'Boosting human mental function with brain stimulation'

 In a pilot human study, researchers from the University of Minnesota Medical School and Massachusetts General Hospital show it is possible to improve specific human brain functions related to self-control and mental flexibility by merging artificial intelligence with targeted electrical brain stimulation.

Alik Widge, MD, PhD, an assistant professor of psychiatry and member of the Medical Discovery Team on Addiction at the U of M Medical School, is the senior author of the research published in Nature Biomedical Engineering. The findings come from a human study conducted at Massachusetts General Hospital in Boston among 12 patients undergoing brain surgery for epilepsy -- a procedure that places hundreds of tiny electrodes throughout the brain to record its activity and identify where seizures originate.

In this study, Widge collaborated with Massachusetts General Hospital's Sydney Cash, MD, PhD, an expert in epilepsy research; and Darin Dougherty, MD, an expert in clinical brain stimulation. Together, they identified a brain region -- the internal capsule -- that improved patients' mental function when stimulated with small amounts of electrical energy. That part of the brain is responsible for cognitive control -- the process of shifting from one thought pattern or behavior to another, which is impaired in most mental illnesses.

"An example might include a person with depression who just can't get out of a 'stuck' negative thought. Because it is so central to mental illness, finding a way to improve it could be a powerful new way to treat those illnesses," Widge said.

The team developed algorithms, so that after stimulation, they could track patients' cognitive control abilities, both from their actions and directly from their brain activity. The controller method provided boosts of stimulation whenever the patients were doing worse on a laboratory test of cognitive control.

"This system can read brain activity, 'decode' from that when a patient is having difficulty, and apply a small burst of electrical stimulation to the brain to boost them past that difficulty," Widge said. "The analogy I often use is an electric bike. When someone's pedaling but having difficulty, the bike senses it and augments it. We've made the equivalent of that for human mental function."

The study is the first to show that:

• A specific human mental function linked to mental illness can be reliably enhanced using precisely targeted electrical stimulation;
• There are specific sub-parts of the internal capsule brain structure that are particularly effective for cognitive enhancement; and
• A closed-loop algorithm used as a controller was twice as effective than stimulating at random times.

Some of the patients had significant anxiety in addition to their epilepsy. When given the cognitive-enhancing stimulation, they reported that their anxiety got better, because they were more able to shift their thoughts away from their distress and focus on what they wanted. Widge says that this suggests this method could be used to treat patients with severe and medication-resistant anxiety, depression or other disorders.

"This could be a totally new approach in treating mental illness. Instead of trying to suppress symptoms, we could give patients a tool that lets them take control of their own minds," Widge said. "We could put them back in the driver's seat and let them feel a new sense of agency."

The research team is now preparing for clinical trials. Because the target for improving cognitive control is already approved by the Food and Drug Administration for deep brain stimulation, Widge says this research can be done with existing tools and devices -- once a trial is formally approved -- and the translation of this care to current medical practice could be rapid.

"The wonderful thing about these findings is that we are now in a position to conduct clinical trials to further demonstrate effectiveness and then hopefully move to helping treatment-resistant patients who are in desperate need for additional interventions to treat their illnesses," Dougherty said.

This work was supported by grants from the Defense Advanced Research Projects Agency (DARPA) under Cooperative Agreement Number W911NF-14-2-0045 issued by the Army Research Organization (ARO) contracting office in support of DARPA's SUBNETS Program, the National Institutes of Health, Ellison Foundation, Tiny Blue Dot Foundation, MGH Executive Council on Research, OneMind Institute and the MnDRIVE and Medical Discovery Team on Addiction initiatives at the University of Minnesota Medical School.

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Materials provided by University of Minnesota Medical School. Note: Content may be edited for style and length.

