US Pharm. 2024;49(1):15-16.

Brain Scans of Former NFL Players Show Repair Protein Long After Injury

In a new study using brain scans of former National Football League (NFL) athletes, Johns Hopkins Medicine researchers say they found high levels of a repair protein present long after a traumatic brain injury (TBI), such as a concussion, takes place. The repair protein, known as 18 kDa translocator protein (TSPO), is known to be present in the brain at high levels in the immediate aftermath of brain injury as part of the inflammatory response and to facilitate repair.

The findings, published in JAMA Network Open, suggest that brain injury and repair processes persist for years after players end collision sports careers and lead to long-term cognitive problems, such as memory loss.

“The findings show that participating in repeated collision sports like football may have a direct link to long-term inflammation in the brain,” said Jennifer Coughlin, MD, associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. Ongoing studies such as the current one, she said, add details about how the brain heals and how repeated brain injuries, even mild ones that players routinely shake off, may affect cognitive abilties over time.

Dr. Coughlin noted that TSPO is a protein associated with immune cells in the brain known as microglia. This protein is always present at relatively low levels. When a person experiences a TBI of any kind, TSPO levels are greatly increased as part of the immune response.  Past studies have shown the presence of elevated levels of TSPO up to 17 years after injury, which, researchers say, indicates that the brain remains in a heightened state of injury and repair long after the traumatic event.

In the new study, researchers examined MRI and PET scans of 27 former NFL players that were completed between April 2018 and February 2023. They compared these brain scans with those acquired from 27 noncollision sport athletes (swimmers) who all participated for at least 2 years in National Collegiate Athletic Association Division I, II, or III level competition.

All athletes were aged between 24 and 45 years, and all were male. Participants in both groups underwent cognitive assessments, including memory tests.

The results show that former NFL players performed worse in learning and memory tests than the swimmers. Additionally, they found that levels of TSPO in the former NFL athletes were higher on average compared with the swimmers, particularly in areas of the brain associated with memory and attention.

“These findings are relevant to both collision sport athletes and other populations who suffer from single or reoccurring mild TBIs, including those experienced during military training and repeated head-banging behaviors in children,” said Dr. Coughlin.

“Since TSPO is associated with repair, we don’t recommend the use of drugs or other interventions at this time. Instead, we will continue to monitor TSPO levels through more research in order to test for sign of resolution of the injury with more time away from the game.”

Dr. Coughlin stressed that if there are cases where TSPO remains high, researchers will study those factors that associate with a vulnerability to lasting injury after a professional career in American football. Ultimately, they aim to guide strategies for the use of immunomodulating treatments (possibly anti-inflammatory medications) to heal the brain when needed.

The researchers say they plan to continue to follow the study’s population of former NFL athletes to track TSPO levels over time to see whose brains heal and whose do not. The goal is to inform development of medications and personalized guidelines for rest periods after repeated brain injuries.

The new research adds to a growing stack of evidence that collision sports that involve repeated, even low-level blows to the head, including football, soccer, and boxing, may lead to dementia and other forms of cognitive disorders.

Protein in Brain Linked to Frontotemporal Dementia

An international team of researchers, including experts at the Indiana University (IU) School of Medicine, has identified a protein found in the brains of people with frontotemporal dementia (FTD), discovering a new target for potential treatments for the disease.

According to the National Institutes of Health, FTD results from damage to neurons in the frontal and temporal lobes of the brain. People affected by this type of dementia typically present with symptoms when they are aged between 25 and 65 years, and these include unusual behaviors, emotional problems, trouble communicating, difficulty with work, or in some cases, difficulty walking. Neurodegenerative disorders, including dementias and amyotrophic lateral sclerosis, occur when specific proteins form amyloid filaments in the nerve cells of the brain and spinal cord.

The multidisciplinary team of researchers—including members from the Medical Research Council Laboratory of Molecular Biology, the IU School of Medicine, and the University College London Queen Square Institute of Neurology—found that in cases of FTD, a protein called TAF15 forms these amyloid filaments in the cells of the brain and the spinal cord.

