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Alzheimer’s drug lecanemab receives accelerated FDA approval amid safety concerns

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CNN
 — 

The US Food and Drug Administration granted accelerated approval Friday for the Alzheimer’s disease drug lecanemab, one of the first experimental dementia drugs to appear to slow the progression of cognitive decline.

“Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones,” Dr. Billy Dunn, director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said in a 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.”

Lecanemab will be marketed as Leqembi, the FDA statement said. It has shown “potential” as an Alzheimer’s disease treatment by appearing to slow progression, according to Phase 3 trial results, but it has raised safety concerns due to its association with certain serious adverse events, including brain swelling and bleeding.

In July, the FDA accepted Eisai’s Biologics License Application for lecanemab under the accelerated approval pathway and granted the drug priority review, according to the company. The accelerated approval program allows for earlier approval of medications that treat serious conditions and “fill an unmet medical need” while the drugs continue to be studied in larger and longer trials.

If those trials confirm that the drug provides a clinical benefit, the FDA could grant traditional approval. But if the confirmatory trial does not show benefit, the FDA has the regulatory procedures that could lead to taking the drug off the market.

Lecanemab, a monoclonal antibody, is not a cure but works by binding to amyloid beta, a hallmark of Alzheimer’s disease. In late November, results from an 18-month Phase 3 clinical trial published in The New England Journal of Medicine showed that lecanemab “reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events.”

The results also showed that about 6.9% of the trial participants given lecanemab, as an intravenous infusion, discontinued the trial due to adverse events, compared with 2.9% of those given a placebo. Overall, there were serious adverse events in 14% of the lecanemab group and 11.3% of the placebo group.

The most common adverse events in the lecanemab group were reactions to the intravenous infusions and abnormalities on their MRIs, such as brain swelling and bleeding called amyloid-related imaging abnormalities, or ARIA, which can become life-threatening.

Some people who get ARIA may not have symptoms, but it can occasionally lead to hospitalization or lasting impairment. And the frequency of ARIA appeared to be higher in people who had a gene called APOE4, which can raise the risk of Alzheimer’s disease or other dementias. ARIA “were numerically less common” among APOE4 noncarriers, the study showed.

The drug’s prescribing information carries a warning about ARIA, the FDA says.

The trial results also showed that about 0.7% of participants in the lecanemab group and 0.8% of those in the placebo group died, corresponding to six deaths in the lecanemab group and seven in the placebo group.

The Alzheimer’s Association welcomed Friday’s decision.

“By slowing progression of the disease when taken in the early stages of Alzheimer’s, individuals will have more time to participate in daily life and live independently,” President and CEO Joanne Pike said. “This could mean more months of recognizing their spouse, children and grandchildren. This could also mean more time for a person to drive safely, accurately and promptly take care of family finances, and participate fully in hobbies and interests.”

More than 6.5 million people in the United States live with Alzheimer’s disease, according to the Alzheimer’s Association, and that number is expected to grow to 13.8 million by 2060.

Lecanemab will carry a wholesale price of $26,500 per patient per year, the drug’s manufacturers announced Friday.

Biogen and Eisai have listed the drug slightly below the reduced price of the Alzheimer’s medication Aduhelm, which now costs an average patient about $28,200. The companies had to lower the cost of Aduhelm – originally set at $56,000 per patient per year – after insurers balked at covering it.

In justifying the cost of Leqembi, the companies said in a news release that based on the estimated quality of life gained by people who take it, the value of the medication to society is around $37,000 a year, but they chose to go lower “aiming to promote broader patient access, reduce overall financial burden, and support health system sustainability.”

The wholesale cost of a drug is akin to a car’s sticker price. It isn’t necessarily what patients will pay after insurance or other discounts are factored in.

Insurance coverage for this medication is not a given, however. Medicare restricted its coverage of lecanemab’s sister drug, Aduhelm, after clinical trials showed questionable benefits to patients. The agency agreed to cover the drug only for people enrolled in registered clinical trials, which limited access to the medication.

Center for Medicare and Medicaid Services Administrator Chiquita Brooks-LaSure said after the FDA’s decision Friday that her office would quickly review Leqembi, but for now, because of its accelerated approval, it will be covered the same way Aduhelm is covered.

“At CMS, we will continue to expeditiously review the data on these products as they become available and are committed to timely access to treatments, including drugs, that improve clinically meaningful outcomes,” Brooks-LaSure said in a statement.

Last month, the Alzheimer’s Association filed a formal request asking CMS to provide “full and unrestricted coverage” Alzheimer’s treatments approved by the FDA.

“What the FDA did today in granting accelerated approval to Leqembi was the right decision. But what CMS is doing by severely restricting coverage for approved treatments is unprecedented and wrong,” Pike said in a statement Friday.

“The FDA carefully reviewed the evidence for Leqembi before granting approval. CMS, in sharp contrast, denied coverage for Leqembi months ago before it had even reviewed this drug’s evidence. CMS has never done this before for any drug, and it is clearly harmful and unfair to those with Alzheimer’s. Without access to and coverage of this treatment and others in its class, people are losing days, weeks, months – memories, skills and independence. They’re losing time.”

CMS told CNN that it will review and respond to the association’s request. The agency also noted that it continues to stay informed about ongoing clinical trials, including the most recent lecanemab results published in the New England Journal of Medicine. Also, it has met with drugmakers to learn about their efforts since CMS’s coverage decision was announced.

The FDA approved Aduhelm for early phases of Alzheimer’s disease in 2021 – but that decision has been shrouded in controversy as a congressional investigation found last week that the FDA’s “atypical collaboration” to approve the high-priced drug was “rife with irregularities.”

Before Aduhelm, the FDA had not approved a novel therapy for the condition since 2003.

Aduhelm’s FDA approval and initial hefty price tag hit Medicare’s Part B premiums, driving up the 2022 standard monthly payments by 14.5% to $170.10.

About $10 of the premium spike – or just under half the amount – was due to Aduhelm, a CMS official told CNN in late 2021.

The premium increase was set before Medicare announced its limited coverage of the drug, but its actuaries had to make sure that the program had sufficient funding in case Aduhelm was covered.

