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Califf plans work on opioids, accelerated approvals on return to FDA
Robert M. Califf, MD, plans to take a close look at federal policies on opioid prescriptions in his expected second turn as the top U.S. regulator of medical products, as well as keep closer tabs on the performance of drugs cleared with accelerated approvals.
Dr. Califf on Tuesday fielded questions at a Senate hearing about his nomination by President Joe Biden to serve as administrator of the U.S. Food and Drug Administration, a role in which he served in the Obama administration. He also spoke about the need to bolster the nation’s ability to maintain an adequate supply of key medical products, including drugs.
Members of the Senate Health, Education, Labor and Pensions Committee, which is handling Dr. Califf’s nomination, were largely cordial and supportive during the hearing. Sen. Patty Murray (D-Wash.), the committee chair, and the panel’s top Republican, Sen. Richard Burr of North Carolina, addressed Dr. Califf during the hearing as if he would soon serve again as the FDA’s leader. Both were among the senators who voted 89-4 to confirm Dr. Califf in a February 2016 vote.
Dr. Califf “was previously confirmed to lead FDA in an overwhelming bipartisan vote, and I look forward to working with him again to ensure FDA continues to protect families across the country, uphold the gold standard of safety and effectiveness, and put science and data first,” Sen. Murray said.
Less enthusiastic about Dr. Califf was Sen. Bernie Sanders (I-VT), who was among the seven senators who did not vote on Dr. Califf’s nomination in 2016.
Sen. Sanders objected in 2016 to Dr. Califf’s ties to the pharmaceutical industry, and he did so again Tuesday. A noted leader in conducting clinical trials, Dr. Califf has worked with many drugmakers. But at the hearing, Dr. Califf said he concurs with Sen. Sanders on an idea strongly opposed by the pharmaceutical industry.
In response to Sen. Sanders’ question, Dr. Califf said he already is “on record as being in favor of Medicare negotiating with the industry on prices.”
The FDA would not take direct part in negotiations, as this work would be handled by the Centers for Medicare & Medicaid Services. Democrats want to give Medicare some negotiating authority through their sweeping Build Back Better Act.
People in the United States are dismayed over both the cost of prescription drugs and the widespread distribution of prescription painkillers that helped fuel the current opioid epidemic, Sen. Sanders told Dr. Califf. Many people will be concerned about an FDA commissioner who has benefited from close ties to the industry, Sen. Sanders said.
“How are they going to believe that you’re going to be an independent and strong voice against this enormously powerful, special interest?” Sen. Sanders asked.
“I’m totally with you on the concept that the price of pharmaceuticals is way too high in this country,” Dr. Califf said in reply.
Dr. Califf was paid $2.7 million in salary and bonus by Verily Life Sciences, the biomedical research organization operated by Alphabet, parent company of Google, according to his federal financial disclosure. He also reported holding board positions with pharmaceutical companies AmyriAD and Centessa Pharmaceuticals.
Bloomberg Government reported that Dr. Califf has ties to about 16 other research organizations and biotech companies. Bloomberg Government also said that, in his earlier FDA service, Dr. Califf kept a whiteboard in his office that listed all the activities and projects that required his recusal, citing as a source Howard Sklamberg, who was a deputy commissioner under Dr. Califf.
“He was very, very, very careful,” Mr. Sklamberg, who’s now an attorney at Arnold & Porter LLP, told Bloomberg Government.
‘Work to do’ on opioids
Senators looped back repeatedly to the topic of opioids during Dr. Califf’s hearing, reflecting deep concerns about the FDA’s efforts to warn of the risks of prescription painkillers.
There were an estimated 100,306 drug overdose deaths in the United States in the 12 months ending in April, an increase of 28.5% from the 78,056 deaths during the same period the year before, according to the Centers for Disease Control and Prevention.
Dr. Califf said he plans to focus on what information the FDA conveys to the public about the risks of prescription painkillers, including a look at what the labels for these products say.
“I am committed to do a comprehensive review of the status of opioids, early in my tenure,” Dr. Califf said.
Dr. Califf indicated that physicians are still too quick to provide excess doses of these medicines, despite years of efforts to restrain their use. He said he knows relatives who were given 30-day prescriptions for opioids after minor surgery.
“So I know we have work to do,” Dr. Califf said.
Concerns about the FDA’s previous work in managing opioids has led to protests from a few Democratic senators about the prospect of President Biden nominating the acting FDA commissioner, Janet Woodcock, MD, for the permanent post.
