Methods for aiding in the diagnosis and evaluation of a subject who has sustained an orthopedic injury and that has or may have sustained an injury to the head, such as mild traumatic brain injury (TBI), using glial fibrillary acidic protein (GFAP) and/or ubiquitin carboxy-terminal hydrolase L1 (UCH-L1)

Inventors

McQuiston, Beth • Datwyler, Saul A. • CHANDRAN, RAJ

Assignees

Abbott Laboratories

Abstract

Disclosed herein are methods, and kits for use in said methods, that aid in the diagnosis and evaluation of a subject that has sustained an orthopedic injury and sustained or may have sustained an injury to the head, such as mild traumatic brain injury (TBI), using ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), glial fibrillary acidic protein (GFAP), or a combination thereof. Also disclosed herein are methods, and kits for use in said methods, that aid in determining whether a subject that has sustained an orthopedic injury and sustained or may have sustained an injury to the head would benefit from and thus receive an imaging procedure, such as MRI or head computerized tomography (CT) scan based on the levels of GFAP and/or UCH-L1. These methods involve detecting levels and changes in levels of GFAP and/or UCH-L1 in biological samples taken from a subject at time points within 48 hours after the subject has sustained or may have sustained an injury to the head.

Core Innovation

The disclosed invention provides methods and kits for biomarker-based clinical decision-making in orthopedic-injury patients who may also have sustained an actual or suspected injury to the head. The methods perform at least one assay for ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), glial fibrillary acidic protein (GFAP), or a combination thereof in whole blood, serum, plasma, or cerebrospinal fluid obtained from a human subject within about 48 hours after orthopedic injury, and compare the measured levels to specified reference level ranges.

The measured GFAP and/or UCH-L1 levels are used to determine mild traumatic brain injury (TBI) and/or moderate, severe, or moderate to severe TBI, and in some embodiments to aid in the determination of whether to perform a head computerized tomography (CT) scan or to perform a head CT scan. A subject is determined to be more likely than not to need a CT scan when the level of GFAP and/or UCH-L1 in the sample falls within defined reference ranges, and treatment is based on the TBI determined from the CT scan.

The disclosed treatment regimens are tied to biomarker-defined TBI classification. For mild TBI, treatment comprises rest, abstaining from physical activities, avoiding light, wearing protective eyewear when in light, and/or therapeutic agents selected from a medication for relief of a headache or migraine and an anti-nausea medication, while moderate, severe, or moderate to severe TBI treatment comprises diuretics, anti-convulsant medications, medications to sedate and put an individual in a drug-induced coma, other pharmaceutical or biopharmaceutical medications, surgical procedures including removal of a hematoma, repairing a skull fracture, and decompressive craniectomy, and/or therapies selected from rehabilitation, cognitive behavioral therapy, anger management, and counseling psychology.

The disclosure also describes assay architectures and kit components for measuring GFAP and UCH-L1, including antibody-based labeled immunoassay formats using GFAP- and UCH-L1-capture and detection antibodies that bind non-overlapping epitopes to generate measurable signal. Kits include calibrators and controls composed of GFAP and/or UCH-L1 or fragments.

Claims Coverage

The independent claims provide four inventive features. Each claim uses GFAP and/or UCH-L1 reference levels measured in whole blood, serum, plasma, or cerebrospinal fluid obtained within about 48 hours after orthopedic injury, with downstream decisions for treating mild TBI versus moderate, severe, or moderate to severe TBI, and in two claims, aiding or triggering a head CT scan decision.

Across the independent claims, the inventive coverage centers on assaying GFAP and/or UCH-L1 in blood, serum, plasma, or cerebrospinal fluid within about 48 hours after orthopedic injury with possible head injury, comparing measured biomarker levels to specified GFAP and UCH-L1 reference ranges, and then selecting downstream action either for mild TBI treatment alone or for CT-aided or CT-triggered evaluation followed by CT-based TBI treatment, including distinct mild versus moderate-to-severe treatment regimens.

Stated Advantages

Documented Applications