Autopsies of four U.S. military veterans who served in Iraq and Afghanistan reveal features of the same neurodegenerative disease found previously in athletes, researchers report. Experiments with mice suggest that the underlying mechanisms may be similar.
In the past 10 years, the widely reported suicides and accidental deaths of professional football players and other athletes—such as that of Junior Seau earlier this month -- have sparked inquiries into whether even seemingly minor blows to the head can cause personality changes, dementia, and brain degeneration later in life. Autopsies of dozens of former players have revealed a condition known as chronic traumatic encephalopathy (CTE). Its hallmark is the abnormal accumulation of a protein called tau. Many of the athletes diagnosed with CTE on autopsy (currently the only definitive test) had a history of problems with anger, rash and risky decision-making, impairments of memory and attention, and alcohol or drug abuse.
Clinicians and researchers working with troops returning from Iraq and Afghanistan have seen similar symptoms. The new study, led by Lee Goldstein, a physician-scientist who focuses on neurodegenerative disease at Boston University, and Ann McKee, a neuropathologist at the Bedford Veterans Affairs Medical Center in Massachusetts, ties these troublesome threads together.
McKee examined the brains of four veterans, men between the ages of 22 and 45, who suffered from various combinations of cognitive, emotional, and impulse-control problems before dying from suicide or other causes. Under the microscope, she found tangles of tau and damage to axons, the spindly extensions that convey signals from one neuron to another. In athletes with CTE, these abnormalities occur primarily in the frontal lobes of the brain, McKee says. In the blast-injured veterans, the pathology is more evenly distributed. "But when you look microscopically, it's very, very similar," she says.
"Whether there is a relationship between CTE and blast … is definitely a question that we feel needs to be answered," says Colonel Dallas Hack, a physician who coordinates trauma research for the U.S. Armed Forces. In his view, the new cases are suggestive but not conclusive. He notes that three of the four cases had previous concussions from sports, fights, and accidents, and one was not exposed to a blast in combat. "Was their military service part of the cause? We don't know that yet."
Mouse experiments presented in the new paper, published online today in Science Translational Medicine, may provide a clue. They bolster the case that blasts cause brain pathology because the mice were exposed to a blast and nothing else, says co-author Goldstein. The researchers placed the rodents in a 4.5-meter-long tube and used compressed gas to create a shock wave comparable to what a soldier might experience from a blast at close range. The setup differed from previous blast tube experiments in that the animals' heads were unrestrained. This more closely mimics what happens in combat by allowing the so-called bobblehead effect, in which a blast momentarily causes the head to flop back and forth on the neck, Goldstein says.
In these experiments, 2 weeks after exposure to a single blast, mice exhibited accumulations of chemically modified, or phosphorylated, tau in their brains, suggesting that the pathological process that leads to the fully formed tangles seen in the veterans' brains was already underway. Blast-exposed mice also exhibited inflammation and damage to axons and capillaries in the brain.
The researchers also found sick and dying neurons in the hippocampus, a brain region important for learning and memory. Given the common complaints of forgetfulness and other cognitive problems in veterans, Goldstein and colleagues followed up with additional experiments that revealed abnormalities in the electrical signaling of hippocampal neurons in blast-exposed mice, as well as learning and memory deficits on a maze test. These deficits did not occur when the researchers immobilized the head of a mouse during a blast, which suggests to Goldstein that it's the whipsaw motion of the head that initiates the injury.
"This is a really good piece of work," says David Hovda, a neuroscientist who studies brain injury at the University of California, Los Angeles. Researchers have long debated whether the biomechanics of blast injuries are distinct from those of other types of head injuries, he notes. The new study argues instead that blasts injure the brain by causing acceleration and deceleration of the head: "That would mean we're looking at the same type of injury in Afghanistan that we're looking at on the football field or in a car accident."
Going forward, a major question for both athletes and military personnel is the number and type of hits it takes to cause CTE, says Daniel Perl, a neuropathologist at the Uniformed Services University of the Health Sciences in Bethesda, Maryland. Perl has funding from the Army to create a brain bank repository that he hopes will enable researchers to connect the dots between head injuries, clinical problems, and neuropathology. Such work will help determine whether CTE becomes a bugbear for veterans as it has for athletes.
A longer version of this article will appear in the 18 May issue of Science.