27 Apr 2018

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.

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

Comments

1. • Michelle Mielke
     Mayo Clinic
   • Posted: 27 Apr 2018

   These studies are important contributions to the literature. The study by Drs. Gardner, Yaffe, and colleagues provides further evidence that TBI may be associated with an increased risk of parkinsonism and Parkinson’s disease. This study is consistent with the previous finding by Crane and colleagues who reported, in the largest autopsy study to date, that TBI with loss of consciousness for more than one hour was associated with PD and Lewy body pathology.

   I think the associations between TBI and dementia, including Alzheimer’s disease, are less established compared to the associations between TBI and parkinsonism/Parkinson’s disease. Epidemiological studies have been somewhat inconsistent and have differed, which may in part be due to the different assessments utilized to obtain information on TBI exposure (i.e., self-report, codes, requirement of a certain time for loss of consciousness) and dementia (i.e., clinical assessments, codes).

   The study by Fann and colleagues is one of the largest, if not the largest, population-based study to date assessing TBI and risk of dementia. A major strength of this study is the rigorous methodological assessments, including thorough assessments by sex, consideration of reverse causality (dementia causing/contributing to the TBI), and the consideration of non-TBI trauma. The latter is particularly important but has been assessed by few studies. Previously, Brown and colleagues from the Mayo Clinic demonstrated that after six months, individuals with TBI were not significantly associated with mortality when compared with individuals without TBI but with similar non-trauma comorbidities (Brown et al., 2014). In the Fann et al. study, a TBI was associated with a greater risk of dementia compared to a non-TBI fracture not involving the skull or spine. A potential limitation is that the matching didn’t go beyond the presence of a fracture, which is often the case in instances of TBI due to car crashes, etc. Another limitation is the use of codes for the diagnosis of dementia type. While the use of codes in such a large population-based study is clearly necessary, it is often difficult to ascertain type of dementia, and the clinical diagnosis of dementia type has evolved over time. One wonders whether some of the drivers of the association are due to a stronger association between TBI and Parkinson’s disease dementia or Lewy body dementia as opposed to Alzheimer’s disease, especially given the Crane et al. autopsy study.

   References:

   Brown AW, Leibson CL, Mandrekar J, Ransom JE, Malec JF. Long-term survival after traumatic brain injury: a population-based analysis controlled for nonhead trauma. J Head Trauma Rehabil. 2014 Jan-Feb;29(1):E1-8. PubMed.

   View all comments by Michelle Mielke

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References

News Citations

1. New AlzRisk Analysis: Brain Injury Promotes Dementia, But Is It AD? 24 Aug 2012
2. Dementia Four Times More Likely in Pro Football Players 7 Sep 2012
3. Brain Injury Boosts Dementia Risk 27 Jun 2014
4. Imaging Reveals Amyloid Up To a Year After Traumatic Brain Injury 16 Nov 2013
5. Does a Blow to the Head Mean More Amyloid Down the Road? 10 Jan 2014
6. Meet the New Progressive Tauopathy: CTE in Athletes, Soldiers 20 Nov 2012
7. Paper Alert on CTE in Multiply Concussed Athletes and Veterans 3 Dec 2012
8. Cognitive Decline in Young Football Player Tied to Extensive Brain Damage 15 Jan 2016
9. Traumatic Brain Injury: Aβ Ensues, but Not Quite Alzheimer’s 5 Feb 2016
10. Brain Trauma Linked to Parkinson’s, Not Alzheimer’s 16 Jul 2016

Paper Citations

1. Dams-O'Connor K, Guetta G, Hahn-Ketter AE, Fedor A. Traumatic brain injury as a risk factor for Alzheimer's disease: current knowledge and future directions. Neurodegener Dis Manag. 2016 Oct;6(5):417-29. Epub 2016 Sep 7 PubMed.
2. Kumar RG, Juengst SB, Wang Z, Dams-OʼConnor K, Dikmen SS, OʼNeil-Pirozzi TM, Dahdah MN, Hammond FM, Felix ER, Arenth PM, Wagner AK. Epidemiology of Comorbid Conditions Among Adults 50 Years and Older With Traumatic Brain Injury. J Head Trauma Rehabil. 2018 Jan/Feb;33(1):15-24. PubMed.
3. Gardner RC, Burke JF, Nettiksimmons J, Goldman S, Tanner CM, Yaffe K. Traumatic brain injury in later life increases risk for Parkinson disease. Ann Neurol. 2015 Jun;77(6):987-95. Epub 2015 Mar 28 PubMed.
4. Kenborg L, Rugbjerg K, Lee PC, Ravnskjær L, Christensen J, Ritz B, Lassen CF. Head injury and risk for Parkinson disease: Results from a Danish case-control study. Neurology. 2015 Mar 17;84(11):1098-103. Epub 2015 Feb 13 PubMed.
5. Perry DC, Sturm VE, Peterson MJ, Pieper CF, Bullock T, Boeve BF, Miller BL, Guskiewicz KM, Berger MS, Kramer JH, Welsh-Bohmer KA. Association of traumatic brain injury with subsequent neurological and psychiatric disease: a meta-analysis. J Neurosurg. 2016 Feb;124(2):511-26. Epub 2015 Aug 28 PubMed.

Further Reading

News

1. Do 'Headers' Rack Up Brain Damage in Soccer Players? 17 Feb 2017
2. In NFL Players, Brain Inflammation May Persist Years After Head Trauma 2 Dec 2016
3. Cognitive Decline in Young Football Player Tied to Extensive Brain Damage 15 Jan 2016
4. Traumatic Brain Injury—Focus on Heterogeneity, Secondary Damage 3 Dec 2015
5. Stress and Trauma: New Frontier Lures Alzheimer’s Researchers 20 Apr 2011