ARTICLE IN BRIEF
Military veterans who had mild traumatic brain injury had a 2.3 times higher risk for dementia if they had not lost consciousness, and 2.5 times higher risk if consciousness was lost.
Although the risk of dementia is known to be higher among individuals who have suffered moderate to severe traumatic brain injury, new evidence indicates that the same may hold true for veterans exposed to milder trauma or concussion.
In the first large-scale study of dementia among US veterans with a history of mild traumatic brain injury (mTBI) or concussion, the risk of dementia was 2.3 times higher in those who had not lost consciousness, and 2.5 times higher if consciousness was lost, after adjusting for demographics, medical, and psychiatric comorbidities. The risk was 3.7 times higher for veterans with moderate to severe TBI, according to the findings reported online May 7 in JAMA Neurology.
The results suggest that even mTBI that does not result in loss of consciousness might have long-term neurodegenerative consequences, said the study's principal investigator Kristine Yaffe, MD, professor of psychiatry, neurology, and epidemiology and vice chair of research at the University of California, San Francisco (UCSF) School of Medicine.
“What was striking was the graded association between the degree of injury and dementia in our study,” Dr. Yaffe told Neurology Today. “We don't know if there is some new pathology or process occurring, but there is something that increases the risk of dementia, and we need to connect the dots.”
Dr. Yaffe said that it is possible that trauma leaves the brain more vulnerable to the accumulation of proteins like tau or amyloid, or to the aging processes itself, while lifestyle factors may also make veterans more susceptible.
Researchers from UCSF and the San Francisco Veterans Affairs Health Care System compared mTBI and dementia records for 357,000 veterans. The retrospective cohort study included all service members with brain trauma seen by the Veterans Health Administration and a propensity-matched sample of veterans without TBI for comparison purposes.
In all, 2.6 percent of patients with no history of TBI developed dementia compared with 6.1 percent of those with a TBI history. There was a dose-response curve, with higher risk associated with increased TBI severity; the mean time from the most severe injury to dementia diagnosis was 3.6 years in veterans with a history of TBI and 4.8 years in all others.
The investigators identified TBIs in the VA's Comprehensive Traumatic Brain Injury Evaluation (CTBIE) database (only Iraq and Afghanistan veterans), and the National Patient Care Database, which includes veterans of all eras, and includes civilian and active duty injuries. For TBI diagnostic data, the researchers used VHA inpatient and outpatient medical appointment records.
In the Iraq and Afghanistan veterans group, most injuries were blast-related and defined as mTBI or concussion causing altered consciousness and amnesia for one day or less, based on a comprehensive medical evaluation. In the database of vets from any era, concussion was defined using a wide list of diagnostic codes. Standard ICD-9 codes were used to evaluate medical and psychiatric comorbidities, including mood disorders, posttraumatic stress disorder, substance use, and sleep disorders.
The researchers found that 54 percent of veterans had experienced TBI, and half of these individuals had suffered a concussion.
The implications for the military health system, the VA, and society as a whole “are profound,” wrote Kimbra L. Kenney, MD, FAAN, and Ramon Diaz-Arrastia, MD, PhD, FAAN, in an accompanying editorial. Dr. Kenney is a neurologist at the Uniformed Services University of the Health Sciences in Bethesda, MD, and Walter Reed Medical Center, while Dr. Diaz-Arrastia is a professor of neurology at the University of Pennsylvania Perelman School of Medicine.
It is not the first epidemiological study of mTBI in the VA system, they noted, but it is among the largest to date. However, there were a number of limitations with the study, including the fact that they relied on ICD-9 codes for diagnoses.
“Some TBI ICD-9 codes are not easily categorized into the TBI severity groupings used in this study,” they said, but because of the higher numbers of TBI diagnoses in the CTBIE after 2007, they said the rate of TBIs without loss of consciousness before then likely means the overall rates were underestimated.
Renee M. Pazdan, MD, FAAN, chief of the department of rehabilitation at the Warrior Recovery Center at Evans Army Community Hospital in Fort Carson, CO, said the findings indicate the need for more in-depth study.
Speaking on her own behalf, not that of the Department of Defense, she said service members usually have complex histories, often including multiple concussions and comorbidities, such as sleep disturbance, musculoskeletal pain, and psychological heath conditions, including alcohol and drug use issues; veterans with substance issues were excluded from the study.
She too agreed with the editorialists that differences in diagnostic approaches make interpreting the findings a challenge.
“The major limitation with this study is that we do not know how diagnostic codes were used by all of the physicians,” Dr. Pazdan told Neurology Today. “Also, neuropsychiatric testing for early signs of dementia is challenging because of the time and expertise required. It is very intensive and requires multiple visits, which makes it difficult in large populations. Many of these veterans are also on pain medications, and this needs to be considered.”
Risa Nakase-Richardson, PhD, FACRM, a clinical research neuropsychologist at the James A. Haley Veterans' Hospital, in Tampa, FL, told Neurology Today that she is concerned that veterans and their families may not be aware of the study's limitations.
“I believe there is still no solid evidence that milder TBIs increase the likelihood of dementia. The findings only demonstrate an association between mild TBI and dementia, not causation,” Dr. Nakase-Richardson said. “The media needs to be more careful about misrepresenting the study findings. Incorrect interpretation can cause fear and anxiety among veterans and their families.”
She added: “While it is known that moderate to severe TBI is related to earlier cognitive decline, and there are significant differences between them and milder trauma, more research is needed to identify mechanistic factors in these injuries and comorbid conditions that have not been diagnosed but may contribute to these associations.”
In her own research, she said she has found sleep disorders to be very prevalent in TBI patients, and these are known to contribute to early cognitive decline. Even so, she said the contribution of comorbid conditions such as sleep disorders to dementia is underrecognized. “Disorders like sleep apnea are commonly undiagnosed and may be a key contributor to the association of TBI and early decline in brain health.”
Dr. Yaffe told Neurology Today that the researchers were very careful in screening for comorbidities. “This is one limitation that I am not worried about. That is why we used propensity matching so that all of these variables are included and matched with non-TBI patients.”
Silvia Fossati, PhD, assistant professor of neurology and psychiatry and director of the Biofluid Biomarker Core at New York University Cohen Veteran Center, said the findings did not come as a surprise.
“Our research community has recently uncovered multiple mechanisms initiated by TBI that are considered risk factors for future development of dementia. These include, for example, diffuse axonal injury, as well as neuroinflammation, tau and amyloid beta accumulation, and cerebrovascular dysfunction, which we recently reviewed.”
She said the study “will constitute invaluable evidence for our research field,” even though the evidence of an association of mild TBI, especially a single mild TBI without loss of consciousness, with increased risk for dementia later in life, is not yet broadly accepted.
“It is surprising that the authors didn't find differences in dementia between subjects with single versus multiple mild TBIs. This is likely due to the fact that the number of years with at least one TBI diagnosis was used as a proxy measure for repeated TBIs. Further studies need to discriminate between the effects of single vs repeated TBI.”
Dr. Fossati also underscored the need for better tools to diagnosing and treat mTBI, which can be challenging to diagnose, pointing to progress in several areas.
“Recent efforts in biomarkers have detected molecules in the blood that can indicate the presence of changes in the brain after TBI, such as tau, neurofilament light chain, glial fibrillary acidic protein, and others. Research in this field will help diagnose patients,” she said.
Doctors will be soon able to test for these biomarkers, Dr. Fossati said. She noted that the US Food and Drug Administration approved blood tests for brain bleeds from mTBI and concussion, and advances in biofluid and imaging biomarkers also promise to make better diagnoses possible in the near future.