS and TIA patients (approximately 20% sensitivity). In practise minimal or no tissue damage occurs for TIA due to its transient nature, therefore CT scanning is ineffective as a diagnostic technique.
  • Magnetic Resonance Imaging has improved sensitivity for IS diagnosis (up to approximately 80%) but increased time requirements, machine accessibility, and high cost have limited its use for stroke diagnosis.
  • the poor sensitivity of CT scanning for the detection of IS and TIA means that a biological fluid-based diagnostic biomarker tests for detecting IS and/or TIA would be an invaluable tool to aid clinicians in the diagnosis of stroke sub-type.
  • Biological fluid-based biomarkers have the potential to expedite and increase the accuracy of IS and TIA diagnosis; of particular importance is the diagnosis of IS, as this condition has immediate life-debilitating and life-threatening potential that can be counter-acted by the administration of clot-busting drugs such as TPA.
  • a first aspect of the invention provides a method of aiding the diagnosis of IS, comprising measuring the level one or more of h-FABP, D-dimer, IL-6 and sTNFRI in an ex vivo sample of a patient who has suffered, is suffering or is suspected of suffering from a stroke and comparing this level to a reference sample value in which a measured level in the patient sample that is greater than the reference value is indicative of IS characterised by the reference value of one or more of h-FABP, D-dimer, IL-6 and sTNFRI being derived from its or their level in a patient cohort of stroke mimics or combined stroke mimics and TIA.
  • Figure 1 shows the patient distribution for h-FABP and D-dimer for the various groups
  • 'stroke' encompasses all three forms of stroke.
  • IS ischaemic stroke
  • An ischemic stroke occurs when a blood vessel becomes blocked, usually via a blood clot. This clot may form locally at an atherosclerotic plaque (thrombotic stroke) or alternatively may occur due to a travelling particle or debris that has originated from elsewhere in the bloodstream (embolic stroke).
  • TIA transient ischaemic attack
  • a TIA is diagnosed if symptoms are quickly resolved (within 24 hours with the individual returning to normal health).
  • the term 'haemorrhagic stroke (HS)' occurs when blood accumulates within the skull vault, usually when a weakened blood vessel ruptures.
  • Haemorrhagic stroke can be classified into two major sub-types: intracerebral (within the brain tissue); and subarachnoid (around the surface of the brain and under its protective layer).
  • a 'stroke mimic' is defined as an event that is stroke-like in its effect on a patient but is in fact an event other than a HS, IS or TIA.
  • References herein to 'a patient who has suffered or is suffering a stroke or stroke-like symptoms' include a patient who has been diagnosed as currently suffering from a stroke or who is or has recently had a stroke (within ⁇ 6 hours). That the stroke may have been a recent event initiated the process of the individual, or someone on behalf of the individual, seeking clinical help.
  • 'differentiating stroke' means that specific stroke conditions TIA, IS and HS can be delineated when a patient presents having had or with a stroke condition.
  • subject and patient may be used interchangeably herein and refer to a mammal including a non-primate (e.g. a cow, pig, horse, dog, cat, rat and mouse) and a primate (e.g. a monkey and human).
  • a non-primate e.g. a cow, pig, horse, dog, cat, rat and mouse
  • a primate e.g. a monkey and human
  • the subject or patient is a human.
  • the term 'biomarker' refers to a molecule present in a biological sample obtained from a patient, the concentration of which in said sample may be indicative of a pathological state.
  • the biological sample obtained from a patient is preferably a blood, serum or plasma sample.
  • the term 'ex vivo' has its usual meaning in the art and refers to a sample that has been removed from a patient's body. When a blood sample is taken from the patient for analysis, whole blood, serum or plasma is analysed.
  • Analysis of the blood sample can be by way of several analytical methodologies such as mass spectrometry linked to a pre-separation step such as chromatography.
  • the preferred methodology is based on immuno-detection. Immuno-detection technology is also readily incorporated into transportable or hand-held devices for use outside of the clinical environment.
  • a quantitative immunoassay such as a Western blot or ELISA can be used to detect the amount of protein.
  • a preferred method of analysis comprises using a multi-analyte biochip which enables several proteins to be detected and quantified simultaneously.
  • a biochip is a planar substrate that may be, for example, mineral or polymer based, but is preferably ceramic.
  • Probes are adsorbed on or chemically attached to the surface of the biochip.
  • the probes can be any biomarker-specific probe or binding ligand.
  • the term 'specific' means that the probe binds only to one of the biomarkers of the invention, with negligible binding to other biomarkers of the invention or to other analytes in the biological sample being analysed. This ensures that the integrity of the diagnostic assay and its result using the biomarkers of the invention is not compromised by additional binding events.
