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Aging-related genomic culprit found in Alzheimer’s disease

Researchers at Washington University School of Medicine in St. Louis have developed a way to capture the effects of aging in the development of Alzheimer’s disease. They have devised a method to study aged neurons in the lab without a brain biopsy, an advancement that could contribute to a better understanding of the disease and new treatment strategies.

The scientists transformed skin cells taken from patients with late-onset Alzheimer’s disease into brain cells called neurons. Late-onset Alzheimer’s develops gradually over many decades and only starts to show symptoms at age 65 or older. For the first time, these lab-derived neurons accurately reproduced the hallmarks of this type of dementia, including the amyloid beta buildup, tau protein deposits and neuronal cell death.

By studying these cells, the researchers identified aspects of cells’ genomes — called retrotransposable elements, which change their activity as we age — in the development of late-onset Alzheimer’s disease. The findings suggest new treatment strategies targeting these factors.

The study appears Aug. 2 in the journal Science.

“Sporadic, late-onset Alzheimer’s disease is the most common type of Alzheimer’s disease, representing more than 95% of cases,” said senior author Andrew Yoo, PhD, a professor of developmental biology. “It has been very difficult to study in the lab due to the complexity of the disease stemming from various risk factors, including aging as an important contributor. Until now, we did not have a way to capture the effects of aging in the cells to study late-onset Alzheimer’s.”

To date, animal studies of Alzheimer’s disease have, by necessity, focused on mice with rare genetic mutations known to cause inherited, early-onset Alzheimer’s in younger people — a strategy that has shed light on the condition but differs from disease development for the vast majority of patients with the sporadic, late-onset form. To more faithfully recapitulate the disease in the lab, Yoo’s team turned to an approach called cellular reprogramming.

The method to transform easily obtained human skin cells from living patients directly into neurons makes it possible to study Alzheimer’s effects on the brain without the risk of a brain biopsy and in a way that retains the consequences of the patient’s age on the neurons. Past work by Yoo and his colleagues, who pioneered this transformation technique using small RNA molecules called microRNAs, has focused on understanding the development of Huntington’s disease — an inherited neurological condition that typically shows adult-onset symptoms.

After transforming skin cells into brain cells, the researchers found that the new neurons can grow in a thin gel layer or self-assemble into small clusters — called spheroids — mimicking the 3D environment of the brain. The researchers compared neuronal spheroids generated from patients with sporadic, late-onset Alzheimer’s disease, inherited Alzheimer’s disease and healthy individuals of similar ages.

The Alzheimer’s disease patients’ spheroids quickly developed amyloid beta deposits and tau tangles between neurons. Activation of genes associated with inflammation also emerged, and then the neurons began to die, mimicking what is seen in brain scans of patients. Spheroids from older, healthy donors in the study showed some amyloid deposition but much less than those from patients. The small amyloid deposits in older, healthy spheroids are evidence that the technique is capturing the effects of age and suggest that amyloid beta and tau accumulation correlated with aging. It further demonstrates that the Alzheimer’s disease process makes the buildup far worse.

The researchers, including first author Zhao Sun, PhD, a staff scientist in Yoo’s lab, found that treating spheroids from late-onset Alzheimer’s disease patients with drugs that interfere with the formation of amyloid beta plaques early in the disease process, before neurons start forming toxic amyloid beta buildup, significantly reduced the amyloid beta deposits. But treating at later time points, after some buildup was already present, had no effect or only modestly reduced subsequent amyloid beta deposits. Such data emphasize the importance of identifying and treating the disease early.

The study further found a role for retrotransposable elements — small pieces of DNA that jump to different locations in the genome — in the development of late-onset Alzheimer’s disease. Inhibition of such “jumping genes” with the drug lamivudine (also called 3TC) — an anti-retroviral drug that can dampen the activity of retrotransposable elements — had a positive effect: The spheroids from late-onset Alzheimer’s disease patients had reduced amyloid beta and tau tangles and showed less neuronal death compared with the same spheroids treated with a placebo. Lamivudine treatment had no beneficial effect on spheroids from patients with early-onset, inherited Alzheimer’s disease, providing evidence that sporadic late-onset Alzheimer’s development related to aging has distinct molecular features compared with inherited autosomal dominant Alzheimer’s disease.

“In these patients, our new model system has identified a role for retrotransposable elements associated with the disease process,” Yoo said. “We were pleased to see that we could reduce the damage with a drug treatment that suppresses these elements. We look forward to using this model system as we work toward new personalized therapeutic interventions for late-onset Alzheimer’s disease.”

The researchers are planning future studies with spheroids that include multiple types of brain cells, including neurons and glia.

Nasal COVID-19 vaccine halts transmission

The lightning-fast development of COVID-19 vaccines just months after the virus appeared was a triumph of modern science and saved millions of lives. But for all the good they did in reducing illnesses and deaths, the shots were unable to end the pandemic because of one notable weakness: They couldn’t stop the spread of the virus.

