Andrew Budson, a School of Medicine professor of neurology, has been attending the Alzheimer’s Association International Conference  for more than a decade, and it’s usually fairly routine. He catches up on the latest research, trades ideas and insights with other scientists from around the globe, and hopes that maybe there will be a hint about a new drug that could potentially slow the progression of the disease.

Andrew Budson, a MED neurology professor, was at the Alzheimer’s Association International Conference when drugmakers presented findings on a potentially promising drug for Alzheimer’s. Photo by Cydney Scott

This year, finally, he heard what he’d been hoping for.

Last Wednesday afternoon, midway through the 2018 conference, Biogen and Eisai took the stage at Chicago’s McCormick Place convention center to present the latest results of a therapeutic that shows potential promise for slowing the advance of dementia and reducing the plaques in the brains of patients.

Budson, a physician scientist who has spent more than 20 years studying Alzheimer’s and caring for patients afflicted by it, sat and listened as the drug companies shared the results from the new research that would quickly rocket through the biopharma world.

“It was the most hopeful thing I’ve heard in years,” says Budson, who is associate director of the BU Alzheimer’s Disease Center and associate chief of staff for education at the Veterans Affairs Boston Healthcare System. “We haven’t had a drug approved for Alzheimer’s disease since 2003. And there’s absolutely nothing that slows down the disease. The current treatments for Alzheimer’s, drugs like donepezil (brand name Aricept), can ‘turn the clock back’ on memory loss by six to 12 months, but they can’t slow the speed at which the clock is ticking down. What’s so exciting about the preliminary analyses is that for the first time, ever, we have the hope—we have the preliminary evidence—that we might finally have a drug that can slow the rate of decline.”

Alzheimer’s, a progressive deadly brain disorder that destroys memory and other cognitive abilities, afflicts some 5.7 million people in the US and that number is projected to rise to nearly 14 million by 2050, according to the Alzheimer’s Association. Between 2000 and 2015, deaths from heart disease decreased 11 per cent while deaths from Alzheimer’s increased 123 per cent. Worldwide, nearly 44 million people have Alzheimer’s or a related dementia.

Catching up with Budson in Chicago on Thursday as he was taking a Lyft to a reading downtown of his latest book, Seven Steps to Managing Your Memory—What’s Normal, What’s Not, and What to Do about It (Oxford University Press, 2017), BU Today talked with him about the buzz at the conference over the new findings, the caveats involved, and what has to happen before we’ll know if the drug, BAN2401, really works.

Why is this new result so important?

In addition to its potential importance to help patients, it also means that this research approach works. Once you have one drug working, similar medications—which may work even better—can be developed.

What was it like in the room when the findings were presented? People knew this was coming. There must have been a big crowd.

The room was totally packed. There may have been close to 1,000 people there. They only got this new data three weeks ago. This was the first time they had talked about it. The conference organizers extended the session—it was on recent developments in therapeutics—so these data could be presented. During the scientific presentations that came before this one, people asked very few questions. They just wanted to get to this one. In the session just before it, the speaker himself said, ‘I think everyone’s waiting for the next talk.’”

How did the scientists in the audience respond to the drugmakers’ presentation?

People were cautiously optimistic. There have been other groups that have had results that were promising, but then the full data sets were analyzed and they ended up not being statistically significant.

The main design of the study is that some people were getting a placebo and other people were getting a real drug. How do the people who got the real drug respond versus those who got the placebo? It’s a little more complicated than that because there were multiple doses of the real drug given and only the top doses seemed to work.

If what they show in these slides actually stands up when the data are looked at more carefully and the subgroups are analyzed, I believe it will change how Alzheimer’s disease is treated and diagnosed because this study shows, unequivocally, that you can clear amyloid plaques from the brain.

But haven’t other studies shown something similarly promising? What’s different here?

This is different because, in addition to clearing the plaques, the finding is that the drug also actually slows down cognitive decline over 18 months.

If you have a medication that can slow down the rate of decline, then basically everyone with Alzheimer’s should be taking it.

Assuming that the full analyses look like the preliminary ones, I would put all my patients who have Alzheimer’s disease on this drug.

So what’s next?

The scientists have to finish the analyses and, assuming the full analyses come out the same way as these preliminary analyses, Eisai and Biogen are going to be talking with the FDA about what additional studies they would require in order for the drug to be approved.

And the FDA may say they need one more study. I think it would be likely that they would say that they need replication. It was only the highest doses out of the five they administered that showed an improvement over the placebo. My guess is that the FDA would want them to do a new study with just the one or two highest doses over the placebo. And they would want to see that they came out definitively positive.

These studies are 18 months long, so we’re looking at least a couple of years before we will likely have an approved drug.  

From diagnosing chronic traumatic encephalopathy (CTE) in tight-end-turned-killer Aaron Hernandez to being named the Boston Globe’s Bostonian of the Year and one of TIME’s 100 Most Influential People, Ann McKee has been a media-attention magnet in the last year.