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Journal Reference:

1. Ishita Basu, Ali Yousefi, Britni Crocker, Rina Zelmann, Angelique C. Paulk, Noam Peled, Kristen K. Ellard, Daniel S. Weisholtz, G. Rees Cosgrove, Thilo Deckersbach, Uri T. Eden, Emad N. Eskandar, Darin D. Dougherty, Sydney S. Cash, Alik S. Widge. Closed-loop enhancement and neural decoding of cognitive control in humans. Nature Biomedical Engineering, 2021; DOI: 10.1038/s41551-021-00804-y

https://www.sciencedaily.com/releases/2021/11/211101141757.htm

In COVID-19 vaccinated people, those with prior infection likely to have more antibodies

 In what is believed to be one of the largest studies of its kind, Johns Hopkins Medicine researchers have shown that antibody levels against SARS-CoV-2 (the COVID-19 virus) stay more durable -- that is, remain higher over an extended period of time -- in people who were infected by the virus and then received protection from two doses of messenger RNA (mRNA) vaccine compared with those who only got immunized.

A research letter detailing the study of nearly 2,000 health care workers appears today in the Journal of the American Medical Association.

"This finding adds to our understanding of how immunity against SARS-CoV-2 works, and builds upon an earlier study by our team that showed the mRNA vaccines yielded a robust antibody response, even if a person did not develop significant symptoms following vaccination or did not have a prior SARS-CoV-2 infection," says study senior author Aaron Milstone, M.D., M.H.S., professor of pediatrics at the Johns Hopkins University School of Medicine and pediatric epidemiologist at Johns Hopkins Children's Center.

The two mRNA vaccines evaluated in the study introduce the body's immune system to S1, a protein subunit that's a component of the spikes found on the surface of SARS-CoV-2. The spikes enable the virus to latch onto healthy cells and infect them. Immunoglobulin G antibodies, elicited by S1 from the vaccines stimulating the immune system, neutralize the virus particles, preventing infection by SARS-CoV-2, or at least, reducing the severity of the disease.

For their latest study, the researchers followed 1,960 Johns Hopkins Medicine health care workers who had received both doses of either the Pfizer/BioNTech or Moderna vaccines, including 73 people who had a positive SARS-CoV-2 polymerase chain reaction (PCR) test result before the first vaccine dose. The 73 were divided into two groups -- those who were infected at 90 days or closer to the first vaccine dose, and those whose exposure to the virus was more than 90 days before the initial shot.

After adjusting for vaccine type, age and sex, antibody levels were compared for those with and without prior SARS-CoV-2 infection at one, three and six months following the second vaccine dose. In addition, antibody levels were compared at one and three months following the second dose between the two groups with prior SARS-CoV-2 infection.

"We found that health care workers with prior SARS-CoV-2 infection followed by two doses of mRNA vaccine -- therefore, three independent exposures to the S1 spike protein -- developed higher antibody levels than those with vaccination alone," says study lead author Diana Zhong, M.D., an infectious diseases fellow at the Johns Hopkins University School of Medicine. "The relative differences were 14% higher at 1 month following the second vaccine dose, 19% at three months and 56% at six months."

Zhong adds that the study participants with a PCR-confirmed SARS-CoV-2 infection more than 90 days before their initial vaccination had adjusted antibody levels 9% (one month following the second vaccine dose) and 13% (three months following the second vaccine dose) higher than those who were exposed to the virus less than or equal to the 90-day mark.

"This suggests that a longer interval between infection and first vaccine dose may enhance the antibody response," says Milstone.

Milstone says further investigation is needed to determine whether increased post-vaccination durability in previously infected people is attributable to the number of exposures to the virus, the interval between exposures, or the interplay between natural or vaccine-derived immunity.

The study team at Johns Hopkins Medicine was co-led by Zhong and Shaoming Xiao. Along with them and Milstone, the team includes Amanda Debes, Emily Egbert, Patrizio Caturegli and Elizabeth Colantuoni.

This study was supported by National Institute of Allergy and Infectious Diseases/National Institutes of Health grants T32AI007291 and K24AI141580, along with contributions to the COVID-19 research funds of the Johns Hopkins University School of Medicine and the Johns Hopkins Health System.

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Story Source:

Materials provided by Johns Hopkins Medicine. Note: Content may be edited for style and length.