A new study by researchers at Washington University School of Medicine in St. Louis indicates that next-generation vaccines that target the virus’s points of entry — the nose and mouth — may be able to do what traditional shots cannot: contain the spread of respiratory infections and prevent transmission. Using a nasal COVID-19 vaccine based on Washington University technology, approved for use in India and licensed to Ocugen for further development in the U.S., the researchers showed that vaccinated hamsters that developed infections did not pass the virus on to others, breaking the cycle of transmission. In contrast, an approved COVID-19 vaccine that is injected failed to prevent the spread of the virus.

The findings, published July 31 in Science Advances, provide further evidence that so-called mucosal vaccines sprayed into the nose or dropped into the mouth may be the key to controlling respiratory infections such as influenza and COVID-19 that continue to circulate and cause significant illness and death.

“To prevent transmission, you need to keep the amount of virus in the upper airways low,” said senior author Jacco Boon, PhD, a professor of medicine, of molecular microbiology and of pathology & immunology. “The less virus that is there to begin with, the less likely you are to infect someone else if you cough or sneeze or even just breathe on them. This study shows that mucosal vaccines are superior to injected vaccines in terms of limiting viral replication in the upper airways and preventing spread to the next individual. In an epidemic or pandemic situation, this is the kind of vaccine you’re going to want.”

Developing vaccines that can control virus levels in the nose has proven challenging. Viruses such as influenza virus, SARS-CoV-2 (the virus that causes COVID-19) and respiratory syncytial virus (RSV) multiply rapidly in the nose and spread from person to person within a few days of initial exposure. Traditional injectable vaccines generate immune responses that can take a week to build to full strength and are much less potent in the nose than in the bloodstream, leaving the nose relatively unprotected against a fast-multiplying, fast-spreading virus.

In principle, a vaccine sprayed or dropped directly into the nose or mouth could limit viral reproduction and thereby reduce transmission by eliciting an immune response right where it’s needed most. But gathering evidence that mucosal vaccines actually do reduce transmission has proven tricky. Animal models of transmission are not well-established, and tracking person-to-person transmission is fiendishly complicated, given the number and variety of encounters a typical person has on any given day.

For this study, Boon and colleagues developed and validated a model for community transmission using hamsters and then used it to assess the effect of mucosal vaccination on the spread of SARS-CoV-2. (Unlike mice, hamsters are naturally susceptible to infection with SARS-CoV-2, making them the ideal laboratory animals for a transmission study.)

The researchers immunized groups of hamsters with laboratory versions of approved COVID-19 vaccines: the nasal iNCOVACC used in India or the injected Pfizer vaccine. For comparison, some hamsters were not immunized. After giving the vaccinated hamsters a few weeks for their immune responses to fully mature, the researchers infected other hamsters with SARS-CoV-2 and then placed the immunized hamsters with the infected hamsters for eight hours. This first step of the experiment mimics the experience of vaccinated people who are exposed to a person with COVID-19.

After spending eight hours rubbing shoulders with infected hamsters, most of the vaccinated animals became infected. Virus was found in the noses and lungs of 12 of 14 (86%) hamsters that had received the nasal vaccine, and 15 of 16 (94%) hamsters that had received the injected vaccine. Importantly, while most animals in both groups were infected, they weren’t infected to the same degree. Hamsters that had been nasally immunized had virus levels in the airways 100 to 100,000 times lower than those that had received the shot or had not been vaccinated. The study did not assess the animals’ health, but previous studies have shown that both vaccines reduce the likelihood of severe illness and death from COVID-19.

The second step of the experiment yielded even more striking results. The researchers took vaccinated hamsters that subsequently developed infections and placed them with healthy vaccinated and unvaccinated hamsters for eight hours to model transmission of virus from a vaccinated person to others.

None of the hamsters that were exposed to nasally vaccinated hamsters became infected, regardless of whether the recipient hamster had been vaccinated or not. In contrast, roughly half of the hamsters that were exposed to hamsters vaccinated by injection became infected — again, regardless of the recipient’s immunization status. In other words, vaccination through the nose — but not by injection — broke the cycle of transmission.

These data, Boon said, could be important as the world prepares for the possibility that avian influenza, currently causing an outbreak in dairy cows, might adapt to humans and trigger a flu epidemic. An injectable vaccine for avian influenza already exists, and a team of researchers at Washington University is working toward a nasal vaccine for avian influenza. That team includes Boon and co-author Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine and one of the inventors of the nasal vaccine technology used in this paper.

“Mucosal vaccines are the future of vaccines for respiratory infections,” Boon said. “Historically, developing such vaccines has been challenging. There’s still so much we don’t know about the kind of immune response we need and how to elicit it. I think we’re going to see a lot of very exciting research in the next few years that could lead to big improvements in vaccines for respiratory infections.”

Accuracy of diagnostic blood tests for Alzheimer’s disease varies

Neurologists diagnose cognitive impairment with a clinical exam of memory and thinking skills. To determine whether Alzheimer’s disease is the cause of the cognitive impairment, evidence of the specific brain changes that characterize Alzheimer’s must be obtained, typically via a brain scan or spinal tap. Identifying people whose cognitive symptoms are due to Alzheimer’s disease is critical now that new Alzheimer’s therapies are available that could change the course of the illness.

