There has long been debate about a link between serious blows to the head and the development of neurodegenerative diseases later in life. Research has made cases for and against a relationship between traumatic brain injuries and neurological ailments such as Alzheimer’s, Parkinson’s and general dementia. Now the question is drawing ever more scrutiny as the alarming extent of these injuries becomes better known—and new research is finally casting some light on this murky and often quietly terrifying topic.
A large-scale analysis of three separate studies published this week in JAMA Neurology found no association between unconsciousness-causing traumatic brain injuries (TBI) and Alzheimer’s disease or general dementia—but it did find a strong association between TBI and Parkinson’s disease. “I can’t decide if the positive or negative findings are more surprising,” says one of the study’s investigators, physician and Alzheimer’s researcher Paul Crane at the University of Washington. The positive association his team found between Parkinson’s and TBI was not entirely novel, but Crane says the magnitude of the link was unexpected. The researchers found the risk of Parkinson’s rose threefold for people whose head injuries had caused them to go unconscious for more than an hour.
The more contentious finding is the lack of an association between TBI and Alzheimer’s. Prior research has been divided on whether there is a link, but many of the previous studies have been smaller in scale and conducted less-comprehensive analyses. “Although early studies suggested a clear link between TBI and an increased risk for Alzheimer’s disease, this has not been replicated,” explains Frances Corrigan at the University of Adelaide, who studies how TBI influences neurodegeneration. The intrinsically challenging nature of such research—and the large number of subjects needed to establish a significant result—add to the difficulty of confirming a link, says Corrigan, who was not involved in Crane’s study.
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The fact that this study only looked at late-onset Alzheimer’s, which is far more common than early-onset, may have contributed to the lack of an association with TBI, Crane says. Prior studies, which did not exclude people with early-onset Alzheimer’s, may have found a link only with that form of the disease, and the sheer size of the new analysis may lend that link more credence. “If there were a signal there across the three studies we really should have seen it,” Crane says, “and we didn’t.”
In addition to its scale, this study has another unusual advantage: It used autopsy data. Most of the prior research on the link between TBI and Alzheimer’s used clinical criteria to confirm that subjects had suffered from Alzheimer’s. But the observable signs and symptoms in still-living patients are usually not specific enough to rule out similar problems such as general dementia. Autopsy evidence is clearer because researchers can physically look for brain changes that are known to result from Alzheimer’s and not from other neurodegenerative disorders.
Autopsy data is obviously a lot harder to come by, however. Most people do not get brain autopsies when they die, so a researcher has to enroll subjects in a study while they are alive—so that on their death their brains will be donated. Crane says this difficult approach enabled him and colleagues to gather a great deal of valuable information.
The analysis looked at 7,130 people across three separate studies beginning in 1994 and followed them over the ensuing decades to look for cognitive changes and development of neurodegenerative diseases. Not all participants gave consent for their brains to be donated for autopsies but where that data was available the study authors combed the clinical information for the pathological signs of neurodegeneration. More than 1,500 people in the study did donate their brains and had undergone autopsies at the time the research was analyzed, and the scientists are continuing to collect data as the participants age.
The study did not examine multiple brain injuries like the ones many athletes and soldiers experience, so it does not claim to have concrete findings related to chronic traumatic encephalopathy (CTE), a neurodegenerative disorder that people exposed to repeated head injuries can develop. The new findings only speak to what Crane calls the “garden variety” pattern of head injury—referring to the more common situation of having just one TBI incident—which may have very different implications.
Not looking at CTE raises questions about biased findings. CTE has only been recognized as a distinct disease in the last decade, so it has been fairly easy to attribute CTE-related cognitive problems as a more general form of age-related dementia, explains neuropathologist William Stewart at the University of Glasgow, who was not involved in Crane’s research. Unless you specifically look for and recognize the physical changes during autopsy, he says, you could be missing the signs. “This is why it took so long to identify CTE in TBI survivors other than boxers,” he says. “And here we are now in 2016 realizing that CTE is associated with exposure to TBI, no matter whether boxers or footballers, a single moderate or severe injury, or a repetitive mild one.”
This is perhaps the largest study to-date that uses autopsy data to analyze the long-term outcomes of TBI, and Crane says the findings have shown him that prevention is becoming more important than ever—it is the only surefire way to prevent the neurodegenerative effects. “We found most of our exposure for long durations was under age 25,” he says. With a 40-year lag time between the exposure and the onset of these diseases, he says we have to practice prevention now. “My hashtag is ‘all brains matter’.”