Salivary biomarkers of brain injury

JP2025106509AInactive Publication Date: 2025-07-15MARKER DIAGNOSTICS UK LTD
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Patent Information

Application Number
JP2025065317
Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
Priority Date
2019-08-07
Filing Date
2025-04-10
Publication Date
2025-07-15
Estimated Expiration
Not applicable · inactive patent

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Benefits of technology

【0316】 本開示に自明及び/又は固有の他の利点は、当業者には明らかであろう。特定の特徴及び部分的組み合わせは有用であり、他の特徴及び部分的組み合わせを参照せずに採用され得ることが理解されよう。これは、特許請求の範囲によって企図され、特許請求の範囲内である。本開示の範囲から逸脱することなく、多くの可能な実施形態が本開示から作成され得るので、添付の図面に記載又は図示された全ての事項は、例示として解釈されるべきであり、限定的な意味で解釈されるべきではないことを理解されたい。

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Abstract

To provide methods of diagnosing, monitoring, treating, and predicting the course of traumatic brain injury (TBI), including mild traumatic brain injury (mTBI).SOLUTION: A method includes determining a level of at least one RNA biomarker (e.g., miRNA) in a saliva sample from a subject. Also described are sensor elements, detection systems, compositions, and kits for diagnosing, monitoring, treating, and predicting the course of TBI.SELECTED DRAWING: None
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Claims

**Claim 1** A method for diagnosing and / or monitoring traumatic brain injury (TBI) in a subject, the method comprising determining the level of at least one RNA biomarker in a saliva sample obtained from the subject, wherein the at least one RNA biomarker is a. selected from the group consisting of hsa-miR-1246, hsa-miR-126-3p (miR-126*), hsa-miR-144-3p (miR-144*), hsa-miR-144-5p (=miR-144*), hsa-miR-16-1-3p, hsa-miR-339-5p, hsa-miR-497-5p, put-miR-1204, put-miR-323, put-miR-325, put-miR-444, put-miR-465, put-miR-469, put-miR-594, put-miR-856, put-miR-893, put-miR-958, RNU4-6p, SNORA57, SNORD3B-2, tRNA120-AlaAGC, tRNA18-ArgCCT, tRNA27-MetCAT, tRNA2-LeuTAA, tRNA73-ArgCCG, tRNA8-ThrAGT, tRNA9-TyrGTA, U2.3, U4.64, U6.168, U6.601, UC022CJG1, YRNA-245, and YRNA-684, or any combination thereof, and / or b. selected from the group consisting of put-miR-1003, put-miR-1080, put-miR-1084, put-miR-1146(2), put-miR-1207, put-miR-1306, put-miR-188, put-miR-209, put-miR-468, put-miR-476, put-miR-6, put-miR-71, put-miR-742, put-miR-806, put-miR-92, put-miR-961, RNU6-4, RNU6-45, RNU6-6, RNU6-7, RNU6-73, U6.1249, U6.375, U6.428, and YRNA-255, or any combination thereof. **Claim 2** The method of claim 1, wherein either an up-regulated level or a down-regulated level of the at least one RNA biomarker indicates TBI. **Claim 3** The method according to claim 1, wherein the subject is diagnosed with TBI if the level of the at least one RNA biomarker is above or below a predetermined threshold, or increased or decreased compared to a control.

4. The method according to claim 1, wherein the saliva sample is obtained during a post-injury period selected from the period immediately after injury to any period after injury.

5. The method according to claim 4, wherein the saliva sample is obtained during a post-injury period selected from immediately after injury until the expression level of at least one of the RNA biomarkers returns to the predetermined threshold or the amount of the RNA biomarker in the control sample.

6. The method according to claim 4, wherein the saliva sample is obtained during a post-injury period selected from immediately after injury to 1 year, 10 months, 8 months, 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 25 days, 20 days, 15 days, 7 days, 5 days, 3 days, 2 days, and / or 24 hours after injury.

7. The method according to claim 6, wherein the saliva sample is obtained during a post-injury period selected from 15 days, 1 hour to 15 days, 24 hours to 15 days, 24 hours to 7 days, and 2 to 5 days after injury.

