Biomarkers for acute ischemic stroke
Inventors
Barr, Taura L. • Matarin, Maria Del Mar • Warach, Steven Jay • Singleton, Andrew Barry • Conley, Yvette P.
Assignees
University of Pittsburgh • US Department of Health and Human Services
Publication Number
US-9200322-B2
Publication Date
2015-12-01
Expiration Date
2031-02-22
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Abstract
The present invention provides methods and compositions for the diagnosis of acute ischemic stroke. The invention further provides methods and compositions for distinguishing acute ischemic stroke from other forms of stroke and TIAs and “stroke mimic” events. Moreover, methods and compositions are provided to facilitate the treatment of acute ischemic stroke patients.
Core Innovation
The invention relates to the identification and use of diagnostic biomarkers for acute ischemic stroke. It provides methods and compositions for rapid, sensitive, and specific diagnosis of acute ischemic stroke in patients, distinguishing it from other forms of stroke such as hemorrhagic stroke, transient ischemic attacks (TIAs), and stroke mimics. The invention further includes compositions useful for detecting these biomarkers and facilitating treatment, including enabling treatment decisions such as administration of recombinant tissue plasminogen activator (rtPA).
The underlying problem addressed is the difficulty and inaccuracy of diagnosing acute ischemic stroke due to limitations in current evaluation technologies and varied expertise among clinicians, particularly given that rapid diagnosis is critical for effective treatment. Existing imaging technologies like CT and MRI have limitations including lack of sensitivity, availability, or interpretative expertise, resulting in delayed or missed diagnoses and limited use of effective therapies such as rtPA, which must be administered within a short therapeutic window. Furthermore, prior to this invention, appropriate blood biomarkers for ischemic stroke diagnosis have been elusive due to slow release of brain proteins into blood, confounding factors from other conditions, and insufficient sensitivity and specificity in known markers.
Claims Coverage
The patent claims include multiple independent claims directed to methods for diagnosing acute ischemic stroke using specific biomarker panels in biological samples, primarily employing immunoassays, including filament-based immunoassays. The claims focus on diagnostic methods using panels of identified biomarkers and their use in differential diagnosis and treatment guidance.
Diagnostic method using a panel including four specific biomarkers
A method diagnosing acute ischemic stroke by obtaining a biological sample, extracting total RNA, and determining expression of a panel of biomarkers by biomarker-specific antibody immunoassay, wherein the panel includes at least chemokine receptor 7 (CCR7), chondroitin sulfate proteoglycan 2 (CSPG2), IQ motif-containing GTPase activation protein 1 (IQGAP1), and orosomucoid 1 (ORM1). Expression of these biomarkers indicates acute ischemic stroke.
Diagnostic method using a panel including nine specific biomarkers via filament-based immunoassay
A method diagnosing acute ischemic stroke by obtaining a biological sample, extracting total RNA, and determining expression by filament-based immunoassay of a panel comprising nine biomarkers: CCR7, CSPG2, IQGAP1, ORM1, arginase 1 (ARG1), lymphocyte antigen 96 (LY96), matrix metalloproteinase 9 (MMP9), carbonic anhydrase 4 (CA4), and s100 calcium binding protein A12 (s100A12). Expression of the biomarkers indicates acute ischemic stroke.
Diagnostic method using a subset panel of five biomarkers via filament-based immunoassay
A method for diagnosing acute ischemic stroke by obtaining a biological sample, extracting total RNA, and determining expression by filament-based immunoassay of the following five biomarkers: ARG1, CA4, LY96, MMP9, and s100A12.
Use of whole peripheral blood as the sample
The diagnostic methods specify the use of whole peripheral blood obtained from the subject for biomarker detection and expression analysis.
Execution within specific time windows after symptom onset
The claimed diagnostic methods are executed on the subject no more than 3 hours or no more than 4.5 hours after onset of acute ischemic stroke symptoms, aligning with therapeutic windows for treatments like rtPA.
Combination with brain imaging techniques
The methods optionally include obtaining brain imaging data, such as MRI or CT scans, and evaluating these data to detect acute ischemic stroke in combination with biomarker detection.
Treatment initiation based on diagnosis
Methods further comprise treating subjects diagnosed with acute ischemic stroke with stroke therapies, notably administration of a therapeutically effective amount of recombinant plasminogen activator (rtPA).
Quantitative expression changes for diagnosis
Diagnostic determination includes detecting biomarkers exhibiting at least a 1.5 fold or at least a 2.0 fold increase or decrease in expression level compared to levels in a non-stroke subject.
Differential diagnosis from TIAs, hemorrhagic stroke, and stroke mimics using selected biomarker panels
Methods for differentiating acute ischemic stroke from transient ischemic attack, hemorrhagic stroke, or stroke mimics by detecting presence of a biomarker panel comprising CCR7, CSPG2, IQGAP1, and ORM1, with indication that presence of these biomarkers is indicative of acute ischemic stroke but not of other conditions. Methods include administering rtPA if acute ischemic stroke is diagnosed.
The claims collectively cover diagnostic methods for acute ischemic stroke employing specific biomarker panels detected in peripheral blood samples by immunoassay techniques including filament-based assays, incorporating time-specific diagnosis, optional brain imaging data, and subsequent treatment guidance such as rtPA administration. The invention emphasizes specific biomarker combinations enabling differentiation of acute ischemic stroke from other cerebrovascular events.
Stated Advantages
Provides rapid, sensitive, and specific diagnostic assays for acute ischemic stroke, overcoming limitations of current imaging and clinical expertise.
Enables early and accurate differentiation of acute ischemic stroke from hemorrhagic stroke, transient ischemic attacks, and stroke mimics, critical for appropriate treatment.
Facilitates timely administration of stroke therapies such as recombinant tissue plasminogen activator (rtPA) within therapeutic windows, potentially improving patient outcomes.
Offers a diagnostic method that can be deployed irrespective of the clinician’s level of stroke expertise, thereby expanding accessibility in varied clinical settings.
Utilizes blood biomarkers that can be measured in peripheral whole blood, enabling minimally invasive and rapid testing.
Documented Applications
Diagnosis of acute ischemic stroke in patients through detection of specific biomarker panels in peripheral blood.
Differential diagnosis to distinguish acute ischemic stroke from hemorrhagic stroke, transient ischemic attacks (TIAs), and stroke mimics.
Facilitation of treatment decisions such as identifying candidates for recombinant tissue plasminogen activator (rtPA) therapy based on biomarker detection.
Development of point-of-care (POC) diagnostic tests, including filament-based systems, for rapid bedside diagnosis of acute ischemic stroke.
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