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Fixing the Aging Brain

The number one thing most people fear as they age is developing dementia. As the world’s population becomes increasingly older, this is a growing public…

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The number one thing most people fear as they age is developing dementia. As the world’s population becomes increasingly older, this is a growing public health issue too. The World Health Organization estimates that 55 million people already have dementia worldwide. With a global market estimated to reach $13 billion over the next few years, drug developers are eager to get a bite of this market, but until recently, it has proved to be one of the toughest fields to enter.

Now, Leqembi, the first drug that treats Alzheimer’s underlying biology is finally fully approved and being covered by Medicare. Alzheimer’s is the leading cause of dementia. There are also new data sources, and insights on root causes of this and other forms of cognitive decline, as well as new tests to guide treatment. Plus, we are hearing lots of discussion about whether prominent elderly political figures, such as U.S. president Biden and former U.S. president Trump, have the mental stamina required for public offices.

The aging brain is in the spotlight.

Studying the human brain is always a challenge, and in this case there have been a few detours. “Mouse models just recapitulate certain phenotypes, but even though it looks like Alzheimer’s it really isn’t a good model,” says Ulrich Hengst, PhD, associate professor of Pathology and Cell Biology at Columbia University’s Taub Institute for Research on Alzheimer’s Disease and the Aging Brain.

As a result, it has been extremely difficult to develop drugs for this condition. In the last decade, more than 200 drug discovery programs for Alzheimer’s have failed or been abandoned. The field was a wasteland, and still researchers persisted.

So, how did things change and start to look more hopeful?

Rethinking the amyloid hypothesis

An important step forward, says Hengst, has been a shift in how we think about the famous “amyloid hypothesis,” which is about 30 years old. This hypothesis suggested the accumulation of the peptide amyloid beta, 10-20 years before there are signs of the disease, was the starting point of the disease. After all, this leads to harmful plaques that are a hallmark of Alzheimer’s. Mopping up that molecule, the reasoning went, should help slow or even reverse cognitive decline.

“The idea used to be that it was a straight line from amyloid beta to neurodegeneration,” Hengst says. “But now we think its much more complicated than that, with on and off ramps,”

Even if clearing amyloid beta was sufficient, it occurs in different ways, Hengst points out—inside and outside of cells. “We had to figure out what amyloid to target and which are the best antibodies” he says. Also, importantly, amyloid beta is more easily cleared from the rodent brain than humans.

Seth Gale
co-director, Brain Health Program Division of Cognitive and Behavioral Neurology
assistant professor of Neurology
Harvard Medical School Neurology

“How the monoclonal binds and what it binds to is key,” says Seth Alan Gale, MD, co-director of the Brain Health Program at Harvard Medical School. What triggers the cascade is still not known, but it’s clear it involves more than amyloid beta. “From lab research and studying families with genetic mutations we know they first develop amyloid beta, but there are also tau tangles and inflammation,” he adds.

Both Hengst and Gale agree that Leqembi, (Biogen and Eisai’s lecanemab-irmb), is not the breakthrough drug we were waiting for. But it is the first fully approved treatment shown to reduce the rate of detectable Alzheimer’s progression and slow cognitive and functional decline.

For one thing, Hengst says, the drug only works in about 30% of patients: “It’s a case where the glass is half full and half empty.”

Says Gale, “The cognitive benefits of the drug are modest, sometimes it is hard to even see them. It’s just a beginning. It proves there is something we can do with amyloid beta.”

They both anticipate a future where a combination of therapies will target more than amyloid beta. They may even personalized, according to specific mutations or other factors.

New data and approaches

Among the new targets for Alzheimer’s drugs are tau, apolipoprotein E (APOE)/lipids and lipoprotein receptors, neurotransmitter receptors, neurogenesis, inflammation, growth factors, and more. But how will drug developers pick among these targets?

Hengst’s group recently identified a new amyloid beta-triggered pathway in Alzheimer’s that points to a potential drug for the disease. The team used datasets and a novel chemogenetic method that resolves the genomic binding profile of dimeric transcription factors.

They showed amyloid beta promotes the formation of pathological CREB3L2-ATF4 transcription factor heterodimers in neurons. This process activates a transcription network that interacts with roughly half of the genes differentially expressed in Alzheimer’s. Further, the team determined that the drug dovitinib, Allarity’s pan-tyrosine kinase inhibitor, could be a candidate against this target.

Another recent study, from INSERM, involved a two-stage genome-wide association study of more than 110,000 people with Alzheimer’s. This team found 75 risk loci, 42 of which were new. Genome-wide summary statistics were deposited to the European Bioinformatics Institute GWAS Catalog.

