A traumatic brain injury (TBI) that involves loss of consciousness is not associated with the development of Alzheimer's disease (AD) later in life but is associated with later onset of Parkinson's disease (PD) and accumulation of Lewy bodies, a new study suggests.
The lack of association between TBI and AD, even among those carrying the APOE ε4 allele, contrasts with an influential paper published in Neurology in 1995 in which researchers found a 10-fold increased risk for AD among APOE ε4–positive patients who had sustained a TBI.
"We looked hard in every way we knew how to replicate this important finding from the literature and really we didn't find it," said Paul K. Crane, MD, professor, medicine, University of Washington, Seattle, and lead author of the new study, published online July 11 in JAMA Neurology.
"We had orders of magnitude more than in previous studies, and if there had been anything close to a 10-fold relationship with APOE-positive people, we would have found it."
Although the power to detect PD was lower, the study did find that a single blow to the head resulting in lost consciousness for more than an hour may lead to more than a three-fold increased risk for PD decades later.
The study included data from three large prospective cohort studies of participants free of dementia at baseline:
Adult Changes in Thought (ACT) study, which has been enrolling older Seattle-area Group Health members since 1994;
Religious Orders Study (ROS), which since its start in 1994 has enrolled older religious clergy from more than 40 groups across the United States;
Memory and Aging Project (MAP), which since inception in 1997 has enrolled older residents from Chicago-area retirement facilities and subsidized housing and through church groups and social services.
All studies assessed head injuries at enrollment and at every study visit, and all captured TBI with loss of consciousness (LOC).
Because rates of TBI exposure in ROS and MAP were similar, the researchers combined these data.
The analysis included 7130 participants (40.4% of them men; mean age, 79.9 years) who were followed for 45,190 person-years. In ACT, 15.1% of participants reported TBI with LOC at enrollment, as did 7.7% in ROS and MAP.
Dementia and AD
In ACT, researchers identified 921 incident cases of dementia and 759 incident cases of AD in 28,664 person-years of follow-up.
They found no statistically significant association between TBI with LOC and dementia risk. Compared with people who did not have TBI with LOC, those with LOC for 1 hour or less had an adjusted hazard ratio (HR) of 1.03 (95% confidence interval [CI], 0.83 - 1.27) and those with a TBI with LOC for more than an hour had an adjusted HR of 1.18 (95% CI, 0.77 - 1.78).
In ROS and MAP, researchers identified 616 incident dementia cases and 563 incident AD cases in 16,526 person-years of follow-up.
Here again, they found no statistically significant association between TBI with LOC and dementia risk. The HR for TBI with LOC for 1 hour or less was 0.87 (95% CI, 0.58 - 1.29), and for TBI with LOC more than an hour, it was 0.84 (95% CI, 0.44 - 1.57).
Including APOE genotype did not change findings in either study, and there was no significant interactions with APOE genotype or sex.
Results for AD were similar to those for dementia. There was no association between TBI with LOC and incident mild cognitive impairment in ROS and MAP.
In ACT, there were 83 incident PD cases in 22,800 person-years of follow-up. The adjusted HR for a TBI with LOC for 1 hour or less was 0.66 (95% CI, 0.28 - 1.52). For TBI with LOC for more than an hour, the HR was 3.56 (95% CI, 1.52 - 8.28).
In ROS and MAP, there were 34 incident PD cases in 18,156 person-years of follow-up. Only 3 participants with incident PD reported exposure to TBI with LOC, all of whom had duration of LOC of 1 hour or less.
In an analysis of progression of parkinsonian signs that controlled for baseline age, sex, and time since baseline, the adjusted odds ratio (OR) for increasing scores for a history of TBI with LOC for 1 hour or less was 1.65 (95% CI, 1.23 - 2.21). For TBI with LOC for more than an hour, the OR was 2.23 (95% CI, 1.16 - 4.29).
Dr Crane noted that a "dose-response" relationship was particularly clear for parkinsonian progression. "People who had a shorter duration loss of consciousness were at increased risk and people with longer duration loss of consciousness were at an even higher increased risk."
Of the total number of participants, 1,589 had a comprehensive neuropathologic evaluation at the time of death. Researchers found a "pretty strong" association between head injuries with LOC and Lewy bodies, said Dr Crane.
In pooled analyses, TBI with LOC for 1 hour or less was associated with an increased risk for Lewy bodies in the frontal or temporal cortex (relative risk [RR], 1.59; 95% CI, 1.06 - 2.39).
TBI with LOC for more than an hour was associated with an increased risk for cerebral microinfarcts (RR, 1.58; 95% CI, 1.06 - 2.35) and an even higher point estimate for Lewy bodies in the frontal or temporal cortex (although the 95% CI included the null: RR, 1.78; 95% CI, 0.82 - 3.77).
Another important finding, according to Dr Crane, was that those who had sustained a head injury with loss of consciousness when they were younger than 25 years had an increased risk for Lewy body accumulation compared with those who had never sustained a head injury with lost consciousness.
