Novel biomarkers and methods for diagnosing and evaluating traumatic brain injury

Abstract

The present disclosure relates to methods for diagnosing and evaluating a subject that has sustained or may have sustained an injury to the head, such as a traumatic brain injury (TBI). In particular, the present disclosure identifies various biomarkers, the detection and/or differential expression of which can be used to assess the presence or absence of a TBI in a subject, and can be used as a basis for diagnosing a subject as having a specific type of TBI (e.g., severe TBI or subclasses of mild TBI). The various TBI biomarkers can be detected individually or in combination and can be used as an important diagnostic, prognostic, and/or TBI risk stratification tool as part of assessing a subject's TBI status.

1 . A method of measuring or detecting at least one biomarker, the method comprising:
 obtaining a sample from a subject after an actual or suspected head injury; and   measuring or detecting at least one biomarker or fragment thereof selected from the group consisting of AL9A1, ATPG, C1RL, CAND1, EPIPL, GLO2, IGHA2, PZP, SYTC, SYYC, or any combinations thereof in the sample; and/or   measuring or detecting at least one biomarker of fragment thereof selected from the group consisting of ABHEB, AL9A1, DNM1L, FCN2, INF2, K22E, M3K5, NCOR1, SBSN, SYEP, TPP2, or any combinations thereof in the sample;   wherein the measurement or detection of the at least one biomarker indicates that the subject has sustained a traumatic brain injury (TBI).   
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the at least one biomarker or fragment thereof is selected from the group consisting of AL9A1, ATPG, C1RL, EPIPL, IGHA2, PZP, SYTC, SYYC, or any combinations thereof; and wherein the at least one biomarker is not detectable in a sample obtained from a healthy subject. 
     
     
         4 . The method of  claim 1 , wherein the at least one biomarker or fragment thereof is selected from the group consisting of ATPG, C1RL, SYYC, or any combinations thereof. 
     
     
         5 . The method of  claim 1 , wherein the at least one biomarker or fragment thereof is selected from the group consisting of CAND1, GLO2, or the combination thereof; and wherein levels of CAND1 and GLO2 are higher compared to levels of CAND1 and GLO2 in a sample obtained from a healthy subject. 
     
     
         6 . The method of  claim 1 , wherein the at least one biomarker or fragment thereof is selected from the group consisting of ABHEB, AL9A1, DNM1L, or combinations thereof;
 wherein levels of ABHEB are higher compared to levels of ABHEB in a sample obtained from a healthy subject; and/or   wherein levels of AL9A1 and DNM1L are lower compared to levels of AL9A1 and DNM1L in a sample obtained from a healthy subject.   
     
     
         7 . The method of  claim 1 , wherein the at least one biomarker or fragment thereof is selected from the group consisting of M3K5, SBSN, SYEP, or combinations thereof;
 wherein levels of SBSN and SYEP are higher compared to levels of SBSN and SYEP in a sample obtained from a healthy subject; and/or   wherein levels of M3K5 are lower compared to levels of M3K5 in a sample obtained from a healthy subject.   
     
     
         8 . The method of  claim 1 , wherein the at least one biomarker or fragment thereof is selected from the group consisting of INF2, SYEP, or combinations thereof. 
     
     
         9 . The method of  claim 1 , wherein the at least one biomarker or fragment thereof further comprises at least one biomarker selected from the group consisting of ANXA6, ERAP1, EZRI, FA5, G6PI, MYLK, SAMP, or combinations thereof. 
     
     
         10 . The method of  claim 1 , wherein the at least one biomarker or fragment thereof further comprises at least one biomarker selected from the group consisting of MYLK, SAMP, or a combination thereof. 
     