8. The method according to claim 1, further comprising obtaining one or more additional saliva samples from the subject at one or more additional times after injury and repeating the detection and amplification steps for each additional sample.

9. The method according to claim 8, wherein the one or more additional saliva samples are obtained during a post-injury period selected from the period immediately after injury to any period after injury.

10. The method according to claim 8, wherein the one or more additional saliva samples are obtained during a post-injury period selected from immediately after injury until the expression level of at least one of the RNA biomarkers returns to the predetermined threshold or the amount of the RNA biomarker in the control sample.

11. The method according to claim 8, wherein the one or more additional saliva samples are obtained during a post-injury period selected from immediately after injury to 1 year, 10 months, 8 months, 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 25 days, 20 days, 15 days, 7 days, 5 days, 3 days, 2 days, and / or 24 hours after injury.

12. The method according to claim 11, wherein the one or more additional saliva samples are obtained during a post-injury period selected from 15 days from immediately after injury, 1 hour to 15 days, 24 hours to 15 days, 24 hours to 7 days, and 2 to 5 days.

13. The method according to claim 8, wherein the one or more additional saliva samples are obtained on the 1st, 1.5th, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, or 15th day after the injury.

14. The method according to any one of claims 1 to 13, wherein detecting the amount of the at least one RNA biomarker is performed using a PCR-based assay, a microarray assay, a laminar flow chip assay, or any assay suitable for detecting at least one RNA biomarker.

15. The method according to claim 14, wherein when using the PCR-based assay, a predetermined threshold corresponds to a fold change of 1.5 or more using the 2 - ΔΔCT method.

16. The method according to claim 14, wherein a predetermined threshold corresponds to a fold change of 2 or more using the 2 - ΔΔCT method.

17. The at least one RNA biomarker is a. hsa-let-7i-5p, hsa-miR-107, hsa-miR-126-5p (=miR-126 ＊ ), hsa-miR-135b-5p, hsa-miR-142-3p, hsa-miR-142-5p, hsa-miR-143-3p (=miR-143), hsa-miR-148a-3p, hsa-miR-206, hsa-miR-29c-3p, hsa-miR-34b-3p, hsa-miR-425-5p, hsa-miR-449a, hsa-miR-671-3p, hsa-miR-6748-3p, and hsa-miR-934, or any combination thereof, and / or b. one or more miRNAs selected from the group consisting of hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7f-5p, hsa-miR-103a-3p, hsa-miR-21-5p, and hsa-miR-92a-3p, or any combination thereof, and the method according to any one of claims 1 to 16.

18. The method according to claim 33, further comprising identifying the human subject as being suitable for normal activities after successful treatment of TBI.

19. The at least one RNA biomarker is a. hsa-let-7i-5p, hsa-miR-107, hsa-miR-126-5p (= miR-126 ＊ ), hsa-miR-135b-5p, hsa-miR-142-3p, hsa-miR-142-5p, hsa-miR-143-3p (= miR-143), hsa-miR-148a-3p, hsa-miR-206, hsa-miR-29c-3p, hsa-miR-34b-3p, hsa-miR-425-5p, hsa-miR-449a, hsa-miR-671-3p, hsa-miR-6748-3p, and hsa-miR-934, or any combination thereof, and / or b. one or more miRNAs selected from the group consisting of hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7f-5p, hsa-miR-103a-3p, hsa-miR-21-5p, and hsa-miR-92a-3p, or any combination thereof, and the method according to any one of claims 1 to 18.