To make diagnosis more convenient for patients, many companies have begun selling Alzheimer’s blood tests to consumers, and at least five companies are now offering these tests to doctors for clinical use. Doctors have no way of knowing which tests are most accurate because, until now, the tests have not been evaluated in a head-to-head comparison using the same population, methods and criteria.

Suzanne Schindler, MD, PhD, and her team at Washington University School of Medicine in St. Louis led a data analysis comparing the accuracy of six commercial blood tests, four of which are clinically available, in detecting signs of Alzheimer’s disease, particularly the presence of the characteristic amyloid plaques in the brain. The analysis showed that some of the tests are accurate enough to replace spinal taps and brain scans in many patients with cognitive impairment. The head-to-head comparison was part of a project developed and launched by the Foundation for the National Institutes of Health Biomarkers Consortium, a public-private partnership of which Washington University is a member. The results are being presented today, July 30, in an oral session at the Alzheimer’s Association International Conference in Philadelphia.

“Some of the blood tests are accurate and some are not, and doctors don’t know which tests to use,” said Schindler, an associate professor of neurology at Washington University and the lead author of the study. “With this head-to-head comparison, doctors now have more reliable information about which tests will best help them provide an accurate diagnosis to their patients.”

Confirming that cognitive impairment is due to Alzheimer’s disease – early in the course of the illness – is crucial for ensuring access to the newest generation of Alzheimer’s therapies. In the past two years, the Food and Drug Administration (FDA) has approved two drugs that slow the trajectory of disease, with more in the pipeline. Both FDA-approved drugs target amyloid, so doctors must confirm that a patient has amyloid buildup in the brain before they can prescribe the treatment. In addition, the diagnosis must be confirmed as early in the disease course as possible, because the drugs are only approved for people with very mild to mild symptoms.

The team evaluated the ability of six commercially available blood tests to detect proteins in the blood that correlated with key features of Alzheimer’s disease: amyloid plaques and tangles of the protein tau in the brain, reduced brain volumes and cognitive impairment. The six tests were developed by ALZpath, C2N Diagnostics, Fujirebio Diagnostics, Janssen, Quanterix and Roche Diagnostics. C2N Diagnostics is a Washington University startup, and its Alzheimer’s tests are based on technology licensed to C2N by the university.

Blood samples and participant data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a long-running, multisite collaboration designed to identify Alzheimer’s biomarkers and to advance biomarker development by sharing data and resources within the research community. The study included 392 people who had provided blood samples within six months of undergoing brain scans. The participants had a median age of 78.1 years, and just under half (49%) exhibited cognitive impairment.

Each of the six tests measured the blood levels of one or more biomarkers linked to Alzheimer’s disease. Across the six tests, five distinct biomarkers were measured using various techniques. One biomarker, used in four of the tests, proved exceptionally accurate at identifying signs of Alzheimer’s disease: a form of tau known as phosphorylated tau 217 (p-tau217).

“Some people thought that we might need to measure multiple biomarkers to get at the different features of Alzheimer’s disease,” said Kellen Petersen, PhD, an instructor in neurology at the School of Medicine. Petersen co-led data analysis for the study and will give the oral presentation at the international Alzheimer’s conference. “That’s not what we found. P-tau217 alone can do it all. It accurately predicted levels of amyloid and tau in the brain, brain volumes and cognitive symptoms. It was more accurate than any other biomarker, or even any combination of biomarkers, across the board.”

The four tests that incorporate measures of p-tau217 all performed well, regardless of the approach they took to measuring the protein. The top two performers across all measures were C2N Diagnostics’ PrecivityAD2 and Fujirebio’s Lumipulse.

In June, the Global CEO Initiative on Alzheimer’s Disease published a paper in Nature Reviews Neurology laying out a framework for using blood tests in Alzheimer’s clinical care and recommending minimum criteria for acceptable performance. Schindler is the lead author on that paper.

“We concluded that, to be used without a second test, blood tests need to be as accurate as FDA-approved cerebrospinal fluid tests, which are approximately 90% sensitive and specific at identifying Alzheimer’s disease in cognitive impaired individuals,” Schindler said. “In this current study, the p-tau217 tests met that standard, but the others did not.”

The data and algorithms used in this study are available via ADNI to investigators interested in further studying the performance of these tests.

25 Washington University members selected for medical honor society

The Alpha Omega Alpha (AOA) Honor Medical Society chapter at Washington University School of Medicine in St. Louis has announced 25 inductees for its Class of 2024. The AOA is a national organization with a mission to recognize and support leadership, high educational achievement and effective teaching as well as service to others. The Washington University chapter has more than 450 physicians.

“WashU Medicine values inclusion, diversity, innovation and critical thinking – all of which are aligned with AOA’s core principles,” said Renée Shellhaas, MD, the David T. Blasingame Professor of Neurology and senior associate dean for faculty promotions and career development. “The new AOA members are role models for outstanding patient care, education and science.”

