Gene Variants May Help Predict Recovery from TBI and PTSD

by Kayt Sukel

April 22, 2014

Over the past decade, more than 1 million US military service members have served in Operation Iraqi Freedom and Operation Enduring Freedom. According to the Congressional Research Service, of those deployed service members, more than 100,000 have returned from their time in combat with a diagnosis of traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), or both. While their diagnoses may be the same, these soldiers will not only experience different levels of disability but also show varying levels of functional recovery over time. New research looking at the brain-derived neurotrophic factor (BDNF) gene suggests that having a particular polymorphism could help predict which patients will respond to treatment in both cases.

The power of "brain fertilizer"

BDNF is a small protein found in both the brain and the peripheral nervous system. One of my own neuroscience professors affectionately called BDNF "brain fertilizer:" A neurotrophin, or nerve growth factor, BDNF helps to promote the differentiation, growth, and survival of nerve cells across the nervous system. Problems with BDNF have been linked to a host of neuropsychiatric disorders, including depression, motor disorders, PTSD, and TBI.  

"This is a protein that has a function in preserving and promoting growth of neurons," says David Benedek, a psychiatrist at the Uniformed Services University of the Health Sciences (USUHS) in Bethesda, MD. "So it's not surprising that it would play an important role in a number of neurological and psychiatric disorders. And because BDNF had been identified as a potential biomarker for other illnesses, it seemed a reasonable thing to look at for PTSD as well."

In a study published earlier this year in Molecular Psychiatry, Benedek and colleagues looked at BDNF levels and genotypes of more than 400 US Army Special Operations soldiers. The researchers found that soldiers with a specific genetic variant for BDNF, Met/Met, were at a higher risk for development of PTSD after three or four lifetime stress events. Furthermore, that variant was also linked to stronger startle responses in the soldiers who had not yet developed the disorder.

"It's not just that this allele is a marker for an increased risk of PTSD with lower total life stressors," says Benedek. "It also marked a specific and single symptom of PTSD, even when full-blown PTSD is not developed. This gives us new clues into the role BDNF may play in the development of the disorder."

Benedek thinks the Armed Forces could one day use BDNF genotypes as a biomarker to identify which soldiers may be at an increased risk for PTSD. "This could help us identify people who may particularly vulnerable under specific conditions and get them the right kind of training to prevent it," he says. "But it could also, one day, be used to monitor disease severity after PTSD is developed to indicate the effectiveness of treatments."

Predicting response to PTSD treatment

A different BDNF variation, the Val/Val allele, has been linked to improved treatment outcomes in people with PTSD. After learning that direct shots of BDNF to the rat limbic cortex could all but extinguish the conditioned fear response, Kim Felmingham, a clinical psychologist who works with people with PTSD at the University of Tasmania, wondered if she could find any genetic markers for treatment response in individuals who had been through exposure therapy, a treatment program where patients are exposed to their fears in a controlled and safe setting in order to "re-wire" the fear pathways.

"It was really quite intriguing to me. I realized that we were sitting on all this treatment-related data, including genetic data, and we could actually just take a look and see if there was anything related to BDNF in our outcomes," she says.

Felmingham and colleagues found that, in a sample of 55 patients who had undergone an intensive 8-week exposure therapy program, those with the Val/Val allele showed a better response to the treatment than those with the Met/Met or Val/Met variations. The study was published in the June 2013 issue of Biological Psychiatry.

"The result is quite convergent with much of the animal literature," she says. "But we need to work to join the dots, and better understand just how BDNF may be involved in both the development of the disorder as well as in its treatment."

Predicting TBI outcomes

The BDNF gene has also been tied to how well a person recovers from TBI. Aron Barbey, a neuroscientist at the University of Illinois, says that makes sense-BDNF variance could influence several processes involved in regaining function after injury, including both pre-injury cognitive capabilities and spontaneous molecular repair mechanisms in the brain afterward. Many members of the Armed Forces are diagnosed with both TBI and PTSD.

Barbey and his colleagues looked at BDNF genotypes in 156 Vietnam War veterans with TBI. They found strong differences when it came to outcomes after injury. Those with the Val/Val genotype scored approximately 8 points lower on IQ tests than the others. They also showed greater impairment on cognitive skills like verbal comprehension and working memory than those with the Met/Met or Val/Met allele. The results were published in PLOS ONE in February of this year.

"The size of the effects we observed were quite remarkable. Both the scope and the extent of the impairment observed between these different genotypes was striking," says Barbey. "And by understanding the contribution of this particular polymorphism to TBIs, it may help us determine the best kind of treatment for each individual in the future."

Joining the dots

While these studies suggest that BDNF is important to two conditions that plague the military community today, all of the researchers are quick to say that these studies are very preliminary. As Felmingham said, both clinicians and basic scientists need to work together to "join the dots" in order to gain full understanding of how this neurotrophin influences PTSD and TBI, both in terms of development and recovery.

"What you see are many studies with low sample sizes. We know that, with any disorder, there's not going to be some single genotype effect. Everything is polygenic," she says. "We need to start investing in large-scale studies with thousands and thousands of people in them. We have to look beyond just one genotype. But, that said, I think we've made some really remarkable gains in the past 5 to 10 years and those gains have the power to one day to improve outcomes for the patients who really need help. You have to start somewhere."