Tony Wyss-Coray
Tony Wyss-Coray, PhD
professor of neurology and neurological sciences
Stanford Medicine

Another new tool is a spatiotemporal RNA sequencing atlas of the mouse brain recently constructed by the lab of Tony Wyss-Coray, PhD, professor of Neurology and Neurological Sciences, and director of the Phil and Penny Knight Initiative for Brain Resilience at Stanford University. The team looked at 1,076 samples from 15 regions across seven ages and two rejuvenation interventions. They are planning to repeat this with human samples.

But the mouse data has given them a good start. “We made a number of discoveries,” says Wyss-Coray. “For one thing, these regions do not age in synchrony, a gene’s activity can go up several fold in one region but not in another. Also, the white matter is the connection between regions that show most of the changes.”

There are also other causes than Alzheimer’s of cognitive decline, such as vascular disease.

Women, for example, are more likely than men to develop dementia, and that has long been assumed that to be due to the fact that they live longer. But new evidence suggests that pregnancy complications may also lead to higher risk of earlier cognitive decline.

Among these findings, a Swedish team recently found that risk of later dementia increases for women who experienced pregnancy-induced hypertension, spontaneous preterm labor, or preterm rupture of membranes (placental bed disorders). Such disorders, the team concluded, are associated with vascular dementia even after adjusting for cardiovascular disease.

New tests and clinical protocols are being developed to protect pregnant women from these conditions.

Keys to graceful aging

Lifestyle also has a role in cognitive decline. “It seems to have modest benefits, but people who adopt healthy lifestyles can modify their risk of dementia,” says Gale. He thinks that along with new therapies, lifestyle changes will be a help.

There is also widespread agreement that earlier detection could help clinical care and drug development. So, a priority is improving diagnosis of Alzheimer’s and other conditions that affect cognitive function.

Valentina Garibotto
Valentina Garibotto
Laboratory of Neuroimaging and Innovative Molecular Tracers (NIMTlab), Geneva University Neurocenter
Faculty of Medicine, University of Geneva

“Amyloid deposition is not strongly correlated with cognition, unlike hyperphosphorylated tau, neurofibrillary tangles, and synaptic and neuronal loss,” says Valentina Garibotto, of the Laboratory of Neuroimaging and Innovative Molecular Tracers at Geneva University.

She points out that better selection of patients is crucial to optimal trial design and she sees the measurement of Tau as being an important step forward. “Tau is routinely measured in CSF, and several new blood tests are in development to measure phosphorylated tau,” she says.

Only one tau PET radiopharmaceutical, [18F]-flortaucipir, has FDA approval, also though this test is routinely used in clinical trials. In fact, Garibotto says, “Crucially, participants in TRAILBLAZER-ALZ 2 [a trial of Eli Lilly’s donanemab] were stratified by their level of tau, as assessed by tau PET,

Gale notes that new diagnostic criteria will soon be available from the National Institute on Aging and the Alzheimer’s Association (NIA-AA) The criteria were posted for final review at the end of August this year. Medicare is also planning to expand its coverage of PET scans, which are one of the best means of detecting amyloid beta on the brain.

Former president Trump famously said that he had to remember the words: “Person. Woman. Man. Camera. TV,” as part of a test to demonstrate his mental acuity. The test, the Montreal Cognitive Assessment, is designed to detect signs of Alzheimer’s or other types of dementia.

With advances in precision medicine, we are poised to have much more sophisticated tests in hand. That should make old age much easier for many people.

 

Read More

Atlas of the aging mouse brain reveals white matter as vulnerable fociCell, 2023.

Can precision pregnancy save more mothers?Inside Precision Medicine, 2023.

CREB3L2-ATF4 heterodimerization defines a transcriptional hub of Alzheimer’s disease gene expression linked to neuropathology—Science Advances, 2023.

New insights into the genetic etiology of Alzheimer’s disease and related dementiasNature Genetics, 2022.

Montreal Cognitive Assessment (MoCA) website, 2023.

Person. Woman. Man. Camera. TV,’ didn’t mean what Trump hoped it didThe New York Times, 2020.

Prior placental bed disorders and later dementia: a retrospective Swedish register-based cohort studyBJOG, 2020.

Reasons for failed trials of disease-modifying treatments for Alzheimer Disease and their contribution in recent research—Biomedicines, 2019.

The Alzheimer’s disease drug development landscape—BMC. 2021.