At the hearing, Sen. Ben Ray Luján (D-NM) raised the case of the FDA’s approval of the powerful Zohydro painkiller. The agency approved that drug despite an 11-2 vote against it by the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee.
Sen. Luján asked Dr. Califf what he would do if an FDA advisory committee voted “overwhelmingly” against recommending approval of a medicine, as happened in the Zohydro case.
While not mentioned by Sen. Luján in this exchange during the hearing with Dr. Califf, the FDA staff’s rejection of recommendations of advisory committees has been a growing concern among researchers.
The agency last year approved aducanumab (Aduhelm, Biogen), a drug for Alzheimer’s disease, dismissing the advice of its Peripheral and Central Nervous System Drugs Advisory Committee. That decision triggered the resignation of several members of the panel. The FDA staff also earlier rejected the conclusion the majority of members of the same advisory committee offered in 2016 on eteplirsen (Exondys 51, Sarepta), a drug for Duchenne muscular dystrophy.
Dr. Califf told Sen. Luján he had done recent research into how often the FDA staff does not concur with the recommendations of an advisory committee. He said the FDA takes a different course of action in about 25% of cases. In about three-quarters of those cases, the FDA staff opts for a “more stringent” approach regarding allowing the public access to the drug, as opposed to a more generous one as seen in the Zohydro, Aduhelm, and Exondys 51 cases.
Still, Dr. Califf said that when there’s an 11-2 advisory committee vote against recommendation of a product, “the leaders at FDA really need to take a close look” at what’s happening.
Question on accelerated approvals
The FDA’s approval of aducanumab drew attention to a debate already underway about conditional clearances known as accelerated approvals.
The FDA has used this path since the 1990s to speed access to drugs for serious conditions. The trade-off for early access is that the agency sometimes makes the wrong call based on initial findings, and clears a medicine later found not to benefit patients as expected.
The FDA’s cancer division is in the midst of public efforts to address cases where drugmakers have not been able to deliver studies that support accelerated approvals of their oncology drugs. In addition, the Office of Inspector General of the U.S. Department of Health & Human Services announced in August that it is reviewing the FDA’s handling of the accelerated approval process.
At Tuesday’s hearing, Sen. Burr grilled Dr. Califf about how he would respond to calls to change how the FDA handles the accelerated-approval process.
“Can you commit to me and to patients who may rely on cutting-edge treatments that you will not support efforts to narrow this pathway or raise the bar for drugs to be approved under those pathways?” Burr asked Califf.
Dr. Califf responded by saying he was “a fan of accelerated approval – for the right conditions.”
Earlier, in his opening statement, Dr. Califf had said his mother benefited directly from the accelerated approval of new drugs for multiple myeloma. Dr. Califf told Sen. Burr that he had spent “countless hours with patient groups” and understands the need to speed the approval of medicines for serious diseases.
But the FDA also has to make sure it holds up its end of the bargain struck with accelerated approvals. This involves checking on how these medicines work once they are marketed.
“We’re accepting that there’s more uncertainty,” Dr. Califf said. “That means we’ve got to have a better system to evaluate these products as they’re used on the market. And I think there are ways that we can do that now. Technology is making this possible in ways that it just was not possible before.”
Worries about the medical supply chain
Sen. Susan Collins (R-Maine) asked Dr. Califf about the vulnerability of the U.S. medical system to disruptions of the supply chain. She raised concerns about China’s dominance in antibiotic manufacturing as an example. She asked if Congress could do more to encourage domestic manufacturing of medical supplies, such as by offering tax incentives.
Dr. Califf told Sen. Collins he shared her concern about the U.S. manufacturing of ingredients used in both branded and generic drugs. He said he recently has served on a committee of the National Academy of Medicine that is examining supply chain issues.
This committee will soon release a report with specific recommendations, Dr. Califf said.
“We don’t have enough competitive entities in what’s become sort of a commodity business” of drug manufacturing, Dr. Califf said. “So we need a number of steps to make the system more resilient.”
A version of this article first appeared on Medscape.com.
Robert M. Califf, MD, plans to take a close look at federal policies on opioid prescriptions in his expected second turn as the top U.S. regulator of medical products, as well as keep closer tabs on the performance of drugs cleared with accelerated approvals.
Dr. Califf on Tuesday fielded questions at a Senate hearing about his nomination by President Joe Biden to serve as administrator of the U.S. Food and Drug Administration, a role in which he served in the Obama administration. He also spoke about the need to bolster the nation’s ability to maintain an adequate supply of key medical products, including drugs.
