ARTICLE IN BRIEF
Investigators reported that of 1,229 vets diagnosed with a traumatic brain injury (TBI), 16 percent developed dementia during the nine-year follow-up, compared with 10 percent who did not experience a TBI.
Traumatic brain injury (TBI) increases the risk of dementia by 60 percent and accelerates onset by about two years, according to a study published in the June 25 online edition of Neurology.
However, the findings, based on medical records of 188,784 veterans with an average age of 68 when the study began, do not provide the fine-grained picture needed to differentiate the effects of milder from more severe TBIs, or the contributions from cardiovascular disease, diabetes, and other confounding factors for dementia, according to neurologists who analyzed the findings for Neurology Today.
Of the 1,229 vets diagnosed with a TBI, 196 (16 percent) developed dementia during the nine-year follow-up, compared with 18,255 (10 percent) who did not experience a TBI (adjusted hazard ratio, 1.57; 95% confidence interval: 1.35–1.83). And TBI victims who did not develop dementia died 2.3 years earlier than those not diagnosed with brain trauma.
Also, the authors, after adjusting for demographic factors and medical history, determined that risk of dementia increased among veterans with TBI if they also suffered from other risk factors such as depression, post-traumatic stress disorder (PTSD), or cerebrovascular disease.
The study helps to clarify conflicting evidence regarding the relationship between TBI and the risk of dementia, said the lead author Deborah E. Barnes, PhD, MPH, an associate professor of psychiatry and epidemiology and biostatistics at the University of California, San Francisco School of Medicine, and a researcher at the San Francisco Veterans Affairs Medical Center.
“Some studies have found an association, while others have found no association,” she said. “Our results come down on the side of head injury being associated with increased risk.”
Dr. Barnes acknowledged that the study did not distinguish different types of dementia. “For all-cause dementia, I think our findings are very strong, but we had limited power to look at dementia subtypes,” she said.
Also, the study relied on diagnoses made by clinicians, which could obscure the types of dementias acquired by the veterans. “We don't know what criteria they used, so I have less confidence in the subtype data than I do in the all-cause dementia data,” she said.
A closer analysis of the medical records would yield more information about the severity and frequency of head trauma, “but it would be a time-intensive process,” Dr. Barnes said. “That is something we would like to do in the future, but it would be a massive undertaking, and we don't have funding to do it now.”
An editorial in the same issue of Neurology praised the study for linking brain trauma to an increased risk of dementia, but also cited the need a more detailed analysis of the correlation. “The relationship of HT [head trauma] with individual genetic and epigenetic predisposition must be further explored in an at-risk population (veterans, athletes, victims of traumatic accidents),” said the author of the editorial, Rodolfo Savica, MD, an assistant professor of neurology at University of Utah Hospitals and Clinics, and director of the Dementia with Lewy Bodies/Parkinson's disease Dementia clinic at University of Utah Health Care. “HT may be one of the best available in vivo models in humans to study the gene/environment relationship in the development of all neurodegeneration.”
While a correlation between TBI and dementia may seem logical and direct, since TBI presumably causes physical damage to brain tissue, Kristine Yaffe, MD, a senior author of the Neurology paper, previous research has also found a correlation between dementia and PTSD, which produces psychological symptoms. Studies have shown that people with PTSD do poorly on cognitive tests and have smaller hippocampal volumes, but she and her colleagues were the first to show a relationship between PTSD and dementia. “Other groups have replicated that finding, so I think it's real,” said Dr. Yaffe, the Roy and Marie Scola endowed chair in psychiatry, and professor of psychiatry, neurology, and epidemiology and biostatistics at the University of California, San Francisco. “We adjusted for a lot of possible confounders and comorbidities, and we still saw something.”
But as the Neurology paper shows, PTSD is merely one of several problems that could amplify the effects of TBI, and make veterans more susceptible to dementia later in life. “We think there are probably a lot of reasons why veterans may be at a much higher risk of developing dementia,” said Dr. Yaffe, who is also chief of geriatric psychiatry and director of the Memory Disorders Clinic at the San Francisco VA Medical Center. “It might be PTSD, TBI, cardiovascular disease, or genetic causes that are harder to explore. Another explanation might involve the cortisol/HPA (hypothalamic-pituitary-adrenal) axis. There are also changes in that in people with PTSD.”
Robert Ruff, MD, PhD, FAAN, praised the Neurology paper for providing strong support for the growing body of evidence linking tauopathy to head trauma and to a greater risk of dementia. “The strength of the paper is that it provides much stronger support for the concept than prior work had done,” said Dr. Ruff, a professor of neurology at Case Western Reserve University School of Medicine, and neurology service chief at the Louis B. Stokes Cleveland Veterans Affairs Medical Center.