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Journal Reference:

1. Diana Zhong, Shaoming Xiao, Amanda K. Debes, Emily R. Egbert, Patrizio Caturegli, Elizabeth Colantuoni, Aaron M. Milstone. Durability of Antibody Levels After Vaccination With mRNA SARS-CoV-2 Vaccine in Individuals With or Without Prior Infection. JAMA, 2021; DOI: 10.1001/jama.2021.19996

https://www.sciencedaily.com/releases/2021/11/211101190841.htm

SARS-CoV-2 virus can infect inner ear

 Many Covid-19 patients have reported symptoms affecting the ears, including hearing loss and tinnitus. Dizziness and balance problems can also occur, suggesting that the SARS-CoV-2 virus may be able to infect the inner ear.

A new study from MIT and Massachusetts Eye and Ear provides evidence that the virus can indeed infect cells of the inner ear, including hair cells, which are critical for both hearing and balance. The researchers also found that the pattern of infection seen in human inner ear tissue is consistent with the symptoms seen in a study of 10 Covid-19 patients who reported a variety of ear-related symptoms.

The researchers used novel cellular models of the human inner ear that they developed, as well as hard-to-obtain adult human inner ear tissue, for their studies. The limited availability of such tissue has hindered previous studies of Covid-19 and other viruses that can cause hearing loss.

"Having the models is the first step, and this work opens a path now for working with not only SARS-CoV-2 but also other viruses that affect hearing," says Lee Gehrke, the Hermann L.F. von Helmholtz Professor in MIT's Institute for Medical Engineering and Science, who co-led the study.

Konstantina Stankovic, a former associate professor at Harvard Medical School and former chief of otology and neurotology at Massachusetts Eye and Ear, who is now the Bertarelli Foundation Professor and chair of the Department of Otolaryngology -- Head and Neck Surgery at Stanford University School of Medicine, co-led the study. Minjin Jeong, a former postdoc in Stankovic's laboratory at Harvard Medical School, who is now at Stanford Medical School, is the lead author of the paper, which appears today in Communications Medicine.

Models of ear infection

Before the Covid-19 pandemic began, Gehrke and Stankovic began working together on a project to develop cellular models to study infections of the human inner ear. Viruses such as cytomegalovirus, mumps virus, and hepatitis viruses can all cause deafness, but exactly how they do so is not well-understood.

In early 2020, after the SARS-CoV-2 virus emerged, the researchers altered their plans. At Massachusetts Eye and Ear, Stankovic started to see patients who were experiencing hearing loss, tinnitus, and dizziness, who had tested positive for Covid-19. "It was very unclear at the time whether this was causally related or coincidental, because hearing loss and tinnitus are so common," she recalls.

She and Gehrke decided to use the model system they were working on to study infection of SARS-CoV-2. They created their cellular models by taking human skin cells and transforming them into induced pluripotent stem cells. Then, they were able to stimulate those cells to differentiate into several types of cells found in the inner ear: hair cells, supporting cells, nerve fibers, and Schwann cells, which insulate neurons.

These cells could be grown in a flat, two-dimensional layer or organized into three-dimensional organoids. In addition, the researchers were able to obtain samples of hard-to-obtain inner ear tissue from patients who were undergoing surgery for a disorder that causes severe attacks of vertigo or for a tumor that causes hearing loss and dizziness.

In both the human inner ear samples and the stem-cell-derived cellular models, the researchers found that certain types of cells -- hair cells and Schwann cells -- express the proteins that are needed for the SARS-CoV-2 virus to enter the cells. These proteins include the ACE2 receptor, which is found on cell surfaces, and two enzymes called furin and transmembrane protease serine 2, which help the virus to fuse with the host cell.

The researchers then showed that the virus can actually infect the inner ear, specifically the hair cells and, to a lesser degree, Schwann cells. They found that the other cell types in their models were not susceptible to SARS-CoV-2 infection.

The human hair cells that the researchers studied were vestibular hair cells, which are involved in sensing head motion and maintaining balance. Cochlear hair cells, which are involved in hearing, are much harder to obtain or generate in a cellular model. However, the researchers showed that cochlear hair cells from mice also have proteins that allow SARS-CoV-2 entry.

Viral connection

The pattern of infection that the researchers found in their tissue samples appears to correspond to the symptoms observed in a group of 10 Covid-19 patients who reported ear-related symptoms following their infection. Nine of these patients suffered from tinnitus, six experienced vertigo, and all experienced mild to profound hearing loss.