Medicare’s decision, as well as Biogen’s slashing of the drug’s cost, prompted a decline in monthly premiums for 2023 to $164.90.

The FDA’s accelerated approval of lecanemab was expected, said Dr. Richard Isaacson, director of the Alzheimer’s Prevention Clinic in the Center for Brain Health at Florida Atlantic University’s Schmidt College of Medicine.

Isaacson said lecanemab can be “another tool” in his toolbox to fight Alzheimer’s disease.

“I will prescribe this drug in the right person, at the right dose and in a very carefully monitored way, but this drug is not for everyone,” he said.

“I would do genetic testing for APOE4 first. I would have a frank discussion with my patients,” he said. “If someone is having side effects, if someone is on a blood-thinning medication, if someone has a problem, they need to discuss this with the treating physician, and they need to seek medical attention immediately.”

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Health

Is Muscle Weakness the New Smoking? Grip Strength Tied to Accelerated Biological Age

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Summary: Muscle weakness marked by grip strength was associated with accelerated biological aging, a new study reports.

Source: University of Michigan

Everyone ages at a different pace. That’s why two 50-year-olds, despite living the same number of years, may have different biological ages—meaning that a host of intrinsic and extrinsic factors have caused them to age at varying paces with different levels of risk for disease and early death.

Lifestyle choices, such as diet, and smoking, and illness all contribute to accelerating biological age beyond one’s chronological age. In other words, your body is aging faster than expected.

And for the first time, researchers have found that muscle weakness marked by grip strength, a proxy for overall strength capacity, is associated with accelerated biological age.

Specifically, the weaker your grip strength, the older your biological age, according to results published in the Journal of Cachexia, Sarcopenia and Muscle.

Researchers at Michigan Medicine modeled the relationship between biological age and grip strength of 1,274 middle aged and older adults using three “age acceleration clocks” based on DNA methylation, a process that provides a molecular biomarker and estimator of the pace of aging. The clocks were originally modeled from various studies examining diabetes, cardiovascular disease, cancer, physical disability, Alzheimer’s disease, inflammation and early mortality.

Results reveal that both older men and women showed an association between lower grip strength and biological age acceleration across the DNA methylation clocks.

“We’ve known that muscular strength is a predictor of longevity, and that weakness is a powerful indicator of disease and mortality, but for the first time, we have found strong evidence of a biological link between muscle weakness and actual acceleration in biological age,” said Mark Peterson, Ph.D., M.S., lead author of the study and associate professor of physical medicine and rehabilitation at University of Michigan.

“This suggests that if you maintain your muscle strength across the lifespan, you may be able to protect against many common age-related diseases. We know that smoking, for example, can be a powerful predictor of disease and mortality, but now we know that muscle weakness could be the new smoking.”

The real strength of this study was in the 8 to 10 years of observation, in which lower grip strength predicted faster biological aging measured up to a decade later, said Jessica Faul, Ph.D., M.P.H., a co-author of the study and research associate professor at the U-M Institute for Social Research.

Past studies have shown that low grip strength is an extremely strong predictor of adverse health events. One study even found that it is a better predictor of cardiovascular events, such as myocardial infarction, than systolic blood pressure—the clinical hallmark for detecting heart disorders. Peterson and his team have previously shown a robust association between weakness and chronic disease and mortality across populations.

This evidence coupled with their study’s recent findings, Peterson says, shows potential for clinicians to adopt the use of grip strength as a way to screen individuals for future risk of functional decline, chronic disease and even early mortality.

“Screening for grip strength would allow for the opportunity to design interventions to delay or prevent the onset or progression of these adverse ‘age-related’ health events,” he said.

Lifestyle choices, such as diet, and smoking, and illness all contribute to accelerating biological age beyond one’s chronological age. Credit: Justine Ross, Michigan Medicine

“We have been pushing for clinicians to start using grip strength in their clinics and only in geriatrics has this sort of been incorporated. However, not many people are using this, even though we’ve seen hundreds of publications showing that grip strength is a really good measure of health.”

Investigators say future research is needed to understand the connection between grip strength and age acceleration, including how inflammatory conditions contribute to age-related weakness and mortality.

Previous studies have shown that chronic inflammation in aging—known as “inflammaging”—is a significant risk factor for mortality among older adults. This inflammation is also associated with lower grip strength and may be a significant predictor on the pathway between lower grip strength and both disability and chronic disease multimorbidity.

Additionally, Peterson says, studies must focus on how lifestyle and behavioral factors, such as physical activity and diet, can affect grip strength and age acceleration.

“Healthy dietary habits are very important, but I think regular exercise is the most critical thing that somebody can do to preserve health across the lifespan,” he said. “We can show it with a biomarker like DNA methylation age, and we can also test it with a clinical feature like grip strength.”

See also

Additional authors include Stacey Collins, M.A., Helen C.S. Meier, Ph.D., M.P.H., Alexander Brahmsteadt, M.D., all of University of Michigan.

About this aging and muscle strength research news

Author: Noah Fromson
Source: University of Michigan
Contact: Noah Fromson – University of Michigan
Image: The image is credited to Justine Ross, Michigan Medicine

Original Research: Open access.
“Grip strength is inversely associated with DNA methylation age acceleration” by Mark D. Peterson et al. Journal of Cachexia, Sarcopenia and Muscle

Abstract

Grip strength is inversely associated with DNA methylation age acceleration

Background

There is a large body of evidence linking muscular weakness, as determined by low grip strength, to a host of negative ageing-related health outcomes. Given these links, grip strength has been labelled a ‘biomarker of aging’; and yet, the pathways connecting grip strength to negative health consequences are unclear. The objective of this study was to determine whether grip strength was associated with measures of DNA methylation (DNAm) age acceleration.

Methods

Middle age and older adults from the 2006 to 2008 waves of the Health and Retirement Study with 8–10 years of follow-up were included. Cross-sectional and longitudinal regression modelling was performed to examine the association between normalized grip strength (NGS) and three measures of DNAm age acceleration, adjusting for cell composition, sociodemographic variables and smoking. Longitudinal modelling was also completed to examine the association between change in absolute grip strength and DNAm age acceleration. The three DNAm clocks used for estimating age acceleration include the established DunedinPoAm, PhenoAge and GrimAge clocks.