They published their findings in Nature.

Bernardino Ghetti, MD, a distinguished professor at the IU School of Medicine, has studied neurodegenerative dementias for 50 years. As a lead neuropathologist on the project, Dr. Ghetti and his team examined the protein aggregates from brains that were donated by four people who had FTD and motor weakness.

Together with their colleagues in the United Kingdom, IU researchers used neuropathological and molecular techniques and cutting-edge cryo-electron microscopy at atomic resolution to discover the presence of the amyloid filaments made of TAF15 protein in multiple brain areas.

However, importantly, TAF15 amyloid also affects nerve cells of the motor system.

“This discovery represents an important breakthrough that recognizes TAF15 as a potential target for the development of diagnostic and therapeutic strategies toward a lesser-known form of frontotemporal lobar degeneration associated with frontotemporal dementia,” Dr. Ghetti said.

Study: Why Some Older Adults Show Spatial Memory Decline

Aging becomes apparent in various ways, including changes in memory function. But some older adults experience a faster decline in memory compared with others.

A new study by University of Arizona psychologists investigated the possible scenarios that could lead to waning memory in some older people. The researchers also studied both age-dependent and age-independent factors that could contribute to memory decline in younger and older people alike.

The study suggests that the hippocampus, a brain region associated with memory and navigation, could contribute to the difficulty in learning new environments and locations in some older adults. Neural representations in the hippocampus could explain why some people have a hard time remembering locations, said Li Zheng, a research scientist in the Department of Psychology and the lead author of the study.

“The study’s findings will be helpful in predicting the level of memory decline in early stages of dementia,” Dr. Zheng said.

Published in the journal Proceedings of the National Academy of Sciences, the new study is designed based on a similar study conducted in rats by Carol Barnes, a regents professor of psychology, neurology, and neuroscience.

Dr. Barnes’ study investigated specialized cells in the hippocampus called place cells, or neurons that are triggered and fire when a person or animal enters a particular place. When an individual goes to another location, another place cell fires, helping the brain’s hippocampus build a mental representation of each space.

When an animal or human enters a new environment, the place cells undergo a process called remapping. The study observed that the older rats showed difficulties in remapping for different environments more so than younger rats, indicating an inferior spatial memory performance.

Building on Dr. Barnes’ study, Dr. Zheng and her team recruited 25 younger adults and 22 older adults, all of them healthy. The participants were instructed to take part in a virtual reality experiment. On a computer screen, the younger and older adults memorized the layouts and locations of six shops in two virtual cities. The participants were asked to complete a series of questions to test their spatial memory, while the researchers simultaneously scanned the participants’ brain using a functional MRI scanner. The scanner captured the neural signals in the hippocampus.

Researchers found, in line with Dr. Barnes’ study, that older adults on average showed neural representations that did not differentiate well between environments when compared with younger adults.

However, the study found that there is an age-independent factor that affects memory retention. Suggesting that distinct neurons in the hippocampus serve different functions, Dr. Zheng explained that one neuron might respond to the shape of an environment while another responds to the ground color or other features. These neurons collaborate to create a comprehensive representation of the entire environment.

If a group of neurons takes up the same function, there is a risk that some of the features of the environment may not be accurately represented, meaning the fidelity of the neural signals becomes compromised and is low, said Arne Ekstrom, a professor of cognition and neural systems at the University of Arizona and a senior author on the study. At this time, the reason for low-fidelity signals in younger and older adults is not clear, he said.

“Anyone with poor memory performance will show a lower-fidelity neural signal,” Dr. Zheng said. “Age doesn’t have anything to do with that.”

The study also mentioned that there is an age-dependent factor, which the researchers describe as the quality of neural signals coming from other parts of the brain into the hippocampus, for example, visual information that comes through the back part of the brain. Even some high-performing older adults in the experiment exhibited a decrease in the quality of incoming neural signals into the hippocampus.

It has long been suspected that one age-related factor influencing memory could be the quality of the signal entering a brain region, which may relate to changes in plasticity in the aging brain, Dr. Ekstrom said. The study’s findings linked reductions in the quality of input into the hippocampus with age and worse spatial memory, he added.