The director of BU’s CTE Center has been honored with another accolade, this one from a group of peers. McKee recently received the Henry Wisniewski Lifetime Achievement Award from the Alzheimer’s Association International Conference, the world’s largest gathering of researchers of that disease and other dementias.

CTE is associated with dementia, mood changes, and aggression and afflicts many athletes and soldiers. In giving her the award, the Alzheimer’s Association noted, among other achievements, that she created the “McKee criteria” for diagnosing CTE and established its four progressive stages.

McKee, professor of neurology and pathology at the School of Medicine, and the associate director of BU’s Alzheimer’s Disease Center, was one of three researchers honored by the Alzheimer’s Association. The other honorees were Jeffrey L. Cummings from the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, and John Q. Trojanowski from the University of Pennsylvania Perelman School of Medicine.

Maria C. Carrillo, the Alzheimer’s Association’s chief science officer, lauded the three for their “lasting contributions to help accelerate the progress towards finding the underlying causes, treatments, and preventions for Alzheimer’s and related dementias.”

Calling herself “deeply honored” by the award, McKee notes that it was named for a noted neuropathologist who “was an early inspiration to my career in Alzheimer’s disease research and, later, in my fascination” with CTE.

She also credited colleagues at the CTE Center, as well as BU’s Alzheimer’s Disease Center, the Framingham Heart Study, and the VA Boston Healthcare System, with contributing to her research.

That research in the last few years has included uncovering important facts about CTE at seemingly breakneck speed. This year, McKee and her team published a study reporting that CTE, once thought to be caused by concussions, actually might be the result of repeated hits to the head.

If confirmed, the finding would upend current efforts to cushion athletes against concussions, raising instead the daunting question of how to reduce head hits. That would require that sports face “the fundamental danger these activities pose to human health,” McKee said at the time the study was published.

Last December, the Globe wrote that “football may never be the same” as a result of her research, noting the irony that McKee grew up in Wisconsin as “a devoted Green Bay Packers fan.”

Faced with a problem, David Boas will invent a way around it. Boas, the founding director of the Boston University Neurophotonics Center and a world leader in the field of neurophotonics, which uses light to peer inside the living brain, built a homemade Ethernet connection to speed his doctoral research (one year before the first web browser was unveiled) and wrote a software program to make a girlfriend’s research go faster. The machines he engineers to shed light on the inner workings of the brain—from sophisticated microscopes to lasers that beam infrared light through the skull—are often peppered with homespun ingenuity: he once jammed coffee stirrers into a wheel of color filters rotating under a microscope, using them to trigger a camera as each color whirled by, in order to show how blood absorbs different wavelengths of light.

The Neurophotonics Center, the first facility of its kind in the United States and only the second in North America, pulls in 30 faculty from fields as diverse as biology, mechanical engineering, brain sciences, and nanomedicine. Its mission, says Boas, a College of Engineering professor of biomedical engineering, who formerly taught at Harvard Medical School and was the founder of the Optics Division of the Martinos Center at Massachusetts General Hospital (MGH), is to cultivate technologies that give researchers new insights into the brain. Most of Boas’ work is funded by the National Institutes of Health (NIH) and feeds into its ambitious BRAIN Initiative, a decadelong multibillion-dollar project to speed the development and application of innovative neurotechnologies.

Since opening in fall 2017, the Neurophotonics Center has started studies analyzing the brain as it recovers from a stroke, confronts autism, and slides into dementia. It’s also helping to nurture a community of student neurophotonics researchers with a $2.9 million National Science Foundation Research Traineeship.

“David is the pioneer of techniques and methods to use light to interact with the brain,” says Thomas Bifano, an ENG professor of mechanical engineering and director of the BU Photonics Center. “He’s going to make a difference in our understanding of the brain, specifically by making tools that allow us to see it in ways we haven’t seen it before.”

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The National Academy of Medicine (NAM) is made up of more than 2,000 international members, elected by their peers, for outstanding achievements in medicine. Ann McKee, a School of Medicine professor of neurology and pathology, director of the Chronic Traumatic Encephalopathy Center, and chief of neuropathology at the Boston VA Healthcare System, has been elected in recognition of the huge impact that her research on brain injuries in football players and military servicepeople has had on public health.

BU Today: Your work on concussions has been nothing short of groundbreaking. Can you recall the moment when you realized this was a defining issue that you wanted to pour your research into?

McKee: I had become very interested in the deterioration found in boxers’ brains, and when I saw the brain of John Grimsley, a 45-year-old football player in 2008, I was stunned to see the same pattern of pathology that I found in the boxers. I knew immediately that this was very important. I was a lifelong football fan; I knew that football players damaged their knees and hips, but it was a shock to find that they were damaging their brains as well. And with each additional case that came into the lab, the evidence grew stronger and the importance of the findings to public health became more evident.

