Turning brain cells on using the power of light

 University of Rochester researchers have demonstrated a noninvasive method using BL-OG, or bioluminescent optogenetics, that harnesses light to activate neurons in the brain. The ability to regulate brain activation could transform invasive procedures such as deep brain stimulation that are used to treat Parkinson's disease and other neurological conditions.

The advantage of this new technique is that it can create brain activation without the use of an implanted device in the brain to deliver physical light, according to Manuel Gomez-Ramirez, an assistant professor of brain and cognitive sciences and with the University's Del Monte Institute for Neuroscience, and the senior author of the study, which appears in the journal NeuroImage

"BL-OG is an ideal method for noninvasively teasing apart neural circuits in the brain," says Emily Murphy, the first author of the study and manager of the Haptics Lab, led by Gomez-Ramirez. "There are still so many things to learn about the structure and function of distinct brain areas and neuronal cell types that will help us understand how healthy brains function."

How to turn on a light -- without a switch

To turn on light in the brain, researchers need a few tools. The first one is optogenetics, an established research technique that uses light to activate or inactivate cells in the brain. The next tool is bioluminescence, the same chemical reaction that gives a firefly its glow, which provides the light optogenetics needs to work.

Combining these tools creates the material needed for BL-OG. But in order to work, BL-OG still needs something to "turn on" the light. The organic substance luciferin, when combined with bioluminescence, creates light that activates the optogenetics and modulates cellular response in the brain without an incision. Previous work by Gomez-Ramirez has shown that the chemical luciferin is harmless to the body.

The researchers in the Haptics Lab tested this combination. They put BL-OG into a pre-determined brain region in mice. They then injected luciferin through a vein in the animal's tail to activate the targeted cells in the brain. They found that BL-OG effects occur rapidly in the brain, but that these effects could be controlled by scaling the dosage of the luciferin in the animal.

'Fine-tuning' bioluminescent optogenetics

"The advantage of this technique is we can create brain activation without a cable. There is less risk for infection and other things to go awry because it is a noninvasive method," Gomez-Ramirez says. "If we want to standardize this technique in the lab, and potentially in the clinic, it is critical to map all the important parameters around using it. These latest findings allow us to now work on fine-tuning the desired effects of BL-OG based on need and requirements."

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Neuroscientists spark shelter-seeking response by reactivating memory circuit

 Using a sophisticated brain-imaging system, neuroscientists at Johns Hopkins Medicine say they have successfully reactivated a specific memory circuit in mice, causing them to seek out shelter when no shelter is actually present.

The researchers say the study, published Sept. 27 in Nature Neuroscience, advances understanding of how memories are structured in the mammalian brain. The findings could one day point to new ways of slowing down or preventing the memory loss that accompanies Alzheimer's and other neurodegenerative diseases.

Specifically, the team found that stimulating neurons in two areas of mouse brains -- the nucleus accumbens, also known as the brain's "pleasure center" responsible for relaying dopamine-dependent behaviors, and the dorsal periaqueductal gray (dPAG), responsible for defensive behavior -- reactivated a "spatial memory" and caused the mice to seek shelter.

"When we artificially reactivate those memory circuits in the brain, it triggers the mouse to do the same thing it did naturally, even without the fear stimuli that cause them to seek shelter to begin with," says senior author Hyungbae Kwon, Ph.D., associate professor of neuroscience at the Johns Hopkins University School of Medicine.

The scientists say they aimed to map out which areas of the brain are responsible for navigating one's surroundings, a high-level cognitive function among mammals, including humans. Thus, these experiments, which tested whether such cognitive brain functions can be replayed randomly, may have applications in understanding how other mammals behave, perceive and sense their environment.

In the new experiments, the researchers first allowed laboratory mice to explore their surroundings in a box with a shelter in the corner. The team placed a series of visual cues, including triangles, circles and stripes in different colors, to help the mice locate the shelter based on nearby landmarks. The mice acclimated to the area for seven minutes, entering and exiting the shelter.

Then, the researchers added a visual or auditory looming signal to spur them to seek shelter -- also forming a spatial memory relative to their location and the visual cues.

To selectively tag shelter memory neurons, the researchers used a light-activated gene-expression switching system called Cal-light, which Kwon developed in 2017. Once the scientists identified these neurons in the nucleus accumbens, they switched on expression of the genes associated with them, reactivating the shelter-seeking memory in mice while also activating neurons in the dPAG.

In turn, the mice sought out the area of the box where the shelter had once been, when neither the original threat nor the shelter were present.

To get to this point, the researchers first selectively activated neurons in the nucleus accumbens and then, separately, in the dPAG, to see whether switching on neurons in just one area of the brain would cause this behavior.

"Surprisingly, we found that the mice did not seek out shelter when we activated neurons in the nucleus accumbens alone," Kwon says. "Whereas switching on neurons in the dPAG caused the mice to react randomly, but did not guide them specifically to the area where they sought shelter before."

"The Cal-light system allowed us to selectively tag a specific function in the brain, helping us to map out memory on a cellular level," says Kwon.

Eventually, Kwon says this research could provide a foundation for reactivating or engineering memory circuits in people with Alzheimer's.

"If we understand the macro-level structure of memory, then we may be able to develop more effective strategies to prevent or slow down neurodegenerative diseases using this method," he says.

The researchers say they hope to understand brain-wide memory structure by selectively tagging and reactivating neurons with different functions in different areas of the brain that lead to other specific behaviors.

"Understanding how all of these memory circuits work together will help us understand brain function better," he says.

Other researchers involved in the study are Kanghoon Jung, Sarah Krüssel, Sooyeon Yoo, Benjamin Burke, Nicholas Schappaugh, Youngjin Choi and Seth Blackshaw of Johns Hopkins; Myungmo An of the Max Planck Florida Institute for Neuroscience; and Zirong Gu and Rui M. Costa of the Zuckerman Mind Brain Behavior Institute at Columbia University and the Allen Institute.