20. A sensor element for a detection system for diagnosing and / or monitoring TBI, wherein the sensor element is a. hsa-miR-1246, hsa-miR-126-3p (miR-126 ＊ ), hsa-miR-144-3p (miR-144 ＊ ), hsa-miR-144-5p (=miR-144 ＊ ), hsa-miR-16-1-3p, hsa-miR-339-5p, hsa-miR-497-5p, put-miR-1204, put-miR-323, put-miR-325, put-miR-444, put-miR-465, put-miR-469, put-miR-594, put-miR-856, put-miR-893, put-miR-958, RNU4-6p, SNORA57, SNORD3B-2, tRNA120-AlaAGC, tRNA18-ArgCCT, tRNA27-MetCAT, tRNA2-LeuTAA, tRNA73-ArgCCG, tRNA8-ThrAGT, tRNA9-TyrGTA, U2.3, U4.64, U6.168, U6.601, UC022CJG1, YRNA-245, and YRNA-684, or any combination thereof, and / or b. put-miR-1003, put-miR-1080, put-miR-1084, put-miR-1146(2), put-miR-1207, put-miR-1306, put-miR-188, put-miR-209, put-miR-468, put-miR-476, put-miR-6, put-miR-71, put-miR-742, put-miR-806, put-miR-92, put-miR-961, RNU6-4, RNU6-45, RNU6-6, RNU6-7, RNU6-73, U6.1249, U6.375, U6.428, and YRNA-255, or any combination thereof, selected from the group consisting of A sensor element comprising a substrate functionalized with a probe specific for at least one RNA biomarker.

21. The sensor element according to claim 20, wherein the probe comprises a nucleic acid capable of binding to the at least one RNA biomarker.

22. The sensor element according to claim 20 or 21, wherein the probe comprises a nucleic acid having at least 70% identity with a sequence that is complementary to the sequence of the target RNA biomarker.

23. The sensor element according to claim 20 or 21, wherein the probe comprises a nucleic acid having at least 70% identity with a sequence that is complementary to the sequences of SEQ ID NOs: 1, 2, 14, 16, 23, 26, 27, 29, 39, 40, 48, 71, 72, 73, 74, 75, 77, 78, 79, 80, 81, 82, 84, 85, 86, 87, 89, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, and 150.

24. The at least one RNA biomarker is a. hsa-let-7i-5p, hsa-miR-107, hsa-miR-126-5p (=miR-126 ＊ ), hsa-miR-135b-5p, hsa-miR-142-3p, hsa-miR-142-5p, hsa-miR-143-3p (=miR-143), hsa-miR-148a-3p, hsa-miR-206, hsa-miR-29c-3p, hsa-miR-34b-3p, hsa-miR-425-5p, hsa-miR-449a, hsa-miR-671-3p, hsa-miR-6748-3p, and hsa-miR-934, or any combination thereof, and / or The sensor element according to any one of claims 21 to 23, further comprising one or more miRNAs selected from the group consisting of b. hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7f-5p, hsa-miR-103a-3p, hsa-miR-21-5p, and hsa-miR-92a-3p, or any combination thereof.

25. A detection system for diagnosing and / or monitoring TBI, comprising the sensor element according to any one of claims 20 to 24, and a detection device capable of detecting the binding of a target RNA biomarker to the probe.

26. The detection system according to claim 25, further comprising means for determining whether the target RNA biomarker is upregulated or downregulated.

27. A method for determining a series of treatments for a subject suspected of having TBI, the method comprising applying a saliva sample obtained from the subject to the detection system according to claim 25 or 26, and providing treatment for TBI if an upregulated level or a downregulated level of the at least one RNA biomarker is detected.

28. A method for treating a subject suspected of having TBI, a. hsa-miR-1246, hsa-miR-126-3p (miR-126 ＊ ), hsa-miR-144-3p (miR-144 ＊ ), hsa-miR-144-5p (=miR-144 ＊ ), hsa-miR-16-1-3p, hsa-miR-339-5p, hsa-miR-497-5p, put-miR-1204, put-miR-323, put-miR-325, put-miR-444, put-miR-465, put-miR-469, put-miR-594, put-miR-856, put-miR-893, put-miR-958, RNU4-6p, SNORA57, SNORD3B-2, tRNA120-AlaAGC, tRNA18-ArgCCT, tRNA27-MetCAT, tRNA2-LeuTAA, tRNA73-ArgCCG, tRNA8-ThrAGT, tRNA9-TyrGTA, U2.3, U4.64, U6.168, U6.601, UC022CJG1, YRNA-245, and YRNA-684, or any combination thereof, and / or b. at least one RNA biomarker selected from the group consisting of put-miR-1003, put-miR-1080, put-miR-1084, put-miR-1146(2), put-miR-1207, put-miR-1306, put-miR-188, put-miR-209, put-miR-468, put-miR-476, put-miR-6, put-miR-71, put-miR-742, put-miR-806, put-miR-92, put-miR-961, RNU6-4, RNU6-45, RNU6-6, RNU6-7, RNU6-73, U6.1249, U6.375, U6.428, and YRNA-255, or any combination thereof, determining whether an upregulated level or a downregulated level of the at least one RNA biomarker is detectable in a saliva sample obtained from the subject. A method comprising providing treatment for TBI to the subject when an up-regulated level or a down-regulated level of at least one RNA biomarker is detected.