Members of the Senate Health, Education, Labor and Pensions Committee, which is handling Dr. Califf’s nomination, were largely cordial and supportive during the hearing. Sen. Patty Murray (D-Wash.), the committee chair, and the panel’s top Republican, Sen. Richard Burr of North Carolina, addressed Dr. Califf during the hearing as if he would soon serve again as the FDA’s leader. Both were among the senators who voted 89-4 to confirm Dr. Califf in a February 2016 vote.
Dr. Califf “was previously confirmed to lead FDA in an overwhelming bipartisan vote, and I look forward to working with him again to ensure FDA continues to protect families across the country, uphold the gold standard of safety and effectiveness, and put science and data first,” Sen. Murray said.
Less enthusiastic about Dr. Califf was Sen. Bernie Sanders (I-VT), who was among the seven senators who did not vote on Dr. Califf’s nomination in 2016.
Sen. Sanders objected in 2016 to Dr. Califf’s ties to the pharmaceutical industry, and he did so again Tuesday. A noted leader in conducting clinical trials, Dr. Califf has worked with many drugmakers. But at the hearing, Dr. Califf said he concurs with Sen. Sanders on an idea strongly opposed by the pharmaceutical industry.
In response to Sen. Sanders’ question, Dr. Califf said he already is “on record as being in favor of Medicare negotiating with the industry on prices.”
The FDA would not take direct part in negotiations, as this work would be handled by the Centers for Medicare & Medicaid Services. Democrats want to give Medicare some negotiating authority through their sweeping Build Back Better Act.
People in the United States are dismayed over both the cost of prescription drugs and the widespread distribution of prescription painkillers that helped fuel the current opioid epidemic, Sen. Sanders told Dr. Califf. Many people will be concerned about an FDA commissioner who has benefited from close ties to the industry, Sen. Sanders said.
“How are they going to believe that you’re going to be an independent and strong voice against this enormously powerful, special interest?” Sen. Sanders asked.
“I’m totally with you on the concept that the price of pharmaceuticals is way too high in this country,” Dr. Califf said in reply.
Dr. Califf was paid $2.7 million in salary and bonus by Verily Life Sciences, the biomedical research organization operated by Alphabet, parent company of Google, according to his federal financial disclosure. He also reported holding board positions with pharmaceutical companies AmyriAD and Centessa Pharmaceuticals.
Bloomberg Government reported that Dr. Califf has ties to about 16 other research organizations and biotech companies. Bloomberg Government also said that, in his earlier FDA service, Dr. Califf kept a whiteboard in his office that listed all the activities and projects that required his recusal, citing as a source Howard Sklamberg, who was a deputy commissioner under Dr. Califf.
“He was very, very, very careful,” Mr. Sklamberg, who’s now an attorney at Arnold & Porter LLP, told Bloomberg Government.
‘Work to do’ on opioids
Senators looped back repeatedly to the topic of opioids during Dr. Califf’s hearing, reflecting deep concerns about the FDA’s efforts to warn of the risks of prescription painkillers.
There were an estimated 100,306 drug overdose deaths in the United States in the 12 months ending in April, an increase of 28.5% from the 78,056 deaths during the same period the year before, according to the Centers for Disease Control and Prevention.
Dr. Califf said he plans to focus on what information the FDA conveys to the public about the risks of prescription painkillers, including a look at what the labels for these products say.
“I am committed to do a comprehensive review of the status of opioids, early in my tenure,” Dr. Califf said.
Dr. Califf indicated that physicians are still too quick to provide excess doses of these medicines, despite years of efforts to restrain their use. He said he knows relatives who were given 30-day prescriptions for opioids after minor surgery.
“So I know we have work to do,” Dr. Califf said.
Concerns about the FDA’s previous work in managing opioids has led to protests from a few Democratic senators about the prospect of President Biden nominating the acting FDA commissioner, Janet Woodcock, MD, for the permanent post.
At the hearing, Sen. Ben Ray Luján (D-NM) raised the case of the FDA’s approval of the powerful Zohydro painkiller. The agency approved that drug despite an 11-2 vote against it by the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee.
Sen. Luján asked Dr. Califf what he would do if an FDA advisory committee voted “overwhelmingly” against recommending approval of a medicine, as happened in the Zohydro case.
While not mentioned by Sen. Luján in this exchange during the hearing with Dr. Califf, the FDA staff’s rejection of recommendations of advisory committees has been a growing concern among researchers.