We hear so much talk about head trauma from football. Can you talk about how prevalent head trauma is in the military and why that became a second focus of your work?

I’ve worked at the Veterans Affairs (VA) hospital for 25 years. Over 360,000 military service members were exposed to traumatic brain injury from blast and impact injury in the Iraq and Afghanistan conflicts. Although there are similarities between blast injury and athletic injury, we know far less about military-related injuries. We are hoping to raise the number of brain donations from veterans in order to solve this knowledge gap.

I read that you love to paint. Does art help your work in medicine in any way?

Medicine is an observational science, and being a visual person, with a strong visual memory, tends to increase your powers of observation. I also think that creativity, which is a central component of painting and visual arts, is absolutely essential to science.

If you were to look ahead one generation, say in 20 years, do you think football, as we know it today, will be the same game, with the same popularity?

The risk of CTE is directly related to the cumulative exposure to subconcussive hits. If football rules do not change, if players continue to experience hundreds of subconcussive hits per season, and if nothing is done to better detect and treat early brain injury, then I think that the future of football will parallel the trajectory of boxing. It will become less popular in mainstream America, less common in institutions of higher learning, and the province of the disadvantaged.

What would you tell a young mother today with a 10-year-old begging to play football? And what might you tell the child?

I would encourage the mother and son to play another sport with less head contact. The truth is inconvenient and unwelcome, but football damages brains, and young brains especially.

You have faced a lot of criticism with your findings. But I read that your nieces refer to you as “Auntie Badass.” Where did that come from?

In this case, it is a term of endearment. My nieces are proud of me, not just because I had the right cognitive skills at the right time, but because I’ve had to face dismissiveness and sexism, people trying to claim credit for my work, and people and organizations trying to derail me. I’ve had to fight for where I am with persistence and determination and my eyes focused straight ahead.

You’ve received so many honors and accolades; can you put this one from the National Academy of Medicine in perspective for us?

It is recognition of professional achievement and commitment to service; I am very honored to be recognized for my work to improve public health.

After 10 years of studying brains donated by families of deceased military servicepeople, football players, and other contact-sport athletes, researchers from the BU School of Medicine and the VA Boston Healthcare System have amassed more than 600 brains, a collection they say has grown large enough to enable meaningful analysis of the genetics related to chronic traumatic encephalopathy (CTE).

Their latest discovery—about the CTE-related significance of genetic variation in a gene called TMEM106B—could explain why similar levels of head trauma in different people can cause some of them to suffer more drastic symptoms of CTE than others. The findings are described in a study published in Acta Neuropathologica Communications November 3, 2018.

“In order to understand how genetic variants influence disease or severity, you need hundreds of cases,” says paper co–senior author Ann McKee, a MED professor of neurology and pathology, chief of neuropathology at the VA Boston Healthcare System, and director of the BU CTE Center.

With more than 600 participants in the brain bank and counting, “we’ve reached a critical mass,” McKee says. “I expect to find a flood of new genes that influence the pathology of CTE. This is just the beginning.”

Toward predicting—and preventing—severe CTE

Today, CTE can only be diagnosed by studying a person’s brain after death. And until now, it’s been unknown why repeated head injuries can lead to a range of mild to severe CTE symptoms among individual college and professional athletes. The newly discovered genetic association between CTE and TMEM106B could someday help predict which people, while they are still alive, are most likely to develop severe symptoms of CTE, including dementia and the buildup of phosphorylated tau (p-tau) protein, a feature also associated with other neurodegenerative disorders like ALS, Alzheimer’s, and Parkinson’s.

“Among athletes who developed CTE pathology, those with the risk variation of TMEM106B were 2.5 times more likely to have dementia and increased levels of p-tau,” says paper co–first author Jesse Mez, a MED assistant professor of neurology and a member of both the Alzheimer’s Disease Center and CTE Center.

TMEM106B was hardly a needle-in-the-haystack discovery. The team—which also included co–first author Jonathan Cherry, a postdoctoral fellow at the CTE Center, and co–senior author Thor Stein—had good reason to question a link between TMEM106B and CTE.

Repeat offenders: head injuries and TMEM106B

“We focused on this gene because of its role in altering brain pathology in other neurological diseases and its role in inflammatory responses,” says Stein, a MED assistant professor of pathology and laboratory medicine, a neuropathologist at VA Boston Healthcare System, and the Alzheimer’s Disease Center neuropathology core associate director.

Jonathan Cherry (from left), Thor Stein, and Jesse Mez are part of the CTE Center research team that has discovered one of the first genes linked to CTE symptoms. Photo by Jackie Ricciardi

From the brain bank—which first started recruiting brain donations from families of deceased athletes in 2008 in coordination with the Concussion Legacy Foundation and its founder, former professional wrestler Chris Nowinski—the team analyzed TMEM106B and evidence of CTE in Caucasian football players, a sample size of 86 brain bank participants, all of whom had been diagnosed with CTE.