Funding for this work was provided by the Max Planck Florida Institute for Neuroscience, a National Alliance for Research on Schizophrenia and Depression Young Investigator Grant and National Institutes of Health Grants R01MH107460, 5U19NS104649, K99 NS119788, DK108230 and DP1MH119428.

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Study of monkey fossils found in cave sheds light on the animals' extinction centuries ago

 By studying rare fossils of jaws and other skull parts of a long-extinct Caribbean monkey, a team of researchers that includes a Johns Hopkins University School of Medicine professor says it has uncovered new evidence documenting the anatomy and ecology of an extinct primate once found on Hispaniola -- the Caribbean island on which Haiti and the Dominican Republic are located.

The fossils were found in flooded caves in the Dominican Republic. The cache, including seven skulls, five mandibles (jawbones) and dozens of other skeleton parts, makes the fossil site, Cueva Macho, the richest one yet for primate fossils on Hispaniola, the researchers say.

The research was published Sept. 30 in the Journal of Human Evolution.

Evidence indicates that the monkey, Antillothrix bernensis, became extinct sometime during the last 10,000 years, says senior author Siobhán Cooke, Ph.D., associate professor of functional anatomy and evolution at the Johns Hopkins University School of Medicine.

"These fossils help us to better understand the anatomy of Antillothrix, which can help us identify ecological factors that might have predisposed it to extinction," Cooke says. "These data can ultimately guide policy for preserving the remaining mammalian diversity on the Caribbean islands and elsewhere."

Cooke was part of the team that identified the first skull of a juvenile Hispaniolan monkey from a flooded cave in the Dominican Republic in 2009. Since then, divers from the Dominican Republic Speleological Society, in collaboration with Juan Almonte-Milán, curator at the Museo Nacional de Historia Natural "Prof. Eugenio de Jesús Marcano," continued to search similar wet caves nearby, leading to discovery of the most recent set of fossils in 2018.

The opportunity to study this many fossils of South American and Caribbean monkeys is rare, Cooke says. Only one other species of extinct South American monkey, Homunculus patagonicus (a long extinct animal lived in Patagonia), is known for a comparably large sample of fossils.

"The number and quality of the Antillothrix crania outlined in this paper allow us to describe the skull completely and understand variation between individuals," Cooke says. "This can tell us about the diet and social systems of these animals."

Using virtual three-dimensional models the researchers made of the fossils, which are housed in the National Museum of Natural History in Santo Domingo, Dominican Republic, scientists concluded that male and female Hispaniola monkeys were monomorphic (they were about the same size as one another) and weighed up to five pounds.

"This indicates that there was little competition for mates among males," says Cooke. "They may have lived in small family groups consisting of a female, male and dependent offspring."Looking at the fossils' rounded teeth and relatively small canines, researchers also say the extinct monkeys' diet consisted mainly of fruit.

Antillothrix may have a modern relative. At just over two pounds, the South American Titi monkey, with its short canine teeth, offers the closest glimpse at what the Hispaniola monkey may have looked like in the wild.

But how did seven or eight Hispaniola monkeys end up at the bottom of a cave approximately 10,000 years ago?

Cooke says it could be a matter of bad luck -- though it seems unlikely that up to eight tree-dwelling primates would fall into a cave.

Evidence of injuries in the monkeys' jaw fossils provided the researchers with another potential answer: an owl predator.

One Antillothrix skull includes only the front teeth, but not the ramus, or the back portion of the jaw. Other skulls are missing small pieces or large chunks of their jaws.

"When owls feed, they will sometimes preferentially consume the masseter, a major muscle attached to the jaw, and these injuries are consistent with that," Cooke says. "It could be possible that a now extinct owl, which would have been quite large, caught these monkeys and brought them into the cave where it was living -- rather than the monkeys falling in at random. Owl feeding deposits are not uncommon in Hispaniolan caves."

The researchers next intend to take a closer look at other Antillothrix bones, including limb bones, ribs and vertebrae.

"Learning more about these animals provides a window into the past and helps us better appreciate the current and past biological diversity of the Dominican Republic and Haiti," Cooke says.

She notes that these countries once had not only monkeys and giant owls but also giant sloths, large rodents and several species of insect-eating shrews, crocodiles and tortoises.In addition to Cooke and Milán, other researchers involved in the study are first author Lauren Halenar-Price of Farmingdale State College, Zachary Klukkert of Oklahoma State University, Phillip Lehman of the Dominican Republic Speleological Society and Zana Sims, a postdoctoral fellow at the University of Southern California who conducted work on this study as a Johns Hopkins doctoral student.

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The true global impact of species-loss caused by humans is far greater than expected

 The extinction of hundreds of bird species caused by humans over the last 130,000 years has has led to substantial reductions in avian functional diversity -- a measure of the range of different roles and functions that birds undertake within the environment -

and resulted in the loss of approximately 3 billion years of unique evolutionary history, according to a new study published today in Science.

Whilst humans have been driving a global erosion of species richness for millennia, the consequences of past extinctions for other dimensions of biodiversity are poorly known. New research lead by the University of Birmingham highlights the severe consequences of the ongoing biodiversity crisis and the urgent need to identify the ecological functions being lost through extinction.

From the well-documented Dodo to the recent Kauaʻi ʻōʻō songbird declared extinct in 2023, scientists currently have evidence of at least 600 bird species having become extinct as a result of humans since the Late Pleistocene when modern humans started to spread throughout the world. Using the most comprehensive dataset to date of all known bird extinctions during the Late Pleistocene and Holocene, the paper 'The global loss of avian functional and phylogenetic diversity from anthropogenic extinctions' looks beyond the number of extinctions to the wider implications on the planet.