Insights gained from the remapping index and fidelity of neural signals can be useful in predicting how much memory decline can occur in people who are diagnosed with dementia, Dr. Zheng said. In the near future, the research team is planning to replicate the study with immersive virtual reality experiments, which Dr. Zheng said would use body-based cues and navigation to the target in a more naturalistic way.

Repeated Blasts May Harm Brain Health of Military Personnel

The brains of special warfare community personnel repeatedly exposed to blasts show increased inflammation and structural changes compared with a control group, potentially increasing the risk of long-term, brain-related disease, according to a new study.

Researchers from the University of Virginia (UVA) School of Medicine and the Naval Medical Research Command (NMRC) led the study, which compared the brains of nine special operations personnel exposed to blasts with a control group of nine military service members with only minimal exposures to blasts.

Participants’ brains were analyzed using sophisticated imaging techniques, combined with surveys that measured exposure to weapons and explosives as well as symptoms related to brain injury, including mood and sleep issues.

The study found that increased blast exposure was associated with increased brain inflammation and reduced volume and thickness of brain structures. This could affect several key brain functions, including memory, motor skills, and regulating emotions.

Previous studies have shown that people with many neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, all have chronic brain inflammation that may be detectable before the conditions fully develop.

“This is the first study to directly demonstrate increased inflammation in the brains of service members who are exposed to small blasts over a career,” said James Stone, MD, PhD, a UVA Health radiologist who led the study.

“Brain inflammation is such a key process in other brain-related illnesses. These findings raise concerns about the long-term brain health of those exposed to repeated low-level blasts.”

The next step for researchers is a larger study with more participants to determine precisely what levels of blast exposure cause brain injuries. This follow-up study could guide military leaders in how they deploy soldiers as well as improve the design of equipment to protect against brain injuries caused by repeated blasts. “Work is currently underway to better understand these findings and to be able to answer the question of ‘how much is too much?’ when it comes to blast overpressure exposure,” Dr. Stone said.

The study is one of several projects involving UVA Health researchers seeking to prevent brain injuries in military personnel led by Stephen Ahlers, PhD, from NMRC. UVA is part of a research team backed by an $8 million U.S. Department of Defense grant exploring the role of brain inflammation in military personnel exposed to blast shock waves.

“This research effort will enable us to understand how repetitive exposure to blast over a career is a risk factor for brain health issues, including the possibility of worsening symptoms from a traumatic brain injury unrelated to blast exposure,” according to Dr. Ahlers.

Researchers Connect Neuroinflammation With Alzheimer’s Disease

Immune-regulating brain cells known as microglia are known to play a role in the progression of Alzheimer’s disease (AD). A new study by investigators from Brigham and Women’s Hospital explores how the genetics of microglia contribute to neuroinflammation and, in turn, AD.

The team revealed that a reduction of INPP5D, a gene found in microglia, results in neuroinflammation and increases the risk for AD. Their results, which have important implications for the design of microglia-centered therapeutics for AD and related disorders, were published in Nature Communications.

“We know that microglia play important roles in the healthy and diseased brain, but in many cases the molecular mechanisms underlying this relationship are poorly understood,” said corresponding author Tracy Young-Pearse, PhD, from the Department of Neurology at Brigham and Women’s Hospital. “If we’re able to identify and understand the significance of specific genes that play a role in neuroinflammation, we can more readily develop effective, targeted therapeutics.”

Neuroinflammation is important to monitor in people with neurodegenerative diseases, but it can be difficult to detect, especially in the early stages of AD. The earlier neurologists can identify it, the earlier they can treat it. Microglia are clearly involved in the process of neuroinflammation, but there are many unanswered questions regarding the molecular pathways involved.

The team used a variety of experimental approaches to probe the relationship between levels of INPP5D and a specific type of brain inflammation—activation of the inflammasome. They compared human brain tissue from patients with AD and a control group. They found lower levels of INPP5D in the tissues of patients with AD, and when INPP5D was reduced, it activated inflammation. In parallel, they used living human brain cells derived from stem cells to study the intricate molecular interactions within microglia that mediate inflammatory processes with a reduction of INPP5D.