In the search for genetic factors associated with CTE, football players make ideal study subjects because the nature and frequency of their head injuries make them relatively comparable across the population, in contrast to people who sustain more random head injuries from military-related blasts or other various traumas.

“Football players go through what we call repetitive head impacts,” Stein says.

Given TMEM106B’s association with other neurodegenerative diseases, the team also excluded brain bank participants who had evidence of other related diseases.

A stronger link between TMEM106B and neurodegeneration

Looking at the 86 participants who met the eligibility criteria for their analysis, the team performed genetic sequencing and identified two distinct categories of TMEM106B genetic variation within the group. They found a major genetic variation in about 60 percent of people and a minor genetic variation in the remaining 40 percent.

Then they assessed the participants based on several different traits known to be associated with CTE symptoms, including the loss of synapses, dementia before death, and p-tau accumulation throughout the brain.

When they compared the results with data from people who did not have CTE, the team found that TMEM106B does not influence whether or not a person develops CTE.

But among people diagnosed with CTE, they found that the 60 percent with the major genetic variation were significantly more likely to have higher accumulation of p-tau, more severe brain inflammation associated with CTE symptoms, and dementia during their lifetimes.

Taken with previous studies linking TMEM106B to dementia, ALS, and Alzheimer’s and Parkinson’s diseases, the team’s findings further strengthen a connection between the TMEM106B gene and neurodegeneration.

Unraveling the tangle of CTE genetics

Although it’s not precisely known how TMEM106B influences p-tau accumulation and inflammatory responses, the team has a working hypothesis based on what is known.

In the years since the BU brain bank began in 2008, Ann McKee has found that repetitive subconcussive head impacts in contact sports like football and hockey play a huge role in development of CTE. Photo by Cydney Scott

The TMEM106B gene directs cells to produce proteins of the same name, TMEM106B. In turn, those are thought to play a role in the formation of cell organelles that are responsible for digesting enzymes. Yet too much TMEM106B, which could occur as a result of genetic variation, can make enzyme digestion less efficient. Inside brain cells that play an important role in cleaning the brain of damage-related proteins like p-tau, abnormal enzyme digestion could result in the hallmark buildup of the damaging proteins seen in cases of CTE.

“We’re at a place where we clearly know that there’s a link between contact sports and CTE, but we don’t yet have a good sense of the magnitude of that relationship,” says Mez, who is particularly interested in understanding how genetic and trauma-related factors influence dementia risk.

There’s likely a number of genes that contribute on various levels to bring someone from the neurotypical end of the spectrum to a diagnosis of severe CTE. With the number of brain bank participants continuing to creep above 600, more genetic factors related to CTE could be on the near horizon. McKee, who was named one of Time magazine’s 100 Most Influential People of 2018, has said that unless the rules of the game begin to change, the research around brains with CTE could one day influence the popularity of football in America.

“As your sample size gets bigger, you’re able to identify genes that have smaller and smaller effects,” says Cherry. “It’s an advantage for us that we’re not just operating on clinical diagnoses of dementia, for example, but that we have the actual CTE pathology in front of us to quantify what we’re seeing with the presence of certain genetic variations.”

Kat J. McAlpine can be reached at katjmcal@bu.edu.

Jerry Chen, Boston University College of Arts & Sciences assistant professor of biology. Photo by Jackie Ricciardi

Jerry Chen, a Boston University College of Arts & Sciences assistant professor of biology, has always had a busy schedule. Now, thanks to a major grant from the National Institutes of Health, it’s going to get even busier. On October 2, 2018, the National Institutes of Health announced that Chen is the winner of the 2018 New Innovator Award of $2.5 million over the next five years. That money will fund Chen’s efforts to crack the neural code of the brain and better understand the relationship between the genetic and electrical influences that control cognitive functions like sensory processing, decision-making, and learning and memory.

Chen’s New Innovator award is one of four High-Risk, High-Reward Research Awards presented annually by the NIH, and honoring high-impact programs that cross NIH institutes and centers. The award supports unusually innovative research from early-career investigators who are within 10 years of their final degree or clinical residency and have not yet received a research project grant or equivalent NIH grant. Chen, who came to BU from the University of Zurich, Switzerland, three years ago, also won the 2016 Stuart and Elizabeth Pratt Career Development Professorship, which highlights excellence within CAS.

“It’s an honor to receive this New Innovator Award,” says Chen. “There are few other opportunities out there where we can really try something that is both risky but also has the potential to have a big impact in understanding how the brain works.”

Gloria Waters, vice president and associate provost for research at BU, says it’s wonderful to see junior faculty who have received internal awards now receive external recognition for their work. “An award such as this is particularly impressive,” she says. “It signifies that Jerry is truly doing cutting-edge work that could have a huge impact on his field.”