Results

There was a robust and independent cross-sectional association between NGS and DNAm age acceleration for men using the DunedinPoAm (β: −0.36; P < 0.001), PhenoAge (β: −8.27; P = 0.01) and GrimAge (β: −4.56; P = 0.01) clocks and for women using the DunedinPoAm (β: −0.36; P < 0.001) and GrimAge (β: −4.46; P = 0.01) clocks. There was also an independent longitudinal association between baseline NGS and DNAm age acceleration for men (β: −0.26; P < 0.001) and women (β: −0.36; P < 0.001) using the DunedinPoAm clock and for women only using the PhenoAge (β: −8.20; P < 0.001) and GrimAge (β: −5.91; P < 0.001) clocks. Longitudinal modelling revealed a robust association between change in grip strength from wave 1 to wave 3 was independently associated with PhenoAgeAA (β: −0.13; 95% CI: −0.23, −0.03) and GrimAgeAA (β: −0.07; 95% CI: −0.14, −0.01) in men only (both P < 0.05).

Conclusions

Our findings provide some initial evidence of age acceleration among men and women with lower NGS and loss of strength over time. Future research is needed to understand the extent to which DNAm age mediates the association between grip strength and chronic disease, disability and mortality.

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Health

Genetics May Explain Link Between Unhealthy Teen Lifestyles and Accelerated Biological Aging

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Summary: The epigenetic clocks of those who indulged in unhealthy behaviors as teens were 1.7 to 3.3 years older than individuals who reported more healthy lifestyles as teens.

Source: eLife

Biological aging results from damage to cells and tissues in the body that accumulates over time. The results of the study could lead to new ways of identifying young people at risk of developing unhealthy habits that are associated with accelerated biological aging and suggest interventions to prevent poor health outcomes later on. 

“Unhealthy lifestyles during adolescence when cells are rapidly dividing may have lasting harmful effects,” says lead author Anna Kankaanpää, a doctoral researcher at the Gerontology Research Center and Faculty of Sport and Health Sciences at the University of Jyväskylä, Finland.

“Activities like drinking or smoking, for example, may contribute to increased biological aging and related health conditions like heart or lung disease and premature death.” 

To measure the effects of unhealthy teen behavior on aging at the cellular level, Kankaanpää and colleagues analyzed the link between behavior and cellular aging in 824 twins who participated in the Finn Twin12 Study.

Participants were 21 to 25 years of age and had completed surveys about their behaviors at ages 12, 14 and 17. Most of the teens reported overall healthy, active lifestyles, but the researchers classified two groups as having unhealthy lifestyles.

One group had high body mass index scores – an approximate measure of whether a person is at a healthy weight, based on their height and body mass. The other group regularly smoked, binge-drank alcohol, and did not exercise regularly. 

The team measured DNA methylation, the addition of chemical tags on DNA that can turn on or off gene expression, in blood samples taken from the participants. They used several algorithms or “epigenetic clocks” – biochemical tests based on DNA methylation levels – to determine if the individuals were experiencing accelerated biological aging, and looked to see if there was any connection between unhealthy behaviors and more rapid aging. 

Overall, the clocks suggested that individuals in the two groups classified as having unhealthy behaviors were, on average, 1.7 to 3.3 years older than individuals who reported more healthy lifestyles during their adolescence. This is equivalent to aging about 2 to 3 weeks faster each calendar year.

The results varied depending on which epigenetic clock they used, but the link between lifestyle and accelerated aging was primarily due to shared genetics. 

“Previous studies in twins have shown that lifestyle and biological aging are largely inherited,” Kankaanpää says. “Our study suggests that genetics may underlie the link between unhealthy behaviors and accelerated aging.” 

Overall, the clocks suggested that individuals in the two groups classified as having unhealthy behaviours were, on average, 1.7 to 3.3 years older than individuals who reported more healthy lifestyles during their adolescence. Image is in the public domain

The study benefits from having a large sample size, extended follow-up on participants, and the inclusion of individuals with shared genetic backgrounds. However, because the teens reported their activities themselves, the authors say that some falsely reported having healthy behaviors to appear more virtuous, which may have skewed some of the results. 

More studies are needed to fully disentangle the role that genetics play in lifestyle habits and how these habits in turn affect biological aging in adolescents. Genes that contribute to obesity or substance use may directly cause accelerated biological aging, or the genes may indirectly accelerate aging by contributing to harmful behaviors that cause cell damage. 

“Learning more about the aging process and the role of genetics in it may help us identify individuals early in life who may be at risk of unhealthy behaviors during adolescence or who may be prone to faster aging and related diseases later in life,” concludes senior author Elina Sillanpää, Associate Professor at the Gerontology Research Center, University of Jyväskylä.

“Early identification of at-risk individuals may allow earlier intervention to change behaviors and prevent poor health outcomes later in life.” 

About this epigenetics and neurodevelopment research news

Author: Emily Packer
Source: eLife
Contact: Emily Packer – eLife
Image: The image is in the public domain

See also

Original Research: Open access.
“The role of adolescent lifestyle habits in biological aging: A prospective twin study” by Anna Kankaanpää et al. eLife

Abstract

The role of adolescent lifestyle habits in biological aging: A prospective twin study

Background:

Adolescence is a stage of fast growth and development. Exposures during puberty can have long-term effects on health in later life. This study aims to investigate the role of adolescent lifestyle in biological aging.

Methods:

The study participants originated from the longitudinal FinnTwin12 study (n = 5114). Adolescent lifestyle-related factors, including body mass index (BMI), leisure-time physical activity, smoking, and alcohol use, were based on self-reports and measured at ages 12, 14, and 17 years. For a subsample, blood-based DNA methylation (DNAm) was used to assess biological aging with six epigenetic aging measures in young adulthood (21–25 years, n = 824). A latent class analysis was conducted to identify patterns of lifestyle behaviors in adolescence, and differences between the subgroups in later biological aging were studied. Genetic and environmental influences on biological aging shared with lifestyle behavior patterns were estimated using quantitative genetic modeling.

