A large body of research has tied traumatic brain injuries to an increased risk for neurodegenerative disease, but many questions remained. In particular, there were mixed findings on whether mild TBIs posed a risk. Two huge new epidemiological studies now come down squarely on one side. In the April 10 Lancet Psychiatry, researchers led by Jesse Fann at the University of Washington, Seattle, associated single mild TBIs with a 20 percent greater risk of dementia later in life. The finding comes from Danish databases that contain the medical records of 2.8 million people. And in the April 18 Neurology, researchers led by Kristine Yaffe at the University of California, San Francisco, linked mild TBIs in a cohort of 325,870 veterans to 50 percent higher odds of developing Parkinson’s disease.
- Even a single mild TBI modestly raises the risk for dementia in later life.
- Veterans with mild TBIs run a 50 percent higher risk for Parkinson’s disease.
- Researchers do not yet know what factors influence which disease develops.
Commenters said the size of the work makes it noteworthy. “These studies are important contributions to the literature,” Michelle Mielke at the Mayo Clinic in Rochester, Minnesota, wrote to Alzforum (see comment below). However, neither one is definitive, commenters cautioned. They noted that both studies were limited in what type of information was available in the respective databases; this left gaps, such as the effect of very mild brain injuries that go unreported in the medical record.
Head injuries have been consistently associated with increased risk for dementia, although it is unclear whether that specifically includes Alzheimer’s disease (Aug 2012 news; Sep 2012 news; Jun 2014 news). The strongest links to AD are seen for moderate to severe head injuries, which trigger amyloid plaque buildup in some people (Nov 2013 news; Jan 2014 news). Repetitive mild brain injuries, by contrast, are primarily associated with a degenerative tauopathy known as chronic traumatic encephalopathy (Nov 2012 news; Dec 2012 news; Jan 2016 news). Few studies have examined long-term effects of single mild injuries.
To bring large data sets to bear on this question, Fann and colleagues turned to the Danish National Patient Register and the Civil Registration System, which records medical and demographic data on all of the country’s citizens. The authors analyzed data from 2,794,852 people who were 50 years or older at some point from 1999 to 2013. In this cohort, 132,093 people, or about 5 percent, had been seen at a hospital for TBI. Eighty-five percent of those TBIs were classified as mild, meaning they involved a loss of consciousness of 30 minutes or less, or amnesia or altered consciousness, i.e., grogginess or confusion, for less than a day. Longer loss of consciousness or altered consciousness constitutes moderate to severe TBI.
During the study period, 126,734 people, or 4.5 percent of the whole cohort, developed dementia after age 50. This was evident by diagnoses recorded at a hospital or psychiatric clinic, or by pharmacy records indicating that at least one prescription for an anti-dementia drug was filled. Having had a single prior head injury boosted a person’s risk of dementia by 22 percent. The risk climbed with increasing number of TBIs, mushrooming almost threefold for people with five or more. More severe TBIs conferred about twice the risk as mild ones. Intriguingly, the younger a person was when they sustained a brain injury, the higher their likelihood of having dementia 10, 20, or 30 years later. The reason for this is unknown. In an accompanying editorial, Carol Brayne at the University of Cambridge, U.K., noted that this phenomenon merits further exploration.
“The data are convincing that mild TBIs confer at least a modestly increased risk of dementia,” said Elaine Peskind at the Veterans Affairs (VA) Northwest Network Mental Illness Research, Education, and Clinical Center, Seattle. However, she noted that for very mild knocks to the head, people generally do not seek medical attention. Therefore, it is still unclear whether those put people at risk for any long-term consequences, too.
The databases also lacked information on education and certain medical comorbidities that can affect dementia risk, said Kristen Dams-O’Connor at Icahn School of Medicine, Mount Sinai, New York. For example, while the authors adjusted for several medical and psychiatric comorbidities such as diabetes, cerebrovascular disease, and depression, they did not take into account some conditions, such as hyperlipidemia, that weaken the link between TBI and dementia (Dams-O’Connor et al., 2016). She also noted that after a brain injury people tend to develop health problems, many of which are independent risk factors for dementia and may be driving the association (Kumar et al., 2018).
Because the study was unable to address which pathology underlies the dementia cases, it remains to be seen whether these are Alzheimer’s disease or something else. In a sub-analysis, the authors limited dementia cases to clinical AD diagnoses and found a 16 percent heightened AD risk following mild TBI, but these cases were not autopsy-confirmed.
Other studies suggest that TBI-linked dementia may not be AD. A previous imaging study found an unusual pattern of amyloid accumulation after TBI (Feb 2016 news). Another study reported an increased risk of PD, but not AD, after TBI in a cohort of 7,130 people, of whom 1,589 have come to autopsy so far. In brains with TBI, researchers found more Lewy body pathology and microinfarcts, but no more amyloid plaques than in controls (Jul 2016 news).
The evidence for a link between TBI and Parkinson’s is strongest for moderate to severe brain injuries (Gardner et al., 2015; Kenborg et al., 2015; Perry et al., 2016). To examine the effect of mild TBIs on incident PD, first author Raquel Gardner in Yaffe's group mined Veterans Health Administration data from 2002–2014. They selected 162,935 veterans with TBIs and 162,935 age-matched veterans without. Their mean age at baseline was 48, and average follow-up time per veteran was five years.
During the study period, 1,462 veterans developed PD. A history of any TBI raised their risk by 70 percent, while mild TBI alone boosted it by 56 percent. Veterans with TBI developed PD two years earlier on average than those without. Among the veterans with PD, those with a prior TBI were more likely to be black or Latino, and to have medical and psychiatric comorbidities, suggesting these factors might confer additional risk. The authors adjusted the analysis for comorbidities and demographics.
Peskind noted, however, that these data might overestimate the PD risk from single mild TBIs. The database contains no information on the total number of brain injuries each veteran sustained. Military personnel serving in Iraq and Afghanistan are typically exposed to multiple blast TBIs. In a VA cohort Peskind studies, 90 percent of veterans with TBI experienced more than one, with the average number being a whopping 26. Thus, the veterans with mild TBI in Gardner’s study likely had multiple exposures. “From this study, you can’t tell if a single mild TBI would increase the risk of PD,” Peskind said.
Dams-O’Connor emphasized that although a person’s relative risk of PD rose after brain injury, the absolute number of cases remained quite small. Most people with a TBI do not go on to develop neurodegenerative disease, at least in the next five years. “We really need to understand the individual factors that determine who develops degenerative disease. If we knew who with TBI was at elevated risk, we could stratify people for more intense screening and follow-up,” Dams-O’Connor said.—Madolyn Bowman Rogers
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