“In order to crack the neural code,” says Chen, “you need to know at least two things. First, you need to be able to measure the activity of neurons in the brain as a subject is carrying out different cognitive tasks. And second, you have to know which genes are involved with that activity.”

To do that, researchers in Chen’s lab first use microscopes and imaging technology to measure the activity of the neurons as they fire in a mouse brain. The problem, says Chen, is that all neurons are not the same. “If you think about the brain as a complex computer or circuit, there are many different components that make up a circuit board and they all serve different functions,” he says. So researchers then perform a postmortem examination of the brain and attempt to identify which genes are being expressed in which cells.

“Measuring the molecular composition of each neuron can inform us what kind of component that neuron is in the circuit,” he says. “What we’re trying to do is establish an experimental platform that will allow us to put these two types of information together—measure the activity of neurons in the brain and then determine the molecular composition of those same neurons. The platform will help us understand the neural code and the specific circuits that can generate that code.”

That platform, says Chen, will help reveal how gene expression can define circuits in the brain’s neocortex and their computations. Ultimately, Chen hopes to understand which circuits and computations in the brain are genetically defined, or “hardwired,” and which can have the ability to adapt and change as a result of learning and memory.

As you read the words stretched across this page, your brain is doing something magnificent. Each sentence lingers in your mind for a fleeting moment, the letters melding into a symphony of neural signals. These intricate electrical rhythms form the language of the brain, a language we have only begun to understand within the last century.

Rob Reinhart, a BU College of Arts & Sciences assistant professor of psychological and brain sciences, says we’ve reached a point where we not only understand this language—we can speak it and harness it to enhance the functioning of the mind. In a groundbreaking study published April 8, 2019, in Nature Neuroscience, Reinhart and BU doctoral researcher John Nguyen demonstrate that electrostimulation can improve the working memory of people in their 70s so that their performance on memory tasks is indistinguishable from that of 20-year-olds.

Reinhart and Nguyen’s research targets working memory—the part of the mind where consciousness lives, the part that is active whenever we make decisions, reason, recall our grocery lists, and (hopefully) remember where we left our keys. Working memory starts to decline in our late 20s and early 30s, Reinhart explains, as certain areas of the brain gradually become disconnected and uncoordinated. By the time we reach our 60s and 70s, these neural circuits have deteriorated enough that many of us experience noticeable cognitive difficulties, even in the absence of dementias like Alzheimer’s disease.

But the duo has discovered something incredible: by using electrical currents to noninvasively stimulate brain areas that have lost their rhythm, we can drastically improve working memory performance.

During the study, which was supported by a National Institutes of Health grant, they asked a group of people in their 20s and a group in their 60s and 70s to perform a series of memory tasks that required them to view an image, and then, after a brief pause, to identify whether a second image was slightly different from the original.

At baseline, the young adults were much more accurate at this, significantly outperforming the older group. However, when the older adults received 25 minutes of mild stimulation delivered through scalp electrodes and personalized to their individual brain circuits, the difference between the two groups vanished. Even more encouraging? That memory boost lasted at least to the end of the 50-minute time window after stimulation—the point at which the experiment ended.

To understand why this technique is so effective, we need to take a look at the two mechanisms that allow working memory to function properly: coupling and synchronization.

Coupling occurs when different types of brain rhythms coordinate with one another, and it helps us process and store working memories. Slow, low-frequency rhythms—theta rhythms—dance in the front of your brain, acting like the conductors of an orchestra. They reach back to faster, high-frequency rhythms called gamma rhythms, which are generated in the region of the brain that processes the world around us.

Just as a musical orchestra contains flutes, oboes, violins—so too, the gamma rhythms that reside within your brain each contribute something unique to the electricity-based orchestra that creates your memories. One gamma rhythm might process the color of an object you’re holding in your mind, for instance, while another captures its shape, another its orientation, and another its sound.

But when the conductors fumble with their batons—when the theta rhythms lose the ability to connect with those gamma rhythms to monitor them, maintain them, and instruct them—the melodies within the brain begin to disintegrate and our memories lose their sharpness.

Meanwhile, synchronization—when theta rhythms from different areas of the brain synchronize with one another—allows separate brain areas to communicate with one another. This process serves as the glue for a memory, combining individual sensory details to create one coherent recollection. As we age, our theta rhythms become less synchronized and the fabric of our memories starts to fray.

Rob Reinhart. Photo by Cydney Scott

Reinhart and Nguyen’s study suggests that by using electrical stimulation, we can reestablish these pathways that tend to go awry as we age, improving our ability to recall our experiences by restoring the flow of information within the brain. And it’s not just older adults that stand to benefit from this technique: it shows promise for younger people as well.