Results:

We identified five subgroups of participants with different adolescent lifestyle behavior patterns. When DNAm GrimAge, DunedinPoAm, and DunedinPACE estimators were used, the class with the unhealthiest lifestyle and the class of participants with high BMI were biologically older than the classes with healthier lifestyle habits. The differences in lifestyle-related factors were maintained into young adulthood. Most of the variation in biological aging shared with adolescent lifestyle was explained by common genetic factors.

Conclusions:

These findings suggest that an unhealthy lifestyle during pubertal years is associated with accelerated biological aging in young adulthood. Genetic pleiotropy may largely explain the observed associations.

Funding:

This work was supported by the Academy of Finland (213506, 265240, 263278, 312073 to J.K., 297908 to M.O. and 341750, 346509 to E.S.), EC FP5 GenomEUtwin (J.K.), National Institutes of Health/National Heart, Lung, and Blood Institute (grant HL104125), EC MC ITN Project EPITRAIN (J.K. and M.O.), the University of Helsinki Research Funds (M.O.), Sigrid Juselius Foundation (J.K. and M.O.), Yrjö Jahnsson Foundation (6868), Juho Vainio Foundation (E.S.) and Päivikki and Sakari Sohlberg foundation (E.S.).

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World

Zelensky pushes “accelerated” application for Ukraine NATO membership

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KYIV, Ukraine — Ukraine is applying for “accelerated ascension” into NATO, President Volodymyr Zelensky said Friday, in an apparent answer to Russia’s move to illegally annex four of the country’s partially occupied regions.

The remarks were more symbolic than practical: The speedy admittance of Ukraine to the alliance would require members to immediately send troops to fight Russia, under collective defense obligations.

Ukraine has long sought NATO membership, but Zelensky conceded in March that Ukraine had to accept that it was not going to be accepted into the Western military alliance, despite receiving security assistance from countries in it.

“De facto, we have already made our way to NATO,” Zelensky said in a Telegram statement. “De facto, we have already proven compatibility with Alliance standards. They are real for Ukraine — real on the battlefield and in all aspects of our interaction. We trust each other, we help each other, and we protect each other.”

In practice, the chances of Ukraine joining NATO have only grown slimmer in the course of the Russian invasion. Member countries, including the United States, have drawn clear lines: They arm Ukraine, but they don’t have their own troops on the ground out of concern for triggering a World War.

Just an hour before Zelensky’s announcement, Russian President Vladimir Putin announced Moscow’s illegal annexation of the Donetsk, Luhansk, Zaporizhzhia and Kherson regions, which Russian forces have partially occupied. At the time of Putin’s speech, Zelensky was meeting with his National Security Council. “There will be no negotiations with Russia while Putin is the president,” Andriy Yermak, Zelensky’s chief of staff, said on Telegram. “We are moving forward. To victory.”

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World

Ukraine has ‘accelerated’ NATO application in wake of Russia annexing territories, Zelenskyy says

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Ukrainian President Volodymyr Zelenskyy on Friday said Kyiv had “accelerated” its application to join the NATO military alliance as Russia moved to annex four Ukrainian regions.

It was not immediately clear how Kyiv has pushed its application along but Zelenskyy, who has vowed to keep fighting Russia despite its illegal annexation, said Ukraine has already proven a “compatible” partner to NATO

“De facto, we have already proven compatibility with alliance standards. They are real for Ukraine – real on the battlefield and in all aspects of our interaction,” he said. “We trust each other, we help each other, and we protect each other. This is the alliance.”

In this photo released by Ukrainian Presidential Press Office, Ukrainian President Volodymyr Zelenskyy leads a meeting of the National Security and Defense Council in Kyiv, Ukraine, Friday, Sept. 30, 2022.
(Ukrainian Presidential Press Office via AP)

RUSSIAN PRESIDENT VLADIMIR PUTIN ANNOUNCES ANNEXATION OF 4 UKRAINIAN TERRITORIES AFTER ‘SHAM’ REFERENDUMS

Zelenskyy’s comments followed a speech and signing ceremony led by Russian President Vladimir Putin in which he claimed Moscow had received overwhelming support for its illegal seizure.

Putin laid claim to the Luhansk, Donetsk, Zaporizhzhia and Kherson regions in a hostile speech that threatened to use “all available means” to guard the territory and the “forever” Russian citizens now residing there.

MASS GRAVE SITE WITH 1,100 BODIES FOUND IN BURN PITS OUTSIDE LIBERATED IZYUM

Putin said the West in supporting Ukraine has acted “as a parasite” by using its financial and technological strength “to rob the entire world.”

NATO Secretary General Jens Stoltenberg has not publicly commented on Putin’s speech.

The European Union responded to Putin’s hostile address by condemning “the illegal annexation” as a “further violation of Ukraine’s independence, sovereignty and territorial integrity.”

Russian President Vladimir Putin delivers speech as he formalizes the annexation of four Ukrainian territories, Friday, Sept. 30, 2022.
(REUTERS)

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Putin called on Ukraine to rejoin peace talks but said handing back the occupied regions was off the table.

Zelenskyy has already said he will not engage with Russia in peace talks if they attempt to unilaterally seize Ukrainian territory. 

The Associated Press contributed to this report. 

Caitlin McFall is a Fox News Digital reporter. You can reach her at caitlin.mcfall@fox.com or @ctlnmcfall on Twitter.

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Science

Paleoclimatologist uncovers ancient climate feedback loop that accelerated effects of Earth’s last warming episode

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A sample of ice that once held methane gas. Credit: WUSEL007⁠—own work, CC BY-SA 3.0 / Wikipedia

Against the backdrop of a rapidly warming planet, the need to better understand the nature and long-term impact of positive climatic feedback loops—processes that accelerate the effects of warming—becomes critically important.

One way to assess the role and impact of climatic feedback processes is to use modeling studies to look into the likely future based on what we know now. Climate projection models, for instance, are the tools behind the 1.5° C global warming threshold adopted by the Intergovernmental Panel on Climate Change.

Alternatively, you can look into the past to see what happened at a time when the Earth was up to 1-1.5°C warmer than today. That is what UC Santa Barbara’s Syee Weldeab did in a paper published in the Proceedings of the National Academy of Sciences. The professor of paleoclimatology found feedback processes that have concerning implications for our modern, ongoing warming.