The agency last year approved aducanumab (Aduhelm, Biogen), a drug for Alzheimer’s disease, dismissing the advice of its Peripheral and Central Nervous System Drugs Advisory Committee. That decision triggered the resignation of several members of the panel. The FDA staff also earlier rejected the conclusion the majority of members of the same advisory committee offered in 2016 on eteplirsen (Exondys 51, Sarepta), a drug for Duchenne muscular dystrophy.
Dr. Califf told Sen. Luján he had done recent research into how often the FDA staff does not concur with the recommendations of an advisory committee. He said the FDA takes a different course of action in about 25% of cases. In about three-quarters of those cases, the FDA staff opts for a “more stringent” approach regarding allowing the public access to the drug, as opposed to a more generous one as seen in the Zohydro, Aduhelm, and Exondys 51 cases.
Still, Dr. Califf said that when there’s an 11-2 advisory committee vote against recommendation of a product, “the leaders at FDA really need to take a close look” at what’s happening.
Question on accelerated approvals
The FDA’s approval of aducanumab drew attention to a debate already underway about conditional clearances known as accelerated approvals.
The FDA has used this path since the 1990s to speed access to drugs for serious conditions. The trade-off for early access is that the agency sometimes makes the wrong call based on initial findings, and clears a medicine later found not to benefit patients as expected.
The FDA’s cancer division is in the midst of public efforts to address cases where drugmakers have not been able to deliver studies that support accelerated approvals of their oncology drugs. In addition, the Office of Inspector General of the U.S. Department of Health & Human Services announced in August that it is reviewing the FDA’s handling of the accelerated approval process.
At Tuesday’s hearing, Sen. Burr grilled Dr. Califf about how he would respond to calls to change how the FDA handles the accelerated-approval process.
“Can you commit to me and to patients who may rely on cutting-edge treatments that you will not support efforts to narrow this pathway or raise the bar for drugs to be approved under those pathways?” Burr asked Califf.
Dr. Califf responded by saying he was “a fan of accelerated approval – for the right conditions.”
Earlier, in his opening statement, Dr. Califf had said his mother benefited directly from the accelerated approval of new drugs for multiple myeloma. Dr. Califf told Sen. Burr that he had spent “countless hours with patient groups” and understands the need to speed the approval of medicines for serious diseases.
But the FDA also has to make sure it holds up its end of the bargain struck with accelerated approvals. This involves checking on how these medicines work once they are marketed.
“We’re accepting that there’s more uncertainty,” Dr. Califf said. “That means we’ve got to have a better system to evaluate these products as they’re used on the market. And I think there are ways that we can do that now. Technology is making this possible in ways that it just was not possible before.”
Worries about the medical supply chain
Sen. Susan Collins (R-Maine) asked Dr. Califf about the vulnerability of the U.S. medical system to disruptions of the supply chain. She raised concerns about China’s dominance in antibiotic manufacturing as an example. She asked if Congress could do more to encourage domestic manufacturing of medical supplies, such as by offering tax incentives.
Dr. Califf told Sen. Collins he shared her concern about the U.S. manufacturing of ingredients used in both branded and generic drugs. He said he recently has served on a committee of the National Academy of Medicine that is examining supply chain issues.
This committee will soon release a report with specific recommendations, Dr. Califf said.
“We don’t have enough competitive entities in what’s become sort of a commodity business” of drug manufacturing, Dr. Califf said. “So we need a number of steps to make the system more resilient.”
A version of this article first appeared on Medscape.com.
Robert M. Califf, MD, plans to take a close look at federal policies on opioid prescriptions in his expected second turn as the top U.S. regulator of medical products, as well as keep closer tabs on the performance of drugs cleared with accelerated approvals.
Dr. Califf on Tuesday fielded questions at a Senate hearing about his nomination by President Joe Biden to serve as administrator of the U.S. Food and Drug Administration, a role in which he served in the Obama administration. He also spoke about the need to bolster the nation’s ability to maintain an adequate supply of key medical products, including drugs.
Members of the Senate Health, Education, Labor and Pensions Committee, which is handling Dr. Califf’s nomination, were largely cordial and supportive during the hearing. Sen. Patty Murray (D-Wash.), the committee chair, and the panel’s top Republican, Sen. Richard Burr of North Carolina, addressed Dr. Califf during the hearing as if he would soon serve again as the FDA’s leader. Both were among the senators who voted 89-4 to confirm Dr. Califf in a February 2016 vote.