     
         11 . A method of measuring or detecting at least one biomarker, the method comprising:
 obtaining a sample from a subject after an actual or suspected head injury; and   measuring or detecting at least one biomarker or fragment thereof selected from the group consisting of 1433G, ACK1, ACY1, AKA12, ARGI1, CADH5, CLH1, COPG2, DPOD2, DSG2, HV307, IQGA2, K1C14, K1C19, KV105, LAMC1, MDHM, NQO2, PERM, PLST, PNCB, PTPRC, SEPT7, SYRC, TRXR2, TXNL1, UGGG1, WDR1 or any combinations thereof in the sample;   wherein the measurement or detection of the at least one biomarker indicates that the subject has sustained a traumatic brain injury (TBI).   
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 11 , wherein the at least one biomarker is not detectable in a sample obtained from a healthy subject. 
     
     
         14 . The method of  claim 11 , wherein the at least one biomarker is not detectable in a sample obtained from a subject that has sustained a severe TBI. 
     
     
         15 . The method of  claim 11 , wherein the at least one biomarker or fragment thereof is selected from the group consisting of ACK1, ACY1, PLST, PNCB, PTPRC, UGGG1, or any combinations thereof in the sample;
 wherein the measurement or detection of the at least one biomarker indicates that the subject has sustained a mild TBI of subclass 1.   
     
     
         16 . The method of  claim 11 , wherein the at least one biomarker or fragment thereof is selected from the group consisting of AKA12, HV307, PERM, KV105, NQO2, SEPT7, SYRC, TRXR2, or any combinations thereof in the sample;
 wherein the measurement or detection of the at least one biomarker indicates that the subject has sustained mild TBI of subclass 2.   
     
     
         17 . The method of  claim 11 , wherein the at least one biomarker or fragment thereof is selected from the group consisting of 1433B, ARGI1, CADH5, CLH1, COPG2, DPOD2, DSG2, IQGA2, K1C14, LAMC1, MDHM, TXNL1, or any combinations thereof in the sample;
 wherein the measurement or detection of the at least one biomarker indicates that the subject has sustained a mild TBI of subclass 3.   
     
     
         18 . The method of  claim 11 , wherein:
 (1) the at least one biomarker or fragment thereof further comprises at least one biomarker selected from the group consisting of AHNK, AL1A1, AMPN, CAPZB, CATD, CLIP2, CMGA, FSCN1, GMPR2, GRP78, GSH1, IDHC, K1C20, KRR1, MBL2, NTF2, PCBP2, PGK1, SAA1, TFR1, or combinations thereof; or   (2) the at least one biomarker or fragment thereof further comprises at least one biomarker selected from the group consisting of ANXA6, MASP2, MYLK, SAMP, or a combination thereof.   
     
     
         19 . (canceled) 
     
     
         20 . A biomarker panel for determining traumatic brain injury (TBI) status of a subject, wherein:
 (i) the biomarker panel comprises at least one of the following biomarkers: TPP2, CAND1, NCOR1, K22E, AL9A1, ABHEB, DNM1L, INF2, or any combinations thereof, wherein measurement or detection of the at least one biomarker indicates that the subject has sustained a mild TBI of subclass 4;   (ii) the biomarker panel comprises at least one of the following biomarkers: TPP2, NCOR1, HV103, INF2, IGHD, CK054, M3K5, ABHEB, AL9A1, DNM1L, or any combinations thereof, wherein measurement or detection of the at least one biomarker indicates that the subject has sustained a mild TBI of subclass 3;   (iii) the biomarker panel comprises at least one of the following biomarkers: NCOR1, TPP2, K22E, ABHEB, INF2, SBSN, AL9A1, MA2B2, or any combinations thereof, wherein measurement or detection of the at least one biomarker indicates that the subject has sustained a mild TBI of subclass 2; or   (iv) the biomarker panel comprises at least one of the following biomarkers: K22E, DNM1L, DIAP1, ABHEB, PLOD1, SYEP, KV133, AL9A1, EPHB4, or any combinations thereof, wherein measurement or detection of the at least one biomarker indicates that the subject has sustained a mild TBI of subclass 1.   
     
     
         21 . The biomarker panel (i) of  claim 20 , wherein levels of CAND1, NCOR1, K22E, ABHEB, and DNM1L are higher compared to levels of CAND1, NCOR1, K22E, ABHEB, and DNM1L in a sample obtained from a healthy subject; and/or
 wherein levels of TPP2, AL9A1, and INF2 are lower compared to levels of TPP2, AL9A1, and INF2 in a sample obtained from a healthy subject.   
     