To get a paleoclimate perspective on global warming, Weldeab and his colleagues went back some 128,000 to 125,000 years ago to the peak Eemian warm episode. Oceans were up to 1-1.5°C warmer than during the Holocene (our current geological epoch). The authors examined marine sediment from the tropical Atlantic and found exceptionally strong warming of the intermediate water column during a brief interval within the peak Eemian warm episode.

“Remarkably, a substantially diminished Greenland Ice Sheet was capable of producing enough meltwater to perturb the density-driven circulation of the Atlantic Ocean,” Weldeab said. “This contributed significantly to the large warming of the intermediate waters we reconstructed.”

Typically, warm, salty water travels north from the tropics along the surface of the ocean and cools as it reaches northern mid and high latitudes. At this point, the now colder, denser water drops to the deep sea and travels back down toward the tropics. This interplay of density differences results in the currents that we’re familiar with today.

“What happens when you put a large amount of fresh water into the North Atlantic is basically it disturbs ocean circulation and reduces the advection of cold water into the intermediate depth of the tropical Atlantic, and as a result warms the waters at this depth,” he said.

While previous studies have discussed the disruption that meltwater caused to currents and temperatures at intermediate depths, the new paper reveals that this warming was “larger than previously thought.”

“We show a hitherto undocumented and remarkably large warming of water at intermediate depths, exhibiting a temperature increase of 6.7°C from the average background value,” Weldeab said.

This exceptionally strong warming has serious consequences, as the warm water impinges on marine sediment that contains abundant methane hydrates—a mixture of frozen water and methane. These deposits are not far below the surface of the seafloor.

Weldeab explained that at high pressure and low temperatures, the introduction of unusually warm water heats the seafloor sediment, and the ice-encapsulated gases begin to dissolve, releasing methane. Weldeab and colleagues used carbon isotopes (13C/12C) in the shells of microorganisms to uncover the fingerprint of methane release and methane oxidation across the water column.

“This is one of several amplifying climatic feedback processes where a warming climate caused accelerated ice sheet melting,” he said. “The meltwater weakened the ocean circulation, and as a consequence, the waters at intermediate depth warmed significantly, leading to destabilization of shallow subsurface methane hydrates and release of methane, a potent greenhouse gas.”

It is not known for sure whether this feedback cycle will play out in the current round of global warming, though anthropogenic activity has created a higher rate of warming than the one that occurred in the Eemian period. These findings, according to the researchers, “document and connects a sequence of climatic events and climatic feedback processes associated with and triggered by the penultimate peak climate warming that can serve as a paleo-analog for modern ongoing warming.”

“Paleo perspective is a useful approach to help us assess what might come,” Weldeab said. “It doesn’t have to happen exactly like we found; every situation is different, but it gives you a direction where to look.”

Deep ocean warming as climate changes

More information:
Syee Weldeab et al, Evidence for massive methane hydrate destabilization during the penultimate interglacial warming, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2201871119
Provided by
University of California – Santa Barbara

Citation:
Paleoclimatologist uncovers ancient climate feedback loop that accelerated effects of Earth’s last warming episode (2022, August 22)
retrieved 23 August 2022
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Health

COVID-19 Infection in Crucial Brain Regions May Lead To Accelerated Brain Aging

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Summary: The effects of COVID-19 infection on neurological health are becoming more apparent. A new study reveals COVID-19 can predispose people to irreversible neurological conditions, accelerate brain aging, and increase the risk of stroke and brain bleeds.

Source: Houston Methodist

A new study by Houston Methodist researchers reviews the emerging insights and evidence that suggest COVID-19 infections may have both short- and long-term neurological effects.

Major findings include that COVID-19 infections may predispose individuals to developing irreversible neurological conditions, may increase the likelihood of strokes and may increase the chance of developing persistent brain lesions that can lead to brain bleeding.

Led by corresponding authors Joy Mitra, Ph.D., Instructor, and Muralidhar L. Hegde, Ph.D., Professor of Neurosurgery, with the Division of DNA Repair within the Center for Neuroregeneration at the Houston Methodist Research Institute, the research team described their findings in an article titled “SARS-CoV-2 and the Central Nervous System: Emerging Insights into Hemorrhage-Associated Neurological Consequences and Therapeutic Considerations” in the journal Ageing Research Reviews.

Still a major burden on our daily lives, a great deal of research has shown that the impacts of the disease go far beyond the actual time of infection. Since the onset of the pandemic, COVID-19 has surpassed a death toll of more than 5.49 million worldwide and more than 307 million confirmed positive cases, with the U.S. accounting for almost 90 million of those cases, according to the Our World in Data website.

COVID-19 is known to invade and infect the brain, among other major organs. While a lot of research has been done to help us understand the evolution, infection and pathology of the disease, there is still a great deal that remains unclear about the long-term effects, especially on the brain.

The coronavirus infection can cause long-term and irreversible neurodegenerative diseases, particularly in the elderly and other vulnerable populations. Several brain imaging studies on COVID-19 victims and survivors have confirmed the formation of microbleed lesions in deeper brain regions related to our cognitive and memory functions.

In this review study, researchers have critically evaluated the possible chronic neuropathological outcomes in aging and comorbid populations if timely therapeutic intervention is not implemented.

Microbleeds are emerging neuropathological signatures frequently identified in people suffering from chronic stress, depressive disorders, diabetes and age-associated comorbidities. Based on their earlier findings, the investigators discuss how COVID-19-induced microhemorrhagic lesions may exacerbate DNA damage in affected brain cells, resulting in neuronal senescence and activation of cell death mechanisms, which ultimately impact brain microstructure-vasculature.

These pathological phenomena resemble hallmarks of neurodegenerative conditions like Alzheimer’s and Parkinson’s diseases and are likely to aggravate advanced-stage dementia, as well as cognitive and motor deficits.

Still a major burden on our daily lives, a great deal of research has shown that the impacts of the disease go far beyond the actual time of infection. Image is in the public domain

The effects of COVID-19 infection on various aspects of the central nervous system are currently being studied. For instance, 20-30% of COVID-19 patients report a lingering psychological condition known as “brain fog” where individuals suffer from symptoms such as memory loss, difficulty in concentrating, forgetting daily activities, difficulty in selecting the right words, taking longer than usual time to complete a regular task, disoriented thought processes and emotional numbness.