  • identifying the various biomarkers of the invention it will be apparent to the skilled person that as well as identifying the full-length protein, the identification of a fragment or several fragments of a protein is possible, provided this allows accurate identification of the protein.
  • a preferred probe of the invention is a polyclonal or monoclonal antibody
  • other probes such as aptamers, molecular imprinted polymers, phages, short chain antibody fragments and other antibody-based probes
  • a solid-state device is used in the methods of the present invention, preferably the Biochip Array Technology system (BAT) (available from Randox Laboratories Limited). More preferably, the Evidence Evolution and Evidence Investigator apparatus (available from Randox Laboratories) may be used to determine the levels of biomarkers in the sample. 2D Gel Electrophoresis is also a technique that can be used for multi-analyte analysis.
  • D-dimer refers to the fibrin degradation product.
  • sTNFRV as used herein refers to soluble Tumour Necrosis Factor Receptor 1 (UniProt P19438).
  • IL-6 as used herein refers to interleukin 6 (UniProt P05231 ).
  • PARK7 as used herein refers to Parkinson disease protein 7, also known as DJ-1 (UniProt Q99497).
  • FBP3 as used herein refers to fatty acid-binding protein 3 (UniProt P05413).
  • GFAP as used herein refers to Glial fibrillary acid protein (UniProt P14136).
  • GSTP Glutathione S-transferase P
  • NDKA Nucleoside diphosphate kinase A
  • classification algorithms include multinominal logistic regression, multilayer perceptron neural network (MLP), artificial neural networks, support vector machines, N Bayes classification and random forest classifiers.
  • MLP multilayer perceptron neural network
  • the present inventors have found that both multinominal logistic regression and Na ' ive Bayes Classification achieve similar performance in the context of the present invention, suggesting the importance of the analytes (i.e. biomarkers) used in the methods of the invention, rather than the method used to generate the algorithmic model.
  • the statistical algorithm includes Na ' ive (N) Bayes classification. The accuracy of statistical methods used in accordance with the present invention can be best described by their receiver operating
  • ROC ROC characteristics
  • the ROC curve addresses both the sensitivity, the number of true positives, and the specificity, the number of true negatives, of the test. Therefore, sensitivity and specificity values for a given combination of biomarkers are an indication of the accuracy of the assay. For example, if a biomarker combination has sensitivity and specificity values of 80%, out of 100 patients which have stroke, 80 will be correctly identified from the determination of the presence of the particular combination of biomarkers as positive for stroke, while out of 100 patients who have not suffered a stroke 80 will accurately test negative for the disease. Sensitivity and specificity values are defined by the cut-off value assigned to the biomarker - depending upon the sensitivity or specificity required in an assay i.e.
  • a suitable mathematical model such as logistic regression equation
  • the logistic regression equation might include other variables such as age and gender of patient.
  • the ROC curve can be used to assess the accuracy of the logistic regression model.
  • the logistic regression equation can be used independently or in an algorithm to aid clinical decision making. Although a logistic regression equation is a common mathematical/statistical procedure used in such cases and is preferred in the context of the present invention, other mathematical/statistical procedures can also be used.
  • the invention describes a method of diagnosing or differentiating stroke comprising measuring the level of one or more of the biomarkers h-FABP, D-dimer, sTNFRI and IL-6 in a sample taken from a patient who has suffered or is suffering stroke-like symptoms and comparing the measured level to a
  • reference value characterised by the reference value being derived from a stroke mimic patient cohort and/or a TIA patient cohort; in a preferred embodiment the reference value is derived from either a stroke mimic patient cohort or a combined stroke mimic and TIA patient cohort.
  • the reference value or control value is the level or concentration of the biomarker (h-FABP, D-dimer, sTNFRI or IL-6) measured in samples taken from (i.e. an ex vivo or in vitro sample) patients (subjects) of a cohort (group) who are suffering or have recently suffered from a stroke mimic event and/or TIA. It is preferred that the reference value is derived from samples taken from a combined stroke mimic and TIA patient cohort; this allows ischaemic stroke to be differentiated from stroke mimic events and TIAs and supports a more informed decision on the administration of thrombolytic therapy (e.g. tissue plasminogen activator or ⁇ ') to IS patients.
  • thrombolytic therapy e.g. tissue plasminogen activator or ⁇ '
  • the reference value is derived from samples taken from a stroke mimic patient cohort; this enables the more accurate discrimination of IS and stroke mimic patients.
  • the diagnosis of the patient's condition the diagnosis can be improved through a combination of information derived from the biomarker measurements and clinician examination and the application of authoritative clinical stroke diagnosis guidelines (see Methods).