The impact of tau deposition and hypometabolism on cognitive impairment and longitudinal cognitive declineAlzheimer’s & Dementia, 2023.

 

Malorye Branca is a contributing editor at Inside Precision Medicine and a freelance medical science journalist. She has written hundreds of articles, as well as managed and launched health and science magazines, newsletters, and market research report businesses. She has also co-authored two books: “Moneyball Medicine” and “Walmart’s Second Opinion.”

The post Fixing the Aging Brain appeared first on Inside Precision Medicine.

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Veterans Affairs Kept COVID-19 Vaccine Mandate In Place Without Evidence

Veterans Affairs Kept COVID-19 Vaccine Mandate In Place Without Evidence

Authored by Zachary Stieber via The Epoch Times (emphasis ours),

The…

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Veterans Affairs Kept COVID-19 Vaccine Mandate In Place Without Evidence

Authored by Zachary Stieber via The Epoch Times (emphasis ours),

The U.S. Department of Veterans Affairs (VA) reviewed no data when deciding in 2023 to keep its COVID-19 vaccine mandate in place.

Doses of a COVID-19 vaccine in Washington in a file image. (Jacquelyn Martin/Pool/AFP via Getty Images)

VA Secretary Denis McDonough said on May 1, 2023, that the end of many other federal mandates “will not impact current policies at the Department of Veterans Affairs.”

He said the mandate was remaining for VA health care personnel “to ensure the safety of veterans and our colleagues.”

Mr. McDonough did not cite any studies or other data. A VA spokesperson declined to provide any data that was reviewed when deciding not to rescind the mandate. The Epoch Times submitted a Freedom of Information Act for “all documents outlining which data was relied upon when establishing the mandate when deciding to keep the mandate in place.”

The agency searched for such data and did not find any.

The VA does not even attempt to justify its policies with science, because it can’t,” Leslie Manookian, president and founder of the Health Freedom Defense Fund, told The Epoch Times.

“The VA just trusts that the process and cost of challenging its unfounded policies is so onerous, most people are dissuaded from even trying,” she added.

The VA’s mandate remains in place to this day.

The VA’s website claims that vaccines “help protect you from getting severe illness” and “offer good protection against most COVID-19 variants,” pointing in part to observational data from the U.S. Centers for Disease Control and Prevention (CDC) that estimate the vaccines provide poor protection against symptomatic infection and transient shielding against hospitalization.

There have also been increasing concerns among outside scientists about confirmed side effects like heart inflammation—the VA hid a safety signal it detected for the inflammation—and possible side effects such as tinnitus, which shift the benefit-risk calculus.

President Joe Biden imposed a slate of COVID-19 vaccine mandates in 2021. The VA was the first federal agency to implement a mandate.

President Biden rescinded the mandates in May 2023, citing a drop in COVID-19 cases and hospitalizations. His administration maintains the choice to require vaccines was the right one and saved lives.

“Our administration’s vaccination requirements helped ensure the safety of workers in critical workforces including those in the healthcare and education sectors, protecting themselves and the populations they serve, and strengthening their ability to provide services without disruptions to operations,” the White House said.

Some experts said requiring vaccination meant many younger people were forced to get a vaccine despite the risks potentially outweighing the benefits, leaving fewer doses for older adults.

By mandating the vaccines to younger people and those with natural immunity from having had COVID, older people in the U.S. and other countries did not have access to them, and many people might have died because of that,” Martin Kulldorff, a professor of medicine on leave from Harvard Medical School, told The Epoch Times previously.

The VA was one of just a handful of agencies to keep its mandate in place following the removal of many federal mandates.

“At this time, the vaccine requirement will remain in effect for VA health care personnel, including VA psychologists, pharmacists, social workers, nursing assistants, physical therapists, respiratory therapists, peer specialists, medical support assistants, engineers, housekeepers, and other clinical, administrative, and infrastructure support employees,” Mr. McDonough wrote to VA employees at the time.

This also includes VA volunteers and contractors. Effectively, this means that any Veterans Health Administration (VHA) employee, volunteer, or contractor who works in VHA facilities, visits VHA facilities, or provides direct care to those we serve will still be subject to the vaccine requirement at this time,” he said. “We continue to monitor and discuss this requirement, and we will provide more information about the vaccination requirements for VA health care employees soon. As always, we will process requests for vaccination exceptions in accordance with applicable laws, regulations, and policies.”

The version of the shots cleared in the fall of 2022, and available through the fall of 2023, did not have any clinical trial data supporting them.

