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The radial-arm water maze is a common test to assess working memory in rodents.

Memory-enhancing drug reverses effects of traumatic brain injury in mice

By Ryan Cross, Jul. 10, 2017, sciencemag.org

Whether caused by a car accident that slams your head into the dashboard or repeated blows to your cranium from high-contact sports, traumatic brain injury can be permanent. There are no drugs to reverse the cognitive decline and memory loss, and any surgical interventions must be carried out within hours to be effective, according to the current medical wisdom. But a compound previously used to enhance memory in mice may offer hope: Rodents who took it up to a month after a concussion had memory capabilities similar to those that had never been injured.

The study “offers a glimmer of hope for our traumatic brain injury patients,” says Cesario Borlongan, a neuroscientist who studies brain aging and repair at the University of South Florida in Tampa. Borlongan, who reviewed the new paper, notes that its findings are especially important in the clinic, where most rehabilitation focuses on improving motor—not cognitive—function.

Traumatic brain injuries, which cause cell death and inflammation in the brain, affect 2 million Americans each year. But the condition is difficult to study, in part because every fall, concussion, or blow to the head is different. Some result in bleeding and swelling, which must be treated immediately by drilling into the skull to relieve pressure. But under the microscope, even less severe cases appear to trigger an “integrated stress response,” which throws protein synthesis in neurons out of whack and may make long-term memory formation difficult.

In 2013, the lab of Peter Walter, a biochemist at the University of California, San Francisco (UCSF), discovered a compound—called ISRIB—that blocked the stress response in human cells in a dish. Surprisingly, when tested in healthy mice, ISRIB boosted their memory. Wondering whether the drug could also reverse memory impairment, Walter teamed up with UCSF neuroscientist Susanna Rosi to study mouse models of traumatic brain injury. First, they showed that the stress response remains active in the hippocampus, a brain region important for learning and memory, for at least 28 days in injured mice. And they wondered whether administering ISRIB would help.

Rosi and her team first used mechanical pistons to hit anesthetized mice in precise parts of their surgically exposed brains, resulting in contusive injuries, focused blows that can also result from car accidents or being hit with a heavy object. After 4 weeks of rest, Rosi trained the mice to swim through a water maze, where they used cues to remember the location of a hidden resting platform. Healthy mice got better with practice, but the injured ones didn’t improve. However, when the injured mice were given ISRIB 3 days in a row, they were able to solve the maze just as quickly as healthy mice up to a week later, the researchers report today in the Proceedings of the National Academy of Sciences.

“We kept replicating experiments, thinking maybe something went wrong,” Rosi says. So the team decided to study ISRIB in a second model of traumatic brain injury known as a closed head injury, which resembles a concussion from a fall. They again used a mechanical piston, but this time landed a broad blow to the back of the skull. Two weeks later, the mice were trained on a tougher maze, full of bright lights and loud noise. They had to scurry around a tabletop with 40 holes, looking for the one with an escape hatch. Again, while the uninjured mice improved at the task, the concussed mice never got the hang of it. But after four daily doses of ISRIB, the concussed mice performed as well as their healthy counterparts. “This is the most exciting piece of work I’ve ever done, no doubt,” Rosi says.

“Paradigm shift is not too strong a term to use,” says Ramon Diaz-Arrastia, neurologist and director of clinical traumatic brain injury research at the University of Pennsylvania. “This … shows for the first time that a therapy in the chronic period of traumatic brain injury can have pretty potent effects.” Walter agrees. “Normally you would give up on these mice and say nothing can be done here,” he says. “But ISRIB just magically brings the cognitive ability back.”

Still, Borlongan cautions that studies in animals often don’t pan out when tested in humans. He says that this drug has a leg up, though, because it was tested in two models and also readily crosses the blood-brain barrier, which prevents many drugs that look good on paper from entering the brain and having an effect.

If the therapy translates to humans, it could be a boon for soldiers returning from war, who sometimes wait weeks between leaving the battlefield and arriving home for treatment. Brian Head, a neurobiologist at the VA San Diego Healthcare System in California notes that traumatic brain injury is still hard to diagnose, especially with veterans that show up to the clinic long after the injury. “But right now nothing else is working, and giving a compound [that works] a month later is really impressive.”