Faculty members chosen for the society’s 2024 class:

  • Kevin Baumgartner, MD, assistant professor of emergency medicine
  • Fouad Boulus, MD, associate professor of pathology & immunology
  • Ramaswamy Govindan, MD, the Anheuser Busch Endowed Chair in Medical Oncology and chief of the section of medical oncology
  • Richard T. Griffey, MD, professor of emergency medicine
  • Sarah Hartz, MD, PhD, associate professor of psychiatry
  • Lori Holtz, MD, associate professor of pediatrics
  • Bethany C. Sacks, MD, associate professor of surgery
  • Marilyn J. Siegel, MD, professor of radiology
  • Nancy Sweitzer, MD, PhD, professor of medicine, vice chair of clinical research for the Department of Medicine and director of clinical research for the Cardiovascular Division
  • Gregory Wu, MD, PhD, associate professor of neurology and of pathology & immunology

Washington University alumni chosen for this year’s class:

  • David Carpenter, MD, professor of neurology and medical director of the Comprehensive Stroke Center
  • Joseph P. Gaut, MD, PhD, the Ladenson professor of pathology and immunology and the division chief of anatomic and molecular pathology
  • Jennifer Griffith, MD, PhD, assistant professor of neurology

House officers selected to the society:

  • Manoj Arra, MD, PhD, resident, emergency medicine
  • Thomas Barrett, MD, resident, otolaryngology – head & neck surgery
  • Katharine Caldwell, MD, chief resident, surgery
  • Salena Cui, MD, resident, neurology
  • Bree Goodman, MD, assistant professor of obstetrics & gynecology
  • Alison Kosmacki, MD, clinical fellow, obstetrics & gynecology
  • Michelle Lee, MD, administrative chief resident, neurology
  • Rawan Safa, MD, chief resident, emergency medicine 2023-24
  • Daniel Suarez, MD, chief resident, emergency medicine 2024-25
  • Sydney Thayer, MD, clinical fellow, obstetrics & gynecology
  • Mitsukuni Yoshida, MD, PhD, resident, anesthesiology
  • Jorge Zárate Rodriguez, MD, resident, surgery

Wahl honored for leadership in nuclear medicine and imaging

The Society of Nuclear Medicine and Molecular Imaging (SNMMI) recently presented the 2024 Minoshima-Pappas Transformative Leadership Award to Richard Wahl, MD, professor of radiology and of radiation oncology at Washington University School of Medicine in St. Louis.

Wahl is only the second recipient of the award, which the SNMMI established to recognize individuals who have brought meaningful improvements to the science and practice of nuclear medicine and molecular imaging.

Wahl, a member of the National Academy of Medicine, practices at Barnes Jewish Hospital and is the former director of the School of Medicine’s Mallinckrodt Institute of Radiology, has contributed to several advances in the field of nuclear medicine and imaging, most notably by developing the first FDA-approved radioimmunotherapies — radioactive compounds that bind specifically to cancerous cells — for non-Hodgkin’s lymphoma. He also pioneered the use of PET imaging to assess a  wide range of cancers.  His work has also resulted in a number of FDA-approved drugs and devices that use radioactive tracing compounds to bind to specific proteins to diagnose and treat cancers.

As past president of SNMMI, Wahl was the driving force behind the creation of the SNMMI Mars Shot Fund. The $100 million fund provides grant support for research in nuclear medicine and molecular imaging that has the potential to improve patient outcomes. The fund started disbursing grants last year and is supporting seven research projects across the country.

Fort Neuroscience Research Building earns LEED Gold

The Jeffrey T. Fort Neuroscience Research Building at Washington University School of Medicine in St. Louis has earned LEED Gold certification from the U.S. Green Building Council. To earn this rating, buildings must meet stringent standards in energy use, material recycling, water consumption, and other measures indicating low environmental impact.

“This achievement not only underscores our commitment to responsible environmental practices but also signifies our dedication to promoting community health through innovation and collaboration,” said Melissa Rockwell-Hopkins, the School of Medicine’s associate vice chancellor for operations & facilities management.

The building, which officially opened in January, has high-efficiency chillers and cooling towers, and heat- and energy-recovery technology. Everything from the lab equipment to the elevators was designed with an eye toward conservation and efficient energy use. For example, the parking garage has charging stations for electric vehicles; native plants were used for landscaping, which helps with water efficiency; and the building was designed to minimize urban heat island effect during the day and light pollution at night.

“We are excited to celebrate this accomplishment, but the certification is only a small component of our sustainability goal,” Rockwell-Hopkins said. “Sustainability at WashU Medicine transcends certification for it embodies our commitment to improving lives within our buildings, on our campus, in St. Louis and surrounding communities, and across the world.

“We are continuously striving to create a supportive environment where every individual can thrive comfortably and safely. Our project team is grateful for collaborative campus leadership, including Exterior Committee Board Members, Chancellor Martin and Dean Perlmutter, and for the tireless dedication of the Neuroscience Research Building Project Core Advisory and research lab representatives who made this project and certification possible.”

Vedantham honored for innovation in interventional radiology

Suresh Vedantham, MD, a professor of radiology and of surgery at Washington University School of Medicine in St. Louis, has been awarded the 2024 Leader in Innovation Award by the Society of Interventional Radiology Foundation. Vedantham was recognized for his advances in image-guided therapies for venous blood clots, known as venous thromboembolism (VTE), and their complications.