A new version was approved in the fall of 2023 because there were indications that the shots not only offered temporary protection but also that the level of protection was lower than what was observed during earlier stages of the pandemic.

Ms. Manookian, whose group has challenged several of the federal mandates, said that the mandate “illustrates the dangers of the administrative state and how these federal agencies have become a law unto themselves.”

Tyler Durden Sat, 03/09/2024 - 22:10

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Are Voters Recoiling Against Disorder?

Are Voters Recoiling Against Disorder?

Authored by Michael Barone via The Epoch Times (emphasis ours),

The headlines coming out of the Super…

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Are Voters Recoiling Against Disorder?

Authored by Michael Barone via The Epoch Times (emphasis ours),

The headlines coming out of the Super Tuesday primaries have got it right. Barring cataclysmic changes, Donald Trump and Joe Biden will be the Republican and Democratic nominees for president in 2024.

(Left) President Joe Biden delivers remarks on canceling student debt at Culver City Julian Dixon Library in Culver City, Calif., on Feb. 21, 2024. (Right) Republican presidential candidate and former U.S. President Donald Trump stands on stage during a campaign event at Big League Dreams Las Vegas in Las Vegas, Nev., on Jan. 27, 2024. (Mario Tama/Getty Images; David Becker/Getty Images)

With Nikki Haley’s withdrawal, there will be no more significantly contested primaries or caucuses—the earliest both parties’ races have been over since something like the current primary-dominated system was put in place in 1972.

The primary results have spotlighted some of both nominees’ weaknesses.

Donald Trump lost high-income, high-educated constituencies, including the entire metro area—aka the Swamp. Many but by no means all Haley votes there were cast by Biden Democrats. Mr. Trump can’t afford to lose too many of the others in target states like Pennsylvania and Michigan.

Majorities and large minorities of voters in overwhelmingly Latino counties in Texas’s Rio Grande Valley and some in Houston voted against Joe Biden, and even more against Senate nominee Rep. Colin Allred (D-Texas).

Returns from Hispanic precincts in New Hampshire and Massachusetts show the same thing. Mr. Biden can’t afford to lose too many Latino votes in target states like Arizona and Georgia.

When Mr. Trump rode down that escalator in 2015, commentators assumed he’d repel Latinos. Instead, Latino voters nationally, and especially the closest eyewitnesses of Biden’s open-border policy, have been trending heavily Republican.

High-income liberal Democrats may sport lawn signs proclaiming, “In this house, we believe ... no human is illegal.” The logical consequence of that belief is an open border. But modest-income folks in border counties know that flows of illegal immigrants result in disorder, disease, and crime.

There is plenty of impatience with increased disorder in election returns below the presidential level. Consider Los Angeles County, America’s largest county, with nearly 10 million people, more people than 40 of the 50 states. It voted 71 percent for Mr. Biden in 2020.

Current returns show county District Attorney George Gascon winning only 21 percent of the vote in the nonpartisan primary. He’ll apparently face Republican Nathan Hochman, a critic of his liberal policies, in November.

Gascon, elected after the May 2020 death of counterfeit-passing suspect George Floyd in Minneapolis, is one of many county prosecutors supported by billionaire George Soros. His policies include not charging juveniles as adults, not seeking higher penalties for gang membership or use of firearms, and bringing fewer misdemeanor cases.

The predictable result has been increased car thefts, burglaries, and personal robberies. Some 120 assistant district attorneys have left the office, and there’s a backlog of 10,000 unprosecuted cases.

More than a dozen other Soros-backed and similarly liberal prosecutors have faced strong opposition or have left office.

St. Louis prosecutor Kim Gardner resigned last May amid lawsuits seeking her removal, Milwaukee’s John Chisholm retired in January, and Baltimore’s Marilyn Mosby was defeated in July 2022 and convicted of perjury in September 2023. Last November, Loudoun County, Virginia, voters (62 percent Biden) ousted liberal Buta Biberaj, who declined to prosecute a transgender student for assault, and in June 2022 voters in San Francisco (85 percent Biden) recalled famed radical Chesa Boudin.

Similarly, this Tuesday, voters in San Francisco passed ballot measures strengthening police powers and requiring treatment of drug-addicted welfare recipients.

In retrospect, it appears the Floyd video, appearing after three months of COVID-19 confinement, sparked a frenzied, even crazed reaction, especially among the highly educated and articulate. One fatal incident was seen as proof that America’s “systemic racism” was worse than ever and that police forces should be defunded and perhaps abolished.