29. The at least one RNA biomarker is a. hsa-let-7i-5p, hsa-miR-107, hsa-miR-126-5p (=miR-126 ＊ ), hsa-miR-135b-5p, hsa-miR-142-3p, hsa-miR-142-5p, hsa-miR-143-3p (=miR-143), hsa-miR-148a-3p, hsa-miR-206, hsa-miR-29c-3p, hsa-miR-34b-3p, hsa-miR-425-5p, hsa-miR-449a, hsa-miR-671-3p, hsa-miR-6748-3p, and hsa-miR-934, or any combination thereof, and / or b. one or more miRNAs selected from the group consisting of hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7f-5p, hsa-miR-103a-3p, hsa-miR-21-5p, and hsa-miR-92a-3p, or any combination thereof, the method according to claim 28.

30. A method for detecting an RNA biomarker in a saliva sample, the method comprising obtaining a saliva sample from a human subject, contacting the saliva sample with a. hsa-miR-1246, hsa-miR-126-3p (miR-126 ＊ ), hsa-miR-144-3p (miR-144 ＊ ), hsa-miR-144-5p (=miR-144 ＊ ), hsa-miR-16-1-3p, hsa-miR-339-5p, hsa-miR-497-5p, put-miR-1204, put-miR-323, put-miR-325, put-miR-4 44, put-miR-465, put-miR-469, put-miR-594, put-miR-856, put-miR-893, put-miR-958, RNU4-6p, SNORA57, SNOR D3B-2, tRNA120-AlaAGC, tRNA18-ArgCCT, tRNA27-MetCAT, tRNA2-LeuTAA, tRNA73-ArgCCG, tRNA8-ThrAGT, tRNA9-TyrGTA, U2.3, U4.64, U6.168, U6.601, UC022CJG1, YRNA-245, and YRNA-684, or any combination thereof; and / or b. at least one oligonucleotide primer complementary to at least one RNA biomarker selected from the group consisting of put-miR-1003, put-miR-1080, put-miR-1084, put-miR-1146(2), put-miR-1207, put-miR-1306, put-miR-188, put-miR-209, put-miR-468, put-miR-476, put-miR-6, put-miR-71, put-miR-742, put-miR-806, put-miR-92, put-miR-961, RNU6-4, RNU6-45, RNU6-6, RNU6-7, RNU6-73, U6.1249, U6.375, U6.428, and YRNA-255, or any combination thereof, amplifying the at least one RNA biomarker using polymerase chain reaction, detecting the amplified RNA biomarker, the method comprising.

31. The at least one RNA biomarker is b. selected from the group consisting of hsa-let-7a-5p, hsa-let-7b-has hsa-let-7f-5has hsa-miR-103a-3p, hsa-miR-21-5p, and hsa-miR-92a-3p, or any combination thereof, a. has-let-7i-5 hashs a-miR-107, hsa-miR-126-5p (=miR-126 ＊ ), hsa-miR-135 hasp, hsa-miR-142-3p, hsa-miR-142-5p, hsa-miR-143-3p (=mhas143), hsa-mhas148a-3p hass a-miR-206 hass a-miR-29c has, hsa-miR-has-3p, hsahasR-425-5p, has-miR-449a, hsa-has-671-3p, hsa-miR-6748-3p, and hsa-miR-934, or any combination thereof, and / or The method according to claim 30, further comprising one or more miRNAs.

