Concussion sequelae increase the risk of Alzheimer’s

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Post-traumatic amnesia (PTA) and chronic vascular damage caused by traumatic brain injury (TBI) are linked to an increased risk of later Alzheimer’s disease (AD), according to new research.

Results of a retrospective case-control study showed that the presence of ATP or vascular lesions on neuroimaging in patients with TBI was significantly associated with an almost four-fold increased risk of AD.

The study highlights the severity of head trauma, which some people still view as “just a blow to the head,” co-investigator Jehane H. Dagher, MD, associate professor, Department of Physical Medicine and Rehabilitation, University of Montreal, and head of the TBI program at the Rehabilitation Institute of Montreal, Quebec, Canada, recounted Medscape Medical News.

“These patients end up with cognitive decline, difficulty organizing, planning, re-entering the labor market and resuming a normal life. They need a lot of help from their loved ones and their community and their medical system,” Dagher added.

The results were published online on December 30, 2021, in Alzheimer’s disease and related disorders.

Increase in prevalence

The prevalence of neurocognitive disorders (NCDs) is increasing due, in part, to an aging population, Dagher noted. AD is the most common cause of NCD and about 35% of people aged 85 and over develop the disease.

TBI is increasingly recognized as a major risk factor for NCDs. The fact that less than 7% of patients with TBI develop dementia suggests that some patients may be more vulnerable than others.

Using medical records and medical insurance data, researchers identified 5642 patients with TBI admitted to a tertiary trauma center over a 12-year period (2000 to 2012). Head injuries, most of which were mild, resulted from motor vehicle accidents, falls, assaults, and sports-related accidents.

The current analysis included 30 patients with TBI who developed AD dementia before the end of 2018 and 80 people who did not have dementia to act as a control group.

Patients in the dementia group had a median age at injury of 58.3 years versus 70.4 years for the control group. The median time to diagnosis of dementia after injury was 3.3 years.

Of the study population, 25.5% were diagnosed with ATP, which is characterized by confusion and disorientation; 16.7% had a history of at least one TBI. A history of diabetes (19.4%), hypertension (55.5%), dyslipidemia 37.0%) or coronary artery disease (25.0%) was also recorded. None of the participants had a history of peripheral arterial disease.

Initial scans showed vascular lesions and atrophy in 23.6% and 27.6% of patients, respectively.

Significant association

The results showed a significant association between ATP and AD dementia, with higher odds for those with or without AD diagnosis (odds ratio [OR], 2.88; 95% CI, 1.06-7.81; P = 0.04).

As ATP is related to the severity of brain injury, this finding suggests “that someone with severe TBI is at higher risk of developing dementia,” Dagher noted.

The risk of developing AD dementia was also higher in people with evidence of vascular damage on neuroimaging compared to those without damage (OR, 3.81; 95% CI, 1. 04-4.07; P = 0.04).

Chronic vascular lesions may indicate small vessel disease (SVD), which may act synergistically with tau proteins, a hallmark of AD, the researchers note. It could be that ischemia resulting from SVD accelerates the pathogenesis of AD and that TBI may accelerate this process, they add.

Risk factors such as diabetes, hypertension and dyslipidemia do not significantly affect dementia risk, likely due to the small number of participants with dementia, Dagher said. Age was also not a significant risk factor for dementia, possibly because the patients were only followed for 10 years, she noted.

Dagher added that the lack of association with the Glasgow Coma Scale (GCS) was due to the fact that most of the study population had mild TBI.

The researchers excluded patients diagnosed with dementia within 6 months of injury to avoid reverse causation. For example, falls causing brain damage can be an early sign of dementia.

This reinforces the suggestion that TBI is a factor leading to dementia and not a consequence, the investigators write.

Dagher stressed the importance of having trauma neurosurgeons caring for TBI patients, and for those physicians to follow “appropriate guidelines to minimize harm” after injury.

In the longer term, preventing TBI-related dementia should involve improving resources to test and treat TBI patients, she said.

Strengths weaknesses

Commenting for Medscape Medical News, David Knopman, MD, professor of neurology, Mayo Clinic, Rochester, Minnesota, said the finding that ATP and cerebrovascular disease are associated with dementia “makes sense.”

Also, a strength of the study was its large sample size of older individuals, said Knopman, who was not involved in the research.

However, he noted several features of the study that limit interpretation. “The main thing is that an insurance record diagnosis of ‘Alzheimer’s disease’ has a very noisy and imprecise relationship to the laboratory diagnosis of plaque and tangle disease, for example, Alzheimer’s disease. Alzheimer’s,” he said.

Additionally, the study’s use of the term AD dementia is “misleading” because in clinical practice it corresponds to dementia of a number of etiologies, Knopman noted. “This creates a false impression of specificity for the plaque and tangle pathology that is actually Alzheimer’s disease.”

It would have been clearer if the investigators had labeled the primary finding “all-cause dementia,” he said.

Knopman also questioned the exclusion of patients diagnosed with dementia until only 6 months after their TBI to avoid reverse causation. Instead, the researchers “should have at least provided analyzes where they excluded people where the lag between TBI and diagnosis of dementia was up to 2 or 3 years,” he said.

“The TBI could have been caused by a fall which in turn was due to an incipient cerebrovascular or neurodegenerative disease,” such as Parkinson’s disease, Knopman added.

The shorter threshold could mean that “what was diagnosed as dementia was really a direct extension of post-traumatic cognitive impairment and not really a separate event,” he said.

Knopman would also have liked an analysis stratified by age, for example, those under 70 versus those who were older. “I would be surprised if age hadn’t played a role in the results,” although it was not significant in the main analysis, he concluded.

The study was funded by the Research Institute of the McGill University Health Centre. Investigators have not reported any relevant financial relationships.

Alzheimer’s disease and related disorders. Published online December 30, 2021. Summary

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