     
         22 . (canceled) 
     
     
         23 . The biomarker panel (ii) of  claim 20 , wherein levels of NCOR1, HV103, IGHD, ABHEB, and DNM1L are higher compared to levels of NCOR1, HV103, IGHD, ABHEB, and DNM1L in a sample obtained from a healthy subject; and/or
 wherein levels of TPP2, IGHD, CK054, M3K5, and AL9A1 are lower compared to levels of TPP2, IGHD, CK054, M3K5, and AL9A1 in a sample obtained from a healthy subject.   
     
     
         24 . (canceled) 
     
     
         25 . The biomarker panel (iii) of  claim 20 , wherein levels of NCOR1, K22E, ABHEB, and SBSN are higher compared to levels of NCOR1, K22E, ABHEB, and SBSN in a sample obtained from a healthy subject; and/or
 wherein levels of TPP2, INF2, AL9A1, and MA2B2 are lower compared to levels of TPP2, INF2, AL9A1, and MA2B2 in a sample obtained from a healthy subject.   
     
     
         26 . (canceled) 
     
     
         27 . The biomarker panel (iv) of  claim 20 , wherein levels of K22E, DNM1L, DIAP1, ABHEB, PLOD1, SYEP, and EPHB4 are higher compared to levels of K22E, DNM1L, DIAP1, ABHEB, PLOD1, SYEP, and EPHB4 in a sample obtained from a healthy subject; and/or
 wherein levels of KV133 and AL9A1 are lower compared to levels of KV133 and AL9A1 in a sample obtained from a healthy subject.   
     
     
         28 . A biomarker panel for determining traumatic brain injury (TBI) status of a subject, wherein:
 (i) the biomarker panel comprises at least one of the following biomarkers: CAND1, NCOR1, K22E, ABHEB, DNM1L, SBSN, GLO2, SYEP, or any combinations thereof, wherein measurement or detection of higher levels of the at least one biomarker in the subject as compared to levels of the at least one biomarkers in a healthy subject indicates that the subject has sustained a mild TBI of subclass 4;   (ii) the biomarker panel comprises at least one of the following biomarkers: NCOR1, HV103, IGHD, ABHEB, DNM1L, ALBU, THIM, IGHA2, KV139, and, or any combinations thereof, wherein measurement or detection of higher levels of the at least one biomarker in the subject as compared to levels of the at least one biomarkers in a healthy subject indicates that the subject has sustained a mild TBI of subclass 3;   (iii) the biomarker panel comprises at least one of the following biomarkers: NCOR1, K22E, ABHEB, SBSN, DNM1L, DIAP1, DYL1, PSA, EPHB4, or any combinations thereof, wherein measurement or detection of higher levels of the at least one biomarker in the subject as compared to levels of the at least one biomarkers in a healthy subject indicates that the subject has sustained a mild TBI of subclass 2; or   (iv) the biomarker panel comprises at least one of the following biomarkers: K22E, DNM1L, DIAP1, ABHEB, PLOD1, SYEP, EPHB4, FBLN3, or any combinations thereof, wherein measurement or detection of higher levels of the at least one biomarker in the subject as compared to levels of the at least one biomarkers in a healthy subject indicates that the subject has sustained a mild TBI of subclass 1.   
     
     
         29 .- 31 . (canceled) 
     
     
         32 . A biomarker panel for determining that a subject has not sustained a traumatic brain injury (TBI), the panel comprising at least one of the following biomarkers: ACTBL, ALDH2, ANXA5, CAMP, CPNE3, CRAC1, CYTC, DNPEP, EIF3I, GSHB, ICAM1, HV323, HNRPD, KVD33, FA9, FHR4, FRPD1, HS90B, MA2A1, PCYOX, PNPH, PROC, RL3, SH3L3, SRRM2, TBB1, TENA, TRAP1 or any combinations thereof;
 wherein measurement or detection of the at least one biomarker in the subject indicates that the subject has not sustained a TBI.