PARIS—Older veterans who had suffered any type of traumatic brain injury (TBI) — whether on or off the battlefield — were more than twice as likely to receive a diagnosis of dementia as those without such injuries, researchers reported here at the Alzheimer's Association International Conference.
In a large retrospective cohort study, 15 percent of veterans with a history of TBI had a diagnosis of dementia indicated on their charts, compared with 7 percent of veterans with no TBI, said Kristine Yaffe, MD, professor of psychiatry, neurology, and epidemiology at the University of California, San Francisco and director of the Memory Disorders Program at the San Francisco VA Medical Center. While some studies have shown that TBI is associated with an increased risk of dementia, others have not shown such a link, Dr. Yaffe said.
The current report is timely, Dr. Yaffe said, as TBI is often referred to as the “signature wound” of the Iraq and Afghanistan conflicts. A 2008 report from the Institute of Medicine found that TBI accounts for 22 percent of causalities overall, and 59 percent of those in soldiers with blast exposures.
To determine if there was an association between specific TBI diagnoses and the risk of developing dementia in older veterans, Dr. Yaffe and colleagues analyzed the medical records of 281,540 US veterans age 55 years and older who had a least one inpatient or outpatient visit during two periods: a baseline period from 1997 to 2000 and a follow-up interval from 2001 to 2007. None of the subjects had dementia prior to their follow-up visits.
The International Classification of Diseases 9th edition, or ICD-9, medical record codes were used to determine the presence of TBI diagnoses during the baseline period and dementia diagnoses during the follow-up interval.
Overall, 1.7 percent, or 4,902, of the veterans had a TBI diagnosis during the baseline period, Dr. Yaffe reported.
The most common type of brain trauma was intra-cranial injury, which accounted for 40 percent of TBI diagnoses. This was followed by unspecified head injury, which accounted for 34 percent of TBIs; concussion, which accounted for 15 percent; post-concussion syndrome, which accounted for 12 percent, and skull fracture, which accounted for 5 percent of TBI diagnoses. More than one diagnosis was noted in 6 percent of subjects.
After adjustment for demographic factors (age, sex, and race), medical conditions — diabetes, hypertension, ischemic heart disease, myocardial infarction, cerebrovascular disease, cancer, and psychiatric conditions (post-traumatic stress disorder, major depression, bipolar disorder, schizophrenia, and substance abuse) — the risk of dementia was a significant 2.3-times higher among veterans with a TBI diagnosis than among those without a TBI diagnosis.
“It really didn't matter what type of TBI diagnosis,” Dr. Yaffe said. A total of 16 percent of those with unspecified head injuries received a diagnosis of dementia, as did 15.7 percent of those with intra-cranial injuries, 15.6 percent with post-concussion syndrome, 14.9 percent with skull fractures, and 11.6 percent of those who had a concussion.
TBI AND DEMENTIA LINK
Several potential mechanisms have been proposed to explain the link between TBI and dementia, according to Dr. Yaffe.
“Perhaps the most plausible is that TBI is associated with diffuse axonal injury caused by shearing forces on neurons. This swelling is accompanied by accumulation of proteins, including amyloid beta [Abeta],” she said, noting that Abeta plaques similar to Alzheimer plaques are present in up to 30 percent of TBI patients who die acutely following TBI, even children.
“Over the longer-term, axonal degeneration may occur, even after a single TBI,” Dr. Yaffe said.
Other potential mechanisms include direct neuronal loss, which could lead to earlier manifestation of symptoms, as well as persistent inflammation or cytoskeletal pathology, she said.
The study was supported through funding from the Department of Defense.
While the large sample size gives strength to the study, it has the inherent biases of a retrospective design that utilizes chart review, said Mel B. Glenn, MD, director of Outpatient and Community Brain Injury Rehabilitation at Spalding Rehabilitation Hospital and associate professor of physical medicine at Harvard Medical School.
“For example, we don't know if people with TBI-associated dementia might have been more likely to come back to the clinic than people with Alzheimer's disease and no TBI,” he said.
Still, clinicians should closely follow and monitor any patient who has suffered a TBI, concussion or other brain injury, no matter whether the diagnosis is concussion or skull injury, Dr. Glenn urged.
Jeff J. Bazarian, MD, associate professor of emergency medicine at the University of Rochester Medical Center in New York, said that a link between TBI and dementia “was already on many people's radar screens” following the Institute of Medicine's 2008 report, Gulf War and Health: Long-term Consequences of TBI.
In the report, the Institute of Medicine concluded that that there is “sufficient evidence” of an association between moderate and severe TBI and dementia of the Alzheimer type and that there is “limited evidence” of an association between mild TBI with loss of consciousness and dementia.
“But those conclusions were based primarily on the general population. This study is important because it involves the types of injuries we're concerned about with our young veterans. Now we can say to them, ‘we have data on veterans suggesting that mild trauma can put you at risk [of dementia],’” he said.
“This is another piece of evidence that even a single concussion — whether from a car accident or a blast — is worth preventing. And if we can't prevent it from happening, we should at least prevent the sequelae,” Dr. Bazarian continued.
One of the major problems is that there is no objective method for diagnosing concussions, he said. Unless there is a witness, diagnosis usually involves the clinician asking the patient with brain injury “who is having trouble remembering whether he can remember losing consciousness,” Dr. Bazarian noted.
In Europe, a blood test that measures levels of serum S-100B protein, a biochemical marker of brain cell damage, is used to screen patients with TBI. “It's used to decide whether to do a CT scan, but even a CT scan doesn't tell you definitively whether there has been a TBI,” Dr. Bazarian said.
Dr. Bazarian and colleagues reported in an October 2009 paper in the Journal of Neurotrauma that despite its high sensitivity for abnormal head CT scans, serum S-100B has low specificity and low positive predictive value, limiting its ability to reduce numbers of CT scans and hospital costs.
Dr. Bazarian and other researchers are working on developing better biomarker tests as well as neuroimaging scans for the diagnosis of brain injuries.
Diffuse tensor imaging shows promise, he said. In a 2007 study in the Journal of Neurotrauma, Dr. Bazarian and colleagues showed damage to the axons occur within 24 hours of a concussion and that such damage correlates with worse symptoms at one month.
In another study of 10 high school athletes that is currently undergoing review, pre- and post-season scans showed that sub-concussive head blows were associated with low-level damage to the white matter, he said.
Other researchers are evaluating drugs to slow or halt the progression from TBI to dementia, Dr. Bazarian said. These include neuroprotective agents to prevent neurons from dying after injury, protective agents to prevent axons from disconnecting, and immune-modulating agents to blunt the immune response that can further injure the brain, he said.
One drug that is already in phase 3 testing is progesterone. The 17-center study follows successful pilot testing — reported in 2007 in the Annals of Emergency Medicine — demonstrating a 50 percent reduction in death among severe TBI patients and less disability among moderate TBI patients.