32. ​ A kit for use in a method of diagnosing and / or monitoring traumatic brain injury (TBI) in saliva from a human subject, said kit comprising a. hsa-miR-1246, hsa-miR-126-3p (miR-126 ＊ ), hsa-miR-144-3p (miR-144 ＊ ), hsa-miR-144-5p (=miR-144 ＊ ), hsa-miR-16-1-3p, hsa-miR-339-5p, hsa-miR-497-5p, put-miR-1204, put-miR-323, put-miR-325, put-miR-444, put-miR-465, put-miR-469, put-miR-594, put-miR-856, put-miR-893, put-miR-958, RNU4-6p, snoRA57, snoRD3B-2, tRNA120-AlaAGC, tRNA18-ArgCCT, tRNA27-MetCAT, tRNA2-LeuTAA, tRNA73-ArgCCG, tRNA8-ThrAGT, tRNA9-TyrGTA, U2.3, U4.64, U6.168, U6.601, UC022CJG1, YRNA-245, and YRNA-684, or any combination thereof, and / or b. at least one probe specific to at least one RNA biomarker selected from the group consisting of put-miR-1003, put-miR-1080, put-miR-1084, put-miR-1146(2), put-miR-1207, put-miR-1306, put-miR-188, put-miR-209, put-miR-468, put-miR-476, put-miR-6, put-miR-71, put-miR-742, put-miR-806, put-miR-92, put-miR-961, RNU6-4, RNU6-45, RNU6-6, RNU6-7, RNU6-73, U6.1249, U6.375, U6.428, and YRNA-255, or any combination thereof A kit comprising at least one probe specific to at least one RNA biomarker.

33. The kit according to claim 32, wherein the probe comprises a nucleic acid capable of binding to the at least one RNA biomarker.

34. The kit according to claim 32 or 33, wherein the probe comprises a nucleic acid having at least 70% identity with a sequence that is complementary to the sequence of the target RNA biomarker.

35. The kit according to claim 32 or 33, wherein the probe comprises a nucleic acid having at least 70% identity with a sequence that is complementary to the sequences of SEQ ID NOs: 1, 2, 14, 16, 23, 26, 27, 29, 39, 40, 48, 71, 72, 73, 74, 75, 77, 78, 79, 80, 81, 82, 84, 85, 86, 87, 89, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, and 150.

36. The at least one RNA biomarker is a. hsa-let-7i-5p, hsa-miR-107, hsa-miR-126-5p (=miR-126 ＊ ), hsa-miR-135b-5p, hsa-miR-142-3p, hsa-miR-142-5p, hsa-miR-143-3p (=miR-143), hsa-miR-148a-3p, hsa-miR-206, hsa-miR-29c-3p, hsa-miR-34b-3p, hsa-miR-425-5p, hsa-miR-449a, hsa-miR-671-3p, hsa-miR-6748-3p, and hsa-miR-934, or any combination thereof, and / or The kit according to any one of claims 32 to 35, further comprising one or more miRNAs selected from the group consisting of b. hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7f-5p, hsa-miR-103a-3p, hsa-miR-21-5p, and hsa-miR-92a-3p, or any combination thereof.