The findings support his own research, published in 2012 in BMJ Open, linking both PTSD and mild TBI to neurological deficits among veterans who have experienced mild TBI. Dr. Ruff concluded that the two conditions interact, with TBI causing both psychological trauma and overt damage to the ventromedial prefrontal cortex, which may contribute to excessive fear and anxiety of PTSD.
“The amount of injury may be small, but I think it may alter the regulation of the amygdala, allowing an intensified fear reaction,” he said.
Impaired olfaction — the most frequently recognized neurological deficit among the 126 combat veterans Dr. Ruff studied who experienced mild TBI — suggests to him damage to the ventromedial prefrontal cortex (VMPFC). “It is certainly possible the VMPFC is not working properly to suppress the amygdala, and allowing the state of exaggerated anxiety to exist.”
The Neurology paper, based on a retrospective analysis of medical records, establishes moderate-to-severe TBI and penetrating TBI as independent risk factors for dementia, said Michael S. Jaffee, MD, FAAN, but it also demonstrates the need for a prospective study that would allow a more comprehensive analysis of the relationship between TBI and dementia.
“Prospective longitudinal studies will allow us to better understand the association between traumatic brain injury and dementia,” said Dr. Jaffee, an associate professor in the departments of neurology and psychiatry with the University of Virginia Health System, the medical director of the University of Virginia Brain Injury and Sports Concussion Institute, and a prior national director of the Defense & Veterans Brain Injury Center (DVBIC), with the Medical Research and Materiel Command in Washington DC.
“A prospective longitudinal study would allow us to better understand the differing contributions from different severities of injury, and the role of recurrent injuries. They would give us more understanding of affected cognitive domains and the time course of their involvement, as well as a better understanding of the very important role of comorbidities that may be affecting the cognitive performance of our veterans.”
The Department of Defense and the Department of Veterans Affairs started standardized screening for concussion and traumatic brain injury in 2007, Dr. Jaffee said. “Since then they've been better able to identify milder injuries and concussions, but we still don't have definitive prospective data on the long-term effects of concussions on cognitive performance as we get older,” he said.
The Neurology paper benefited from a large sample size culled from a uniform health system, but ultimately it may only add to the ambiguity of evidence linking TBI to dementia, according to Jordan Grafman, PhD, who holds the Coleman chair in rehabilitation medicine at the Rehabilitation Institute of Chicago (RIC), and is also director of Brain Injury Research and chief of the Cognitive Neuroscience Laboratory at the RIC.
“It's adding to the confusion that was already in the literature,” said Dr. Grafman, who is also a professor in the departments of physical medicine and rehabilitation, cognitive neurology and the Alzheimer's Disease Center, Psychiatry, and Behavioral Sciences at the Northwestern University Feinberg School of Medicine.
“You can't say TBI is going to make you a lot more at risk for dementia when there are all these other factors involving family history and lifestyle that can't be controlled for,” he added. “Are these people smokers? Do they have high blood pressure? We also don't have information about repetitive vs. single TBI, and there's certainly no information about whether they carry genes for dementia, such as ApoE4 [apolipoprotein E 4].”
In addition, the number, severity, and location of TBIs would undoubted have an effect, but they're not reported in this study, Dr. Grafman said.
“Then there are other factors like attitude, motivation, and social skills,” he said. “These are all factors I'd want to know about. I'd also want an objective data base with evidence you can use for more fine-grained analysis, such as imaging data. They did the best they could with 180,000 vets, which is not a bad number, but I think the findings are modest.”
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is conducting a study of Vietnam veterans with a history of TBI and PTSD designed to examine the findings of the Neurology paper, according to Michael Weiner, MD, ADNI principal investigator.
“Our study is designed to test the overall hypothesis that TBI increases risk of Alzheimer's disease as measured by biomarkers, and that PTSD increases the risk of Alzheimer's disease,” said Dr. Weiner, also Director of the Center for Imaging of Neurodegenerative Disease at the San Francisco VA Medical Center, and a Professor in the Department of Radiology at the University of California, San Francisco.
The findings of the Neurology paper are so important, in Dr. Weiner's opinion, because they point to the long-term consequences of TBI, widely regarded as the signature injury of the wars in Iraq and Afghanistan.
“When our soldiers go to war and have head injuries, it's not just the immediate consequence of the head injury that the soldier has to deal with,” said Dr. Weiner. “It's the long-term consequences of war and the injuries of war that also can have devastating effects on patients and their families. And we need to do more to adjust these long-term consequences, including government funding of treatment trials or prevention trials for Alzheimer's disease.”