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
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