37. A composition for use in a method for diagnosing and / or monitoring traumatic brain injury (TBI) in saliva from a human subject, wherein the composition a. hsa-miR-1246, hsa-miR-126-3p (miR-126 ＊ ), hsa-miR-144-3p (miR-144 ＊ ), hsa-miR-144-5p (=miR-144 ＊ ), hsa-miR-16-1-3p, hsa-miR-339-5p, hsa-miR-497-5p, put-miR-1204, put-miR-323, put-miR-325, put-miR-444, put-miR-465, put-miR-469, put-miR-594, put-miR-856, put-miR-893, put-miR-958, RNU4-6p, SNORA57, SNORD3B-2, tRNA120-AlaAGC, tRNA18-ArgCCT, tRNA27-MetCAT, tRNA2-LeuTAA, tRNA73-ArgCCG, tRNA8-ThrAGT, tRNA9-TyrGTA, U2.3, U4.64, U6.168, U6.601, UC022CJG1, YRNA-245, and YRNA-684, or any combination thereof, and / or b. at least one probe specific for at least one RNA biomarker selected from the group consisting of put-miR-1003, put-miR-1080, put-miR-1084, put-miR-1146(2), put-miR-1207, put-miR-1306, put-miR-188, put-miR-209, put-miR-468, put-miR-476, put-miR-6, put-miR-71, put-miR-742, put-miR-806, put-miR-92, put-miR-961, RNU6-4, RNU6-45, RNU6-6, RNU6-7, RNU6-73, U6.1249, U6.375, U6.428, and YRNA-255, or any combination thereof A composition comprising at least one probe specific for at least one RNA biomarker.

38. The composition according to claim 37, wherein the probe comprises a nucleic acid capable of binding to the at least one RNA biomarker.

39. The composition according to claim 37 or 38, wherein the probe comprises a nucleic acid having at least 70% identity with a sequence that is complementary to the sequence of the target RNA biomarker.

40. The composition according to claim 37 or 38, wherein the probe comprises a nucleic acid having at least 70% identity with a sequence that is the complement of the sequences of SEQ ID NOs: 1, 2, 14, 16, 23, 26, 27, 29, 39, 40, 48, 71, 72, 73, 74, 75, 77, 78, 79, 80, 81, 82, 84, 85, 86, 87, 89, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, and 150.

41. The at least one RNA biomarker is a. hsa-let-7i-5p, hsa-miR-107, hsa-miR-126-5p (=miR-126 ＊ ), hsa-miR-135b-5p, hsa-miR-142-3p, hsa-miR-142-5p, hsa-miR-143-3p (=miR-143), hsa-miR-148a-3p, hsa-miR-206, hsa-miR-29c-3p, hsa-miR-34b-3p, hsa-miR-425-5p, hsa-miR-449a, hsa-miR-671-3p, hsa-miR-6748-3p, and hsa-miR-934, or any combination thereof, and / or b. one or more miRNAs selected from the group consisting of hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7f-5p, hsa-miR-103a-3p, hsa-miR-21-5p, and hsa-miR-92a-3p, or any combination thereof, and the composition according to any one of claims 37 to 40.

42. A method for diagnosing and treating traumatic brain injury (TBI) in a human subject in need thereof, the method comprising obtaining a saliva sample from the subject, contacting the saliva sample with a. hsa-miR-1246, hsa-miR-126-3p (miR-126 ＊ ), hsa-miR-144-3p (miR-144 ＊ ), hsa-miR-144-5p (=miR-144 ＊ ), hsa-miR-16-1-3p, hsa-miR-339-5p, hsa-miR-497-5p, put-miR-1204, put-miR-323, put-miR-325, put-miR-444, put-miR-465, put-miR-469, put-miR-594, put-miR-856, put-miR-893, put-miR-958, RNU4-6p, SNORA57, SNORD3B-2, tRNA120-AlaAGC, tRNA18-ArgCCT, tRNA27-MetCAT, tRNA2-LeuTAA, tRNA73-ArgCCG, tRNA8-ThrAGT, tRNA9-TyrGTA, U2.3, U4.64, U6.168, U6.601, UC022CJG1, YRNA-245, and YRNA-684, or any combination thereof, and / or b. a probe comprising a nucleic acid capable of binding to at least one RNA biomarker selected from the group consisting of put-miR-1003, put-miR-1080, put-miR-1084, put-miR-1146(2), put-miR-1207, put-miR-1306, put-miR-188, put-miR-209, put-miR-468, put-miR-476, put-miR-6, put-miR-71, put-miR-742, put-miR-806, put-miR-92, put-miR-961, RNU6-4, RNU6-45, RNU6-6, RNU6-7, RNU6-73, U6.1249, U6.375, U6.428, and YRNA-255, or any combination thereof and contacting it with a probe comprising a nucleic acid capable of binding to at least one RNA biomarker. Determining the amount of the at least one RNA biomarker in the saliva sample; Identifying a subject having TBI as one in which the amount of the at least one RNA biomarker increases or decreases relative to a predetermined threshold or relative to the amount of the RNA biomarker in a control sample; One or more of the following: Administering one or more neuroprotective therapies to the subject; Treating the subject identified as having TBI according to; a method comprising.