Because study participants were at least 65 years old, "simple math" suggests that "there's a more than 40-year latency between the head injury exposure and when we're seeing microscopic evidence of abnormal proteins in the brain at a higher rate than in those who didn't have head injury exposure."
That TBI early in life is linked to neurodegeneration four-plus decades later may shed light on how the brain is able to address trauma, commented Dr Crane.
The study results give researchers "a great deal of impetus to continue looking at the PD relationship and perhaps to emphasize the AD relationship a lot less," said Dr Crane.
The number of study participants reporting more than one head injury with LOC was small. "We did what we could with the people who had more than one head injury and didn't see much more of a signal there than what we saw with people who had exactly one," said Dr Crane.
It's also not clear from this study the circumstances surrounding the TBI — whether it was from a car accident, playground accident, or other mishap.
"Mechanistically, it's hard to imagine that the biology would care what context in which you were receiving the head injury," said Dr Crane.
The study findings are "hypothesis generating," according to the authors. "We are very cautious about trying to avoid overinterpreting our results," said Dr Crane.
The reason for this, he said, is that the study is not a randomized controlled trial (it would be impossible to randomly assign participants to receive a TBI, and also because the number of PD cases in the study was relatively small).
"We had robust power for AD, and so we are a little bit more comfortable trumpeting those findings" whereas for PD the findings may be less firm, he said.
A limitation of the study is that it didn't adjust for occupational history, smoking, physical activity, alcohol intake, body mass index, or risk taking. It's possible that it's not the head injury itself but something that goes along with a head injury (eg, risk-taking behavior) that leads to PD risk.
"But we don't see hazard ratios of 3.5 very often and that's what we found in ACT for the PD rate," said Dr Crane. "If it were risk-taking or some other factor, that factor would have to have a very strong numeric relationship with PD, and a very strong relationship with head injury exposure, in order to make our findings entirely due to that, and I think that's unlikely."
Invited to comment, Raquel C. Gardner, MD, assistant professor, Memory and Aging Center, Department of Neurology, University of California, San Francisco, said she was "not convinced" by the negative findings.
The definition of TBI exposure was based on a brief self-report instrument that is "insensitive," said Dr Gardner, adding that the prevalence of TBI with LOC in this study was low compared with other studies that used more detailed TBI interview methods.
"A poorly sensitive TBI definition essentially means that the 'no TBI' group in this study is likely contaminated with a fair number of participants who actually had prior TBI. This blurring of the lines between exposed and unexposed participants would mask potentially positive associations between the exposure and outcome of interest."
However, Dr Gardner thought that the study's positive findings — that TBI with LOC is associated with progression of parkinsonism and Lewy bodies — were "compelling."
Medscape Medical News also asked Michelle M. Mielke, PhD, professor of epidemiology, Department of Health Sciences Research, and associate professor of neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, to comment. She called the study "very interesting" and "an important contribution."
"It is above and beyond 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."
Dr Mielke noted that the authors didn't find an association between TBI and AD pathology. While some studies have reported such a link, her own research group didn't find an association between a self-reported history of TBI, with at least momentary loss of consciousness, and brain amyloid levels using Pittsburgh compound B positron emission tomography imaging among cognitively normal individuals enrolled in the population-based Mayo Clinic Study of Aging.
"The similar study designs with consistent outcomes are reaffirming," she said.
Dr Mielke stressed that the results of this new study don't mean that TBI has no role in predicting risk for AD. "It is still likely that the severity of the injury or the number of injuries could be associated with an increased risk for AD and AD pathology."
Although she found the results related to PD and Lewy body pathology "intriguing," Dr Mielke noted that the sample size was small and the pathologic findings were not fully consistent across studies. "Large-scale studies are needed to confirm the results."
Offering her views to Medscape Medical News, Beth Vernaleo, PhD, associate director of research programs, Parkinson's Disease Foundation, said that although most people who experience head injury won't develop PD, the new study "may provide clinicians with an additional diagnostic tool."
For example, she said, "asking patients about history of head injury, amongst other symptoms and risk factors, may prove a valuable means of ascertaining the likelihood of a Parkinson's diagnosis."
This study was supported by grants from the National Institutes of Health and a grant from the Paul G. Allen Family Foundation (data collection and analysis). Dr Crane reports receiving support from the National Institute on Aging , the Patient-Centered Outcome Research Institute, the National Human Genome Research Institute (NHGRI), the National Institute of Neurological Disorders and Stroke, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Drug Abuse, the National Heart, Lung, and Blood Institute, the National Institute of Mental Health, the National Institute on Alcohol Abuse and Alcoholism, and the Paul G. Allen Family Foundation. He also has served as an associate editor of the Journal of the American Geriatrics Society. Dr Gardner and Dr Mielke have disclosed no relevant financial relationships.
JAMA Neurol. Published online July 11, 2016. Abstract
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Cite this: Traumatic Brain Injury Linked to PD, Not Dementia - Medscape - Jul 15, 2016.