TBI, Even Without Loss of Consciousness, May Up Dementia Risk

Traumatic brain injury (TBI) with, and without, loss of consciousness (LOC) is linked to increased neurodegenerative and vascular pathology associated with dementia, new research suggests.

Results from a large cross-sectional analysis showed patients with TBI and LOC had a significantly greater amyloid-β load — and higher odds for having gross infarcts and microinfarcts, including subcortical microinfarcts, vs those without TBI.

Participants with TBI without LOC had higher odds for cortical microinfarcts and neocortical Lewy bodies.

Sonal Agrawal, PhD

The study illustrates that "all forms of TBI, even milder forms that don't result in loss of consciousness, are important in producing brain pathologies in older people," lead author Sonal Agrawal, PhD, assistant professor at Rush Alzheimer's Disease Center and Department of Pathology, Rush University Medical Center, Chicago, Illinois, told Medscape Medical News.

Therefore, clinicians might consider more careful screening of patients with mild TBI and provide dietary, cognitive, and physical activity advice that may reduce risk for brain pathologies later on, Agrawal noted.

The findings were published online April 27 in JAMA Network Open.

Greater Amyloid Load

Previous research has shown TBI is a risk factor for cognitive impairment and dementia, although most of this evidence is from moderate or severe TBI. Most TBIs in the general population are relatively mild, Agrawal noted.

She added that most previous related studies were also derived from clinic-based and autopsy-based samples and may not reflect TBI in community-based samples.

The new analysis assessed brains of 1689 autopsied older individuals who were enrolled in one of three longitudinal community-based studies of aging: the Religious Orders Study, the Rush Memory and Aging Project, or the Minority Aging Research Study.

Of the total patient population, 67% were women, the mean age at death was 89.2 years, and about 95% were white. Unlike with previous research, participants in this study did not have dementia at enrollment.

Self-reported TBI and LOC were assessed at enrollment and annual follow-up visits. The mean follow-up was 8.7 years.

Researchers classified 1024 participants as not having TBI, 161 as having TBI with LOC, and 504 as having TBI without LOC.

Neuropathologic evaluations included: amyloid-β, paired helical filament tangles, neocortical Lewy bodies, gross infarcts, microinfarcts, and other neuropathologic changes. Complete neuropathologic measures were available for 1578 of the decedents.

Compared with participants without TBI, those with TBI with LOC had a greater amyloid-β load (estimate, 0.25; 95% CI, 0.06 to 0.43; P = .008), after adjusting for age at death, sex, and educational level.

The TBI with LOC group had both higher mesial temporal and neocortical amyloid-β load than those without TBI, after adjustments.

Different Pathways?

Previous evidence has suggested amyloid is an early marker in the development of Alzheimer's disease (AD), appearing to begin in the neocortex and affecting the mesial temporal lobe in advanced age, the investigators note.

However, while results from the current study showed a link between TBI with LOC and neocortical and mesial temporal amyloid, there was no association between TBI and pathologic diagnosis of AD.

Agrawal explained that a diagnosis of AD involves both neurofibrillary tangle accumulation as well as amyloid-beta. "In this study, we see that people with TBI have more amyloid burden but we did not see any relation with tau accumulation," she said.

Results also showed participants categorized as having TBI and LOC had higher odds of having one or more gross infarcts (odds ratio [OR], 1.45; 95% CI, 1.04 - 2.02; P = .02) and microinfarcts (OR, 1.70; 95% CI, 1.21 - 2.38; P = .002). This association was particularly strong for subcortical microinfarcts, with 85% higher odds (OR, 1.85; 95% CI, 1.23 - 2.79; P = .002).

The TBI without LOC group did not have higher rates of AD pathology — but did have higher adjusted odds of neocortical Lewy bodies (OR, 1.37; 95% CI, 1.01 - 1.87; P = .04) and of one or more cortical microinfarcts (OR, 1.43; 95% CI, 1.09 - 1.87; P = .008) compared with the group without TBI.

The association of TBI, with and without LOC, with vascular pathologic outcomes persisted after controlling for vascular risk factors and vascular disease burden.

Some prior studies have described APOE ε4 risk alleles and male sex as risk factors for neuropathologic outcomes in patients with TBI, while other studies have not. The current study did not demonstrate different associations by APOE ε4 group or by sex.

The new results suggest TBI with LOC could involve different pathways than TBI without LOC, the investigators note. For example, TBI with LOC may affect the amyloid clearance pathway whereas TBI without LOC may involve a mechanism that leads to Lewy bodies, Agrawal said.

A limitation was that the study did not take into account several TBI factors, including age when the head injury occurred and the number of injuries received.

In addition, participants were relatively highly educated and older at the time of death, so the findings may not be generalizable to younger populations with less education, the investigators note.

Questions Raised

Commenting on the findings for Medscape Medical News, Javier Cárdenas, MD, director of the concussion and brain injury center, Barrow Neurological Institute, Phoenix, Arizona, said he found the study useful.

He also noted that stroke was the most significant difference between those classified with LOC vs those without LOC.

"These little strokes throughout the brain were far more prevalent in those classified as losing consciousness versus those who did not," said Cárdenas, who was not involved with the research.

That raises the question of whether there's a change in blood flow or in the vasculature of the brain when someone loses consciousness, he noted. "That's very significant because we know that cardiovascular diseases such as high blood pressure are risk factors for things like dementia," he added.

However, Cárdenas questioned how researchers determined loss of consciousness. Asking patients if they lost consciousness without a witness verifying it may not be reliable, with patients possibly mistaking amnesia for loss of consciousness, he said.

It is also unclear for how long those classified as LOC actually lost consciousness, "and that matters in terms of severity," Cárdenas noted.

"There's a distinction between those who had amnesia or lost consciousness for a short period of time and those who were in a coma for a week," he added.

The study was supported by grants from the National institutes of Health. Agrawal and Cárdenas have disclosed no relevant financial relationships.

JAMA Netw Open. 2022;5:e229311. Full article

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