Dr. Califf “was previously confirmed to lead FDA in an overwhelming bipartisan vote, and I look forward to working with him again to ensure FDA continues to protect families across the country, uphold the gold standard of safety and effectiveness, and put science and data first,” Sen. Murray said.
Less enthusiastic about Dr. Califf was Sen. Bernie Sanders (I-VT), who was among the seven senators who did not vote on Dr. Califf’s nomination in 2016.
Sen. Sanders objected in 2016 to Dr. Califf’s ties to the pharmaceutical industry, and he did so again Tuesday. A noted leader in conducting clinical trials, Dr. Califf has worked with many drugmakers. But at the hearing, Dr. Califf said he concurs with Sen. Sanders on an idea strongly opposed by the pharmaceutical industry.
In response to Sen. Sanders’ question, Dr. Califf said he already is “on record as being in favor of Medicare negotiating with the industry on prices.”
The FDA would not take direct part in negotiations, as this work would be handled by the Centers for Medicare & Medicaid Services. Democrats want to give Medicare some negotiating authority through their sweeping Build Back Better Act.
People in the United States are dismayed over both the cost of prescription drugs and the widespread distribution of prescription painkillers that helped fuel the current opioid epidemic, Sen. Sanders told Dr. Califf. Many people will be concerned about an FDA commissioner who has benefited from close ties to the industry, Sen. Sanders said.
“How are they going to believe that you’re going to be an independent and strong voice against this enormously powerful, special interest?” Sen. Sanders asked.
“I’m totally with you on the concept that the price of pharmaceuticals is way too high in this country,” Dr. Califf said in reply.
Dr. Califf was paid $2.7 million in salary and bonus by Verily Life Sciences, the biomedical research organization operated by Alphabet, parent company of Google, according to his federal financial disclosure. He also reported holding board positions with pharmaceutical companies AmyriAD and Centessa Pharmaceuticals.
Bloomberg Government reported that Dr. Califf has ties to about 16 other research organizations and biotech companies. Bloomberg Government also said that, in his earlier FDA service, Dr. Califf kept a whiteboard in his office that listed all the activities and projects that required his recusal, citing as a source Howard Sklamberg, who was a deputy commissioner under Dr. Califf.
“He was very, very, very careful,” Mr. Sklamberg, who’s now an attorney at Arnold & Porter LLP, told Bloomberg Government.
‘Work to do’ on opioids
Senators looped back repeatedly to the topic of opioids during Dr. Califf’s hearing, reflecting deep concerns about the FDA’s efforts to warn of the risks of prescription painkillers.
There were an estimated 100,306 drug overdose deaths in the United States in the 12 months ending in April, an increase of 28.5% from the 78,056 deaths during the same period the year before, according to the Centers for Disease Control and Prevention.
Dr. Califf said he plans to focus on what information the FDA conveys to the public about the risks of prescription painkillers, including a look at what the labels for these products say.
“I am committed to do a comprehensive review of the status of opioids, early in my tenure,” Dr. Califf said.
Dr. Califf indicated that physicians are still too quick to provide excess doses of these medicines, despite years of efforts to restrain their use. He said he knows relatives who were given 30-day prescriptions for opioids after minor surgery.
“So I know we have work to do,” Dr. Califf said.
Concerns about the FDA’s previous work in managing opioids has led to protests from a few Democratic senators about the prospect of President Biden nominating the acting FDA commissioner, Janet Woodcock, MD, for the permanent post.
At the hearing, Sen. Ben Ray Luján (D-NM) raised the case of the FDA’s approval of the powerful Zohydro painkiller. The agency approved that drug despite an 11-2 vote against it by the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee.
Sen. Luján asked Dr. Califf what he would do if an FDA advisory committee voted “overwhelmingly” against recommending approval of a medicine, as happened in the Zohydro case.
While not mentioned by Sen. Luján in this exchange during the hearing with Dr. Califf, the FDA staff’s rejection of recommendations of advisory committees has been a growing concern among researchers.
The agency last year approved aducanumab (Aduhelm, Biogen), a drug for Alzheimer’s disease, dismissing the advice of its Peripheral and Central Nervous System Drugs Advisory Committee. That decision triggered the resignation of several members of the panel. The FDA staff also earlier rejected the conclusion the majority of members of the same advisory committee offered in 2016 on eteplirsen (Exondys 51, Sarepta), a drug for Duchenne muscular dystrophy.