In the study, 14 of the young-adult participants performed poorly on the memory tasks despite their age—so he called them back to stimulate their brains too.

“We showed that the poor performers who were much younger, in their 20s, could also benefit from the same exact kind of stimulation,” Reinhart says. “We could boost their working memory even though they weren’t in their 60s or 70s.”

Coupling and synchronization, he adds, exist on a continuum: “It’s not like there are people who don’t couple versus people who couple.”

On one end of the spectrum, someone with an incredible memory may be excellent at both synchronizing and coupling, whereas somebody with Alzheimer’s disease would probably struggle significantly with both. Others lie between these two extremes—for instance, you might be a weak coupler but a strong synchronizer, or vice versa.

And when we use this stimulation to alter neural symphonies, we aren’t just making a minor tweak, Reinhart emphasizes. “It’s behaviorally relevant. Now, [people are] performing tasks differently, they’re remembering things better, they’re perceiving better, they’re learning faster. It is really extraordinary.”

Looking ahead, he foresees a variety of future applications for his work.

“It’s opening up a whole new avenue of potential research and treatment options,” he says, “and we’re super excited about it.”

Reinhart would like to investigate electrostimulation’s effects on individual brain cells by applying it to animal models, and he’s curious about how repeated doses of stimulation might further enhance brain circuits in humans. Most of all, though, he hopes his discovery will one day lead to a treatment for the millions of people around the world living with cognitive impairments—particularly those with Alzheimer’s disease.

He loves his line of work as a neuroscientist—especially when it leads to breakthroughs like this one. “It’s wild,” he adds, a smile in his voice. “It’s wild to think that we can target the electricity of a brain circuit the same way we would target a neurotransmitter chemical in the brain.”

For the time being, the only way for scientists to detect whether a person has chronic traumatic encephalopathy (CTE) is to examine their brain tissue after death. But to get any closer to being able to treat or even prevent CTE, researchers must first find a way to diagnose it in the living.

That critical goal may finally be within sight, according to a new study published April 10, 2019, in the New England Journal of Medicine, by Robert Stern, director of clinical research at the Boston University Chronic Traumatic Encephalopathy (CTE) Center, and collaborators from Avid Radiopharmaceuticals, Banner Alzheimer’s Institute, Brigham and Women’s Hospital, the Mayo Clinic, and the University of Arizona. Their findings reveal that an experimental PET (positron emission tomography) scan on living people is able to detect abnormal brain tissue—called tau protein—in patterns similar to those found in the brains of deceased people diagnosed with CTE after death.

MED Professor Robert Stern. Photo courtesy of BU School of Medicine

Tau protein—a hallmark of several neurodegenerative diseases, including CTE, Alzheimer’s, and certain kinds of dementias—“becomes toxic and destroys brain tissue” as it accumulates, says Stern. In their study, the researchers found evidence of abnormal tau proteins in living people by comparing experimental PET scans of 31 control subjects without any history of head trauma or psychological symptoms against 26 former National Football League players who have self-reported cognitive, mood, and behavior symptoms associated with CTE.

The experimental PET scan detected greater amounts of abnormal tau protein buildup in the group of living former NFL players compared to the control group.

“It can’t yet be used for individual diagnosis,” Stern cautions. “We analyzed group data, not individual findings.”

Yet, after a decade of doing CTE research himself, he admits it’s a crucial step toward the ultimate goal of diagnosing CTE in living individuals. “From day one,” he says, “I had hoped for there to be a tau tracer for PET scans in humans. It’s such an important thing…to be able to see and quantify tau.”

Stern says scientific data suggest that it’s not necessarily concussions that cause the neurodegenerative disease known to have affected hundreds of military veterans and former NFL stars Aaron Hernandez, Dave Duerson, Junior Seau, and Andre Waters, among others.

“CTE is a buzzword these days,” Stern says. But “a lot of people are confused about what it is, what causes it…. There’s a lot of misconception out there that it’s caused by concussions.”

Instead, repetitive subconcussive hits to the head—like you commonly see in tackle football—appear to be the root of the disease. Studying the brains of deceased NFL players, other athletes, and veterans—BU CTE Center scientists have amassed nearly 700 such brains—has yielded new clues to what drives CTE. But he says there are still a lot of unanswered questions, such as how common CTE is, why some people get it and others don’t, and how it can be treated and possibly prevented.

To find those answers, he says, researchers need to be able to diagnose CTE in the living.

“Most importantly,” to best learn about how and why the disease develops, “it would be great to detect it early before it progresses to the point where there’s too much destruction of brain tissue,” says Stern, who is also director of the clinical core of the BU Alzheimer’s Disease Center and a BU School of Medicine professor of neurology, neurosurgery, and anatomy and neurobiology.