These studies identified specific proteins that could be inhibited to block inflammasome activation in microglia.

Although the team’s work represents the most comprehensive analysis of INPP5D in the AD brain, it remains to be determined whether INPP5D should be targeted with therapeutics. The team notes that their findings suggest INPP5D activity in AD brains is complex, and future studies are needed to understand if INPP5D can be targeted to prevent cognitive decline in patients with AD.

“Our results highlight an exciting promise for INPP5D, but some questions still remain,” said Dr. Young-Pearse. “Future studies examining the interaction between INPP5D activity and inflammasome regulation are essential to improve our understanding of microglia in AD and to help develop a comprehensive toolbox of therapeutics that can be deployed to treat each of the molecular roads that lead to AD.”

Certain Migraine Medications May Be More Effective Than Ibuprofen

For many people with migraine, it can be difficult to find a treatment that is effective and reliable, and information on how medications compare to one another is lacking. A new study draws data from nearly 300,000 people using a smartphone app to help people make decisions about their medications. The study found that certain migraine medications, such as triptans, ergots, and antiemetics, may be two to five times more effective than ibuprofen for treating migraine attacks, according to new research published online in Neurology.

Migraine attacks are characterized by intense throbbing head pain, sensitivity to light and sound, nausea, or vomiting. Previous research has shown that migraine can also be associated with cognitive issues, and all of these symptoms may impact a person’s quality of life and productivity.

“There are many treatment options available to those with migraine. However, there is a lack of head-to-head comparisons of the effectiveness of these treatment options,” said study author Chia-Chun Chiang, MD, of the Mayo Clinic in Rochester, Minnesota, and member of the American Academy of Neurology. “These results confirm that triptans should be considered earlier for treating migraine, rather than reserving their use for severe attacks.”

For the study, researchers included over 3 million migraine attacks from nearly 300,000 users that were self-reported by people using a smartphone app during a 6-year period. The app allows users to monitor the frequency of migraine attacks, triggers, symptoms, and medication effectiveness.

For those migraine attacks, participants entered into the app 4.7 million treatment attempts with various medications. They recorded in the app whether a medication was helpful or not. Researchers then used that information to calculate the effectiveness of each drug compared with ibuprofen. Researchers examined 25 medications among seven drug classes, and different dosages and formulas of each medication were combined in this analysis.

The study found that the top three classes of medications that were more effective than ibuprofen were triptans, ergots, and antiemetics. Triptans were five times more effective than ibuprofen, ergots were three times more effective, and antiemetics were two-and-a-half times more effective.

When looking at individual medications, the top three were eletriptan, which was six times more effective than ibuprofen; zolmitriptan, which was five-and-a-half times more effective; and sumatriptan, which was five times more effective.

The researchers found that when using eletriptan, participants found it helpful 78% of the time. Zolmitriptan was helpful 74% of the time, and sumatriptan was helpful 72% of the time. Ibuprofen was helpful 42% of the time.

Researchers also looked at other groups of medication, such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs other than ibuprofen were 94% more effective than ibuprofen. Participants found ketorolac helpful 62% of the time, indomethacin helpful 57% of the time, and diclofenac helpful 56% of the time.

However, acetaminophen was helpful 37% of the time and was found to be 17% less effective than ibuprofen when used for treating migraines. Additionally, a common combination of medications used to treat migraine—aspirin, acetaminophen, and caffeine—was also evaluated and found to be 69% more effective than ibuprofen.

“For people whose acute migraine medication is not working for them, our hope is that this study shows that there are many alternatives that work for migraine, and we encourage people to talk with their doctors about how to treat this painful and debilitating condition,” said Dr. Chiang.

A limitation of the study was that evaluations of medications could be influenced by a user’s expectations of the medication or the dosage he or she took. Another limitation was that newer migraine medications, gepants and ditans, were not included in the study due to the low amount of data when the study was conducted and lack of availability in many countries.

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