Methods and compositions for diagnosing brain injury or neurodegeneration

Abstract

Methods and compositions for diagnosing brain injury, neurodegeneration; or a predisposition thereto, in a subject are provided. Particularly, the present invention relates to specific antigen antibody reactivities useful in diagnosing brain injury, neurodegeneration or a predisposition thereto, in a subject.

1 . A method for detecting brain injury in a subject, the method comprising the steps of:
 (i) obtaining a sample from a subject;   (ii) contacting the sample with at least one antigen having an amino acid sequence selected from the group consisting of SEQ ID NOS: 1-115, isoforms thereof, post-translationally modified forms thereof, fragments thereof, or any combinations thereof to determine the reactivity of said at least one antigen with antibodies in the subject's sample;   (iii) measuring the reactivity of antibodies in the sample relative to the reactivity of antibodies in a healthy control; and   (iv) detecting brain injury in the subject by measuring a difference in the reactivity of the antibodies in the sample compared to the reactivity of the antibodies in the healthy control.   
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the difference in the reactivities of the antibodies in the sample and the antibodies in the healthy control comprises differential IgG and IgM reactivities. 
     
     
         4 . The method of  claim 1 , wherein said brain injury is selected from the group consisting of: concussions, chronic traumatic encephalopathy, mild traumatic brain injuries, moderate traumatic brain injuries, severe traumatic brain injuries, head trauma, concussive blasts and brain neurodegenerative condition. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 4 , wherein said neurodegenerative condition is selected from Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, demyelinating disease, HTLV-1-associated myelopathy (HAM), multiple sclerosis (MS), amyotrophic lateral sclerosis, pathological neurological symptoms after injury or trauma, loss of memory, loss of motor function, encephalopathy, or viral encephalopathy. 
     
     
         7 . The method of  claim 1 , wherein the sample is selected from the group consisting of blood, serum, plasma, cerebrospinal fluid (CSF), urine and saliva. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the reactivity of a healthy control is selected from the group consisting of a reactivity of at least one healthy individual, a baseline sample from the same individual, a panel of control samples from a set of healthy individuals, and a stored set of data from healthy control individuals. 
     
     
         10 . The method of  claim 1 , comprising determining the reactivity of antibodies in the sample to a plurality of antigens provided in the form of an antigen probe set, an antigen array, or an antigen chip. 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 1 , further comprising measuring the levels of one or more biomarkers in the sample; and comparing the levels of the one or more biomarkers with predefined levels of the same biomarkers in a subject having brain injury and predefined levels of the same biomarkers in a healthy control, wherein a correlation of the levels in the subject's sample to one of the predefined levels provides the determination of brain injury in the subject. 
     
     
         13 . The method of  claim 12 , wherein the one or more biomarkers is selected from the group consisting of glial fibrillary acidic protein (GFAP), Synuclein beta (SNCB), Metallothionein-3 (MT3), Neurogranin (NRGN), intercellular adhesion molecule-5 (ICAM5) and Brain derived neurotrophic factor (BDNF), or citrullinated forms thereof. 
     
     
         14 . An article of manufacture comprising an antigen probe set comprising a plurality of antigen probes selected from the group consisting of SEQ ID NOs: 1-115, isoforms thereof, post-translationally modified forms thereof, fragments thereof, or any combinations thereof. 
     
     
         15 . (canceled) 
     
     
         16 . The article of manufacture of  claim 14 , further comprising one or more biomarkers selected from the group consisting of glial fibrillary acidic protein (GFAP), Synuclein beta (SNCB), Metallothionein-3 (MT3), Neurogranin (NRGN), intercellular adhesion molecule-5 (ICAM5) and Brain derived neurotrophic factor (BDNF), or citrullinated forms thereof. 
     
     
         17 . The article of manufacture of  claim 14 , which is in a format selected from an antigen probe array, an antigen chip, a dipstick, or a lateral flow test. 
     
     
         18 . (canceled) 
     
     
         19 . A method for qualifying brain injury status in a subject in need thereof, the method comprising the steps of:
 (i) obtaining a sample from a subject;   (ii) determining the reactivity of antibodies in the sample to at least one antigen having an amino acid sequence selected from the group consisting of SEQ ID NOS: 1-115, isoforms thereof, post-translationally modified forms thereof, fragments thereof, or any combinations thereof by contacting the sample with the at least one antigen;   (iii) measuring the reactivity of antibodies in the sample to a predefined reactivity that identifies one or more brain injury statuses selected from the group consisting of having brain injury, not having brain injury, predisposition to brain injury, sub-acute brain injury, acute brain injury, post-acute brain injury, progressing brain injury, regressing brain injury, subclinical brain injury, mild brain injury, moderate brain injury, severe brain injury and chronic brain injury; and   (iv) qualifying brain injury status in the subject as indicated by the measured reactivity in the subject's sample correlating to one of the predefined reactivities.   
     
     
         20 . The method of  claim 19 , further comprising measuring the levels of one or more biomarkers in the sample; and comparing the levels of the one or more biomarkers with predefined levels of the same biomarkers that correlate to one or more brain injury statuses, wherein a correlation to one of the predefined levels determines the brain injury status of the subject. 
     
     
         21 . The method of  claim 20 , wherein the one or more biomarkers is selected from the group consisting of glial fibrillary acidic protein (GFAP), Synuclein beta (SNCB), Metallothionein-3 (MT3), Neurogranin (NRGN), intercellular adhesion molecule-5 (ICAM5) and Brain derived neurotrophic factor (BDNF), or citrullinated forms thereof. 
     
     
         22 . A method of detecting recovery from brain injury in a subject, the method comprising the steps of:
 (i) obtaining a sample from the subject;   (ii) determining the reactivity of antibodies in the sample to at least one antigen having an amino acid sequence selected from the group consisting of SEQ ID NOS: 10, 61, 104, isoforms thereof, post-translationally modified forms thereof, fragments thereof, or any combinations thereof by contacting the sample with the at least one antigen;   (iii) assaying the reactivity of antibodies in the sample relative to a predefined reactivity threshold; and   (iv) detecting a difference in the reactivity of the antibodies in the sample compared to the predefined reactivity threshold, thereby indicating recovery from brain injury in said subject.   
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 22 , wherein the difference in the reactivities of the antibodies in the sample and the antibodies in the healthy control comprises differential IgG and IgM reactivities. 
     
     
         25 . The method of  claim 22 , further comprising:
 measuring the levels of one or more biomarkers selected from the group consisting of glial fibrillary acidic protein (GFAP), Synuclein beta (SNCB), Metallothionein-3 (MT3), Neurogranin (NRGN), intercellular adhesion molecule-5 (ICAM5) and Brain derived neurotrophic factor (BDNF), or citrullinated forms thereof in the sample; and   comparing the levels of the one or more biomarkers with predefined levels of the same biomarkers that correlates with recovery from brain injury, wherein a correlation to one of the predefined levels is indicative of recovery from brain injury of the subject.   
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 25 , wherein said comparing is conducted by using at least one classifier algorithm. 
     
     
         28 . The method of  claim 27 , wherein said at least one classifier algorithm is selected from the group consisting of a decision tree classifier, logistic regression classifier (LR), nearest neighbor classifier, neural network classifier, Gaussian mixture model (GMM), Support Vector Machine (SVM) classifier, nearest centroid classifier, linear regression classifier, linear discriminant analysis (LDA) classifier, quadratic discriminant analysis (QDA) classifier and random forest classifier.