The experimental PET scans in the new study were done using two different tracers—radioactive compounds designed to be injected into the bloodstream, after which they travel into the brain and glom onto specific proteins. The two types of tracers used by Stern’s team, one an experimental tracer designed to detect tau and the other an FDA-approved tracer for detecting amyloid proteins, have been used over the past several years by researchers looking for signs of Alzheimer’s disease. Once these tracers, delivered one at a time during two different PET scans, reach the brain and get stuck to any existing tau and amyloid proteins, the PET scans can pick up their radioactive glow, illuminating their exact location and pattern inside the brain structure.

The FDA-approved amyloid tracer is intended “to be used in people in their 60s and above who have cognitive difficulties, but their doctor isn’t sure if it’s Alzheimer’s,” Stern says. “If they have the PET scan and it comes back negative [without any elevated amyloid], the doctor can’t assume the person has Alzheimer’s.”

Because of tau’s role in Alzheimer’s—which affects more than 5.5 million Americans and is now the sixth leading cause of death in the United States, according to the National Institute on Aging—researchers raced to develop tau tracers for use with PET scans. Stern says the combination of the two scans, amyloid and tau, may help detect the specific brain tissue patterns that make CTE unique from other neurodegenerative diseases.

“At the beginning of CTE, tau is found in patchy areas around small blood vessels located deep in the valleys of the cortex,” he says. From there it can spread throughout other areas of the brain, until the whole brain can become devastated.

In contrast, Alzheimer’s disease starts off “almost backward from CTE development,” Stern says. Deep in the brain, “amyloid buildup seems to kick off first and then tau becomes abnormal,” forming protein tangles along the spreading amyloid network.

In CTE, then, you would expect to find a smattering of tau protein without the presence of elevated amyloid.

The results from the experimental PET scans in the study seem consistent with those facts. Although both tau and amyloid tracers were used in the study, only abnormal tau was detected in the group of former NFL players. As would be expected with CTE, there were no abnormal signs of amyloid buildup.

Looking at the group results as a whole, Stern says, there’s no way to interpret whether any individual person in the study has CTE, but that “it’s likely that there are people in the group who have CTE.”

Ultimately, these early results are a step—albeit a significant one—in the journey toward one day being able to diagnose individuals with CTE while they are still alive.

“We need to study larger numbers of people with greater variability in their history of being hit [in the head] repeatedly and in their history of CTE-related symptoms,” Stern says. By the end of 2019, he and collaborators expect to complete tau and amyloid scans of up to 240 additional people. “In the next five years or so, we will be able to diagnose and detect [CTE] during life,” he says.

But whether or not the experimental PET scans on this group detected signs of CTE, or some other abnormality, won’t become clear unless the study participants’ brains are examined after death. To make that possible someday, Stern says, “most of them have agreed to donate their brains.”

Kat J. McAlpine can be reached at katjmcal@bu.edu.

There is currently no way to track the subtle brain changes caused by traumatic head injuries or degenerative neurological diseases—but that’s finally poised to change. A $4.9 million grant from the Massachusetts Life Sciences Center (MLSC) has been awarded to the Center for Translation Neurotrauma Imaging (CTNI) at the Boston University School of Medicine. With support from the grant, the CTNI will improve brain imaging techniques and open doors to developing diagnostics and treatments for neurodegenerative diseases.

In addition to the MLSC grant, the CTNI has received additional in-kind donations valued at $6.3 million, and it will collaborate with clinicians and researchers at Boston Medical Center, which has the busiest level 1 trauma and emergency services in the region.

Center codirectors Stephan Anderson and Lee Goldstein say that the CTNI’s efforts will bridge a critical imaging gap and will lead to better clinical care for people with diseases like Alzheimer’s, which is difficult to diagnose in its early stages and currently has no cure. The researchers are also interested in developing imaging techniques to be able to see signs of chronic traumatic encephalopathy (CTE), which cannot yet be detected in living people, but has made news headlines for being found in hundreds of brains from deceased National Football League players and military servicepeople who sustained repetitive hits to the head during their lives.

The gap in imaging technology must be filled before emerging treatments for brain injury can be successfully tested and used clinically in humans, says Goldstein, a MED associate professor of psychiatry, neurology, ophthalmology, pathology and laboratory medicine, and radiology, and a College of Engineering associate professor of biomedical engineering and of electrical and computer engineering.

The CTNI will also research new ultrasound imaging and focused ultrasound applications.

“The use of focused ultrasound is an emerging area in neuroscience, enabling fundamental discoveries in neurotrauma as well as the potential development of novel, acoustically enabled therapeutics,” says Anderson, a MED professor of radiology and an ENG professor of mechanical engineering and a faculty member of both the Nanotechnology Innovation Center and the Photonics Center.

MLSC received 45 applicants for grants, ultimately awarding a total of $30.5 million to 11 proposals. The MLSC Competitive Capital Program is designed to provide grants for capital projects that support the life sciences ecosystem in Massachusetts by enabling and supporting life sciences workforce development and training, research and development, commercialization, and/or manufacturing in the commonwealth.