43. The method according to claim 42, wherein the saliva sample is obtained during a post-injury period selected from the period immediately after injury to any period after injury.

44. The method according to claim 43, wherein the saliva sample is obtained during a post-injury period selected from immediately after injury until at least one expression level of the RNA biomarker returns to the predetermined threshold or the amount of the RNA biomarker in the control sample.

45. The method according to claim 43, wherein the saliva sample is obtained during a post-injury period selected from immediately after injury to 1 year after injury, 10 months, 8 months, 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 25 days, 20 days, 15 days, 7 days, 5 days, 3 days, 2 days, and / or 24 hours after injury.

46. The method according to claim 45, wherein the saliva sample is obtained during a post-injury period selected from 15 days after injury, 1 hour to 15 days, 24 hours to 15 days, 24 hours to 7 days, and 2 to 5 days.

47. The method according to claim 42, further comprising obtaining one or more additional saliva samples from the subject at one or more additional times after injury and repeating the detection and amplification steps for each additional sample.

48. The method according to claim 47, wherein the one or more additional saliva samples are obtained during a post-injury period selected from immediately after injury to any period after injury.

49. The method according to claim 47, wherein the one or more additional saliva samples are obtained during a post-injury period selected from immediately after injury until at least one expression level of the RNA biomarker returns to the predetermined threshold or the amount of the RNA biomarker in the control sample.

50. The method of claim 47, wherein the one or more additional saliva samples are obtained during a post-injury period selected from immediately after injury to up to 1 year after injury, up to 10 months, up to 8 months, up to 6 months, up to 5 months, up to 4 months, up to 3 months, up to 2 months, up to 1 month, up to 25 days, up to 20 days, up to 15 days, up to 7 days, up to 5 days, up to 3 days, up to 2 days, and / or up to 24 hours after injury.

51. The method of claim 50, wherein the one or more additional saliva samples are obtained during a post-injury period selected from immediately after injury to 15 days, from 1 hour to 15 days, from 24 hours to 15 days, from 24 hours to 7 days, and from 2 to 5 days after injury.

52. The method of claim 47, wherein the one or more additional saliva samples are obtained on the 1st, 1.5th, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, or 15th day after the injury.

53. The method according to any one of claims 42 to 52, wherein detecting the amount of the at least one RNA biomarker is performed using a PCR-based assay, a microarray assay, a laminar flow chip assay, or any assay suitable for detecting at least one RNA biomarker.

54. The method of claim 53, wherein when using the PCR-based assay, a predetermined threshold corresponds to a fold change of 1.5 or more using the 2-delta delta CT (2-ΔΔCT) method.

55. The method of claim 53, wherein a predetermined threshold corresponds to a fold change of 2 or more using the 2-delta delta CT (2-ΔΔCT) method.

56. The at least one RNA biomarker is a. hsa-let-7i-5p, hsa-miR-107, hsa-miR-126-5p (=miR-126 ＊ ), hsa-miR-135b-5p, hsa-miR-142-3p, hsa-miR-142-5p, hsa-miR-143-3p (=miR-143), hsa-miR-148a-3p, hsa-miR-206, hsa-miR-29c-3p, hsa-miR-34b-3p, hsa-miR-425-5p, hsa-miR-449a, hsa-miR-671-3p, hsa-miR-6748-3p, and hsa-miR-934, or any combination thereof, selected from the group consisting of, and / or b. selected from the group consisting of hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7f-5p, hsa-miR-103a-3p, hsa-miR-21-5p, and hsa-miR-92a-3p, or any combination thereof, The method according to any one of claims 42 to 55, further comprising one or more miRNAs.

57. The method of claim 42, further comprising identifying the human subject as suitable for normal activities after successful treatment of TBI.

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