Damage to cochlear hair cells, which can cause hearing loss, is usually evaluated by measuring otoacoustic emissions -- sounds given off by sensory hair cells as they respond to auditory stimulation. Among the six Covid-19 patients in the study who underwent this testing, all had reduced or absent otoacoustic emissions.

While this study strongly suggests that Covid-19 can cause auditory and balance problems, the overall percentage of Covid-19 patients who have experienced ear-related issues is not known.

"Initially this was because routine testing was not readily available for patients who were diagnosed with Covid, and also, when patients were having more life-threatening complications, they weren't paying much attention to whether their hearing was reduced or whether they had tinnitus," Stankovic says. "We still don't know what the incidence is, but our findings really call for increased attention to audiovestibular symptoms in people with Covid exposure."

Possible routes for the virus to enter the ears include the Eustachian tube, which connects the nose to the middle ear. The virus may also be able to escape from the nose through small openings surrounding the olfactory nerves, Stankovic says. That would allow it to enter the brain space and infect cranial nerves, including the one that connects to the inner ear.

The researchers now hope to use their human cellular models to test possible treatments for the inner ear infections caused by SARS-CoV-2 and other viruses.

The research was funded by the National Institutes of Health, the Remondi Foundation, the Nancy Sayles Day Foundation, and the Barnes Foundation.

Story Source:

Materials provided by Massachusetts Institute of Technology. Original written by Anne Trafton. Note: Content may be edited for style and length.

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Journal Reference:

1. Minjin Jeong, Karen E. Ocwieja, Dongjun Han, P. Ashley Wackym, Yichen Zhang, Alyssa Brown, Cynthia Moncada, Andrea Vambutas, Theodore Kanne, Rachel Crain, Noah Siegel, Valerie Leger, Felipe Santos, D. Bradley Welling, Lee Gehrke, Konstantina M. Stankovic. Direct SARS-CoV-2 infection of the human inner ear may underlie COVID-19-associated audiovestibular dysfunction. Communications Medicine, 2021; 1 (1) DOI: 10.1038/s43856-021-00044-w

https://www.sciencedaily.com/releases/2021/10/211029074929.htm

Noninvasive imaging strategy detects dangerous blood clots in the body

 Atrial fibrillation -- an irregular and often rapid heart rate -- is a common condition that can cause clots to form in the heart that may then dislodge and flow to the brain, potentially leading to a stroke. The standard way to detect these clots requires patients to be sedated and to have a fairly large tube inserted down the throat and esophagus for a transesophageal ultrasound. Investigators at Massachusetts General Hospital (MGH) have now developed and tested a targeted contrast agent to detect and image these clots noninvasively. They verified the potential of this strategy in a study published in JACC: Cardiovascular Imaging.

The agent has a strong affinity for fibrin, a component of blood clots, and is detected with a radioactive copper tag. "The idea behind the technology is that the agent will find and bind to blood clots anywhere in the body -- not just in the heart -- and make the clots detectable like a bright star in the night sky," says senior author David Sosnovik, MD, FACC, director of the Program in Cardiovascular Imaging within MGH's Martinos Center for Biomedical Imaging and an associate professor of Medicine at Harvard Medical School. "In some ways this is analogous to doing a smart search with a search engine such as Google, where the search terms one uses guide the search. We inject the agent into a small peripheral vein and it circulates throughout the human body on its search for clots." If it doesn't find any clots, then it's rapidly excreted from the body; however, if it finds a clot and binds to it, clinicians can detect it with an imaging technique known as positron emission tomography.

Sosnovik and his colleagues first examined how the agent reacts (specifically, its metabolism and pharmacokinetics) in eight healthy volunteers. After injection, the agent was initially stable within the body and then was cleared from tissues within several hours, suggesting that it was safe. Next, the team administered the agent to patients with atrial fibrillation, some with clots in the heart and some without. Imaging tests of the heart revealed bright signals within the clots that were not seen in patients without clots.

"Obviously much more work and many more studies will need to be done before this changes routine clinical practice, but this first-in-human study is an important step," says Sosnovik. "Importantly, this smart or molecularly targeted agent can be used to detect clots anywhere in the body."

