Article In Brief
Investigators identified changes on tau-PET scans and increases of neurofilament protein-light chain in veterans who had been exposed to blast injury and were experiencing psychiatric, behavioral, and/or cognitive symptoms. Similar changes were observed in a rat model of blast injury.
Researchers identified pathological changes—in blood and brain scans—in veterans who had been exposed to blast injury and were experiencing psychiatric, behavioral, and/or cognitive symptoms.
The research team—led by Gregory A. Elder, MD, professor of neurology and psychiatry at Mount Sinai and chief of neurology at the James J. Peters VA Medical Center, and Samuel E. Gandy, MD, PhD, professor of neurology and psychiatry at Mount Sinai and director of the Center for Cognitive Health and NFL Neurological Care—identified changes on tau-PET scans and increases of neurofilament protein-light chain (NfL) that have been associated with other brain injuries and brain diseases.
They also found that a rat model of mild traumatic brain injury (created by delivering mild air pressure to the front of the skull) showed similar findings in the blood and brain.
These biomarkers, together with clinical data from neuropsychological and neurocognitive assessments, could provide a more objective way to diagnose traumatic brain injury (TBI) and study treatments that could target these brain changes, the researchers said.
“There are many young, otherwise healthy veterans who have suffered blast-related TBIs, some of them years in the past, who either are not getting better or, in some cases, are getting worse,” Dr. Elder said. “We do not know why or how to identify those at greatest risk. The work in this study is a step towards answering those questions.”
The study was published in the February issue of Molecular Psychiatry.
Study Design, Findings
To conduct the study, Dr. Gandy and his colleagues recruited 10 male veterans who had been deployed to Iraq or Afghanistan, and seven non-military men as controls. All 10 of the veterans had experienced between one and 50 blast exposures (usually due to improvised explosive devices) and reported behavioral and cognitive complaints that began after the blast exposure. The controls had no history of head injury or behavioral or cognitive complaints. People with significant mental illness (other than post-traumatic stress disorder or depression in the veterans) or neurological disease, TBI, or current drug or alcohol abuse were excluded from the study.
All study subjects underwent MRI and separate PET imaging using first a ligand specific for amyloid-beta deposits and then using a ligand specific for tau tangles (or “tauopathy”). They also underwent neurocognitive, behavioral, and psychological assessments, as well as blood tests and clinical exams.
The researchers reported that the MRI diffusion tensor imaging showed subtle microstructural disruption in five of nine veterans and one of the seven controls. None of the men in either group retained the PET ligand for amyloid-beta deposits. Five of the 10 veterans had excess retention of the [18F]AV1451 (flortaucipir) tauopathy ligand deep in the sulci at the white/gray matter junctions in frontal, parietal, and occipital brain regions. The veterans with the highest level of tau ligand retention were also those with the most severe behavioral, cognitive, and psychiatric symptoms. These veterans also had the highest levels of NfL circulating in their blood. Additionally, there was evidence that these individuals had higher MRI cortical diffusivity analysis scores.
The control group scored higher on IQ tests, but the two groups did not differ on most tests of attention or processing speed, or visual or verbal memory. The veterans did have lower fine-motor dexterity and also had significantly higher levels of depression.
At the same time the human studies were underway, Dr. Elder was testing a rat model developed to mimic a mild TBI or subclinical blast exposure in humans. The animals developed anxiety and behavioral traits, possibly similar to the complaints from the brain-injured veterans.
The researchers found that rats exposed to repetitive, low-level blasts accumulated abnormal tau (“phospho-tau” or p-tau) in various brain regions, and in astrocytes around blood vessels. The p-tau levels were elevated up to a year following the blast exposure.
The animal model has allowed Drs. Gandy and Elder to test potential new drugs for mild TBI. They have identified a molecule that relieves all of the behavior and cognitive changes seen in the rats after the acute injury. They are now applying for federal approval to begin testing the drug in humans.