Vedantham’s work in refining new treatments and in leading clinical trials has influenced clinical guidelines for VTE and post-thrombotic syndrome, which can cause lifelong pain or disability in patients who have experienced VTE. He leads national, multisite trials funded by the National Institutes of Health (NIH) that are focused on the use of optimal catheter therapies for patients with post-thrombotic syndrome and pulmonary embolism, including the Chronic Venous Thrombosis: Relief with Adjunctive Catheter Based Therapy (C-TRACT) trial. He is director of the Trial-CARE clinical trial support service at the School of Medicine and an assistant dean for clinical research.

The award acknowledges Vedantham’s approach to clinical research and interdisciplinary leadership. His success in leading large-scale NIH-funded projects has created a model for interventional radiologists and others to follow in their own research.

Pagliarini named HHMI Investigator

David Pagliarini, PhD, the Hugo F. & Ina C. Urbauer Professor and a BJC Investigator in the Department of Cell Biology & Physiology at Washington University School of Medicine in St. Louis, has been named a Howard Hughes Medical Institute (HHMI) Investigator. HHMI will be supporting Pagliarini’s research on mitochondria, organelles embedded within cells that produce much of the body’s energy, and his effort to shed light on the underlying genetic causes of mitochondrial disorders. These conditions affect one in 5,000 people and can impair growth, muscle strength, vision and other body functions.

HHMI grants investigator awards to accomplished scientists who are pursuing ideas with the potential to answer fundamental questions about biology. The program is intended to support “people, not projects,” and to provide scientists the time, funding and freedom they need to follow their science where it leads. In Pagliarini’s case, it will allow him to add technical capacity to scale up and expand the breadth of his research into mitochondrial proteins and their functions.

As an HHMI Investigator, Pagliarini will receive approximately $11 million in HHMI funding over a seven-year term, which can be renewed after scientific review. Pagliarini is one of 26 scientists in the 2024 cohort of new investigators, of nearly 1,000 that applied.

The sort of freedom that the HHMI seeks to encourage is precisely what drew Pagliarini to the School of Medicine in 2020. At the time, he was an associate professor of biochemistry at the University of Wisconsin – Madison and lead metabolism investigator of that school’s Morgridge Institute for Research. In the latter role, he was responsible for developing a program in metabolic research and had assumed a number of administrative duties. The opportunity to join Washington University as one of the first BJC Investigators – a program modeled after the HHMI Investigators – came at the right moment, when he was looking to devote more energy into his own lab.

The BJC Investigator Program brings to the School of Medicine scientists who will have a transformational impact on research programs, bring innovative approaches to major biological questions, and whose discoveries stand to inform new ways of understanding disease and developing treatments.

“The BJC Investigator Program provided my laboratory ample freedom to pursue our most ambitious research, and it’s allowed us to expand and take new risks,” Pagliarini said.

Pagliarini is well regarded for his effort in leading the creation of MitoCarta, which catalogs known mitochondrial proteins and how they are expressed in different tissues. The data have had a profound effect on the field, demonstrating how little was known about the function of hundreds of mitochondrial proteins. By illuminating where the blank spots on the mitochondrial map are, MitoCarta has enabled a systematic effort to uncover the functions of these “orphan” proteins, and potentially their role in mitochondrial-linked disorders. There are a wide range of these conditions, including a subtype of diabetes, and they often involve conditions in which muscles or nerves do not function properly, leading to stunted growth, or deafness and vision disorders.

The HHMI Investigator award will allow Pagliarini and his team to continue that work to better understand mitochondrial functions and possible medical interventions. A current research passion of Pagliarini’s, coenzyme Q (CoQ), has its roots in classical biochemistry. Discovered 70 years ago, CoQ is a lipid (fatty compound) that is revealing itself to be a Swiss Army knife for the cell, crucial to processes as varied as protecting cell membranes from damage to driving enzyme activity. When he applied for the HHMI Investigator award, Pagliarini wasn’t sure that the program would share his interest.

“I love the biochemistry of CoQ, and I love trying to understand how it’s made in mitochondria and distributed throughout the cell to support diverse biology. And yet, in my mind I was concerned this pursuit would appear esoteric,” he said.

This is precisely what the HHMI Investigators program is looking to support: identifying fundamental questions about biology, and then setting scientists free with the resources they need to pursue the answers wherever they might be.

“We don’t know what untapped biology will prove most important for human health. CoQ is undeniably essential for cellular operations and yet there are so many fundamental things about it that we don’t know. We’re figuring those out, and HHMI embraces the philosophy that pursuing fundamental biology is the right long-term bet,” said Pagliarini.

That said, the implications of understanding the biology of CoQ reach could reach far beyond the lab. Deficiencies in CoQ are implicated in several diseases, including type 2 diabetes, certain kinds of movement disorders, and chronic kidney and liver conditions. It can be administered therapeutically when needed, but because the body cannot absorb it properly it is not very effective. Pagliarini says that being able to build on his “esoteric” understanding of CoQ to develop effective delivery systems for the lipid could transform current treatments.