Sosnovik stressed that the multidisciplinary nature of this project was critical to its success, with vital roles played by diverse scientists, including Peter Caravan, PhD, who invented and developed the study's agent and is the co-director of MGH's Institute for Innovation in Imaging. "This probe was invented and optimized in my laboratory by a dedicated team of chemists and biologists through the support of the National Heart Lung and Blood Institute of the National Institutes of Health," says Caravan. "It is extremely gratifying to see these years of effort come to fruition with a fibrin-specific PET probe with the potential to make a real impact on human health."

Others playing a major role in the study included David Izquierdo-Garcia, PhD, an assistant in Biomedical Engineering at MGH, and Ciprian Catana, MD, PhD, director of Integrated MR-PET Imaging at MGH's Martinos Center for Biomedical Imaging. Izquierdo-Garcia, the lead author on the paper, and Catana both stressed the innovative nature of the imaging platform used in the study. "Not only did we use a novel molecular imaging probe in humans for the first time, but also, this is one of the first studies to fully explore the synergies and advantages of integrated PET-MRI scanners," says Izquierdo-Garcia.

"It is a privilege to work at the Martinos Center for Biomedical Imaging and be part of multidisciplinary teams that collaborate to develop and apply cutting-edge imaging technologies," adds Catana. "We were the first site in the U.S. to install a fully integrated PET-MRI scanner and have played a major role in the advancement and clinical translation of this technology."

Additional co-authors include Pauline Désogère, PhD, Anne L. Philip, MPH, Choukri Mekkaoui, PhD, Rory B. Weiner, MD, Onofrio A. Catalano, MD, Yin-Ching Iris Chen, PhD, Doreen DeFaria Yeh, MD, and Moussa Mansour, MD.

Funding for the study was provided by the National Institutes of Health.

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Story Source:

Materials provided by Massachusetts General Hospital. Note: Content may be edited for style and length.

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Journal Reference:

1. David Izquierdo-Garcia, Pauline Désogère, Anne L. Philip, Choukri Mekkaoui, Rory B. Weiner, Onofrio A. Catalano, Yin-Ching Iris Chen, Doreen DeFaria Yeh, Moussa Mansour, Ciprian Catana, Peter Caravan, David E. Sosnovik. Detection and Characterization of Thrombosis in Humans Using Fibrin-Targeted Positron Emission Tomography and Magnetic Resonance. JACC: Cardiovascular Imaging, 2021; DOI: 10.1016/j.jcmg.2021.08.009

https://www.sciencedaily.com/releases/2021/11/211101105402.htm

Children, adults equally vulnerable to co infection, but children less likely to become sick

 New research addresses the misconception that children are less susceptible to infection with the new coronavirus. According to a recent report in JAMA Pediatrics, children and adults have similar risks of becoming infected with SARS-CoV-2, but a much larger proportion of infected children do not show symptoms of COVID-19. When one household member is infected, there is a 52% chance they will transmit it to at least one other person with whom they live.

The findings are based on the Coronavirus Household Evaluation and Respiratory Testing (C-HEaRT) study led by the Centers for Disease Control and Prevention (CDC) in collaboration with investigators at University of Utah Health, Columbia University, Marshfield Virology Laboratory, and Abt Associates.

"Often, it seemed like children weren't sick because they didn't have any symptoms," says Christina Porucznik, Ph.D., professor of public health at U of U Health, who led investigation of 189 families in Utah. "But some were actually infected, and they could still spread COVID-19."

Early in the pandemic, reports indicated that children accounted for the minority of COVID-19 cases. However, the observation was not able to distinguish between two scenarios. One was that children were less susceptible to infection. Another was that reported case rates in children were artificially low because they did not show symptoms, and therefore were not tested.

To better understand infection dynamics, the C-HEaRT study followed 310 households with one or more children aged 0 to 17 years in Utah and New York City. More than 1,236 study participants submitted samples for weekly molecular testing (PCR) for SARS-CoV-2 infections and completed weekly questionnaires about symptoms. On average, each person was observed for 17 weeks, and the report included a total of 21,465 person-weeks of surveillance time. The results were from September 2020 through April 2021, before the Delta variant emerged in the U.S.