  • the level of the biomarkers h-FABP, D-dimer, sTNFRI and IL-6 have all been found to increase in patients suffering from or have recently suffered IS compared to patients suffering from or have recently suffered a stroke mimic or TIA.
  • the invention describes the diagnosis or differentiation of stroke comprising measuring the level of one or more of the biomarkers h-FABP, D-dimer, sTNFRI and IL-6 in a sample taken from a patient who has suffered or is suffering stroke-like symptoms and comparing the measured level or levels to a corresponding reference value which is derived from a stroke mimic patient cohort, a TIA patient cohort or a combined stroke mimic +TIA patient cohort, in which the reference values are about 40%, 60%, 63% and 6% greater for h-FABP, D-dimer, sTNFRI and IL-6 , respectively, than a corresponding HC value; the slight fluctuation of measured biomarker values due to factors such as assay platform, inter-run variability, inter- operator variability etc.
  • a further aspect of the invention is a method of diagnosing or differentiating stroke in a patient who has suffered or is suffering stroke-like symptoms comprising taking a sample from the patient and determining the sample concentration of one or more of h-FABP, D-dimer, sTNFRI and IL-6 in which the following concentrations ('cut-off' concentration) taken individually support the diagnosis of IS in the patient: h-FABP ⁇ about 4.70 ng/ml, D- dimer ⁇ about 200 ng/ml, sTNFRI ⁇ about 2.30 pg/ml, IL-6 ⁇ about 5.90 pg/ml.
  • cut-offs are displayed in Table 2 and are based on the ROC curves derived using stroke mimics and stroke mimics + TIA populations as the control group.
  • the problem using healthy controls as the reference population to derive the ROC curve is that the cut-off values are reduced resulting in an increase in the number of false stroke diagnoses i.e. an increase in stroke mimic and TIA patients being diagnosed as IS.
  • any suitable patient sample type such as urine, saliva, tears, hair, cerebrospinal fluid (CSF) can be used but preferably the sample type is blood, serum or plasma.
  • the invention describes a method of determining whether to administer thrombolytic therapy to a patient who has suffered or is suffering strokelike symptoms comprising ruling out haemorrhagic stroke and measuring the level of one or more of h-FABP, D-dimer, sTNFRI and IL-6 in a sample taken from the patient and comparing it to a reference value in which an amount of one or more of h-FABP, D-dimer, sTNFRI and IL-6 which is greater than the reference value is indicative of an ischaemic stroke and therefore administering thrombolytic therapy, in which the reference value is derived from a stroke mimic patient cohort or a stroke mimic and/or a TIA patient cohort; a stroke mimic or a stroke mimic + TIA reference value is especially preferred.
  • HS can be ruled out using one or more of a patient sample GFAP biomarker measurement, a neuroimaging technique such as a CAT scan or MRI and face to face diagnosis by clinician. If as a result of carrying out the method of the invention it is determined that the patient has not suffered, or is not suffering, an IS or HS, further investigations can be made and blood thinners such as warfarin and aspirin may be prescribed and administered if necessary i.e. if TIA is diagnosed. If as a result of carrying out the method of the invention it is determined that the patient has suffered, or is suffering, a HS then these patients would typically be sent to a surgical unit to repair the damaged blood vessels.
  • a stroke mimic and/or a TIA patient cohort sample biomarker measurement value as a reference value in an assay for stroke diagnosis or differentiation, especially IS diagnosis or differentiation using a stroke mimic or stroke mimic + TIA patient cohort reference value is thus clearly outlined, especially in relation to the biomarkers h-FABP, D-dimer, IL-1 and sTNFRI .
  • mRS modified Rankin scale
  • Clinical evaluation using criteria highlighted in the background section above
  • neuroimaging techniques identified 10 haemorrhagic stroke (HS), 53 ischaemic stroke (IS), 13 transient ischaemic attack (TIA) and 37 stroke mimics (M); 79 healthy subjects served as controls (C).
  • the following proteins were tested against EDTA plasma samples of blood obtained from the patients of the study group: h-FABP, D-dimer, GFAP, NDKA, IL-6, PARK-7, GSTPi and sTNFRL
  • the proteins were detected and quantified using multiplexed biochips incorporating biomarker-specific antibodies and the Evidence Investigator (Randox Laboratories Ltd, Crumlin, UK).
  • the simultaneous immunoassays were performed according to manufacturer's instructions. A nine-point calibration curve and three reference controls were assayed for each biomarker to allow validation of results.
  • Table 1 Statistical analysis of healthy control cohort (HC) vs stroke mimic cohort (mimics) and ischaemic stroke cohort vs HC, mimics and TIA + mimics.
  • GFAP is a specific biomarker of HS and can be incorporated in an analysis of stroke or suspected stroke, enabling HS to be ruled in or ruled out; alternatively, or in addition a brain scan can be used to rule in or rule out HS. Rule out of HS allows IS assessment incorporating a reference value derived from stroke mimic values and/or TIA values using one or more of the stroke biomarkers of Table 1 .
  • IL-6 (pg/ml) 1.00 1.71 71 % 1.00 3.02 202% 5.98 6.07 sTNFRI (ng/ml) 1.48 1.59 7% 1.48 1.66 12% 2.37 2.55