Creating new cellular models, procuring advanced equipment, and conducting large-scale screens are all time consuming and expensive, forcing limitations on pursuing promising leads. With the support from the HHMI Investigator program, the Pagliarini lab can place its bets on multiple options, without the concern that a single failure to pay off would set back the project.

“It’s empowering for our team. People get excited about taking a chance on an idea, knowing that they’re not going to tank the lab or their own PhD if something doesn’t work,” he said.

Pagliarini said the HHMI Investigator award provides gratification in knowing that his peers find value in his work. “It’s easy to peruse the top journals or go to meetings and feel like everybody else is doing the cool stuff. Having such accomplished and respected scientists see promise in our approach and vision is invigorating.”

Fehniger Named to Lymphoma Research Foundation Advisory Board

Todd Fehniger, MD, PhD, a physician-scientist at Washington University School of Medicine in St. Louis who specializes in treating patients with lymphoma and developing innovative immune therapies to treat the disease, has been appointed a member of the scientific advisory board of the Lymphoma Research Foundation.

Fehniger treats patients at Siteman Cancer Center, based at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis. A professor of medicine, he also co-leads the Hematopoietic Development and Malignancy Program at Siteman.

The advisory board comprises 45 renowned lymphoma experts, who guide the planning of the foundation’s research program. They select innovative and promising research aimed at improving outcomes for patients with lymphoma, a broad term for cancer that begins in cells of the lymph system, which is part of the immune system.

Board members review grant proposals, make recommendations regarding research priorities and funding to the foundation’s board of directors, evaluate the progress of ongoing research projects, and guide the strategic direction of the foundation’s research programs and consortia.

Can we predict who will develop migraine headaches?

A migraine is not just a bad headache. It is a much-dreaded part of a neurologic disorder that has an array of possible symptoms, including pulsating cranial pain, waves of queasiness, bouts of vomiting, and hypersensitivity to light and sound. They frequently materialize unannounced and at the most inopportune of moments.

Pubescent girls with a family history of migraine headaches are especially vulnerable — yet there remain many unknowns regarding the who, when and why of the disorder. Hadas Nahman-Averbuch, PhD, a scientist at Washington University School of Medicine in St. Louis with expertise in pediatric pain and migraine disorder, is trying to change that. She is leading two observational studies: One will examine why some adolescent girls develop migraine headaches and others do not, and the other will explore how puberty plays a role in migraine headaches among boys and girls.

The single-center studies at the School of Medicine are supported by two grants totaling $6 million from the National Institutes of Health (NIH).

“During adolescence, we see a significant increase in the prevalence of migraine diagnoses in girls,” said Nahman-Averbuch, who runs the Pain Across the Lifespan lab at the university and is an assistant professor of anesthesiology. “We want to understand the changes that come before migraine headache onset and identify the girls who are at risk of developing them. The hope is that this knowledge leads to new therapies and interventions that, if given early, could prevent, manage or treat migraine headaches in adolescent girls.

“We also want to investigate how puberty affects the severity and incidence of migraine headaches in adolescent girls and boys who already experience them, to better understand the trajectory of the disorder.”

Treatments for young migraine sufferers are limited — newer migraine medications that have hit the market in recent years are limited to those 18 and older — and more research into the often-debilitating condition in adolescents is needed.

Among the issues in getting to the bottom of why migraine headaches occur are the many triggers: among them, stress, certain foods, sleep deprivation, caffeine and fluctuating hormones. On top of that are the wide-ranging and inconsistent time delays between triggers and migraine headache onset, which complicate pinpointing a migraine’s exact cause.

The first study led by Nahman-Averbuch focuses on 200 girls ages 10 to 13. During three visits, study participants undergo magnetic resonance imaging (MRI) to look at brain connectivity between two brain regions – the amygdala and the prefrontal cortex. The amygdala plays a critical role in how we perceive and respond to pain. It communicates and interacts with the prefrontal cortex. Changes in that interaction are found in patients with migraine headaches compared with those without migraine headaches and are linked with changes in headache frequency in adolescents with the disorder, Nahman-Averbuch said.

Girls with a family history of migraine disorder are compared with girls without such history to determine if brain changes can be used to predict who will be diagnosed with the illness. The girls, migraine-free at the start of the study, are monitored for migraine development for two years.

Adolescents who have a first-degree relative with migraine disorder have been found in previous work to have higher sensitivity to pain. Nahman-Averbuch, who was involved in such research, suspects that a heightened response to sensory testing involving heat, cold and pressure stimuli may predict who will be diagnosed with the disorder. The participants rate such experiences as part of the study.

Migraine headache incidence is higher in boys before puberty and in girls during puberty, when fluctuating sex hormones aid in the transition to early adulthood. The researchers seek to figure out if a particular sex hormone – for example, estrogen, testosterone or progesterone – can help predict why adolescent girls are more likely to be affected. The research team is monitoring blood levels of various sex hormones as part of the study.

“There are many changes ­– biological, psychological and social – happening during puberty,” Nahman-Averbuch said. “Each could impact the pain system and be responsible for this pattern. We want to figure out what those changes are, and if they can predict who is at risk of developing migraine headaches.”