The study showed that:

• Children and adults 18 years and older had similar rates of infection.
• Children in different age groups (birth to 4 years; 5 to 11 years; 12 to 17 years) also had similar rates of infection. Infection rates in each group were between 4.4 to 6.3/1,000 person-weeks.
• About half of the cases in children were symptomatic, compared with 88% of adult cases.
• In households with one or more infected individuals, the overall average household infection risk was 52%.
• The mean household infection risk was 40% in Utah and 80% in New York City.

More research will need to be done to investigate whether differences in housing density, the timing of emergence of the Delta variant, or other factors contributed to differences in household transmission rates in Utah and New York. Additionally, infection rates and household infection risk may be higher in the general population since study participants could be more likely to carry out COVID-19 prevention behaviors.

This study's results highlight that many infections in children go undetected, underscoring the need for surveillance testing and for children to continue public health safety measures to protect the people around them, Porucznik says. "We know that until kids can be vaccinated, it's still important for them to wear masks when they're in groups and to keep them apart," she says. "And most of all, when they are sick, keep them home."

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Incidence rates of SARS-CoV-2 similar for children, adults

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More information: Fatimah S. Dawood et al, Incidence Rates, Household Infection Risk, and Clinical Characteristics of SARS-CoV-2 Infection Among Children and Adults in Utah and New York City, New York, JAMA Pediatrics (2021). DOI: 10.1001/jamapediatrics.2021.4217

https://medicalxpress.com/news/2021-11-children-adults-equally-vulnerable-coronavirus.html

Treatments for Alzheimer's sitting on pharmacy shelves for decades?

 Two drugs approved decades ago not only counteract brain damage caused by Alzheimer's disease in animal models, the same therapeutic combination may also improve cognition.

Sounds like a slam dunk in terms of a cure—but not yet. Researchers currently are concentrating on animal studies amid implications that remain explosive: If a surprising drug combination continues to destroy a key feature of the disease, then an effective treatment for Alzheimer's may have been hiding for decades in plain sight.

A promising series of early studies is highlighting two well known medicine cabinet standbys—gemfibrosil, an old-school cholesterol-lowering drug, and retinoic acid, a vitamin A derivative. Gemfibrosil, is sold as Lopid and while it's still used, it is not widely prescribed. Doctors now prefer to prescribe statins to lower cholesterol. Retinoic acid has been used in various formulations to treat everything from acne to psoriasis to cancer.

The two drugs are being studied for their robust impact on the brain and a potential new role that could one day thrust them into fighting what is now an incurable brain disease. Both medications have an uncanny capability to zero in on the brain's astrocytes, cells that originally got their name because they look like stars. But astrocytes are intimately involved in a key process that progressively—and insidiously—destroys the brain.

Researchers at Rush University Medical Center in Chicago have found that astrocytes may be responsible for the accumulation of amyloid beta (Aβ), the gooey plaque that damages neurons. As a result, these star-like cells aid in the cascade of deleterious events that rob people of their sense of self, their memories, and ultimately steals their lives.

The team of medical investigators also has discovered that gemfibrozil and retinoic acid, when used in combination, force astrocytes to reverse their destructiveness, and instead reduce amyloid beta in the brain—improving cognitive function. The findings suggest that, perhaps in the not-too-distant future, these drugs can be repurposed to coax astrocytes into a beneficial role, serving as Aβ "clearing machines," eliminating the accumulation of plaques and preventing Alzheimer's from unraveling the brain.

"From a therapeutic angle, these results suggest that low-dose [gemfibrozil and retinoic acid] might be repurposed as a treatment for reducing the plaque burden and improving cognition," wrote Dr. Sumita Raha, first author of a paper published in Science Translational Medicine.

"Astrocytes are a type of glial cell that are implicated in the buildup of amyloid beta in Alzheimer's disease," Raha added about the drug duo. Along with her Rush Medical Center colleagues, the team is proposing that rather than being intricately involved in the promotion of Aβ accumulation "astrocytes could be induced to take up and destroy Aβ fibrils with an orally ingested combination of drugs that are approved for other indications."