More severe long-term effects analyzed in the Houston Methodist review article include predispositions for Alzheimer’s, Parkinson’s and related neurodegenerative diseases, as well as cardiovascular disorders due to internal bleeding and blood clotting-induced lesions in the part of the brain that regulates our respiratory system, following the COVID-19 symptoms.

Additionally, cellular aging is thought to be accelerated in COVID-19 patients. A plethora of cellular stresses inhibit the virus-infected cells from undergoing their normal biological functions and let them enter into “hibernation mode” or even die completely.

The study also suggests various strategies to improve some of these long-term neuropsychiatric and neurodegenerative outcomes, as well as outlines the importance of the therapeutic regimen of the “nanozyme” in combination with various FDA-approved drugs that may prove successful to fight against this catastrophic disease.

However, given the ever-evolving nature of this field, associations like the ones described in this review show the fight against COVID-19 is far from over, say the investigators, and reinforce the message that getting vaccinated and maintaining proper hygiene are key in trying to prevent such long-term and detrimental consequences.

About this COVID-19 and neurology research news

Author: Press Office
Source: Houston Methodist
Contact: Press Office – Houston Methodist
Image: The image is in the public domain

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Original Research: Open access.
“SARS-CoV-2 and the central nervous system: Emerging insights into hemorrhage-associated neurological consequences and therapeutic considerations” by Joy Mitra et al. Ageing Research Reviews

Abstract

SARS-CoV-2 and the central nervous system: Emerging insights into hemorrhage-associated neurological consequences and therapeutic considerations

Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to impact our lives by causing widespread illness and death and poses a threat due to the possibility of emerging strains. SARS-CoV-2 targets angiotensin-converting enzyme 2 (ACE2) before entering vital organs of the body, including the brain. Studies have shown systemic inflammation, cellular senescence, and viral toxicity-mediated multi-organ failure occur during infectious periods.

However, prognostic investigations suggest that both acute and long-term neurological complications, including predisposition to irreversible neurodegenerative diseases, can be a serious concern for COVID-19 survivors, especially the elderly population.

As emerging studies reveal sites of SARS-CoV-2 infection in different parts of the brain, potential causes of chronic lesions including cerebral and deep-brain microbleeds and the likelihood of developing stroke-like pathologies increases, with critical long-term consequences, particularly for individuals with neuropathological and/or age-associated comorbid conditions.

Our recent studies linking the blood degradation products to genome instability, leading to cellular senescence and ferroptosis, raise the possibility of similar neurovascular events as a result of SARS-CoV-2 infection.

In this review, we discuss the neuropathological consequences of SARS-CoV-2 infection in COVID survivors, focusing on possible hemorrhagic damage in brain cells, its association to aging, and the future directions in developing mechanism-guided therapeutic strategies.

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Cumulative Loneliness Associated With Accelerated Memory Aging in Older Adults

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Summary: Feeling lonely for extended periods of time was associated with more rapid memory decline in those aged over 65.

Source: University of Michigan

Prolonged loneliness in adults over 65 may be an important risk factor for accelerated memory aging, according to a new study led by University of Michigan School of Public Health researchers.

“We found that feeling lonely for a longer duration of time was associated with more rapid memory decline, suggesting that it is never too late in life to work on reducing feelings of loneliness to support healthy aging,” said Lindsay Kobayashi, assistant professor of epidemiology and senior author of the study published in the journal Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

Kobayashi and colleagues analyzed interview data from more than 9,000 adults over age 50 from the U.S. Health and Retirement Study from 1996 to 2016. They evaluated participants’ cumulative durations of loneliness from 1996 to 2004 in relation to changes in memory function over the following 12 years from 2004 to 2016.

Prolonged loneliness in adults over 65 may be an important risk factor for accelerated memory aging. Image is in the public domain

Xuexin Yu, a doctoral candidate in epidemiology and lead author of the study, said the association between loneliness and memory aging was strongest in individuals aged 65 and over, with women experiencing stronger and faster memory declines than men.

“Women tend to have larger social networks than men, which may make women less likely to feel lonely than men, but more vulnerable once experiencing long-term loneliness,” Yu said. “Social stigma and the reluctance to admit loneliness may also be a factor in this observed gender-specific association.”

Credit: University of Michigan

Loneliness and objective social isolation are important factors in the health of older adults, and researchers say that reducing loneliness in mid-to-late life may help maintain memory function for a longer duration.

In addition to Yu and Kobayashi, Ashly Westrick, postdoctoral fellow at U-M’s Center for Social Epidemiology and Population Health, is a co-author of the study.

About this aging and loneliness research news

Author: Press Office
Source: University of Michigan
Contact: Press Office – University of Michigan
Image: The image is in the public domain

Original Research: Open access.
“Cumulative loneliness and subsequent memory function and rate of decline among adults aged ≥50 in the United States, 1996 to 2016” by Xuexin Yu et al. Alzheimer’s & Dementia

Abstract

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Cumulative loneliness and subsequent memory function and rate of decline among adults aged ≥50 in the United States, 1996 to 2016

Introduction

The study objective was to investigate the association between loneliness duration and memory function over a 20-year period.

Methods

Data were from 9032 adults aged ≥50 in the Health and Retirement Study. Loneliness status (yes vs. no) was assessed biennially from 1996 to 2004 and its duration was categorized as never, 1 time point, 2 time points, and ≥3 time points. Episodic memory was assessed from 2004 to 2016 as a composite of immediate and delayed recall trials combined with proxy-reported memory. Mixed-effects linear regression models were fitted.

Results

A longer duration of loneliness was associated with lower memory scores (P < 0.001) and a faster rate of decline (P < 0.001). The association was stronger among adults aged ≥65 than those aged <65 (three-way interaction P = 0.013) and was stronger among women than men (three-way interaction P = 0.002).

Discussion

Cumulative loneliness may be a salient risk factor for accelerated memory aging, especially among women aged ≥65.