In the second study, the researchers track 180 girls and boys ages 10 to 13 diagnosed with migraine disorder over two years. Migraine-free boys with no family history of migraine disorder and migraine-free girls from the first study are part of the control group. Using the same methods as in the first study, the researchers look at how puberty impacts migraine headaches.

“Understanding the changes that come before migraine headache onset and the changes during puberty that improve migraine disorder in a certain population can help us develop new interventions and preventive strategies,” Nahman-Averbuch said. “Meanwhile, identifying adolescents who are at risk may allow us to start such interventions earlier.”

Risk of long COVID declined over course of pandemic

The risk of developing long COVID has decreased significantly over the course of the COVID-19 pandemic, according to an analysis of data led by Washington University School of Medicine in St. Louis.

Researchers attributed about 70% of the risk reduction to vaccination against COVID-19 and 30% to changes over time, including the SARS-CoV-2 virus’s evolving characteristics and improved detection and management of COVID-19.

The research is published July 17 in The New England Journal of Medicine.

“The research on declining rates of long COVID marks the rare occasion when I have good news to report regarding this virus,” said the study’s senior author, Ziyad Al-Aly, MD, a Washington University clinical epidemiologist and global leader in COVID-19 research. “The findings also show the positive effects of getting vaccinated.”

Long COVID encompasses the lingering and debilitating effects on health experienced by about 10% of people who have been infected with COVID-19. To date, the World Health Organization has documented more than 775 million cases of COVID-19.

In more than 30 high-profile studies, Al-Aly has detailed the virus’s indiscriminate, long-term health impacts across nearly all organ systems affecting the heart, brain, kidneys and gastrointestinal (GI) tract.

Although his latest findings sound more reassuring than previous studies, Al-Aly tempered the good news. “Long COVID is not over,” said the nephrologist, who treats patients at Washington University-affiliated John J. Cochran Veterans Hospital in St. Louis. “We cannot let our guard down. This includes getting annual COVID vaccinations, because they are the key to suppressing long COVID risk. If we abandon vaccinations, the risk is likely to increase.”

Since the pandemic’s beginning, Al-Aly has dedicated himself to analyzing long COVID with the aim of helping the public make informed health choices; supporting scientists in generating research-backed recommendations on prevention and treatment; and enabling politicians to make educated decisions regarding funding and public policies. Al-Aly’s latest study builds on this body of work by examining the virus’s variants and overall evolution.

To do this, Al-Aly and his team analyzed millions of de-identified medical records in a database maintained by the U.S. Department of Veterans Affairs, the nation’s largest integrated health-care system. The study included 441,583 veterans with SARS-CoV-2 infections and more than 4.7 million uninfected veterans, from March 1, 2020, through Jan. 31, 2022.

Patients included people of diverse ages, races and sexes; statistical modeling ensured parity in representation.

The researchers divided the veterans into five groups: unvaccinated COVID-19 sufferers who acquired the original strain in 2020; the delta variant in 2021; and the omicron variant in 2022. The other two groups included vaccinated people who had the delta variant, and vaccinated people with omicron. No vaccines existed while the original strain circulated.

The team estimated rates of long COVID one-year postinfection for each of the five groups.

Unsurprisingly, the rate of long COVID was the highest among those with the original strain, Al-Aly said, with 10.4% of those who had infections that developed into long COVID.

That declined to 9.5% among those in the unvaccinated groups during the delta era and 7.7% during omicron.

Among the vaccinated, the rate of long COVID during delta was 5.3% and 3.5% during omicron.

“You can see a clear and significant difference in risk during the delta and omicron eras between the vaccinated and unvaccinated,” said Al-Aly, who is also director of the Clinical Epidemiology Center at the VA St. Louis Health Care System and head of the research and development service. “So, if people think COVID is no big deal and decide to forgo vaccinations, they’re essentially doubling their risk of developing long COVID.”

Al-Aly also emphasized that even with the overall decline, the lowest rate — 3.5% — remains a substantial risk. “That’s three to four vaccinated individuals out of 100 getting long COVID,” he said. “Multiplied by the large numbers of people who continue to get infected and reinfected, it’s a lot of people. This remaining risk is not trivial. It will continue to add an already staggering health problem facing people across the world.”

Matt Miller
Since the pandemic’s beginning, Ziyad Al-Aly, MD, a clinical epidemiologist at Washington University School of Medicine in St. Louis, has dedicated himself to analyzing long COVID with the aim of helping the public make informed health choices and educating scientists and policymakers on prevention and treatment. Al-Aly’s latest study in The New England Journal of Medicine builds on his research by examining the virus’s variants and overall evolution.

Another notable finding offers clues to the virus’s evolution, Al-Aly added. While analyzing the risk among all people infected with COVID-19 during the omicron era of 2022, the likelihood of heart, brain, kidney and lung problems declined. In contrast, diseases and illnesses associated with metabolic function and the GI system increased.

“People tend to think of SARS-CoV-2 as a homogeneous virus,” Al-Aly said. “But each variant has its own fingerprint. The original virus hit the respiratory system hard. Omicron targeted metabolic and GI issues. It’s important because while the risk of long COVID is quantitatively lower, a person can be at a higher risk of developing an illness based on the part of the body that the COVID variant targets.