Lead author Dr Tom Matthews from the University of Birmingham explained: "The sheer number of bird species that have become extinct is of course a big part of the extinction crisis but what we also need to focus on is that every species has a job or function within the environment and therefore plays a really important role in its ecosystem. Some birds control pests by eating insects, scavenger birds recycle dead matter, others eat fruit and disperse the seeds enabling more plants and trees to grow, and some, like hummingbirds, are very important pollinators. When those species die out, the important role that they play (the functional diversity) dies with them.

"In addition to functional diversity each species also carries a certain amount of evolutionary history, therefore when that species becomes extinct, it's basically like chopping off a branch of the tree of life and all of that associated phylogenetic diversity is also lost."

The research found that the scale of anthropologenic bird extinctions to date has resulted in a loss of approximately 3 billion years of unique evolutionary history, and 7% of global avian functional diversity -- a significantly larger amount than expected based on the number of extinctions. Given the wide range of important ecological roles performed by birds, the loss of avian functional diversity in particular will likely have had far-reaching implications. These post-extinction aftershocks include reduced flower pollination, reduced seed dispersal, the breakdown of top-down control of insect populations -- including many pests and disease vectors -- as well as increased disease outbreaks due to reduced consumption of carrion. In addition, the downsizing of the global avifauna documented in the research will likely affect the ability of many plant species to track present and future climate change.

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Ant agriculture began 66 million years ago in the aftermath of the asteroid that doomed the dinosaurs

 When humans began farming crops thousands of years ago, agriculture had already been around for millions of years. In fact, several animal lineages have been growing their own food since long before humans evolved as a species.

According to a new study, colonies of ants began farming fungi when an asteroid struck Earth 66 million years ago. This impact caused a global mass extinction but also created ideal conditions for fungi to thrive. Innovative ants began cultivating the fungi, creating an evolutionary partnership that became even more tightly intertwined 27 million years ago and continues to this day.In a paper published today, Oct. 3, in the journal Science, scientists at the Smithsonian's National Museum of Natural History analyzed genetic data from hundreds of species of fungi and ants to craft detailed evolutionary trees. Comparing these trees allowed the researchers to create an evolutionary timeline of ant agriculture and pinpoint when ants first began cultivating fungi."Ants have been practicing agriculture and fungus farming for much longer than humans have existed," said entomologist Ted Schultz, the museum's curator of ants and the lead author of the new paper. "We could probably learn something from the agricultural success of these ants over the past 66 million years."Nearly 250 different species of ants in the Americas and Caribbean farm fungi. Researchers organize these ants into four agricultural systems based on their cultivation strategies. Leafcutter ants are among those that practice the most advanced strategy, known as higher agriculture. These ants harvest bits of fresh vegetation to provide sustenance for their fungi, which in turn grow food for the ants called gongylidia. This food helps fuel complex colonies of leaf cutter ants that can number in the millions.Schultz has spent 35 years studying the evolutionary relationship between ants and fungi. He has conducted more than 30 expeditions to locales in Central and South America to observe this interaction in the wild and has reared colonies of leafcutter and other fungus-farming ants in his lab at the museum. Over the years, Schultz and colleagues have collected thousands of genetic samples of ants and fungi from throughout the tropics.This stockpile of samples was crucial to the new paper."To really detect patterns and reconstruct how this association has evolved through time, you need lots of samples of ants and their fungal cultivars," Schultz said.The team used the samples to sequence genetic data for 475 different species of fungi (288 of which are cultivated by ants) and 276 different species of ants (208 of which cultivate fungi) -- the largest genetic dataset of fungus-farming ants ever assembled. This allowed the researchers to create evolutionary trees of the two groups. Comparing wild fungal species with their cultivated relatives helped the researchers determine when ants began utilizing certain fungi.

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2-billion-year-old rock home to living microbes

 Pockets of microbes have been found living within a sealed fracture in 2-billion-year-old rock. The rock was excavated from the Bushveld Igneous Complex in South Africa, an area known for its rich ore deposits. This is the oldest example of living microbes being found within ancient rock so far discovered. The team involved in the study built on its previous work to perfect a technique involving three types of imaging -- infrared spectroscopy, electron microscopy and fluorescent microscopy -- to confirm that the microbes were indigenous to the ancient core sample and not caused by contamination during the retrieval and study process. Research on these microbes could help us better understand the very early evolution of life, as well as the search for extraterrestrial life in similarly aged rock samples brought back from Mars.

Deep in the earth lies something ancient and alive. Colonies of microbes live in rocks far beneath the surface, somehow managing to survive for thousands, even millions of years. These tiny, resilient organisms appear to live life at a slower pace, scarcely evolving over geological time spans and so offering us a chance to peek back in time. Now, researchers have found living microbes in a rock sample dated to be 2 billion years old.

"We didn't know if 2-billion-year-old rocks were habitable. Until now, the oldest geological layer in which living microorganisms had been found was a 100-million-year-old deposit beneath the ocean floor, so this is a very exciting discovery. By studying the DNA and genomes of microbes like these, we may be able to understand the evolution of very early life on Earth,"said Yohey Suzuki, lead author and associate professor from the Graduate School of Science at the University of Tokyo.

The rock sample was taken from the Bushveld Igneous Complex (BIC), a rocky intrusion in northeastern South Africa which formed when magma slowly cooled below the Earth's surface. The BIC covers an area of approximately 66,000 square kilometers (roughly the size of Ireland), varies in thickness by up to 9 km, and contains some of the richest ore deposits on Earth including about 70% of the world's mined platinum.

Due to the way it was formed and minimal deformation or change occurring to it since then, the BIC is believed to have provided a stable habitat for ancient microbial life to continue until today.

With the aid of the International Continental Scientific Drilling Program, a nonprofit organization that funds exploration at geological sites, the team obtained a 30-centimeter-long rock core sample from about 15 meters belowground. The rock was cut into thin slices and analyzed, which is when the team discovered living microbial cells densely packed into cracks in the rock. Any gaps near these cracks were clogged with clay, making it impossible for the organisms to leave or for other things to enter.