Astrocytes studied in cell cultures and in Alzheimer's mouse models were stimulated by retinoic acid to phagocytose—destroy Aβ—through the activation of the low-density lipoprotein cholesterol receptor and triggered to subsequently degrade Aβ in lysosomes by the cholesterol-lowering drug gemfibrozil.

Earlier research led by Raha's colleague, Dr. Kalipada Pahan, also of Rush, and an author of the current study, found that a combination of gemfibrozil and retinoic acid accelerated the formation of lysosomes in mouse brain cells. Lysosomes are the organelles that contain digestive enzymes and are involved in the breakdown of excess or worn-out cell parts. The word organelle means "little organ," a term for the components in cells with specialized functions, such as the Golgi apparatus or mitochondria.

Raha, Pahan, and colleagues discovered that gemfibrosil and retinoic acid also caused mouse astrocytes to take in more amyloid beta from outside of the cell. Their experiments revealed that the drug combination activated a receptor called PPARα, which encouraged astrocytes to destroy the mind-damaging amyloid, the cause of plaques. PPARα stands for peroxisome proliferator-activated receptor-alpha. PPARα is a transcriptional factor that regulates the expression of genes involved in fatty acid oxidation and is also a major regulator of energy homeostasis. PPARα is critical in the elimination of amyloid beta, Aβ.

Gemfibrosil is an old drug, first patented in the 1968 as a cholesterol reducer. Retinoic-acid-based drugs are even older. For example, Tretinoin, a retinoic acid medication, was patented in 1957. If the gemfibrosil/retinoic acid drug combination ultimately works in humans, then the Chicago-based team will have ushered into use a new treatment made up of two very old medications.

Although the team at Rush University Medical Center is well into its pursuit of the two-drug combination, it's not yet known when the experiments might advance to a full-blown human clinical trial. Yet, along with identifying a potential two-drug approach to Alzheimer's disease, the Chicago experiments also have added to the scholarship about the biology of astrocytes in the brain.

Astrocytes, or astroglia, as they are also known, are a type of glial cell, and they dramatically outnumber neurons. Some estimates suggest there is a fivefold difference between the two types of brain cells favoring astrocytes. While neurons are the cells of all higher functions, such as learning and memory, astrocytes play a major role regulating increases in intracellular calcium. Upping intracellular calcium is required to maintain astrocyte-to-astrocyte and astrocyte-to-neuron communication, studies have shown.

Yet as the gemfibrosil/retinoic acid combination evolves as a potential Alzheimer's therapy, the larger story about drugs to treat Alzheimer's has been a tale marred by setbacks and disappointments for decades. The most recent involves questions that arose following the approval in June of Biogen's Aduhelm, a medication that carries a breathtakingly high price tag—$56,000 a year in the United States.

Medical experts voiced concern about studies leading to the drug's approval. Taken as a whole, the research demonstrated mixed results. But the drug, which is administered as an infusion, was fast-tracked through the U.S. Food and Drug Administration's authorization process.

Worse, Aduhelm is one of slightly more than a half dozen drugs approved in a quarter century to treat Alzheimer's, a disease that is rapidly becoming one of the largest health crises on the planet, according to the World Health Organization.

Currently, an estimated 55 million people globally have Alzheimer's disease, and that number could explode to more than 152 million worldwide by 2050 unless a cure is found.

In Chicago, meanwhile, the team at Rush University Medical Center has found a novel way to control Alzheimer's progression in mouse models using drugs off the shelf. "We found that the same combination of gemfibrosil and retinoic acid enhanced the uptake of Aβ from the extracellular space and its subsequent degradation in astrocytes through a PPARα-dependent pathway," Raha asserted. "These findings uncover a new function of PPARα in stimulating astroglial uptake and degradation of Aβ and suggest possible repurposing of gemfibrosil-retinoic acid combination therapy for Alzheimer's disease."

