Ramon Diaz-Arrastia, MD, PhD
Department of Neurology

Christopher Madden, MD
Asst Professor Neurological Surgery

Candidate genetic polymorphisms in outcome after traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity, particularly among persons below the age of 45. In the US, approximately 55,000 deaths each year are attributed to TBI, and an additional 50,000 individuals each year suffer long-term physical and psychological problems that limit their independence and ability to work. Factors such as severity of injury, age, and complications during the acute hospitalization only partly account for outcome, and it is likely that inherited genetic factors predispose certain individuals to have a poor functional outcome after brain trauma. Recent progress in the Human Genome Project has identified common polymorphisms in a number of genes that have been proposed, on the basis of human and animal studies, to regulate the response of neural tissue to injury. Our hypothesis is that inheritance of certain alleles of these polymorphic candidate genes is predictive of poor neurologic recovery after TBI. Understanding which genes may predispose to poor outcome after TBI will be useful in developing tailored therapy to limit damage or improve functional recovery after TBI. This proposal has two specific aims: (1) To characterize and collect DNA from a population of patients who suffered TBI, as well as prospectively collect information on the severity of injury and functional outcome six months after injury. In order to obtain a sufficiently large sample, patients with TBI will be recruited from two busy brain injury centers: Parkland Memorial Hospital/Univ. of Texas Southwestern (Dallas site), and Harborview Hospital Center/Univ. of Washington (Seattle site). Our goal is to collect DNA from 1000 subjects with TBI, anticipating that 50% of them will have a poor outcome, as measured the University of Washington Functional Status Examination. (2) To determine, using a case-cohort approach, whether inheritance of certain polymorphic alleles is associated with poor outcome after TBI. Using the Illumina GoldenGate Platform, we will carryout genotyping at 756 loci in 250 candidate genes, selected because of their association with other human diseases pathophysiologically related to TBI, or due to their functional role in TBI-related pathogenetic mechanisms.

Role of the Doris Duke Fellow:

The fellow will be primarily involved in prospectively collecting clinical information relating to the severity of the initial traumatic injury, following the patients daily during their acute hospitalization, and obtaining outcome data at 6 months, using a structured interview. This will be accomplished by having the fellow attend daily morning rounds with the neurosurgical service at Parkland Memorial Hospital, identify patients who are meet eligibility criteria for the study, obtain informed consent from patients or family members, and collect intake information. Afternoons will be spent analyzing genetic information and performing statistical analysis.

Diffusion Tensor Magnetic Resonance Imaging (DT-MRI) as a biomarker of Diffuse Axonal Injury

Diffuse Axonal Injury (DAI) results from high velocity deceleration and shear strain, and is believed to be the predominant mechanism of injury in 40 - 50% of TBIs requiring hospital admission in the US. DAI is poorly imaged by CT scanning, and conventional MRI, the current method of choice, has not been carefully studied and is of uncertain sensitivity and specificity. 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. The anatomy and integrity of white matter fiber tracts can be determined noninvasively with DTI, providing new information about brain networks and connectivity. Preliminary data from our group indicates that DTI is more sensitive than conventional structural MRI for identifying DAI lesions. 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 with DAI in the subacute period (within 1 week after injury). Patients enrolled will have suffered moderate and severe closed head injuries during high-velocity motor vehicle collisions. Patients requiring craniotomies as well as those with significant midline shift will be excluded. We plan to enroll 40 patients in the study over a 14-month period. Patients will be scanned at 3T and DTI performed in 18 - 30 directions. 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 outcome information 6-months after injury. Patients who survive the acute period will be asked to return for a repeat MRI 6 months after injury. In addition to the sequences used in the first scan, we will also obtain functional connectivity MRI (fcMRI). Additionally, outcome will be assessed using a focused neuropsychological battery and validated structured interviews. We anticipate a 10% acute death rate and a 15% loss to FU rate, thus we anticipate obtaining 30 follow-up scans.

Role of the Doris Duke Fellow:

The fellow will be primarily involved in identifying eligible patients, prospectively collecting clinical information relating to the severity of the initial traumatic injury, following the patients daily during their acute hospitalization, as well as obtaining outcome data at 6 months post-injury. These tasks will be accomplished by having the fellow attend daily morning rounds with the neurosurgical service at Parkland Memorial Hospital, identifying patients who meet eligibility criteria for the study, obtaining informed consent from patients or family members, and collecting intake information. Afternoons will be spent obtaining outcome information via telephone interviews and analyzing MRI data using MRICro and DTI Studio.