Grants Totaling $10 Million Facilitate Traumatic Brain Injury Research

Ramon Diaz-Arrastia, MD, PhD, is leading the charge to advance understanding and treatment of traumatic brain injury.

Three grants awarded to Penn Neurology in recent months are facilitating ancillary studies to two major, multicenter clinical trials exploring the effects of traumatic brain injury (TBI). The grants total approximately $10 million.

“There’s been a significant increase in the amount of funding provided by the federal government for the study of TBI over the last 10 years,” says Ramon Diaz-Arrastia, MD, PhD, Presidential Professor of Neurology and Attending Neurologist at Penn Presbyterian Medical Center. “It’s come as a consequence of the recent combat in the Middle East as well as the evolving realization that athletes who participate in contact sports often suffer head injuries that have consequences.”

Strategies for Monitoring and Treating Intensive Care TBI Patients

BOOST3 (Brain Oxygen Optimization in Severe TBI Phase 3) is a large, multicenter study, launched last year through a $32-million investment by the National Institute of Neurologic Disorders and Stroke (NINDS). The randomized, clinical trial is attempting to determine the comparative effectiveness of two strategies for monitoring and treating patients with TBI in the intensive care unit.

Dr. Diaz-Arrastia is the protocol principal investigator (PI) for BOOST3. He was the contact PI for BOOST Phase 2. One of the three new grants is called Bio-BOOST, which will collect blood and spinal fluid samples from a subset of patients enrolled in BOOST3. Funded by the Department of Defense, Bio-BOOST will determine the relationship between brain injury biomarkers and abnormal physiology monitored by invasive intracranial probes.

Analyzing Data Across the Injury Spectrum

The other two grants are earmarked for supplemental studies to TRACK-TBI (Transforming Research and Clinical Knowledge in Traumatic Brain Injury), a multi-institutional, observational study that began several years ago. In collaboration with public-private partners, researchers are collecting and analyzing detailed clinical data on subjects at 18 sites in the United States across the injury spectrum, along with CT/MRI imaging, blood biospecimens, and detailed clinical outcomes.

During the initial phase of TRACK-TBI, 3,000 patients were enrolled and followed for one year after their injuries. “We’re very interested in continuing to follow-up with them because we know that not everything that’s important in their recovery happens within the first year,” says Dr. Diaz-Arrastia.

TBI and Post-Traumatic Epilepsy

One of the ancillary studies, called TRACK-TBI Epi, will focus that ongoing follow-up on post-traumatic epilepsy. People who have had a TBI are at an increased risk of developing epilepsy—in severe cases, the risk is over 25%—and it often occurs several years after the injury, according to Dr. Diaz-Arrastia. Through TRACK TBI Epi, which is also being funded by the Department of Defense, the follow-up will be extended through five years for all 3,000 patients enrolled in TRACK-TBI.

“A telephone evaluation will be part of TRACK-TBI Epi and will include a screening questionnaire to see if they’re having events that could be post-traumatic seizures,” Dr. Diaz-Arrastia says. “Those who screen positive will be invited to come in for an in-person evaluation, which will include an MRI, EEG, and an evaluation by an epilepsy specialist to adjudicate whether they’re in fact having epilepsy or they’re having some other kinds of spells that may be non-epileptic.”

TRACK-TBI Epi is the first study of this magnitude that will allow prospective assessment of the development of post-traumatic epilepsy in people for whom so much data was collected during their acute period, according to Dr. Diaz-Arrastia. “We’re very interested in this project allowing us to identify predictive biomarkers that ultimately inform the design of potential anti-epileptogenic therapies because the therapies we have now can only control the seizures once the epileptogenic process has already taken place,” he says.

Assessing Neurofiliment Light as a Biomarker of External Injury

TRACK-TBI Bio is the second ancillary study funded by one of the newly-awarded grants. This NINDS-funded study will analyze neurofilament light—a protein found in the axons—in blood samples collected through TRACK-TBI. Samples were taken on the day of the patient’s injury, three days later, five days later, two weeks later, and six months later. “We’re going to evaluate how the elevations of neurofilament light correspond to the MRIs that we have,” Dr. Diaz-Arrastia says. “There are studies that point in this direction, but this will be by far the largest study to date to assess whether neurofilament light is a biomarker of external injury.

“One of the major pathologies in people that have had a brain injury is diffuse axonal injury to the large myelinated axons in the central nervous system,” Dr. Diaz-Arrastia. “Much of that occurs early on, but it appears to continue for a long period as well.”

TBI and Dementia

There’s early evidence that people who have sustained a TBI are at greater risk of developing dementia later in their lives. Neurofilament light measured in the subacute and chronic period after injury could be helpful in identifying the subset of people who have suffered a TBI and are at risk of developing progressive neurodegeneration and dementia.

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