Brain Trauma Linked to Parkinson’s, Not Alzheimer’s

Even when people seem to fully recover from a severe head injury, are they at risk for neurodegenerative disease later on? A July 11 JAMA Neurology paper reports that contrary to a number of well-publicized studies, a single previous head injury doesn’t predispose to Alzheimer’s disease (AD). However, the scientists, led by Paul Crane, University of Washington, Seattle, and Eric Larson, Group Health Research Institute, also in Seattle, report that head injury increased risk for Parkinson’s-related disorders and PD pathology. “The paper calls into question the long-held belief that traumatic brain injury is a significant risk factor for AD,” said Robert Stern, Boston University School of Medicine, who was not involved in the study.

Previous epidemiological studies suggest that even a single traumatic brain injury (TBI) can raise a person’s risk of developing AD or PD later in life (Plassman et al., 2000; Perry et al., 2016; Wong and Hazrati, 2013). And the more severe and frequent the TBI, the greater the disease risk, according to some reports (Gardner et al., 2015; Guo et al., 2000). Other studies did not replicate these findings (Mehta et al., 1999; Launer et al., 1999; Rugbjerg et al., 2008). However, many of these studies lacked neuropathological or biomarker confirmation of clinical diagnoses. Many examined small populations at particularly high risk for multiple TBIs, such as military personnel or athletes. In the current study, Larson and colleagues looked for a relationship between TBI and neurodegenerative disease in a large sample of the general population that included autopsy data.

Crane combined data from the Seattle-based Adult Changes in Thought (ACT) study with data from two other prospective cohort studies headed by co-author David Bennett of Rush University Medical Center in Chicago. They are the Religious Orders Study (ROS) and the Memory and Aging Project (MAP). The 7,130 participants included in the present analysis at baseline averaged 79.9 years old and were free of dementia. When they enrolled, 865 of them reported having had a head injury with some loss of consciousness in the past. To estimate the severity of the trauma, the researchers divided the volunteers by how long they thought they had been unconscious: 618 were out for less than 60 minutes, 142 for more than an hour, and 105 were unsure.

The ACT study followed people for a median of 6.2 years; ROS and MAP for 4.7 years. During that time, 1,537 people developed dementia, of whom 1,322 had AD. New Parkinson’s cases numbered 117. The researchers adjusted their models for age, sex, educational level, and study cohort.  

Surprisingly, a history of TBI had no bearing on whether a person developed mild cognitive impairment, Alzheimer’s, or any type of dementia. Likewise, TBI with loss of consciousness of less than an hour had no correlation with PD. However, head injury that knocked a person out for more than an hour increased the risk for PD by 3.56-fold in the ACT study. In the ROS and MAP studies, too few people had both TBI and PD for a reliable analysis of risk.

However, in ROS and MAP, the authors did have sufficient data on the progression of PD symptoms—such as tremor, slowness, or rigid muscles—to analyze a link with TBI. Here they saw that a TBI with less than an hour of unconsciousness raised the chance that these symptoms would worsen by 65 percent; it more than doubled if a person had been out for more than an hour after the head trauma.  

To look for relationships with pathology, a team of neuropathologists examined 1,589 brains that came to autopsy from the combined cohorts. Those with a TBI that knocked them out for less than an hour were 59 percent more likely to have Lewy bodies in the frontal or temporal cortex. That number rose to 78 percent for people who were unconscious for longer. Among samples from the ACT study, trauma also increased the likelihood of inclusions in the substantia nigra, a major site of pathology in Parkinson’s. There was no increased risk for the typical Alzheimer’s plaques specified by CERAD criteria, or tau tangles characteristic of Braak stage V/VI (Mirra et al., 1991; Braak and Braak, 1991). 

“It turns out that full-blown, autopsy-confirmed Alzheimer’s disease is not necessarily associated with traumatic brain injury,” said Peter Nelson, University of Kentucky, Lexington. However, he cautioned that since the researchers only considered variables as present or absent, rather than capturing a range of values, they may have missed more subtle associations. He pointed out that this study looks at pure AD, not other types of neurodegeneration, such as chronic traumatic encephalopathy (CTE), which has been associated with repeated mild TBI (Jan 2016 news; Smith et al., 2013). Co-author Dirk Keene, also at University of Washington, is now leading an effort to examine ACT brains for the presence of CTE.