What if scientists could manipulate your brain so that a traumatic memory lost its emotional power over your psyche? Steve Ramirez (CAS’10), a Boston University neuroscientist fascinated by memory, believes that a small structure in the brain could hold the keys to future therapeutic techniques for treating depression, anxiety, and PTSD, someday allowing clinicians to enhance positive memories or suppress negative ones.

Steve Ramirez. Photo by Cydney Scott

Inside our brains, a cashew-shaped structure called the hippocampus stores the sensory and emotional information that makes up memories, whether they be positive or negative ones. No two memories are exactly alike, and likewise, each memory we have is stored inside a unique combination of brain cells that contain all the environmental and emotional information associated with that memory. The hippocampus itself, although small, comprises many different subregions working in tandem to recall the elements of a specific memory.

Now, in a new paper in Current Biology, Ramirez, a BU College of Arts & Sciences assistant professor of psychological and brain sciences, and a team of collaborators have shown just how pliable memory is if you know which regions of the hippocampus to stimulate—which could someday enable personalized treatment for people haunted by particularly troubling memories.

“Many psychiatric disorders, especially PTSD, are based on the idea that after there’s a really traumatic experience, the person isn’t able to move on because they recall their fear over and over again,” says Briana Chen, first author of the paper and a Columbia University graduate researcher studying depression.

In their study, Chen and Ramirez, the paper’s senior author, show how traumatic memories—such as those at the root of disorders like PTSD—can become so emotionally loaded. By artificially activating memory cells in the bottom part of the brain’s hippocampus, negative memories can become even more debilitating. In contrast, stimulating memory cells in the top part of the hippocampus can strip bad memories of their emotional oomph, making them less traumatic to remember.

Well, at least if you’re a mouse.

Using a technique called optogenetics, Chen and Ramirez mapped out which cells in the hippocampus were being activated when male mice made new memories of positive, neutral, and negative experiences. A positive experience, for example, could be exposure to a female mouse. In contrast, a negative experience could be receiving a startling but mild electrical zap to the feet. Then, identifying which cells were part of the memory-making process (which they did with the help of a glowing green protein designed to literally light up when cells are activated), they were able to artificially trigger those specific memories again later, using laser light to activate the memory cells.

Their studies reveal just how different the roles of the top and bottom parts of the hippocampus are. Activating the top of the hippocampus seems to function like effective exposure therapy, deadening the trauma of reliving bad memories. But activating the bottom part of the hippocampus can impart lasting fear and anxiety-related behavioral changes, hinting that this part of the brain could be overactive when memories become so emotionally charged that they are debilitating.

That distinction, Ramirez says, is critical. He says that it suggests suppressing overactivity in the bottom part of the hippocampus could potentially be used to treat PTSD and anxiety disorders. It could also be the key to enhancing cognitive skills, “like [in] Limitless,” he says, referencing the 2011 film starring Bradley Cooper in which the main character takes special pills that drastically improve his memory and brain function.

“The field of memory manipulation is still young…. It sounds like sci-fi, but this study is a sneak preview of what’s to come in terms of our abilities to artificially enhance or suppress memories,” says Ramirez. Although the study got its start while Chen and Ramirez were both doing research at Massachusetts Institute of Technology, its data has been the backbone of the first paper to come out of the new laboratory group that Ramirez established at BU in 2017.

“We’re a long way from being able to do this in humans, but the proof of concept is here,” Chen says. “As Steve likes to say, ‘never say never.’ Nothing is impossible.”

“This is the first step in teasing apart what these [brain] regions do to these really emotional memories…the first step toward translating this to people, which is the holy grail,” says memory researcher Sheena Josselyn, a University of Toronto neuroscientist who was not involved in this study. “[Steve’s] group is really unique in trying to see how the brain stores memories with the goal being to help people…. They’re not just playing around but doing it for a purpose.”

Although mouse brains and human brains are very different, Ramirez, who is also a member of the BU Center for Systems Neuroscience and the Center for Memory and Brain, says that learning how these fundamental principles play out in mice is helping his team map out a blueprint of how memory works in people. Being able to activate specific memories on demand, as well as targeted areas of the brain involved in memory, allows the researchers to see exactly what side effects come along with different areas of the brain being overstimulated.

“Let’s use what we’re learning in mice to make predictions about how memory functions in humans,” he says. “If we can create a two-way street to compare how memory works in mice and in humans, we can then ask specific questions [in mice] about how and why memories can have positive or negative effects on psychological health.”

This work was supported by a National Institutes of Health Early Independence Award, a Young Investigator Grant from the Brain and Behavior Research Foundation, a Ludwig Family Foundation Grant, and the McKnight Foundation Memory and Cognitive Disorders Award.

Kat J. McAlpine can be reached at katjmcal@bu.edu.