The team built on a technique they had previously developed to confirm that the microbes were native to the rock sample, and not due to contamination during the drilling or examination process. By staining the DNA of the microbial cells and using infrared spectroscopy to look at the proteins in the microbes and surrounding clay, the researchers could confirm that the microorganisms were both alive and not contaminated.

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Pterosaurs needed feet on the ground to become giants

 The evolutionary adaptations that allowed ancient pterosaurs to grow to enormous sizes have been pinpointed for the first time by palaeontologists in the Centre for Palaeobiology and Biosphere Evolution at the University of Leicester.

The discovery revealed a surprising twist -- the ability to walk efficiently on the ground played a crucial role in determining how large the biggest flying animals could grow, with some reaching wingspans of up to 10 metres.

In a new study published in Current Biology, a team of researchers led by the University of Leicester examined the hands and feet of pterosaurs from around the world and across their entire evolutionary history.

They uncovered a surprising level of variation similar to that seen across living birds. This discovery indicates that pterosaurs were not confined to a life in the skies but were also adapted to a wide range of terrestrial lifestyles, from tree-climbing in early species to more ground-based lifestyles in later ones.

The evolution of pterosaurs, the first true flying vertebrates, showcases some of the most remarkable adaptations in the history of life. While these creatures are best known for their ability to soar through the prehistoric skies of the Mesozoic era (252-66 million years ago), a new study has revealed a surprisingly high degree of diversity in where and how pterosaurs lived when they were not airborne.

Lead author Robert Smyth, a doctoral researcher in the in the Centre for Palaeobiology and Biosphere Evolution (School of Geography, Geology and the Environment at the University of Leicester), explained: "Early pterosaurs were highly specialised for climbing, with extreme modifications in their hands and feet, similar to those found in climbing lizards and birds like woodpeckers today. Clinging to vertical surfaces by your fingertips for long periods is hard work -- it's a lot easier for small, lightweight animals."

These early pterosaurs were likely restricted to arboreal habitats and consequently, small body sizes. However, a major evolutionary shift occurred during the Middle Jurassic period, when pterosaur hands and feet changed to look much more like those of ground-dwelling animals. These adaptations to ground-based movement opened up new ecological opportunities, leading to a wide variety of feeding strategies. Freedom from the size constraints imposed by vertical living allowed some pterosaurs to evolve to gigantic size with wingspans of up to 10 metres.

Co-author Dr David Unwin from the University of Leicester added: "In early pterosaurs the hind limbs were connected by a flight membrane which severely impeded walking and running. In later, more advanced pterosaurs, this membrane became separated along the midline, allowing each hind limb to move independently. This was a key innovation that, combined with changes to their hands and feet, greatly improved pterosaurs' mobility on the ground.

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Lecanemab: Why a new Alzheimer's drug has drawn praise and some concern

 With the number of Alzheimer’s cases increasing, the medical community needs treatments for this disease now more than ever. One experimental drug, lecanemab, has been hailed by some experts as the treatment we have all been waiting for. But just how much hope should we place in lecanemab? In this Special Feature, we ask Alzheimer’s disease experts to explain how exactly lecanemab works, side effects, and what the most realistic perspective on this drug is.

More than 55 million peopleTrusted Source around the world have dementia — a group of diseases that affect the way a person’s brain works. Between 60% and 80% of all dementia cases are Alzheimer’s disease.

Researchers further predict the number of people living with dementia will increase to almost 153 millionTrusted Source by 2050.

There is currently no cure for Alzheimer’s disease. However, there are a few Food and Drug Administration (FDA)-approved drugs for Alzheimer’s disease aimed at either slowing disease progression or helping reduce some symptoms of the condition, with more potential treatments — such as lecanemab — currently in research and development.

On January 6, the U.S. Food and Drug Administration (FDA) grantedTrusted Source accelerated approval for the use of lecanemab in treating people with early Alzheimer’s disease.

“Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones,” said Dr. Billy Dunn, the director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, in a press statement. “This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease.”

The approval came amid reports that three deaths have occurred during the drug’s clinical trials.

What is lecanemab?

Lecanemab is an investigational drug for the treatment of Alzheimer’s disease developed jointly by pharmaceutical companies Eisai and Biogen.

Lecanemab is a type of drug called a monoclonal antibodyTrusted Source. The human body naturally produces antibodies to defend itself from infection.

Scientists create a monoclonal antibody in a laboratory setting to attack a specific foreign material in the body, known as an antigenTrusted Source. When introduced into a person’s body, the monoclonal antibody stimulates the immune system to destroy the targeted antigen.

Doctors have recently used monoclonal antibodies to treat COVID-19 and certain cancersTrusted Source.

Lecanemab is directed against amyloid proteinTrusted Source, Dr. Christopher H. van Dyck, professor of psychiatry, neurology, and neuroscience, director of the Alzheimer’s Disease Research Unit, director of the Yale Alzheimer’s Disease Research Center, and director of the Division of Aging and Geriatric Psychiatry and Yale School of Medicine, explained for Medical News Today.

Dr. van Dyck is also the lead author of a study in the New England Journal of Medicine reporting on Eisai’s Phase 3 confirmatory Clarity AD clinical trial of lecanemab.

“The hope is for it to interfere with Alzheimer’s disease pathogenesis and to slow the clinical progression of the disease,” he told MNT.

What is amyloid protein buildup?

Amyloid protein buildup in the brainTrusted Source is associated with Alzheimer’s disease.

According to Dr. Emer MacSweeney, CEO and medical director at Re:Cognition Health, and principal investigator for the Phase 3 confirmatory Clarity AD clinical trial of lecanemab, beta-amyloid protein that builds up in the brain in people with Alzheimer’s disease is ultimately toxic to certain brain cells, most experts seem to agree.

