Study Title:

Widespread Tau and Amyloid-Beta Pathology Many Years After a Single Traumatic Brain Injury in Humans

Study Abstract

Whilst a history of single traumatic brain injury (TBI) is associated with the later development of syndromes of cognitive impairment, such as Alzheimer's disease (AD), the long-term pathology evolving after single TBI is poorly understood. However, a progressive tauopathy, chronic traumatic encephalopathy, is described in selected cohorts with a history of repetitive concussive / mild head injury. Here, post-mortem brains from long-term survivors of just a single TBI (1 to 47 years survival; n = 39) versus uninjured, age-matched controls (n = 47) were examined for neurofibrillary tangles (NFTs) and amyloid-β (Aβ) plaques using immunohistochemistry and thioflavin-S staining. Detailed maps of findings permitted classification of pathology using semi-quantitative scoring systems.NFTs were exceptionally rare in young, uninjured controls, yet were abundant and widely distributed in approximately one third of TBI cases. In addition, Aβ-plaques were found in a greater density following TBI versus controls. Moreover, thioflavin-S staining revealed that while all plaque-positive control cases displayed predominantly diffuse plaques, 64% of plaque-positive TBI cases, displayed predominantly thioflavin-S positive plaques or a mixed thioflavin-S positive / diffuse pattern. These data demonstrate widespread NFT and Aβ plaque pathologies are present in a proportion of patients following a single TBI, suggesting that some individuals who experience a single TBI may develop long-term neuropathological changes akin to those found in neurodegenerative disease.

From press release:

Years after a single traumatic brain injury (TBI), survivors still show changes in their brains. In a new study, researchers from the Perelman School of Medicine at the University of Pennsylvania suggest that Alzheimer's disease-like neurodegeneration may be initiated or accelerated following a single traumatic brain injury, even in young adults.

Over 1.7 million Americans suffer a traumatic brain injury each year, and beyond the immediate effects, growing evidence demonstrates that a single TBI may initiate long-term processes that further damage the brain. TBI is an established risk factor for later development of cognitive impairments, such as Alzheimer's disease.

"A single traumatic brain injury is very serious, both initially, and as we're now learning, even later in life," said Douglas Smith, MD, professor of Neurosurgery and director of the Center for Brain Injury and Repair at Penn's Perelman School of Medicine, the study's co-senior author. "Plaques and tangles are appearing abnormally early in life, apparently initiated or accelerated by a single TBI."

The study appears online in Brain Pathology, and was done in conjunction with neuropathologist Dr. William Stewart, from the University of Glasgow and Southern General Hospital in Glasgow, UK.

The researchers found both tau tangles and amyloid-beta plaques in survivors, years after a single moderate-to-severe TBI. In repetitive head injury, previous studies have shown a tau accumulation as the signature pathology of a condition called chronic traumatic encephalopathy. In studies of people less than 4 weeks after dying from a single TBI, no similar tau pathology was found. In addition, while widespread amyloid-beta plaques have been found in about 30 percent of people shortly after injury, previous work showed that plaques disappeared within months.

In this study, researchers examined post-mortem brains from 39 long-term survivors of a single TBI, extending the survival time from 1-47 years survival after TBI, and compared them to uninjured, age-matched controls.

TBI survivors showed a high density and wide distribution of neurofibrillary tau tangles and amyloid-beta plaque pathology far beyond what was found in controls. Specifically, about a third of the cases showed tangle pathology years after a single TBI, similar in appearance to the tangles found after repetitive TBI and in neurodegenerative diseases such as Alzheimer's disease. Moreover, the amyloid-beta plaques were not only found years after TBI, but the majority of cases displayed diffuse as well as "neuritic" plaques with the same character as "senile" plaques also found in Alzheimer's disease. This suggests that years after a single TBI, amyloid-beta plaques may return and become neuritic.

The present findings, showing that two hallmark pathologies of Alzheimer's disease can be found years after a single TBI, may provide a pathological link with the epidemiological observation of an increased risk of developing Alzheimer's disease. Moreover, future research to better understand this long-term neurodegenerative process after a single TBI may reveal important targets for treatment with emerging anti-tau and anti-amyloid therapies.

The study was funded by the U.S. National Institutes of Health.

Study Information

Victoria E. Johnson, William Stewart, Douglas H. Smith.
Widespread Tau and Amyloid-Beta Pathology Many Years After a Single Traumatic Brain Injury in Humans
Perelman School of Medicine at the University of Pennsylvania
2011 June
Brain Pathology

Full Study