Protein Related to Long Term Traumatic Brain Injury Complications Discovered

A protein previously linked to acute symptoms following a traumatic brain injury (TBI), may also be responsible for long-term complications that can result from TBI, according to research from the National Institute of Nursing Research (NINR), a component of the National Institutes of Health.

Using an ultra-sensitive technology, researchers — led by NIH Lasker Clinical Research Scholar and Chief of NINR’s Brain Injury Unit, Tissue Injury Branch Jessica Gill, Ph.D., R.N., — were able to measure levels of the protein, tau, in the blood months and years after individuals (in this case, military personnel) had experienced TBI. They found that these elevated levels of tau — a protein known to have a role in the development of Alzheimer’s disease and Parkinson’s disease — are associated with chronic neurological symptoms, including post-concussive disorder (PCD), during which an individual has symptoms such as headache and dizziness in the weeks and months after injury. These chronic neurological symptoms have been linked to chronic traumatic encephalopathy (CTE) — progressive brain degeneration that leads to dementia following repetitive TBIs — independent of other factors such as depression and post-traumatic stress disorder (PTSD). 

“Our study was limited to identifying the effects of tau accumulation in military personnel who experienced long-term neurological symptoms after a TBI. With further study, our findings may provide a framework for identifying patients who are most at risk for experiencing chronic symptoms related to TBI. Identifying those at risk early in the progression of the disease provides the best opportunity for therapies that can lessen the cognitive declines that may result from these long-term effects,” said Dr. Gill, the study’s lead author.

About one-third of all U.S. military personnel who serve in combat operations experience at least one TBI. Individuals with TBI are more likely to experience ongoing complications such as PCD, PTSD, and depression and are also more likely to develop CTE — however, there is currently no way to identify those who are at greatest risk for developing these chronic symptoms.

To help identify biomarkers to better pinpoint those at-risk, the researchers explored whether elevated levels of tau are related to chronic neurological symptoms in military personnel who had experienced TBI.

“The work of Dr. Gill and colleagues has demonstrated that tau plays a continuing role in TBI and highlights its significant effects on long-term health and quality of life,” said NINR Director Patricia A. Grady, Ph.D., R.N.

Tau is released from nerve cells, and is the protein that helps provide structural support to the axonal cytoskeleton — the framework that helps control the growth of the brain’s neurons. Elevated levels of tau are a known sign of axonal injury — a serious type of TBI in which the brain’s neurons are unable to communicate with other parts of the body, often leading to coma — and can be measured in the cerebrospinal fluid and blood immediately following a severe TBI. Levels of tau in the blood can be elevated in the hours and days following an injury, but were thought to return to normal levels within the months following a TBI.

Included in the study were military personnel, with or without a history of TBI, who had been deployed for combat in Operation Enduring Freedom (Afghanistan) and/or Operation Iraqi Freedom within the previous 18 months. The researchers examined participant medical records as well as responses to the Warrior Administered Retrospective Casualty Assessment Tool to determine if participants had been diagnosed with or treated for a TBI.

A total of 70 military personnel with a history of TBI and 28 without a history of TBI were enrolled in the study. Researchers used standard assessments to measure PTSD, depression, and other neurological and psychological symptoms among participants. Additionally, researchers took blood samples from each participant.

The researchers also linked the physical PCD symptoms that can persist after TBI to elevated levels of tau, independent of other psychological symptoms such as PTSD and depression. These findings suggest that long after the primary brain injury, tau accumulations alone may contribute to chronic neurological symptoms.

Tau concentrations in the blood of patients who experience chronic symptoms or negative effects of TBI have proven difficult to measure. Because of this difficulty, tau’s role in chronic complications following TBI has been unclear. The investigators hoped that by using a new, ultrasensitive immunoassay technology, they could more easily measure the protein and clarify its role in long-term complications of TBI. The technology’s increased sensitivity (it is about 1,000 times more sensitive than conventional methods of measurement) allowed researchers to accurately measure levels of tau in participants’ blood, finding elevated tau levels in the blood samples of these military participants with a history of TBI compared with participants who had never suffered a TBI.

Additionally, researchers found that participants with three or more deployment-related TBIs had significantly higher levels of tau compared with participants who had fewer TBIs.

Knowledge of the relationship of tau accumulation to chronic complications related to TBI may also someday provide a therapeutic target for treating the causes of CTE and other neurodegenerative and psychological conditions that can result from these types of injury. “It’s possible that further research could examine methods to reduce the accumulation of tau and discover ways to mitigate or eliminate associated chronic neurological symptoms,” noted Dr. Grady.