In 2015, ISRIB was licensed to the secretive Google spinout company Calico, which studies the biology of aging and life span. Walter says his lab has a research agreement with Calico to pursue “basic mechanistic work” on ISRIB, but that the new study was not funded by Calico. Google declined to comment on the new research.

Although the protein target of ISRIB is known, the exact manner in which the drug restores memory is hazy. The team hypothesizes that ISRIB may work by allowing normal protein synthesis—essential for making new neuronal connections and thus forming new memories—to resume, which would otherwise be blunted by the integrated stress response. “Even if this drug doesn’t materialize, other ways of manipulating the integrated stress response may lead to an effective treatment in the future,” Walter says.

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UCSF Researchers Advocate Prioritizing Teens for Education and Prevention

by Scott Maier (August 17, 2016) — The number of Americans diagnosed with concussions is growing, most significantly in adolescents, according to researchers at UC San Francisco. They recommend that adolescents be prioritized for ongoing work in concussion education, diagnosis, treatment and prevention.

The findings appear online August 16, 2016, in the Orthopaedic Journal of Sports Medicine.

“Our study evaluated a large cross-section of the U.S. population,” said lead author Alan Zhang, MD, UCSF Health orthopaedic surgeon. “We were surprised to see that the increase in concussion cases over the past few years mainly were from adolescent patients aged 10 to 19.”

Concussions are a form of mild traumatic brain injury resulting in transient functional and biochemical changes in the brain. They can lead to time lost from sports, work and school, as well as significant medical costs.

Though symptoms resolve in most concussion patients within weeks, some patients’ symptoms last for months, including depression, headache, dizziness and fogginess. Neuroimaging and neuropathological studies also suggest there may be chronic structural abnormalities in the brain following multiple concussions.

Recent studies have shown an increase in traumatic brain injuries diagnosed in many U.S. emergency departments. Smaller cohort studies of pediatric and high school athletes also have indicated a rise in concussions for certain sports, such as football and girls’ soccer. However, this is the first study to assess trends in concussion diagnoses across the general U.S. population in various age groups.

In this study, Zhang and his colleagues evaluated the health records of 8,828,248 members of Humana Inc., a large private payer insurance group. Patients under age 65 who were diagnosed with a concussion between 2007-2014 were categorized by year of diagnosis, age group, sex, concussion classification, and health care setting of diagnosis (emergency department or physician’s office).

Overall, 43,884 patients were diagnosed with a concussion, with 55 percent being male. The highest incidence was in the 15-19 age group at 16.5 concussions per 1,000 patients, followed by ages 10-14 at 10.5, 20-24 at 5.2 and 5-9 at 3.5.

The study found that 56 percent of concussions were diagnosed in the emergency department, 29 percent in a physician’s office, and the remainder in urgent care or inpatient settings. As such, outpatient clinicians should have the same confidence and competence to manage concussion cases as emergency physicians, Zhang said.

A 60 percent increase in concussions occurred from 2007 to 2014 (3,529 to 8,217), with the largest growth in ages 10-14 at 143 percent and 15-19 at 87 percent. Based on classification, 29 percent of concussions were associated with some loss of consciousness.

A possible explanation for the significant number of adolescent concussions is increased participation in sports, said Zhang, MD, who is also assistant professor of orthopaedic surgery at UCSF. It also may be reflective of an improved awareness for the injury by patients, parents, coaches, sports medical staff and treating physicians.

For example, the U.S. Centers for Disease Control and Prevention “HEADS UP” initiative has caused numerous states such as California to alter guidelines for youth concussion treatment.

Many medical centers also are establishing specialty clinics to address this, which could be contributing to the increased awareness. At UCSF, the Sports Concussion Program evaluates and treats athletes who have suffered a sports-related concussion. The team includes experts from sports medicine, physical medicine and rehabilitation, neuropsychology and neurology. Their combined expertise allows for evaluation, diagnosis and management of athletes with sports concussions, helping them safely recover and return to sports.

Other UCSF orthopaedic surgery contributors to the Orthopaedic Journal of Sports Medicine study were senior author Carlin Senter, MD, associate professor; Brian Feeley, MD, associate professor; Caitlin Rugg, MD, resident; and David Sing, clinical research associate.

UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital San Francisco, and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.

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