Stern wondered if TBI may still lead to pathologies—aggregates of proteins such as α-synuclein, tau, TDP-43, and Aβ—in areas of the brain not typically associated with AD. A recent study reported that amyloid accumulates after a single TBI, but in a pattern that differs from that seen in typical AD (Feb 2016 news). Crane acknowledged that he and colleagues looked for classical AD pathology, and not for protein accumulations in other areas of the brain. Stern said that which protein accumulates, and where, may depend on the type of injury, the neuroimmune response, underlying genetic predisposition, and whether the person suffers additional head impacts.

Nelson added that he would be interested to see a stringent analysis of sex differences. Because men have both a higher risk of PD and a higher likelihood of military and sports-related TBI, sex is a potential confounder in this study, he said. Crane said that there were too few PD cases to allow the authors to analyze men and women separately. Nelson said a link between TBI and PD could help explain the higher rate of PD seen in men.

What mechanism could tie TBI to Parkinson’s? Crane said he was unsure, but that finding an association between TBI and PD, progression of symptoms, and α-synucleinopathy in different cohorts made a convincing argument that the association is real. “Each of those independently provides pretty good evidence, but the three considered together is a really strong indication of a relationship between head injury and Parkinson-spectrum disorders.”

Michelle Mielke of the Mayo Clinic in Rochester, Minnesota, called the link with Parkinson’s intriguing, but cautioned that the PD sample size was small. Confirming the findings in larger studies is essential, she said. She and Stern both pointed out that self-reported TBI, rather than that confirmed in medical records, limits the study. Nevertheless, Mielke wrote to Alzforum, the study is a major contribution to the field. “Very few studies have examined the relationship between TBI and neurodegenerative diseases among the general population,” she wrote. “It is above and beyond the largest study to date and includes three separate well-characterized community-based cohort studies.”—Gwyneth Dickey Zakaib 

Comments

  1. This is a very interesting article and an important contribution. There is much media attention regarding TBI, CTE, and neurodegenerative diseases among professional and amateur athletes. However, very little research has examined the relationship between TBI and neurodegenerative diseases among the general population. Given the media attention, patients who have a mild TBI are often concerned, some extremely anxious, that they will develop Alzheimer's disease. Indeed, some previous epidemiological studies did report that a history of TBI is associated with an increased risk of AD. However, just as many studies did not find an association.  

    These discrepant findings reflect methodological variation in defining TBI and AD and related dementia (e.g., Parkinson's disease or Lewy Body Dementia), study populations of TBI cases, classifying TBI severity, and in the types and definitions of controls used. The study populations in previous reports vary widely, including at-risk groups such as active-duty military personnel, veterans, or professional athletes, which are almost exclusively male. Thus, it remains unknown whether the results are generalizable to women, the general population, or even non-active-duty military personal who experience a single mild TBI.

    With this background, it is evident why this study is a major contribution to the field. It is by far the largest study to date and includes three separate community-based cohort studies that have well-characterized participants, including cognitive diagnoses and autopsy, with longitudinal follow-up. Their findings suggest that a history of TBI is not associated with an increased risk of AD in community populations. Interestingly the authors also did not find interactions between a history of TBI and either APOE or sex in predicting risk of AD. A few other studies have reported that TBI is a risk factor for AD, especially among those with an APOE E4 allele.

    Notably, the authors also did not find an association between TBI and AD pathology. While some other studies have reported such an association, we also did not find an association between a self-reported history of TBI, with at least momentary loss of consciousness, and brain amyloid levels using PiB-PET imaging among cognitively normal individuals enrolled in the population-based Mayo Clinic Study of Aging (Mielke et al., 2014). The similar study designs with consistent outcomes are reaffirming.

    This does not, however, mean that TBI has no role in predicting risk of AD. It is still likely that the severity of the injury or the number of injuries could be associated with an increased risk of AD and AD pathology. Further, an important limitation of the study is the self-reported TBI. Additional studies with confirmation of brain trauma and severity, rather than self-reported instances, in the population are needed to elucidate the relationship between TBI and risk of AD for the general population.

    The findings with PD and Lewy body pathology are intriguing. However, the sample size is small and the pathological findings are not fully consistent across studies. Large-scale studies are needed to confirm the results.