“It’s really good news that the risk has declined,” he said. “But we know millions of people already have long COVID, and millions more will continue to get long COVID. We need to double down on our efforts to understand it so we can prevent suffering and treat affected individuals.”

Psilocybin generates psychedelic experience by disrupting brain network

People who consume psilocybin-containing mushrooms — otherwise known as magic mushrooms — typically undergo a surreal experience in which their sense of space, time and self is distorted. Advocates have long argued that, under the right conditions, psychedelic experiences can alleviate mental distress, and a smattering of scientific studies suggests they may be right. Understanding precisely how the drug affects the brain will help scientists and doctors harness its therapeutic potential.

In a new study, researchers at Washington University School of Medicine in St. Louis report that psilocybin, the active compound in magic mushrooms, temporarily scrambles a critical network of brain areas involved in introspective thinking such as daydreaming and remembering. The findings provide a neurobiological explanation for the drug’s mind-bending effects and lay some of the groundwork for the development of psilocybin-based therapies for mental illnesses such as depression and post-traumatic stress disorder.

“There’s a massive effect initially, and when it’s gone, a pinpoint effect remains,” said co-senior author Nico U. F. Dosenbach, MD, PhD, a professor of neurology. “That’s exactly what you’d want to see for a potential medicine. You wouldn’t want people’s brain networks to be obliterated for days, but you also wouldn’t want everything to snap back to the way it was immediately. You want an effect that lasts long enough to make a difference.”

The study, available July 17 in Nature, creates a road map other scientists can follow to evaluate the effects of psychoactive drugs on brain function, potentially accelerating drug development efforts for any number of psychiatric illnesses.

Psilocybin showed promise as a treatment for depression in the 1950s and ‘60s, but restrictive federal drug policy in subsequent decades quashed nearly all further research. In recent years, though, regulations have loosened, and interest in the field has been revived.

“These days, we know a lot about the psychological effects and the molecular/cellular effects of psilocybin,” said first author Joshua S. Siegel, MD, PhD, an instructor in psychiatry. “But we don’t know much about what happens at the level that connects the two — the level of functional brain networks.”

To fill that gap, Siegel pulled together a team including Dosenbach, who is an expert in brain imaging, and co-senior author Ginger E. Nicol, MD, an associate professor of psychiatry who has experience running clinical trials with controlled substances. Together, they devised a way to visualize the impact of psilocybin on individual participants’ functional brain networks – neural communication pathways that connect different brain regions – and to correlate changes in these networks with subjective experiences.

The team recruited seven healthy adults to take a high dose of psilocybin or methylphenidate, the generic form of Ritalin, under controlled conditions. Because psychedelic trips carry the risk of users having negative or scary experiences, a pair of trained experts stayed with each participant throughout the experience. The experts helped prepare the participants for what they were likely to experience, provided guidance and support during each experiment, and helped the volunteers process what had occurred afterward. Each participant underwent an average of 18 functional MRI brain scans in the days to weeks before, during and up to three weeks after their experiences with psilocybin. Four participants returned six months later to repeat the experiment.

Psilocybin caused profound and widespread — yet not permanent — changes to the brain’s functional networks. In particular, it desynchronized the default mode network, an interconnected set of brain areas that, ordinarily, are simultaneously active when the brain is not working on anything in particular. After falling out of sync, the network re-established itself when the acute effects of the drug wore off, but small differences from pre-psilocybin scans persisted for weeks. The default mode network remained stable in people who received methylphenidate.

“The idea is that you’re taking this system that’s fundamental to the brain’s ability to think about the self in relation to the world, and you’re totally desynchronizing it temporarily,” Siegel said. “In the short term, this creates a psychedelic experience. The longer-term consequence is that it makes the brain more flexible and potentially more able to come into a healthier state.”

An infographic showing changes in brain activity patterns before, during and after treatment with psilocybinSara Moser
Click on image to enlarge.

Normally, each individual’s functional brain network is as distinctive as a fingerprint. Psilocybin distorted brain networks so thoroughly that individuals could no longer be identified until the acute affects wore off.

“The brains of people on psilocybin look more similar to each other than to their untripping selves,” Dosenbach said. “Their individuality is temporarily wiped out. This verifies, at a neuroscientific level, what people say about losing their sense of self during a trip.”

During the experience, participants were asked to rate their feelings of transcendence, connectedness and awe using the validated Mystical Experience Questionnaire. The magnitude of the changes to the functional networks tracked with the intensity of each participant’s subjective experience.

“We were able to get very precise data on the effects of the drug in each individual,” Nicol said. “This is a step toward precision clinical trials. In psychiatry, we often don’t know who should get a particular medicine and how much or how often. As a result, we end up prescribing one medicine after another, tinkering with the dosage, until we find something that works. By using this approach in clinical trials, we can identify the factors that determine who benefits and who doesn’t, and make better use of the medicines we have.”

Nicol, Siegel and Dosenbach emphasize that people should not interpret their study as a reason to self-medicate with psilocybin. The drug is not approved by the Food and Drug Administration (FDA) as a treatment for depression or any other condition, and there are risks to taking it without the supervision of trained mental health experts.