“Gradual destruction of these brain cells results in the development of the cognitive and other symptoms, which typically develop and progress, relentlessly, in individuals with Alzheimer’s disease, leading to severe dementia,” she explained.

Dr. Karen D. Sullivan, a board-certified neuropsychologist and owner of I CARE FOR YOUR BRAIN in Pinehurst, North Carolina, stated that what is exciting about this class of medications is they are the first disease-modifying drugs we have ever had for Alzheimer’s disease.

“What this means is that these medications actually remove amyloid beta deposits from the brain. “Everything we’ve had to date has only been able to offer mild symptom reduction and has done nothing to impact the severity or course of the disease.”

– Dr. Karen D. Sullivan

“There have been a few other medications within the category of monoclonal antibodies that have gotten provisional FDA approval, but have had disappointing showings in the end,” she continued.

“In a direct comparison with the anti-amyloid antibodies aducanumabTrusted Source and gantenerumabTrusted Source, lecanemab is reported to most robustly remove the amyloid plaques because it intervenes earlier in the pathological process that contributes to Alzheimer’s disease and with less side effects. The hope is that by clearing amyloid plaque from the brain we can restore some degree of function and prevent, or at least significantly slow down, decline,” Dr. Sullivan added.

How well does lecanemab work? 

In late November 2022, Eisai presented the full findings of its Phase 3 Clarity AD clinical trial for lecanemab at the 15th Clinical Trials on Alzheimer’s Disease (CTAD) conference.

During the clinical trial, about 1,800 adults ages 50 to 90 with early Alzheimer’s disease received either lecanemab or a placebo. Participants also received assessments of certain cognitive and functional skills both before the trial began, and 18 months later.

Finally, the participants undertook PET scans to check for the presence of amyloid in the brain.

At the 18-month follow-up, researchers reported people who took lecanemab slowed their cognitive decline by 27% compared to those who took the placebo.

“Results of the Clarity clinical trial also demonstrated lecanemab had beneficial effects on biomarkers for amyloid, tauTrusted Source, and other pathophysiology measures,” Dr. MacSweeney said. “So lecanemab not only directly removed amyloid plaques but also had downstream effects on tau pathology.”

‘Clinically meaningful’ results

Upon hearing the presented data at the CTAD conference, Dr. Ronald Petersen, a neurologist and director of the Mayo Clinic Alzheimer’s Disease Research Center and the Mayo Clinic Study of Aging, told MNT the data were “pretty impressive.”

“The drug did what it was supposed to do — it engaged the appropriate target in the brain, namely amyloid, and removed a bunch of it such that most of the people got down to the actual threshold level for amyloid, meaning they removed it down to the negative threshold for having amyloid in the brain,” he explained.

“And then there was a corresponding clinical response to that as well,” Dr. Petersen added. “It was a modest clinical response — it didn’t stop the disease, it didn’t make anybody better, not that it was supposed to. And it did what it was supposed to. And I think the level of stabilization in the people who were treated with the drug is clinically meaningful.”

Lecanemab potential side effects

Upon the conclusion of the trial, researchers also reported some potential side effects from the use of lecanemab.

According to Dr. MacSweeney, lecanemab was generally well tolerated and the most common side effects were:

• an infusion-related reaction, as the medication is delivered by intravenous infusionTrusted Source every 2 weeks
• Amyloid Related Imaging AbnormalityTrusted Source (ARIA)-E, ARIA-H
• headaches.

ARIA, she explained, is a side effect that involves a bleed or build-up of fluid in the brain.

“The ARIA incidence profile was within expectations in the Clarity study and symptomatic ARIA was low,” Dr. MacSweeney said.

“So for those who did develop evidence of ARIA, this was mostly asymptomatic, meaning the patient was unaware they had developed the condition; it was detected only by MRI, and in most cases treatment continued and did not result in the study not reaching its conclusion and will not influence application to [the] FDA and regulatory bodies in other countries for a license for lecanemab to be available in the market,” she noted.

MNT also spoke with Dr. Verna Porter, a neurologist and director of the Dementia, Alzheimer’s Disease and Neurocognitive Disorders at Providence Saint John’s Health Center in Santa Monica, CA, who stated that although ARIA can sometimes be lethal, it is treatable if the medication that causes it is stopped or the dose reduced.

“In the approval process, the FDA will need to consider data from the trial showing that people taking anticoagulant drugs may have a slightly higher risk of bleeding events, before determining whether lecanemab requires an additional warning label about potential hemorrhage risk,” she said. “The FDA will also need to review and compare the risk of ARIA-E among people taking lecanemab with the risk associated with other amyloid-lowering drugs.”

Three deaths reportedly linked to lecanemab 

On December 22, 2022, the journal Science published a report of a third death connected to the clinical trials.

The journal stated that a 79-year-old Florida woman had died in mid-September after experiencing brain swelling and seizures.

On November 27, 2022, Science had published another article reporting a second death linked to lecanemab. A 65-year-old woman who reportedly received infusions of lecanemab experienced a stroke and ultimately died from a brain hemorrhage.

The first death reportedly happened in June. All three deaths occurred during an extended period of the trial.

When asked about the second death in November, Dr. Petersen explained that while lecanemab removes amyloid from the brain, it also removes it from blood vessels in the brain.

“People with Alzheimer’s disease also have this amyloid protein in the blood vessels, so when they remove some of the amyloid from the blood vessels, it can make them leaky,” he detailed. “And that means that there can be swelling in the brain and there can be bleeding in the brain.”

“That needs to be told to the patients and the patients, families, and doctors will have to make a collective decision about the risks versus the benefits,” Dr. Petersen continued.

“The risks are real,” he stressed, “but I think they’re relatively low and they generally can be monitored by serial imaging with MRI scans to make sure this doesn’t take off. But there’s always the unexpected risk of somebody having a major bleed in the brain.”

How promising is lecanemab? 