2020 was “the year America went crazy,” I wrote in January 2021, a year in which police funding was actually cut by Democrats in New York, Los Angeles, San Francisco, Seattle, and Denver. A year in which young New York Times (NYT) staffers claimed they were endangered by the publication of Sen. Tom Cotton’s (R-Ark.) opinion article advocating calling in military forces if necessary to stop rioting, as had been done in Detroit in 1967 and Los Angeles in 1992. A craven NYT publisher even fired the editorial page editor for running the article.

Evidence of visible and tangible discontent with increasing violence and its consequences—barren and locked shelves in Manhattan chain drugstores, skyrocketing carjackings in Washington, D.C.—is as unmistakable in polls and election results as it is in daily life in large metropolitan areas. Maybe 2024 will turn out to be the year even liberal America stopped acting crazy.

Chaos and disorder work against incumbents, as they did in 1968 when Democrats saw their party’s popular vote fall from 61 percent to 43 percent.

Views expressed in this article are opinions of the author and do not necessarily reflect the views of The Epoch Times or ZeroHedge.

Tyler Durden Sat, 03/09/2024 - 23:20

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Low Iron Levels In Blood Could Trigger Long COVID: Study

Low Iron Levels In Blood Could Trigger Long COVID: Study

Authored by Amie Dahnke via The Epoch Times (emphasis ours),

People with inadequate…

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Low Iron Levels In Blood Could Trigger Long COVID: Study

Authored by Amie Dahnke via The Epoch Times (emphasis ours),

People with inadequate iron levels in their blood due to a COVID-19 infection could be at greater risk of long COVID.

(Shutterstock)

A new study indicates that problems with iron levels in the bloodstream likely trigger chronic inflammation and other conditions associated with the post-COVID phenomenon. The findings, published on March 1 in Nature Immunology, could offer new ways to treat or prevent the condition.

Long COVID Patients Have Low Iron Levels

Researchers at the University of Cambridge pinpointed low iron as a potential link to long-COVID symptoms thanks to a study they initiated shortly after the start of the pandemic. They recruited people who tested positive for the virus to provide blood samples for analysis over a year, which allowed the researchers to look for post-infection changes in the blood. The researchers looked at 214 samples and found that 45 percent of patients reported symptoms of long COVID that lasted between three and 10 months.

In analyzing the blood samples, the research team noticed that people experiencing long COVID had low iron levels, contributing to anemia and low red blood cell production, just two weeks after they were diagnosed with COVID-19. This was true for patients regardless of age, sex, or the initial severity of their infection.

According to one of the study co-authors, the removal of iron from the bloodstream is a natural process and defense mechanism of the body.

But it can jeopardize a person’s recovery.

When the body has an infection, it responds by removing iron from the bloodstream. This protects us from potentially lethal bacteria that capture the iron in the bloodstream and grow rapidly. It’s an evolutionary response that redistributes iron in the body, and the blood plasma becomes an iron desert,” University of Oxford professor Hal Drakesmith said in a press release. “However, if this goes on for a long time, there is less iron for red blood cells, so oxygen is transported less efficiently affecting metabolism and energy production, and for white blood cells, which need iron to work properly. The protective mechanism ends up becoming a problem.”

The research team believes that consistently low iron levels could explain why individuals with long COVID continue to experience fatigue and difficulty exercising. As such, the researchers suggested iron supplementation to help regulate and prevent the often debilitating symptoms associated with long COVID.

It isn’t necessarily the case that individuals don’t have enough iron in their body, it’s just that it’s trapped in the wrong place,” Aimee Hanson, a postdoctoral researcher at the University of Cambridge who worked on the study, said in the press release. “What we need is a way to remobilize the iron and pull it back into the bloodstream, where it becomes more useful to the red blood cells.”

The research team pointed out that iron supplementation isn’t always straightforward. Achieving the right level of iron varies from person to person. Too much iron can cause stomach issues, ranging from constipation, nausea, and abdominal pain to gastritis and gastric lesions.

1 in 5 Still Affected by Long COVID

COVID-19 has affected nearly 40 percent of Americans, with one in five of those still suffering from symptoms of long COVID, according to the U.S. Centers for Disease Control and Prevention (CDC). Long COVID is marked by health issues that continue at least four weeks after an individual was initially diagnosed with COVID-19. Symptoms can last for days, weeks, months, or years and may include fatigue, cough or chest pain, headache, brain fog, depression or anxiety, digestive issues, and joint or muscle pain.

Tyler Durden Sat, 03/09/2024 - 12:50

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