Dr. Califf told Sen. Luján he had done recent research into how often the FDA staff does not concur with the recommendations of an advisory committee. He said the FDA takes a different course of action in about 25% of cases. In about three-quarters of those cases, the FDA staff opts for a “more stringent” approach regarding allowing the public access to the drug, as opposed to a more generous one as seen in the Zohydro, Aduhelm, and Exondys 51 cases.
Still, Dr. Califf said that when there’s an 11-2 advisory committee vote against recommendation of a product, “the leaders at FDA really need to take a close look” at what’s happening.
Question on accelerated approvals
The FDA’s approval of aducanumab drew attention to a debate already underway about conditional clearances known as accelerated approvals.
The FDA has used this path since the 1990s to speed access to drugs for serious conditions. The trade-off for early access is that the agency sometimes makes the wrong call based on initial findings, and clears a medicine later found not to benefit patients as expected.
The FDA’s cancer division is in the midst of public efforts to address cases where drugmakers have not been able to deliver studies that support accelerated approvals of their oncology drugs. In addition, the Office of Inspector General of the U.S. Department of Health & Human Services announced in August that it is reviewing the FDA’s handling of the accelerated approval process.
At Tuesday’s hearing, Sen. Burr grilled Dr. Califf about how he would respond to calls to change how the FDA handles the accelerated-approval process.
“Can you commit to me and to patients who may rely on cutting-edge treatments that you will not support efforts to narrow this pathway or raise the bar for drugs to be approved under those pathways?” Burr asked Califf.
Dr. Califf responded by saying he was “a fan of accelerated approval – for the right conditions.”
Earlier, in his opening statement, Dr. Califf had said his mother benefited directly from the accelerated approval of new drugs for multiple myeloma. Dr. Califf told Sen. Burr that he had spent “countless hours with patient groups” and understands the need to speed the approval of medicines for serious diseases.
But the FDA also has to make sure it holds up its end of the bargain struck with accelerated approvals. This involves checking on how these medicines work once they are marketed.
“We’re accepting that there’s more uncertainty,” Dr. Califf said. “That means we’ve got to have a better system to evaluate these products as they’re used on the market. And I think there are ways that we can do that now. Technology is making this possible in ways that it just was not possible before.”
Worries about the medical supply chain
Sen. Susan Collins (R-Maine) asked Dr. Califf about the vulnerability of the U.S. medical system to disruptions of the supply chain. She raised concerns about China’s dominance in antibiotic manufacturing as an example. She asked if Congress could do more to encourage domestic manufacturing of medical supplies, such as by offering tax incentives.
Dr. Califf told Sen. Collins he shared her concern about the U.S. manufacturing of ingredients used in both branded and generic drugs. He said he recently has served on a committee of the National Academy of Medicine that is examining supply chain issues.
This committee will soon release a report with specific recommendations, Dr. Califf said.
“We don’t have enough competitive entities in what’s become sort of a commodity business” of drug manufacturing, Dr. Califf said. “So we need a number of steps to make the system more resilient.”
A version of this article first appeared on Medscape.com.
When the benchwarmer is a slugger
I still, on occasion, use Felbatol (felbamate).
Thirty years since its explosive entrance to the market, then even more explosive collapse, it remains, in my opinion, the most effective of the second generation of anti-seizure medications. Arguably, even more effective than any of the third generation, too.
That’s not to say I use a lot of it. I don’t. It’s like handling unstable dynamite. Tremendous power, but also an above-average degree of risk. Even after things hit the fan with it in the mid-90s, I remember one of my epilepsy clinic attendings telling me, “This is a home-run drug. In refractory patients you might see some benefit by adding another agent, but with this one, you could stop their seizures and hit it out of the park.”
Like most neurologists, I use other epilepsy options first and second line. But sometimes you get the patient who’s failed the usual ones. Then I start to think about Felbatol. I explain the situation to the patients and their families and let them make the final decision. I worry and watch labs very closely for a while. I probably have no more than three to five patients on it in the practice. But when it works, it’s amazing stuff.
Now, let’s jump ahead to 2021. The year of Aduhelm (and several similar agents racing up behind it).
None of these drugs are even close to hitting home runs. For that matter, I’m not convinced they’re even able to get a man on base. To stretch my baseball analogy a bit, imagine watching a game by looking only at the RBI and ERA stats changing. The numbers change slightly, but you have no evidence that either team is winning. Which is, after all, the whole point.
And, to some extent, that’s the basis of Aduhelm’s approval, and likely the same standards its competitors will be held to.