Knowing what we do so far about lecanemab, what should be our most realistic expectations on its safety and efficacy?

Dr. Heather Snyder, Alzheimer’s Association vice president of medical and scientific relations, told MNT these are the most encouraging results in clinical trials treating Alzheimer’s to date.

“These results indicate lecanemab can give people more time at or near their full abilities to participate in daily life, remain independent and make future healthcare decisions,” she said.

“Treatments that deliver these benefits to those with mild cognitive impairmentTrusted Source (MCI) due to Alzheimer’s disease and early Alzheimer’s dementia are just as valuable as treatments that extend the lives of those with other terminal diseases,” added Dr. Snyder.

“I am hopeful from a research perspective, this is a breakthrough that those of us who study Alzheimer’s disease have been waiting for, but I am less hopeful that this will be the ‘big thing’ that will help most of my current patients. In clinical trials, participants who took this drug saw a 27% reduction over 18 months in expected cognitive decline which sounds really meaningful, but the real-world impact of this may not be noticeable to families and that’s what really matters. What is effective statistically isn’t always effective clinically. The full data set has not been realized yet so I remain open-minded that this could be a game-changer.”

– Dr. Karen D. Sullivan

When will the treatment be available?

Lecanemab may be on track to become available to patients aged 65 years and over in the U.S. as soon as this year, but the experts MNT interviewed cautioned that there is still a long road ahead in finding the best, most effective treatment for Alzheimer’s disease.

“I think this drug is a monumental step in the right direction, but we are still probably 5-10 years from the type of powerful drug intervention we are all waiting for,” Dr. Sullivan added.

And while Dr. Porter called the clinical trial results “encouraging,” she said they are still learning more about Alzheimer’s disease that may impact future medications.

“We are learning that deposition of amyloid plaques leads to disorganization of another protein, tau, which creates ‘tanglesTrusted Source‘ that disrupt the critical connections between neurons,” she explained. “Potentially, combining an anti-amyloid drug (e.g., lecanemab) with an anti-tau compound may prove even more effective in putting the brakes on the neurodegeneration that is associated with Alzheimer’s.”

“We still have more to learn about the pathophysiology of Alzheimer’s disease and the primary, inciting events that lead to its development — which may prove to be the most effective targets for future therapeutic interventions,” Dr. Porter pointed out.

Source - Medical News Today

Alzheimer's: Are newly approved drugs making a real-life difference?

 After a lull of nearly 2 decades, the Food and Drug Administration (FDA) has approved some novel drugs for the treatment of Alzheimer’s disease since 2021. Most of these drugs are antibody therapies targeting toxic protein aggregates in the brain. Their approval has sparked enthusiasm and controversy in equal measure. The core question remains: Are these drugs making a real difference? In this Special Feature, we investigate.

Alzheimer’s disease is a neurodegenerative disease that involves a gradual and irreversible decline in memory, thinking, and, eventually, the ability to perform daily activities. Aging is the leading risk factor for Alzheimer’s disease, and a rapidly aging population has made it a public health crisis.

In 2019, 57 millionTrusted Source individuals around the globe had Alzheimer’s disease, and this number is expected to reach 153 million by 2050. This underscores the need for disease-modifying treatments that produce a lasting change in the trajectory of this disease, slowing its progression.

However, until recently, efforts to develop disease-modifying therapies for Alzheimer’s disease have not been successful.

Most of the clinical research to develop disease-modifying therapies for Alzheimer’s has focused on targeting the beta-amyloid protein, whose abnormal accumulation is generally considered to lead to the development of this neurodegenerative disorder.

Newly approved Alzheimer’s drugs: Breakthrough or slow start?

Aducanumab, an antibody-targeting amyloid-beta protein deposits, received Food and Drug Administration (FDA) approvalTrusted Source for the treatment of Alzheimer’s disease in 2021, and was considered the first disease-modifying therapy for this condition.

However, the clinical trials involving aducanumab failed to produce consistent improvements in cognitive function, which led Biogen, the company that produces it, to announce that it will eventually suspend its sales.

Since then, two other anti-amyloid antibodies, Biogen’s lecanemab and Eli Lily’s donanemab, have demonstrated an ability to slow cognitive decline in individuals with early Alzheimer’s disease in phase 3 clinical trials, and have received FDA approval.

After decades of clinical research failing to produce effective disease-modifying therapies, the approval of lecanemab and donanemab has been viewed as a breakthrough and met with enthusiasm by clinicians and researchers.

However, some researchers have raised concerns about the modest clinical benefits conferred by these anti-amyloid therapies, citing safety risks and a lack of cost-effectiveness.

Dag Aarsland, MD, professor of old age psychiatry at King’s College London in the United Kingdom, told Medical News Today that, “[w]hile there are indeed challenges both at the clinical, societal, and healthcare levels, we should not forget the opportunities and the breakthrough that after decades of very costly negative trials, we finally have unequivocal evidence that it is possible to reduce the disease progression.”

Similarly, Paresh Malhotra, PhD, professor of clinical neurology at Imperial College London in the U.K., noted that despite the modest efficacy of these anti-amyloid therapies, “it is important to recognize that these drugs are the first to have clinical effects which appear to relate to a key mechanism of disease progression, and their introduction may accelerate treatment development and transform clinical services for Alzheimer’s disease, the most common cause of dementia worldwide.”

Amyloid cascade hypothesis and Alzheimer’s research

The development of anti-amyloid antibody treatments such as donanemab and lecanemab is based on the amyloid cascade hypothesis.

According to this hypothesis, the accumulation of the beta-amyloid protein triggers other changes in the brain, leading to the development of Alzheimer’s disease.

Specifically, the formation of beta-amyloid aggregates is considered to lead to inflammation, oxidative stress, damage to neurons, loss of synapses — the “links” between neurons that allow them to “communicate” — and, ultimately, cognitive decline.