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Abstract

Le changement de normes de référence conduit à des procédés améliorés basés sur des biomarqueurs de diagnostic d'accident vasculaire cérébral.
PCT/EP2018/065142 2017-06-14 2018-06-08 Améliorations apportées au diagnostic d'un accident vasculaire cérébral WO2018228935A1 (fr)

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GB1709474.9A GB2563414A (en) 2017-06-14 2017-06-14 Improvements in stroke diagnostics

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022219040A1 (fr) * 2021-04-15 2022-10-20 Fundació Hospital Universitari Vall D'hebron - Institut De Recerca Marqueurs pour diagnostiquer l'occlusion de gros vaisseaux sanguin

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EP2166358A1 (fr) * 2008-09-17 2010-03-24 Fundacio Institut de Recerca de l'Hospital Universitari Vall d'Hebron Biomarqueurs de diagnostic différentiel de conditions simulant l'accident vasculaire cérébral et ses procédés d'utilisation
WO2013079981A2 (fr) * 2011-12-02 2013-06-06 Randox Laboratories Ltd Procédés basés sur des marqueurs biologiques et biopuces pour aider au diagnostic d'un accident vasculaire cérébral
WO2014195698A1 (fr) * 2013-06-04 2014-12-11 Randox Laboratories Ltd. Procédé pour faciliter le diagnostic différentiel d'accident vasculaire cérébral
WO2017011329A1 (fr) * 2015-07-10 2017-01-19 West Virginia University Marqueurs d'accident vasculaire cérébral et de gravité d'accident vasculaire cérébral

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Publication number Priority date Publication date Assignee Title
EP2166358A1 (fr) * 2008-09-17 2010-03-24 Fundacio Institut de Recerca de l'Hospital Universitari Vall d'Hebron Biomarqueurs de diagnostic différentiel de conditions simulant l'accident vasculaire cérébral et ses procédés d'utilisation
WO2013079981A2 (fr) * 2011-12-02 2013-06-06 Randox Laboratories Ltd Procédés basés sur des marqueurs biologiques et biopuces pour aider au diagnostic d'un accident vasculaire cérébral
WO2014195698A1 (fr) * 2013-06-04 2014-12-11 Randox Laboratories Ltd. Procédé pour faciliter le diagnostic différentiel d'accident vasculaire cérébral
WO2017011329A1 (fr) * 2015-07-10 2017-01-19 West Virginia University Marqueurs d'accident vasculaire cérébral et de gravité d'accident vasculaire cérébral

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022219040A1 (fr) * 2021-04-15 2022-10-20 Fundació Hospital Universitari Vall D'hebron - Institut De Recerca Marqueurs pour diagnostiquer l'occlusion de gros vaisseaux sanguin

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