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Military veterans diagnosed with mild traumatic brain injury (mTBI) have a 56% increased risk of developing Parkinson's disease (PD), a large, retrospective cohort study shows.
Investigators also found those with traumatic brain injury (TBI) of any severity had a 71% increased risk for PD and those with mild-to-moderate TBI had an 83% increased risk.
"Our study adds to the mounting evidence that even mild TBI is a risk factor for several neurodegenerative diseases of aging, including both dementia and Parkinson's disease," first author, Raquel C. Gardner, MD, San Francisco Veterans Affairs Medical Center and assistant adjunct professor of neurology at the University of California San Francisco Weill Institute for Neurosciences, told Medscape Medical News.
"I would encourage clinicians to counsel their TBI-exposed veterans to engage in brain healthy activities such as a heart-healthy diet, increased physical activity, cessation of activities that may harm the brain or vasculature, and optimized management of any chronic medical conditions.
"I would also apply fall-prevention strategies to those patients at high risk for falls and would be on the lookout for symptoms of parkinsonism that may further increase fall risk and risk for repeat injury," Gardner said.
The study was published online April 18 in Neurology.
Prior studies have shown a strong association between moderate-to-severe TBI and risk for neurodegenerative disorders such as PD. However, the research on mTBI has been inconclusive, with only one case-controlled study focused on military veterans (Ann Neurol. 2006;60:65-72).
"Our research looked at a very large population of US veterans who had experienced either mild, moderate or severe traumatic brain injury in an effort to find an answer to whether mild traumatic brain injury can put someone at risk," senior author, Kristine Yaffe, MD, said in a release.
The study, which is part of the Chronic Effects of Neurotrauma Consortium research, included 325,870 veterans from three US Veterans Health Administration databases.
Participants were aged 31 to 65 years and had no dementia or PD diagnosis at baseline.
Investigators defined mTBI as loss of consciousness for 0 to 30 minutes, alteration of consciousness for a moment to 24 hours, or amnesia for 0 to 24 hours.
They defined moderate-to-severe TBI as a loss of consciousness for more than 30 minutes, alteration of consciousness of more than 24 hours, or amnesia exceeding 24 hours.
TBI exposure and severity were determined via detailed clinical assessments or International Classification of Diseases, Ninth Revision (ICD-9) codes using Department of Defense and Defense and Veterans Brain Injury Center criteria.
Approximately 50% of the cohort had TBI. At an average follow-up of 4.6 years, 1462 veterans had a PD diagnosis. Of these, 949 had prior TBI and 513 had no TBI history.
Investigators reported that of the veterans with TBI of any severity, 949 (0.58%) developed PD vs 513 (0.31%) of those with no TBI.
Results also showed that 360 of 76,297 veterans with mTBI, or 0.47%, developed the disease and 543 of 72,592 with moderate-to-severe TBI, or 0.75%, developed PD.
After adjustment for age, sex, race, education, diabetes, hypertension, and other health conditions, any kind of TBI was associated with a 71% increased risk for PD.
In addition, those with mTBI had a 56% increased risk and those with moderate-to-severe TBI had an 83% increased risk.
Researchers also found that those with any type of TBI were diagnosed with PD an average of 2 years earlier than those without TBI.
Gardner said the current research is "the first nationwide cohort study to establish an association between mild TBI and Parkinson's disease, and the first cohort study in veterans."
"Based on evidence from prior small case-control studies as well as our prior California-wide cohort study [of civilians] published in Annals of Neurology, [2015;77:987-995] I was not surprised by our result," Gardner said.
"I am, however, very concerned by our result as our study now confirms, via the highest level of epidemiological evidence that a single study can achieve, that this association is not spurious."
The use of physician-diagnosed TBI and PD, the longitudinal cohort design, and the large sample size are strengths of the study, the researchers note.
However, use of ICD-9 codes may have limited the inclusion of all cases of TBI and PD. The investigators attempted to correct for this limitation by including inpatient and outpatient data and by conducting a sensitivity analysis requiring at least three separate healthcare encounters with a PD diagnosis.
Gardner noted it is "critical" for future research to examine whether there are specific high-yield risk factors that can be modified to prevent or delay onset of post-TBI PD.
"Simultaneously," she added, "it is critical to unravel the biological mechanisms and neuropathology of these cases of post-TBI Parkinson's disease, as well as early biomarkers to guide screening and early treatment trials."
Commenting on the findings for Medscape Medical News, Rahul Raj, MD, PhD, adjunct professor of experimental neurosurgery and a neurosurgery resident at the HYKS NeuroCenter in Helsinki, Finland, said, "The epidemiological association between TBI and Parkinson's disease is still somewhat controversial, and at least two nationwide register studies did not find any association between TBI and Parkinson's disease" (BMJ. 2008;337:a2494; PLoS Med. 2017;14:e1002316).
"This might, in part, be due to the fact that the authors used the Veteran Health Administration database, including only US veterans, whose risk-profile might somewhat differ from the [general] population," Raj said.
Also commenting on the findings, Kristen Dams-O'Connor, PhD, associate professor of rehabilitation medicine and associate professor of neurology at the Icahn School of Medicine at Mount Sinai in New York City, noted that TBI history may not have been fully captured because it "isn't always recorded in the health record and many veterans receive care outside of the VA. This would actually bias findings toward the null, and still they still found significantly increased risk for Parkinson's disease."
"This study suggests that mTBI is associated with 56% increased risk of PD, while more severe TBI is associated with greater risk for PD. These findings are consistent with what our group reported previously. We found an even greater risk for Parkinson's disease associated with TBI with loss of consciousness longer than 1 hour," Dams-O'Connor added (JAMA. 2016;73:1062-1069).
"Not all people who serve get care at a VA," agreed Paul Crane, MD, MPH, professor of medicine at the University of Washington in Seattle. "The authors are unable to quantify the extent of care received outside the VA system. They may be under-counting their Parkinson's disease outcomes."
"Likewise, capture of Parkinson's disease from ICD-9 codes as opposed to research-based criteria by trained research personnel is susceptible to incomplete capture," he added.
"Parkinson's disease is a highly age-dependent condition, with rates that go higher with advancing age. The mean age of the cohort is only about 48 years, and they cover only about 5 years on average in follow-up. So the middle of the distribution is not at high risk for Parkinson's disease," Crane said.
"I suspect…the magnitude of effect may be somewhat stronger than the magnitude Gardner et al report in their interesting and carefully conducted study," he added.
Raj noted that "although the relative risk reported in hazard ratios by the authors seems high, the absolute PD risk is still very small — 0.2% to 0.3% increase between non-TBI and TBI."
His point was supported by Dams-O'Connor, who noted that "for people living with a history of mTBI, I do think it's important to bear in mind that the absolute risk for developing PD, even after a TBI, is quite small."
The US Army Medical Research and Material Command and the US Department of Veterans Affairs as part of the Chronic Effects of Neurotrauma Consortium, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, and the American Federation for Aging Research supported the study. Gardner, Raj, Dams-O'Connor, and Crane had disclosed no relevant financial relationships.
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