    References:

    Mielke MM, Savica R, Wiste HJ, Weigand SD, Vemuri P, Knopman DS, Lowe VJ, Roberts RO, Machulda MM, Geda YE, Petersen RC, Jack CR Jr. Head trauma and in vivo measures of amyloid and neurodegeneration in a population-based study. Neurology. 2014 Jan 7;82(1):70-6. Epub 2013 Dec 26 PubMed.

    View all comments by Michelle Mielke

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References

News Citations

  1. Cognitive Decline in Young Football Player Tied to Extensive Brain Damage
  2. Traumatic Brain Injury: Aβ Ensues, but Not Quite Alzheimer’s

Paper Citations

  1. Plassman BL, Havlik RJ, Steffens DC, Helms MJ, Newman TN, Drosdick D, Phillips C, Gau BA, Welsh-Bohmer KA, Burke JR, Guralnik JM, Breitner JC. Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias. Neurology. 2000 Oct 24;55(8):1158-66. PubMed.
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  3. Wong JC, Hazrati LN. Parkinson's disease, parkinsonism, and traumatic brain injury. Crit Rev Clin Lab Sci. 2013 Jul-Oct;50(4-5):103-6. PubMed.
  4. 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.
  5. Guo Z, Cupples LA, Kurz A, Auerbach SH, Volicer L, Chui H, Green RC, Sadovnick AD, Duara R, DeCarli C, Johnson K, Go RC, Growdon JH, Haines JL, Kukull WA, Farrer LA. Head injury and the risk of AD in the MIRAGE study. Neurology. 2000 Mar 28;54(6):1316-23. PubMed.
  6. Mehta KM, Ott A, Kalmijn S, Slooter AJ, van Duijn CM, Hofman A, Breteler MM. Head trauma and risk of dementia and Alzheimer's disease: The Rotterdam Study. Neurology. 1999 Dec 10;53(9):1959-62. PubMed.
  7. Launer LJ, Andersen K, Dewey ME, Letenneur L, Ott A, Amaducci LA, Brayne C, Copeland JR, Dartigues JF, Kragh-Sorensen P, Lobo A, Martinez-Lage JM, Stijnen T, Hofman A. Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work Groups. European Studies of Dementia. Neurology. 1999 Jan 1;52(1):78-84. PubMed.
  8. Rugbjerg K, Ritz B, Korbo L, Martinussen N, Olsen JH. Risk of Parkinson's disease after hospital contact for head injury: population based case-control study. BMJ. 2008 Dec 15;337:a2494. PubMed.
  9. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991 Apr;41(4):479-86. PubMed.
  10. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59. PubMed.
  11. Smith DH, Johnson VE, Stewart W. Chronic neuropathologies of single and repetitive TBI: substrates of dementia?. Nat Rev Neurol. 2013 Apr;9(4):211-21. Epub 2013 Mar 5 PubMed.

Further Reading

Papers

  1. Djordjevic J, Sabbir MG, Albensi BC. Traumatic Brain Injury as a Risk Factor for Alzheimer's Disease: Is Inflammatory Signaling a Key Player?. Curr Alzheimer Res. 2016;13(7):730-8. PubMed.
  2. Gatson JW, Stebbins C, Mathews D, Harris TS, Madden C, Batjer H, Diaz-Arrastia R, Minei JP. Evidence of increased brain amyloid in severe TBI survivors at 1, 12, and 24 months after injury: report of 2 cases. J Neurosurg. 2015 Nov 27;:1-8. PubMed.
  3. Mendez MF, Paholpak P, Lin A, Zhang JY, Teng E. Prevalence of Traumatic Brain Injury in Early Versus Late-Onset Alzheimer's Disease. J Alzheimers Dis. 2015;47(4):985-93. PubMed.
  4. Gupta R, Sen N. Traumatic brain injury: a risk factor for neurodegenerative diseases. Rev Neurosci. 2016 Jan;27(1):93-100. PubMed.

Primary Papers

  1. Crane PK, Gibbons LE, Dams-O'Connor K, Trittschuh E, Leverenz JB, Keene CD, Sonnen J, Montine TJ, Bennett DA, Leurgans S, Schneider JA, Larson EB. Association of Traumatic Brain Injury With Late-Life Neurodegenerative Conditions and Neuropathologic Findings. JAMA Neurol. 2016 Sep 1;73(9):1062-9. PubMed.

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