Consistent with this, the accumulation of the beta-amyloid protein precedes the decline in cognitive function, including memory and decision-making, by several years.

The beta-amyloid protein is formed after the cleavage of a larger amyloid precursor protein by secretase enzymes. Each unit of the beta-amyloid protein is referred to as a monomer, and these monomers can aggregate to form short chains called oligomers, which consist of two to over 50 monomers and are soluble.

Beta-amyloid monomers can also aggregate to form larger, soluble protofibrils and insoluble fibrils. The insoluble fibrils then assemble to form plaques in the extracellular space between neurons.

Previously, the amyloid plaques were thought to be toxic and responsible for the development of Alzheimer’s disease. However, in the past two decades, studiesTrusted Source have suggested that beta-amyloid oligomers are more toxic than amyloid plaques, and oligomers could play a larger role in the development of Alzheimer’s disease.

Targeting beta-amyloid aggregates to treat Alzheimer’s

The accumulation of beta-amyloid aggregates is thought to occur due to the impaired production or clearance of beta-amyloid protein.

In the past two decades, several drugs have been developed that either target the enzymes involved in the production of beta-amyloid or facilitate the clearance of beta-amyloid aggregates. However, these drugs have been unsuccessful in receiving FDA approval due to their severe adverse effects or failure to produce the desired clinical effects.

The anti-amyloid antibodies donanemab, aducanumab, and lecanemab are the only therapies targeting beta-amyloid aggregates to gain FDA approval. These antibodies differ in their affinity for the various types of aggregates of the beta-amyloid protein.

Donanemab binds to a specific form of beta-amyloid that is only found in plaques, whereas aducanumab and lecanemab bind to beta-amyloid oligomers, protofibrils, and plaques.

Lecanemab showsTrusted Source the highest affinity for beta-amyloid protofibrils, whereas aducanumab has a higher affinity for insoluble fibrils.

One of the supposed mechanisms through which anti-amyloid antibodies produce their therapeutic effects is activating an immune response against the beta-amyloid aggregates, resulting in their removal. Anti-amyloid antibodies can also potentially destabilize the plaques or bind to oligomers to neutralize them.

Impact of anti-amyloid antibodies on cognitive function

The FDA granted accelerated approval to aducanumab for the treatment of Alzheimer’s disease in 2021 based on its ability to clear amyloid plaques. While aducanumab was successful in clearing amyloid plaques in the brain, its effects on cognitive function were inconsistent across clinical trials.

The approval of aducanumab, despite the lack of evidence to support its therapeutic effects, led to controversy about the FDA’s approval process and a reluctance to prescribe the drug. And, as previously mentioned, as of 2024, Biogen has suspended aducanumab’s sales and development.

In contrast, both donanemab and lecanemab have shown an ability to clear amyloid plaques while slowing down disease progression. These therapeutics are more effective in individuals with early-stage Alzheimer’s disease and lowerTrusted Source baseline beta-amyloid levels.

The FDA has granted lecanemab and donanemab approval for administration via intravenous infusion in individuals with early Alzheimer’s disease, which includes those with mild cognitive impairment or mild Alzheimer’s disease.

Lecanemab is indicated for administration every 2 weeks, whereas donanemab needs to be administered every 4 weeks.

One of the unique features of donanemab is that participants can discontinue treatment after achieving complete plaque clearance. The build-up of amyloid plaques takes several years, and it is assumed that individuals would potentially require minimal further treatment.

Participants in the phase 3 trials for lecanemab and donanemabTrusted Source showed a 27%Trusted Source and 36% slower decline in cognitive function compared with placebo, respectively.

However, some researchers have argued that these outcomes are modest and comparableTrusted Source to the effects of symptomatic treatments, such as acetylcholinesterase inhibitorsTrusted Source that ameliorate symptoms without changing the trajectory of the disease.

Furthermore, the changes in cognition noted above were measured using the Clinical Dementia Rating Sum of Boxes (CDR-SB).

Researchers have also noted that the impact of these anti-amyloid therapies was not clinically meaningfulTrusted Source when evaluated based on the absolute difference in decline in cognitive function — measured directly in terms of difference in scores on the CDR-SB scale — between the placebo and anti-amyloid antibody treatment groups.

More objective measures of cognition, such as the Mini-Mental State Examination [MMSE], reported only a 14.8% slower decline in cognitive function in individuals treated with donanemab. In other words, it has been argued that currently available evidence suggests that these anti-amyloid drugs may only provide a modest clinical benefit.

Alberto Espay, MD, a professor of neurology at the University of Cincinnati, told MNT that:

“The efficacy of these drugs is not translated into improvements, but they just mean a statistically significant but clinically meaningless slower decline.”

Dr. Espay further noted that the safety concerns, along with modest clinical benefits, “makes the case that the costs are not commensurate with the efficacy.” However, what constitutes a clinically meaningful effect remains a contentious issue

How valid is the amyloid cascade hypothesis?

Some researchers have posited that the clinical benefits of anti-amyloid antibodies indicate the validity of the amyloid cascade hypothesis. However, others have argued that this conclusion is premature, with many questions yet to be answered.

According to the amyloid-beta hypothesis, the ability of aducanumab to clear plaques should have resulted in slower progression of Alzheimer’s disease. However, critics argue that trials involving aducanumab showed effective removal of amyloid plaques without consistently producing clinical benefits.

Similarly, donanemab removed about 85% of plaques in patients in the phase III trial but only resulted in a 14.8% slower decline in cognitive function, as measured using MMSE scores.

Importantly, the FDA’s decision to grant approval to aducanumab was grounded in the amyloid cascade hypothesis. Alzheimer’s disease also involves the accumulation of the tau protein inside neurons, and the extent of tau accumulation, rather than beta-amyloid, is associated with the magnitude of cognitive decline.