Although they treat different conditions, and are chemically unrelated, the similarities between Felbatol and the currently advancing bunch of monoclonal antibody (MAB) agents for Alzheimer’s disease make an interesting contrast.
Unlike Felbatol’s proven efficacy for epilepsy, the current MABs offer minimal statistically significant clinical benefit for Alzheimer’s disease. At the same time the risk of amyloid-related imaging abnormalities (ARIA) and its complications with them is significantly higher than that of either of Felbatol’s known, potentially lethal, idiosyncratic effects.
With those odds, In medicine, every day is an exercise in working through the risks and benefits of each patient’s individual situation.
As I’ve stated before, I’m not in the grandstand rooting for these Alzheimer’s drugs to fail. I’ve lost a few family members, and certainly my share of patients, to dementia. I’d be thrilled, and more than willing to prescribe it, if something truly effective came along for it.
Nor do I take any kind of pleasure in the recent news that, because of Aduhelm’s failings, around 1,000 Biogen employees will lose their jobs. I feel terrible for them, as most had nothing to do with the decision to forge ahead with the product. More may soon follow at other companies working with similar agents.
Here we are, though, going into 2022. I’m still, albeit rarely, writing for Felbatol 30 years after it came to market for one reason: It works. But it seems pretty unlikely that future neurologists in 2052 will say the same about the current crops of MABs for Alzheimer’s disease.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
I still, on occasion, use Felbatol (felbamate).
Thirty years since its explosive entrance to the market, then even more explosive collapse, it remains, in my opinion, the most effective of the second generation of anti-seizure medications. Arguably, even more effective than any of the third generation, too.
That’s not to say I use a lot of it. I don’t. It’s like handling unstable dynamite. Tremendous power, but also an above-average degree of risk. Even after things hit the fan with it in the mid-90s, I remember one of my epilepsy clinic attendings telling me, “This is a home-run drug. In refractory patients you might see some benefit by adding another agent, but with this one, you could stop their seizures and hit it out of the park.”
Like most neurologists, I use other epilepsy options first and second line. But sometimes you get the patient who’s failed the usual ones. Then I start to think about Felbatol. I explain the situation to the patients and their families and let them make the final decision. I worry and watch labs very closely for a while. I probably have no more than three to five patients on it in the practice. But when it works, it’s amazing stuff.
Now, let’s jump ahead to 2021. The year of Aduhelm (and several similar agents racing up behind it).
None of these drugs are even close to hitting home runs. For that matter, I’m not convinced they’re even able to get a man on base. To stretch my baseball analogy a bit, imagine watching a game by looking only at the RBI and ERA stats changing. The numbers change slightly, but you have no evidence that either team is winning. Which is, after all, the whole point.
And, to some extent, that’s the basis of Aduhelm’s approval, and likely the same standards its competitors will be held to.
Although they treat different conditions, and are chemically unrelated, the similarities between Felbatol and the currently advancing bunch of monoclonal antibody (MAB) agents for Alzheimer’s disease make an interesting contrast.
Unlike Felbatol’s proven efficacy for epilepsy, the current MABs offer minimal statistically significant clinical benefit for Alzheimer’s disease. At the same time the risk of amyloid-related imaging abnormalities (ARIA) and its complications with them is significantly higher than that of either of Felbatol’s known, potentially lethal, idiosyncratic effects.
With those odds, In medicine, every day is an exercise in working through the risks and benefits of each patient’s individual situation.
As I’ve stated before, I’m not in the grandstand rooting for these Alzheimer’s drugs to fail. I’ve lost a few family members, and certainly my share of patients, to dementia. I’d be thrilled, and more than willing to prescribe it, if something truly effective came along for it.
Nor do I take any kind of pleasure in the recent news that, because of Aduhelm’s failings, around 1,000 Biogen employees will lose their jobs. I feel terrible for them, as most had nothing to do with the decision to forge ahead with the product. More may soon follow at other companies working with similar agents.
Here we are, though, going into 2022. I’m still, albeit rarely, writing for Felbatol 30 years after it came to market for one reason: It works. But it seems pretty unlikely that future neurologists in 2052 will say the same about the current crops of MABs for Alzheimer’s disease.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
I still, on occasion, use Felbatol (felbamate).
Thirty years since its explosive entrance to the market, then even more explosive collapse, it remains, in my opinion, the most effective of the second generation of anti-seizure medications. Arguably, even more effective than any of the third generation, too.