Highlight

  • A longer duration of loneliness was associated with accelerated memory aging.
  • The association was stronger among women than men and among older adults than the younger.
  • Reducing loneliness in mid- to late life may help maintain memory function.

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Current Monkeypox Virus May Be Showing Accelerated Evolution as More New Cases Rise

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The monkeypox outbreak that health authorities first noticed in Europe back in May is getting worse. According to the World Health Organization’s latest report, there are over 2,100 confirmed cases, and at least one person has died.

Now geneticists finally have enough data to begin getting a handle on how exactly the outbreak started—and where it might be heading.

It’s not good news. Monkeypox, a viral disease that causes fever and a rash and can be fatal in a small percentage of cases, is endemic in Africa. And now it’s running amuck on every other permanently inhabited continent—and evolving quickly. While health officials have all the tools they need to contain it—primarily contact-tracing and vaccines—right now the virus is moving faster than we are, and adapting.

The current strain of monkeypox may have been circulating, undetected, months before we finally diagnosed the first case outside Africa. And because there are so many more copies of the virus than we first expected, each mutating separately, this new pox strain could evolve into dangerous new forms with disturbing speed.

“Our data reveals additional clues of ongoing viral evolution and potential human adaptation,” a team led by Joana Isidro, a geneticist with the National Institute of Health Dr. Ricardo Jorge in Spain, wrote in the new peer-reviewed study published Friday in Nature Medicine.

A medical laboratory technician prepares to test suspected monkeypox samples at the microbiology laboratory of La Paz Hospital.

Pablo Blazquez Dominguez/Getty

Monkeypox first made the leap from monkeys or rodents to people in the Democratic Republic of Congo in 1970—and has frequently flared up in Africa in the decades since then. There are two main strains, one each in West and Central Africa. The milder West African strain can be fatal in up to 1 percent of cases. The more dangerous Central African strain can kill up to 10 percent of the people it infects.

The pox mostly spreads through close physical contact, especially sexual contact. It’s not a sexually transmitted disease, however. It just takes advantage of the skin-to-skin contact that accompanies sex. The virus can also travel short distances on spittle, although probably not far enough to qualify as “airborne.”

Monkeypox occasionally spreads to places where it’s not already endemic. In 2003, 47 people in the U.S. got sick with the West African strain after exposure to a shipment of pet rodents from Ghana to Texas. A rapid response by state and federal health officials—and a few doses of smallpox vaccine, which also works on monkeypox—prevented anyone dying and temporarily eliminated the virus in the U.S.

“Because there are so many more copies of the virus than we first expected, each mutating separately, this new pox strain could evolve into dangerous new forms with disturbing speed.”

Officials first noticed the current outbreak, also of the West African strain, after diagnosing a U.K. traveler returning from Nigeria in early May. Hitching a ride to Europe, the virus spread quickly through physical contact. David Heymann, who formerly headed the World Health Organization’s emergencies department, said that men attending raves in Spain and Belgium “amplified” the outbreak—apparently through close, sometimes sexual, contact with other men.

After that, the virus accompanied travelers on planes heading for countries far and wide. Doctors diagnosed the first U.S. case on May 27. As of Thursday, the U.S. Centers for Disease Control had tallied around 3,500 cases in 44 countries, including 172 in the U.S.

Just one person has died of the pox in the current outbreak—in Nigeria. But serious illness and death can lag an actual diagnosis by several weeks, so it’s possible many more deaths are coming.

Worse, on June 3 the CDC announced it had found genetic evidence of U.S. pox cases that predated the first cases in Europe from May. Doctors may not have noticed or reported these earlier cases, at first, owing to the similarity between pox symptoms and the symptoms of some common sexually-transmitted diseases such as herpes.

There was some speculation that the earlier U.S. cases were part of a totally separate outbreak that just happened to overlap with the May outbreak. Isidro and her team sequenced 15 samples taken from current pox patients and concluded that, no, there’s just one big outbreak. “All outbreak MPX strains sequenced so far tightly cluster together, suggesting that the ongoing outbreak has a single origin,” they wrote, using the scientific acronym for monkeypox.

A passenger walks in front of monkeypox virus information at Soekarno-Hatta International Airport in Tangerang near Jakarta, Indonesia.

Jepayona Delita/Getty

It’s less clear exactly when the current outbreak really began. According to Isidro and company, the virus may have been circulating outside of endemic countries long before officials finally noticed the infections and sounded the alarm. The virus potentially traveled beyond Africa in animals such as pet rodents, and spread from animal to animal before finally jumping to a human host and triggering the current outbreak some time prior to May, the geneticists wrote.

Most likely, however, monkeypox spread the usual person-to-person way—and recently, Isidro’s team concluded. “Current data points for a scenario of more than one introduction from a single origin, with superspreader event(s) (e.g., saunas used for sexual encounters) and travel abroad likely triggering the rapid worldwide dissemination.”

In other words, someone—or several someones—touched an infected person in Africa, then flew home to Europe or the U.S., and spread the virus to other people through direct contact. The “single origin” is the infected human population in Africa. “More than one introduction” means multiple travelers picked up the same pox strain and spread it beyond Africa around the same time.

All that is to say. the May case in the U.K. was the first infection authorities noticed, but chances are it wasn’t the infection that started the outbreak.

“When you start looking for something, you find it.”

— Michael Wiley, University of Nebraska Medical Center

One particularly disturbing possibility is that the pox is often or even usually circulating to some degree in non-endemic countries, but we rarely notice unless there’s a big surge in infections that compels doctors to look more closely at symptoms that could easily be mistaken for something else. Say, herpes. “When you start looking for something, you find it,” Michael Wiley, a public health expert at the University of Nebraska Medical Center who was not involved with the new study, told The Daily Beast.

In any event, undetected or overlapping transmission vectors are alarming—and not just because they could mean faster viral spread to more places before authorities finally, hopefully, contain an outbreak. No, the multiple introductions also represent an opportunity for a virus to mutate more, or more quickly, than usual.

When it comes to viral diseases, every infected person is a kind of living laboratory—a place where the virus can interact with the human immune system’s antibodies and T-cells and develop countermeasures. The more separate chains of transmission we hand the pox, the more likely the virus is to mutate along these vectors in some way that benefits it and hurts us. For example, developing resistance to our vaccines and antibodies.

