TBI and dementia: Link or no link?
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Researchers are using population studies and animal models to investigate how TBIs might lead to progressive neurodegeneration in some patients.
Traumatic brain injuries (TBIs) disrupt the normal function of the brain. They occur as a result of a blow or jolt to the head, or an injury that penetrates it, according to the Centers for Disease Control and Prevention (CDC).
In 2013, 2.8 million people in the U.S. sustained TBI, of which approximately 56,000 resulted in death. The age groups most affected by TBI were small children up to the age of 4, teenagers and young adults between 14 and 25 years, and those over 75 years of age. The most common causes of TBI were falls, being struck by an object, and car accidents.
The immediate symptoms can range from headaches and blurry vision to slurred speech and short-term memory problems. TBIs can also have long-term effects on health, with an increased risk of seizures and infections sometimes following.
Research has suggested a link between TBI and several forms of progressive neurodegeneration - such as dementia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease - but there is conflicting evidence.
Why is it so difficult to find conclusive evidence? And what are the long-term predictions for TBI patients?
The latest findingsLast week, Medical News Today reported on a study by Finnish researchers, which was published in the journal PLOS Medicine. Using the Finnish Care Register for Health Care, the team compared the medical notes of working-age individuals under the age of 65 with mild or moderate to severe TBI, all of whom had subsequently developed dementia, Parkinson's disease, or ALS.
They found a link between moderate to severe TBI and dementia, but no links with Parkinson's disease or ALS were discovered.
Importantly, they found that the incidence rate of dementia in moderate to severe TBI patients was similar to that found in the general population. But dementia occurs mostly in the elderly, highlighting that TBI shifts the risk from old age to working age.
The dataset used in this study was comprehensive; Finland has a tax-funded healthcare system. According to the authors, all acute TBI cases are treated at public hospitals and would therefore have been included in the study.
Yet data were only available for TBI patients who had subsequently been admitted to the hospital with neurodegenerative symptoms. The authors explain that it is possible that other patients with a diagnosis of neurodegeneration may have been missed if they had not been hospitalized at the time.
The results of the Finnish study concurred with data published last year in the Asian Pacific Journal of Public Health. Here, rates of dementia were higher among Taiwanese TBI patients than among those who had not sustained TBI.
Another study, published recently in the Journal of Alzheimer's Disease, failed to establish a link between TBI and Alzheimer's disease.
The authors compared 706 U.S. seniors with and without TBI and found that cognitive decline in participants was not affected by having experienced TBI. But in this study, TBI was self-reported by the study participants rather than assessed in their medical notes, meaning that data may not have been accurate.
A systematic review published earlier this year in Annals of Physical & Rehabilitation Medicine struggled to find a meaningful connection between TBI and Alzheimer's disease.
The review included 18 studies, but the authors were unable to classify TBI by severity. By grouping mild and moderate to severe TBI into the same category, it may not have been possible to establish a connection between TBI and Alzheimer's disease.
Other studies, however, have found clear links between TBI and Alzheimer's disease and Parkinson's disease.
TBI, neurodegeneration link supportedIn an Alzheimer's disease patient cohort, those with histories of moderate to severe TBI began to experience symptoms and received their diagnosis by an average of 2.5 years earlier than non-TBI patients, according to a recent study published in the journal The Clinical Neuropsychologist. But again, TBI was self-reported in this study.
A paper published last year in JAMA Neurology found that while there was no link between TBI and dementia or Alzheimer's disease, there was a connection with Parkinson's disease.
Some of the study participants had consented to brain autopsies after their death. Both mild and moderate to severe TBI patients showed signs of Lewy bodies, a hallmark of Parkinson's disease, in their brains, while moderate to severe TBI patients also had signs of cerebral microinfarcts.
Importantly, while study participants were aged 65 and over, a third of mild and nearly half of moderate to severe TBI patients were age 25 years or younger when they sustained their TBI. This demonstrates that TBI could have long-term neurodegenerative effects.
The problem with this type of study is that they mostly rely on measures of association. This means that researchers establish whether or not there is a link between TBI and neurodegeneration in a particular study population based on the data they are using.
However, it is not possible to establish cause and effect in these studies, meaning that there could be other biological mechanisms involved in causing neurodegeneration in these patients.
To study what happens in the brain after TBI, researchers turn to animals. Here, the events following TBI are beginning to be unraveled.
How can TBI cause neurodegeneration?A recent article in Reviews in the Neurosciences summarized what is known, to date, about the neurological damage following TBI.
The initial injury damages blood vessels, neurons, and other cell types. As a secondary effect, neurons become overstimulated, resulting in oxidative stress and cell death. Water metabolism is also affected, causing swelling in the brain.
The blood-brain barrier, which is normally impenetrable to most substances, becomes disrupted, allowing immune cells to infiltrate the damaged brain.
The combination of oxidative damage, neuroinflammation, edema, and damaged blood flow can cause significant and long-term damage to the brain.
Using a mouse model of brain injury, a recent study published in The Journal of Neuroscience set out to investigate the long-term effects of TBI in more detail.
Damage to the regions surrounding the injury site was immediate. Crucially, long-term damage was observed in distant regions in the brain and was attributed to chronic neuroinflammation.
In a mouse model of Alzheimer's disease, long-term effects were also observed after TBI in a study reported in Neuroscience Letters. Interestingly, there were no immediate differences in the brains of aged mice that had experienced TBI and those that had not.
Both injured and uninjured mice developed senile plaques, a hallmark of Alzheimer's disease, at the same rate for the first week of the study. However, at 28 days after the TBI, significantly more plaques were present in the mice. This was accompanied by impaired spatial learning.
The researchers interpreted this to mean that TBI accelerates Alzheimer's disease symptoms.
For patients who have experienced TBI, what do these data mean?
The need for long-term monitoringWhile it is possible to study the cellular events that follow TBI in model systems, it is more difficult to confidently apply these results to human patients.
Many studies point to long-term effects of TBI on the brains of animals and humans, but the extent of the damage and the precise implications remain unclear.
Regardless of their results, what most studies agree on is the need for long-term monitoring for TBI patients, especially those who have experienced moderate to severe TBI. There is also a call for more accurate diagnostic criteria that would allow physicians to spot the onset of TBI-associated neurodegeneration earlier.
This would enable physicians to closely monitor patients and start treatments or interventions early on, with the aim of slowing the progression of cognitive decline.
It is clear that more studies are needed, specifically those that investigate cause and effect and that can link the results to large-scale, accurate population data.
It is also important to remember that not all of those who have sustained TBI will definitely go on to develop progressive neurodegeneration.
In the Finnish study, 1.6 percent of those with a history of mild TBI went on to develop dementia. Even though those with moderate to severe TBI were 90 percent more likely to receive a dementia diagnosis, this still only equates to a rate of 3.5 percent.
While there is strong evidence to suggest a risk of long-term damage to the brain after sustaining TBI, questions remain on why some patients go on to develop progressive neurodegeneration and how many are likely to be affected.