David Perlmutter, MD, a neurologist and fellow of the American College of Nutrition, commented that:

“Pharmaceutical interventions based on reducing beta-amyloid or reducing its production are leveraging the idea that beta-amyloid is playing a central role in the production and progression of Alzheimer’s disease. This hypothesis has been widely challenged. And the results of clinical trials of these medications reveal minimal efficacy and significant associated risk.”

As a result, some researchers argue that instead of indicating that the beta-amyloid pathway plays a focal the development of Alzheimer’s disease, the modest efficacy of the anti-amyloid antibodies suggests that the beta-amyloid pathway contributes to the development of Alzheimer’s disease along with other pathways.

According to this view, a complex network of factors, including those associated with the environment, oxidative stress, inflammation, metabolic factors, and genes unrelated to the amyloid pathway, also play a role in the development of Alzheimer’s disease.

Also according to this view, anti-amyloid therapies could have a role in the treatment of Alzheimer’s disease in combination with other therapies.

Alternatively, the aggregation of beta-amyloid could be a downstream phenomenon or symptom of other impaired biological pathways. Perlmutter explained, “[i]t is now clear that metabolic dysfunction upstream of amyloid plaque formation is central to the activation of the brain’s microglial cells, and this phenotypic change both enhances beta-amyloid formation while reducing its degradation.”

“In addition, microglial activation threatens the viability of neurons and leads to synaptic degradation, both central features of Alzheimer’s disease. As such, therapies targeting brain metabolism will likely provide substantial benefit for Alzheimer’s disease as has now been demonstrated in preliminary studies using GLP-1 agonists,” added Perlmutter.

Safety risks and accessibility of new Alzheimer’s drugs

The modest clinical benefits conferred by anti-amyloid antibody treatments need to be weighed against the risks, costs, and accessibility of these therapies. Adverse effects have been observed in a significant Trusted Sourceproportion of participants in the phase 3 clinical trials for lecanemab(45%) and donanemab(89%).

For instance, patients undergoing anti-amyloid antibody treatments often show changes in the brain known as amyloid-related imaging abnormalities (ARIA). These changes are observed during routine follow-up magnetic resonance imaging (MRI) scans and involve either brain swelling (edema) or small areas of bleeding due to the rupture of blood vessels (microhemorrhage).

For instance, 21% and 36.8% of individuals treated with lecanemab and donanemab, respectively, showed ARIA during the phase 3 trials. Most cases of ARIA are asymptomatic and resolve within 10 weeks.

While the symptomatic cases of ARIA are typically mild to moderate in severity, severe adverse effects, such as seizures and death, have also been reported. For instance, around 1.6% of participants in the phase III donanemab clinical trial experienced severe adverse effects related to ARIA, whereas the death rate in the donanemab group was 0.35%Trusted Source.

Besides concerns over these serious adverse effects, the long-term effects of amyloid-related imaging abnormalities, even when mild to moderate in severity, are not known. The infusion of these anti-amyloid antibodies is also associated with adverse effects, such as nausea, fever, rash, and dizziness.

Such infusion-related reactions were observed in 24.7%Trusted Source and 8.7%Trusted Source of patients treated with lecanemab and donanemab, respectively. These amyloid-related imaging abnormalities and other adverse effects necessitate frequent MRI scans and clinical follow-ups.

Individuals carrying at least one copy of the APOE4 gene, a gene linked to increased Alzheimer’s disease risk, were at higher risk of brain swelling in the phase III trials for donanemabTrusted Source and lecanemab.

Moreover, these drugs had lower efficacy in individuals with one or more copies of APOE4. Thus, individuals need to be genetically screened before the onset of anti-amyloid treatment.

Anti-amyloid immunotherapies are also associated with a reduction in the whole brain volume accompanied by an increase in the volume of ventricles, the fluid-filled spaces in the brain. An increase in the volume of ventricles and a decrease in whole brain volume are associatedTrusted Source with reduced cognition.

However, whether a causal relationship exists between these changes in brain volume and cognitive function is unclear. Thus, there is a need to examine the impact of these changes in brain volume after anti-amyloid treatments. Interestingly, donanemab treatment resulted in a smaller reduction in the volume of the hippocampus, a brain region that plays a critical role in learning and memory.

Only a few individuals with Alzheimer’s disease in the population are likely to meet the criteria for inclusion in the clinical trials for lecanemab or donanemab.

The patients included in these studies were younger and had few co-occurring medical conditions. The treatment of a real-world population consisting of individuals with Alzheimer’s and co-occurring conditions is thus likely to lead to more adverse events or reduced efficacy.

Besides the management of adverse effects, the screening and diagnosis of individuals eligible for anti-amyloid therapies poses another challenge for the healthcare system.

Most individuals with Alzheimer’s disease are not diagnosed until later stages of the disease, and early diagnosis would require screening a large number of individuals using imaging scans or measuring cerebrospinal fluid biomarkers.

Thus, the broad availability would entail a substantial investment of resources for the screening and diagnosis of individuals with early Alzheimer’s disease, genetic testing for APOE4, and the monitoring and managing ARIAs and infusion-related reactions, regardless of their severity.

Jennifer Keen, Head of Policy at the Alzheimer’s Society in the U.K., told MNT:

“Confirming eligibility for new treatment requires specific diagnostic tests, and currently, a third of people living with dementia in the UK don’t get a diagnosis at all. We need to see investment into diagnostic infrastructure and workforce to ensure that people who are eligible for new treatments can access them when they’re most effective, which appears to be in the early stages of Alzheimer’s.”

The annual cost of receiving infusions of lecanemab and donanemab was around $26,000Trusted Source and $32,000, respectively. However, this does not include the cost of screening and diagnosis, genetic testing, and monitoring and managing adverse effects.

Yet advances in diagnostic methods and the identification of novel biomarkers for monitoring treatment outcomes have the potential to reduce costs and improve the accessibility of anti-amyloid therapies.

Trusted Source.Source - Medical News Today