Many people exhibit bad side effects months or even years after a traumatic brain injury (TBI) – trouble sleeping, difficulty carrying out daily activities, or even sensitivity to basic stimulus. The long-term effects can last a few days or the rest of a person’s life. Recently researchers at Gladstone Institute of Neurological Disease (Gladstone), California, have identified a specific molecule in a part of the brain that may contribute to secondary effects of a TBI; in collaboration with biopharmaceutical company Annexon Biosciences (Annexon), also in California, the researchers were able to find an antibody treatment that was seen to prevent the development and progression of these side effects.

TBIs range from a mild concussion to a severe injury, and can be the result of a fall, sports injury, gunshot injury, blow to the head, explosion, or domestic violence. TBIs affectnearly 70 million people around the world annually and is a major source of disability in adults.

Associate investigator at Gladstone, Dr. Jeanne Paz, and colleagues decided to study this occurrence to hopefully develop new and better treatment options to TBIs long-term effects.

To do so, Paz and her team recorded the activity of different cells and circuits in the brain of mice after a TBI; the mice were monitored continually and wirelessly, meaning they could go about their normal activities without being disrupted.

“We collected so much data, from the time of injury and over the next several months, that it actually crashed our computers,” said Paz. “But it was important to capture all the different stages of sleep and wakefulness to get the whole picture.”

After analysis, the researchers were surprisedto discover a different region of the brain – the thalamus – was even more disrupted than the cerebral cortex, often thought to be the primary site of injury in TBIs because it sits directly beneath the skull.A molecule called C1q was found to be present at abnormally high levels in the thalamus for months after the initial injury, and these high levels were associated with inflammation, dysfunctional brain circuits, and the death of neurons; it was determined that C1q in the thalamus likely came from microglia, the immune cells in the brain.

The C1q molecule has well-documented roles in brain development and normal brain functions. For instance, it protects the central nervous system from infection and helps the brain forget memories; a process needed to store new memories. The accumulation of C1q in the brain has been studied in various neurological and psychiatric disorders and is associated, for example, with Alzheimer’s disease and schizophrenia.

In addition to chronic inflammation, Paz and her team uncovered abnormal brain activity in the mice, firstly, disruptions in sleep spindles, which are normal brain rhythms that occur during sleep. These are important for memory consolidation, among other things. The scientists also found epileptic spikes, or abnormal fluctuations in brain activity. These spikes can be disruptive to cognition and normal behaviour and are indicative of a greater susceptibility to seizures.

It was later observed that a clinical antibody engineered to block the activity of the C1q molecule prevented chronic inflammation and the loss of neurons in the thalamus of mice with TBIs. Conversely, given the antibody treatment at the time of trauma, the brain injury of the animals’ appeared much worse.

Read: Risk of developing dementia increases after traumatic brain injuries

“The C1q molecule shouldn’t be blocked at the time of injury, because it’s likely very important at this stage for protecting the brain and helping prevent cell death,” said Dr. Stephanie Holden, a former graduate student in Paz’s lab at Gladstone. “But at later time points, blocking C1q can actually reduce harmful inflammatory responses. It’s a way of telling the brain, ‘It’s okay, you’ve done the protective part and you can now turn off the inflammation.

“Overall, our study indicates that targeting the C1q molecule after injury could avoid some of the most devastating, long-term consequences of TBI. We hope this could eventually lead to the development of treatments for traumatic brain injury.”

Annexon’s anti-C1q inhibitors are designed to treat multiple autoimmune and neurological disorders, and are already being examined in clinical trials, including for an autoimmune disorder known as Guillain-Barré syndrome, where the drug has been shown to be safe in humans.

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