Questions remain. While these findings link blast injury to tauopathy and neuronal injury, could the use of these biomarker signatures help properly diagnose TBIs in veterans who experienced blast exposures in the theater? Also, could the pathological and neurochemical findings presage a future neurodegenerative condition like chronic traumatic encephalopathy?
“There is so much that we do not know,” said Dr. Gandy. “There are football players and boxers who get pummeled everyday yet never get dementia. We want to understand who is at the highest risk, and why. Until we have effective interventions, we will be challenged in finding a way to disclose these diagnoses to veterans and athletes and their families without inadvertently making the situation worse by causing them to feel responsible and regretful about their decisions.”
This applies not only to adults making decisions for themselves about contacts sports or military enlistment, he said, but also to the parents of children wanting to play extreme contact supports.
The scientists acknowledged limitations in the study. The number of veterans was small and it would be difficult and expensive to replicate the findings in larger samples. The tauopathy-PET scans in living subjects, in this case middle-aged men, also require correlation with post-mortem neuropathological assessments to confirm that they are correctly interpreting the scans and blood tests. The researchers have now enrolled an additional 15 veterans, and plan to bring them all back for additional studies with these same ligands as well as with new ligands as they become available.
The study was primarily supported by the Alzheimer's Drug Discovery Foundation and the Department of Veterans Affairs.
“This is a very important step in understanding long-term consequences of exposure to blast trauma in our military service members,” said Robert A. Stern, PhD, professor of neurology, neurosurgery, and anatomy & neurobiology, and director of clinical research, at Boston University's Chronic Traumatic Encephalopathy (CTE) Center, and senior investigator at the Alzheimer's Disease Center at Boston University School of Medicine.
“This study is also unique in its translational approach including both an animal model and in vivo human data, as well as using both fluid and neuroimaging biomarkers in the same study. It is critical for the field to develop a variety of fluid and neuroimaging biomarkers.”
Dr. Stern added that it is “important to differentiate the effects of traumatic brain injury, post-traumatic stress disorder, and chronic traumatic encephalopathy, and other conditions that our veterans are experiencing. All of these conditions share similar features so differential diagnosis can be difficult. Being able to have objective biomarkers will be important for clinical decision-making now and in the future.”
There are several points that need addressing, he added. “This is a small sample and it would be important to know whether any of the men in the study had a history of playing contact sports. Also, he said, veterans who trained at military service academies are required to take a boxing course, and it isn't clear if any of the veterans in this study had a history of boxing, or if they played contact sports like football.”
“The current study is very comprehensive and should go a long way in helping to translate the findings into new tests that would be useful for arms of the military as well as contact sports, in which there is increased risk for head trauma,” added Rudolph E. Tanzi, PhD, the Joseph P. and Rose F. Kennedy professor of neurology at Harvard Medical School, and vice chair of neurology, and director of the genetics and aging research unit at Massachusetts General Hospital.
“These data are very consistent with, and nicely expand upon, the findings in Science Translational Medicine in 2012.” Dr. Tanzi was a collaborator in that study, as was Dr. Stern.
Bennet Omalu, MD, a pathologist who conducted the first autopsy in a football player and described a disease he termed CTE, said that “for now, the diagnosis of traumatic encephalopathy syndromes, including CTE, should be based on symptoms and exposure history.
“We should be cautious about the interpretation of some of these findings,” Dr. Omalu said. “There is evidence that tau markers may be picking up other proteins when infused into the body. It is not clear whether the PET biomarker is highlighting tau or cross-reacting with other proteins. We usually do not see tau concentrated in the areas described in the paper.”
Dr. Stern has received consulting fees for his role as a member of the Advance Medical Education International Working Group, consulting fees from Eli Lilly as a member of the executive committee for AZS3293 Alzheimer's disease studies, royalties for published neuropsychological tests from Psychological Assessment Resources, Inc., and has stock option as a member of the Board of Directors of King-Devick Technologies, Inc. Drs. Gandy and Tanzi had no disclosures.