The first evidence has been published that a single traumatic brain injury can generate an abnormal form of the dementia associated protein tau, which can slowly spread through the brain, resulting in memory deficits and neuronal damage.
The landmark study comes from the Mario Negri Institute for Pharmacological Research of Milan and the University of Glasgow.
“Traumatic brain injury is a leading cause of death and disability in young adults. Moreover, even in milder cases, it represents a risk factor for dementia, such as chronic traumatic encephalopathy (CTE). Understanding the mechanism linking an acute mechanical event to a progressive, degenerative brain disease would help the development of new therapies,"
said Dr. Elisa Zanier who led the Mario Negri Institute team with Dr. Roberto Chiesa.
Abnormal Tau Proteins
The neuropathological field is coming to understand that longer-term survival of traumatic brain injury involves a complex of different disease mechanisms, including abnormalities in tau, amyloid-beta, loss of neurons, axon degeneration, neuroinflammation and disruption of the blood–brain barrier.
“As part of this study we analysed brain specimens from patients surviving a year or more after a single, severe traumatic brain injury. In this material we saw evidence of much more widespread deposits of abnormal tau proteins in brain injured patients than in normal control brains,"
said Dr. Willie Stewart, Honorary Clinical Associate Professor, Institute of Neuroscience and Psychology, University of Glasgow.
In additional experiments in a mouse model of severe traumatic brain injury, the researchers found progressive and widespread tau pathology, replicating the findings in humans. Brain tissue samples from these mice, injected into the hippocampus and cerebral cortex of mice, resulted in widespread tau pathology, synaptic loss, and memory deficits.
“This progressive spread of tau was reminiscent of the spreading of prions, the infectious proteins more commonly associated with diseases such as CJD,"
said Chiesa. Creutzfeldt–Jakob disease (CJD) is a fatal brain disorder. Early symptoms include memory problems, behavioral changes, poor coordination, and visual disturbances. Later dementia, involuntary movements, blindness, weakness, and coma occur. About 90% of people die within a year of diagnosis.
“This observation that a single brain trauma is associated with widespread tau deposition in humans and to the formation of a self-propagating form of tau in a relevant animal model provides the first evidence for how a mechanical brain injury might evolve into chronic degenerative brain disease, including CTE,"
In Europe, more than 5 million people live with a physical and/or psychological disability due to moderate or severe traumatic brain injury. The new study identifies tau propagation as a possible mechanism responsible for the long-term disability of traumatic brain injury patients, and suggests that blocking tau propagation may have therapeutic effects.
The work was supported by the National Institutes of Health, a NHS Research Scotland Career - Researcher Fellowship, and the Alzheimer’s Association.
Elisa R Zanier, Ilaria Bertani, Eliana Sammali, Francesca Pischiutta, Maria Antonietta Chiaravalloti, Gloria Vegliante, Antonio Masone, Alessandro Corbelli, Douglas H Smith, David K Menon, Nino Stocchetti, Fabio Fiordaliso, Maria-Grazia De Simoni, William Stewart, Roberto Chiesa Induction of a transmissible tau pathology by traumatic brain injury Brain, awy193, https://doi.org/10.1093/brain/awy193
Image: Dr Jonathan Clarke. CC BY