Isidro’s team found 50 single nucleotide polymorphisms, or SNPs, in the monkeypox strain behind the current outbreak. Each SNP is a change in the baseline DNA of a particular organism. Fifty SNPs “is far more (roughly 6-12 fold more) than one would expect,” the geneticists wrote. “Such a divergent branch might represent accelerated evolution.”

That doesn’t mean the pox itself is learning to evolve faster. It’s possible the current outbreak just achieved a kind of genetic critical mass before we had a chance to intervene. More infected people means more opportunities to evolve, even if the individual rate of mutation is the same.

“If I had to guess, I think that we may see more drift in terms of numbers of mutations just based upon the size of the outbreak,” James Lawler, an infectious disease expert and a colleague of Wiley at the University of Nebraska Medical Center, told The Daily Beast. “Drift” is just a fancy term for “increase,” in this context.

Monkeypox may have been hiding in plain sight long before we finally noticed it two months ago. Maybe this strain of the virus got lucky and more than one traveler helped spread it outside Africa nearly simultaneously. Maybe it’s evolving faster because it’s getting cleverer. More likely, it’s changing at its current fast clip because there are so many more copies of the virus than we first expected, each mutating every chance it gets.

It’s all bad news, regardless—and it should stoke an even greater sense of urgency among health officials as they scramble to diagnose and contain a growing number of cases.

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Monkeypox Has Mutated at an Unprecedented Rate with ‘Accelerated Evolution’

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Researchers investigating the genetic make-up of the monkeypox virus have said the virus appears to have mutated far, far more than would normally be expected.

The work has been outlined in a new study published in the journal Nature Medicine. As part of the study, Portuguese researchers collected 15 monkeypox virus sequences in total—mostly from Portugal—and reconstructed their genetic data.

Monkeypox is a rare disease believed to have its origin in animals. It is from the same family of viruses as smallpox. Usually monkeypox is localized within West and Central African countries but this year has seen the first multi-country outbreak, including cases without known links to West or Central Africa, with more than 3,500 cases reported as of Thursday, according to the U.S. Centers for Disease Control and Prevention (CDC).

The virus can be transmitted between people by close contact with lesions, body fluids, respiratory droplets—such as via face-to-face contact—and contaminated materials. The current outbreak has introduced uncertainty about exactly how the virus is spreading, with far more transmission than is normal.

In the latest study, researchers discovered around 50 genetic variations in the viruses they studied compared to ones from 2018 and 2019. This, they said, “is far more than one would expect considering previous estimates” of the mutation rate of orthopoxviruses of which monkeypox is a type—between six and 12 times more.

These significant genetic variations might suggest “accelerated evolution.”

Stock image representing monkeypox. Researchers have found “accelerated evolution” in the latest monkeypox strain that has caused an outbreak in multiple non-endemic countries.
Getty Images

“Our data reveals additional clues of ongoing viral evolution and potential human adaptation,” the team wrote, adding that they had identified proteins that are known to interact with peoples’ immune systems. However, more studies will be needed to find out more about the potential role these might play in adapting the monkeypox virus for human spread.

João Paulo Gomes, head of the Genomics & Bioinformatics Unit at the National Institute of Health in Portugal who co-authored the study, said it is not known whether the mutations have contributed to increased transmissibility between people.

“We do not know that,” he told Newsweek. “We just know that these additional 50 mutations were quite unexpected.

“Considering that this 2022 monkeypox virus is likely a descendant of the one in the 2017 Nigeria outbreak, one would expect no more than five to 10 additional mutations instead of the observed about 50 mutations. We hope that now, specialized groups will perform laboratory experiments in order to understand if this 2022 virus has increased its transmissibility.”

Another notable finding from the study is that most of the mutations are of a particular type that could have been introduced by a human defence mechanism called APOBEC3, which works by introducing mutations to viruses in order to stop them from working properly, said Pam Vallely, professor of medical virology at the University of Manchester.

“However, in this case the mutations are apparently not making the virus non-viable and may be helping it to adapt to human-human transmission,” Vallely, who was not involved in the study, told Newsweek. “This is just a theory that fits the current evidence, and lots more work is going to be needed to see if this is what is really happening. I don’t think we can say the mutations have made it more contagious, but maybe they have made it better adapted to humans.”

The researchers say their work shows that viral genome sequencing of monkeypox might be precise enough to track the spread of the current outbreak and see how transmission might be changing. This, in turn, would allow decision makers to introduce measures to curb monkeypox spread. Vaccines are already available.

Monkeypox virus particles seen in a microscope image, published June 6, 2022. Thousands of cases have been reported as part of a global outbreak this year.
CDC/Goldsmith/Smith Collection/Gado/Getty

Jeremy Kamil, associate professor of microbiology and immunology at Louisiana State University Health Shreveport, told Newsweek the study as “very impressive” but said it is too early to say for sure whether monkeypox is undergoing rapid evolution until we can rule out the possibility that the virus has been circulating and adapting in people “for longer than people assume—perhaps starting out in undersampled regions of the world like parts of Africa where monkeypox is endemic.”

Alex Sigal, a virologist at the Africa Health Research Institute (AHRI) and associate professor at the University of KwaZulu-Natal, who was also not involved in the study, echoed Kamil’s point.

“I think this outbreak was under the radar for a while,” he told Newsweek. “Certainly the diminishing immunity because the smallpox vaccine is no longer given could have helped.

“[The findings are] concerning, but we’ll see if this virus keeps spreading once people start to be aware of the signs and it breaks out in the general population. It’s contact dependent, and unless spread goes respiratory, it should be easier to stop.”

Virus sequencing efforts also confirmed that the viruses studied belonged to a specific type of monkeypox virus known as clade 3, confirming them to be part of the wider West African type as opposed to the Central African type.

The West African version of monkeypox, with a case fatality ratio of usually less than one percent, is much less virulent than the Central African clade 1 version which can cause death in more than 10 percent of cases, according to the study.

Update, 6/24/22, 6:13 a.m. ET: This article has been updated with the most recent monkeypox case numbers.

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