National Data and Statistical Center

North Texas Traumatic Brain Injury Model System

A Phase II, randomized controlled trial of recombinant human Growth Hormone (rhGH) during rehabilitation from traumatic brain injury - Growth Hormone (GH) deficiency, defined by insufficient GH response to a variety of stimulating compounds, is found in 15 - 35% of adults who suffer traumatic brain injuries (TBI) requiring inpatient rehabilitation. However, there is no accepted gold standard for diagnosing GH deficiency in this population. Further, the major effector molecule of the somatotropic axis, Insulin-Like Growth Factor-1 (IGF-1) has recently been recognized as an important neurotrophic agent. Since most repair and regeneration after TBI occurs within the first few months after injury, absolute or relative deficiencies of GH and IGF-1 in the subacute period after TBI may be contributing factors in the limited recovery seen in some patients. The proposed study is a Phase II, randomized, double-blind, placebo-controlled trial of rhGH starting at 1 month post-injury and continuing for 6 months. This study aims to determine if treatment with recombinant human Growth Hormone (rhGH) in the subacute period after TBI results in: (1) improved functional outcome 6 months after injury; (2) increased IGF-1 levels; (3) improved bone mineral density and lean body mass 6 months after injury; and (4) gives persisting benefits up to 1 year after injury. It also hopes to determine if: (5) low GH response to L-arginine stimulation at baseline is associated with poor functional outcome; (6) low IGF-1 levels at baseline are associated with poor functional outcomes; (7) rhGH treatment is more effective in patients who have low GH response to L-arginine stimulation at baseline; and (8) rhGH treatment is more effective in patients who have low IGF-1 levels at baseline.

Imaging Biomarkers of Diffuse Axonal Injury - A common mechanism of traumatic brain injury (TBI) is Diffuse Axonal Injury (DAI). DAI is characterized by microscopic axonal lesions that commonly appear in subcortical white matter of patients with acceleration/deceleration type injuries. DAI is the predominant mechanism of injury in 40 – 50% of traumatic brain injuries that require hospital admission, and it is likely that DAI is a component of injury in all cases of TBI resulting from high-speed motor vehicle collisions. The inability to accurately identify and measure DAI during life is a major limitation in the clinical management of TBI. Additionally, clinical trials of neuro-protective and axono-protective therapies directed at DAI are unlikely to be successful unless there are reliable and validated biomarkers which will allow subphenotyping of injury mechanisms. The goal of our proposal is to develop and validate Diffusion Tensor Imaging (DTI) as a biomarker of DAI. A secondary objective is to determine if other neuroimaging measures are useful biomarkers. We will accomplish our objectives through the following three specific aims: (1) Obtain MRI scans on patients who have suffered moderate and severe closed head injuries during high-velocity motor vehicle collisions within 1 week after injury. Additional image measures will include high resolution T1 weighted, FLAIR images, and susceptibility weighted imaging. An additional 20 controls matched by age and gender to the patients will also be recruited and scanned. (2) Obtain repeat MRI scans and assess outcome 6-months after injury using a focused neuropsychological battery and validated structured interviews. In addition to the sequences used in the first scan, we will also obtain functional connectivity MRI (fcMRI) at 6-months post-injury. Additionally, because neuropathologic analysis is the gold standard for identifying DAI, (3) pathologic confirmation of the DAI lesions identified by DTI in the acute scans will be obtained using standard pathologic criteria and immunohistological techniques. These studies will represent the first attempt to correlate MRI-identified lesions during life with the gold-standard pathologic diagnosis.