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Cholesterol drives Alzheimer's plaque formation, study finds

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More information: Sumita Raha et al, Activation of PPARα enhances astroglial uptake and degradation of β-amyloid, Science Translational Medicine (2021). DOI: 10.1126/scisignal.abg4747

https://medicalxpress.com/news/2021-11-treatment-alzheimer-pharmacy-shelves-decades.html

Despite strong quarter, some wonder how long Gilead can rely on coronavirus drug

 Veklury, the antiviral drug for COVID-19, blew past Wall Street expectations in the third quarter, lifting what would have otherwise been a weak earnings season for its developer, Gilead.

During the three-month period, 2 million people received Veklury or a licensed generic version of it, according to Gilead. That use translated to almost $2 billion in sales, nearly triple what analysts had forecasted.

Yet some wonder how long Veklury can make up for the rest of Gilead’s business, which fell 3% over the same timeframe. More people worldwide are getting vaccinated, while coronavirus cases are on the decline following a major surge due to the delta variant.

Competition is also nearing, as Merck & Co. and others advance oral antiviral drugs that are generally considered more convenient than Veklury, which is used in hospitalized patients and given via an intravenous infusion.

Veklury is "not likely to be a sustainable franchise in our view given our expectations for COVID waning and small molecule antiviral availability," wrote Brian Abrahams, an analyst at RBC Capital Markets, in a note to clients.

Still, Abrahams and his team believe Veklury’s strong sales provide Gilead with "a highly effective hedge against pandemic headwinds to their other franchises." The company recorded $7.4 billion total product sales in the quarter, up 13% from the same period a year prior.

As one of the earliest approved treatments for COVID-19, Veklury has been a valuable asset to both doctors and Gilead. Over 60% of patients hospitalized with the disease in the U.S. receive Veklury, according to the company. On a Thursday call with investors, executives amended their full-year revenue outlook for the drug, increasing it from the old range of $2.7 billion to $3.1 billion to a new one of $4.5 billion to $4.8 billion.

Despite that change, leadership noted how Veklury’s performance is tied to patient hospitalizations. So if case numbers go down, sales are likely to follow.

"After the wave of infections and hospitalizations in recent months, we believe we have moved past the peak of the pandemic for the year," said Andrew Dickinson, the company’s chief financial officer.

"We continue to expect that Veklury will play an important role in the treatment of patients with COVID -19 globally," he added. "However, assuming we do not experience another surge, we expect Veklury revenue to step down significantly in the fourth quarter."

Veklury may run into additional obstacles from Merck, which announced this month that an antiviral pill it’s been developing with partner Ridgeback Biotherapeutics dramatically reduced the number of hospitalizations from COVID-19, compared to a placebo, in a clinical trial.

More specifically, the pill lowered the risk of hospitalization or death by about 50% in patients with mild or moderate disease. Merck is now trying to secure an emergency authorization in the U.S. "as soon as possible," and, on the company’s own earnings call Thursday, executives forecasted between $5 billion and $7 billion in sales of the drug through the end of 2022.

Gilead has been working on oral antivirals too, though they aren’t as far along as Merck’s or other experimental treatments from Pfizer and Atea Pharmaceuticals. The company’s chief medical officer, Merdad Parsay, said data updates will be provided "as those molecules begin to mature," adding that one of the main aims is to provide alternative treatment options, especially in the outpatient setting.

Outside of COVID-19, Gilead is hoping to move the needle in cancer treatment after spending $27 billion last year on deals meant to establish it as a leader there. Among the assets it acquired are magrolimab, an experimental drug for blood cancers, and Trodelvy, an approved therapy for breast cancer.

Investors are now looking forward to data from key clinical trials testing those drugs, though they’ll have to wait a bit longer than expected. Gilead said Thursday that readouts from both trials have been pushed back to the first quarter of 2022.

The company’s cancer work has become a focal point — not only because of how much money it’s wagered, but also because of challenges to its core business of antiviral drugs. In HIV, for example, Gilead’s third quarter product sales were $4.2 billion, an 8% decline that reflected the loss of patent protection on the medicines Truvada and Atripla in the U.S.

"Success from any of the oncology programs or new indications could transform Gilead’s outlook by providing a real growth driver to their top line," wrote SVB Leerink analyst Geoffrey Porges in a note to clients.

https://www.biopharmadive.com/news/gilead-veklury-coronavirus-earnings-oncology-outlook/609160/