That’s not to say I use a lot of it. I don’t. It’s like handling unstable dynamite. Tremendous power, but also an above-average degree of risk. Even after things hit the fan with it in the mid-90s, I remember one of my epilepsy clinic attendings telling me, “This is a home-run drug. In refractory patients you might see some benefit by adding another agent, but with this one, you could stop their seizures and hit it out of the park.”
Like most neurologists, I use other epilepsy options first and second line. But sometimes you get the patient who’s failed the usual ones. Then I start to think about Felbatol. I explain the situation to the patients and their families and let them make the final decision. I worry and watch labs very closely for a while. I probably have no more than three to five patients on it in the practice. But when it works, it’s amazing stuff.
Now, let’s jump ahead to 2021. The year of Aduhelm (and several similar agents racing up behind it).
None of these drugs are even close to hitting home runs. For that matter, I’m not convinced they’re even able to get a man on base. To stretch my baseball analogy a bit, imagine watching a game by looking only at the RBI and ERA stats changing. The numbers change slightly, but you have no evidence that either team is winning. Which is, after all, the whole point.
And, to some extent, that’s the basis of Aduhelm’s approval, and likely the same standards its competitors will be held to.
Although they treat different conditions, and are chemically unrelated, the similarities between Felbatol and the currently advancing bunch of monoclonal antibody (MAB) agents for Alzheimer’s disease make an interesting contrast.
Unlike Felbatol’s proven efficacy for epilepsy, the current MABs offer minimal statistically significant clinical benefit for Alzheimer’s disease. At the same time the risk of amyloid-related imaging abnormalities (ARIA) and its complications with them is significantly higher than that of either of Felbatol’s known, potentially lethal, idiosyncratic effects.
With those odds, In medicine, every day is an exercise in working through the risks and benefits of each patient’s individual situation.
As I’ve stated before, I’m not in the grandstand rooting for these Alzheimer’s drugs to fail. I’ve lost a few family members, and certainly my share of patients, to dementia. I’d be thrilled, and more than willing to prescribe it, if something truly effective came along for it.
Nor do I take any kind of pleasure in the recent news that, because of Aduhelm’s failings, around 1,000 Biogen employees will lose their jobs. I feel terrible for them, as most had nothing to do with the decision to forge ahead with the product. More may soon follow at other companies working with similar agents.
Here we are, though, going into 2022. I’m still, albeit rarely, writing for Felbatol 30 years after it came to market for one reason: It works. But it seems pretty unlikely that future neurologists in 2052 will say the same about the current crops of MABs for Alzheimer’s disease.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
A very strange place to find a tooth
A nose for the tooth
Have you ever had a stuffy nose that just wouldn’t go away? Those irritating head colds have nothing on the stuffy nose a man in New York recently had to go through. A stuffy nose to top all stuffy noses. One stuffy nose to rule them all, as it were.
This man went to a Mount Sinai clinic with difficulty breathing through his right nostril, a problem that had been going on for years. Let us repeat that: A stuffy nose that lasted for years. The exam revealed a white mass jutting through the back of the septum and a CT scan confirmed the diagnosis. Perhaps you’ve already guessed, since the headline does give things away. Yes, this man had a tooth growing into his nose.
The problem was a half-inch-long ectopic tooth. Ectopic teeth are rare, occurring in less than 1% of people, but an ectopic tooth growing backward into the nasal cavity? Well, that’s so uncommon that this man got a case report in the New England Journal of Medicine.
This story does have a happy ending. Not all ectopic teeth need to be treated, but this one really did have to go. The offending tooth was surgically removed and, at a 3-month follow-up, the stuffy nose issue was completely resolved. So our friend gets the best of both worlds: His issue gets cured and he gets a case report in a major medical publication. If that’s not living the dream, we don’t know what is, and that’s the tooth.
Lettuce recommend you a sleep aid
Lettuce is great for many things. The star in a salad? Of course. The fresh element in a BLT? Yep. A sleep aid? According to a TikTok hack with almost 5 million views, the pinch hitter in a sandwich is switching leagues to be used like a tea for faster sleep. But, does it really work? Researchers say yes and no, according to a recent report at Tyla.com.
Studies conducted in 2013 and 2017 pointed toward a compound called lactucin, which is found in the plant’s n-butanol fraction. In the 2013 study, mice that received n-butanol fraction fell asleep faster and stayed asleep longer. In 2017, researchers found that lettuce made mice sleep longer and helped protect against cell inflammation and damage.
OK, so it works on mice. But what about humans? In the TikTok video, user Shapla Hoque pours hot water on a few lettuce leaves in a mug with a peppermint tea bag (for flavor). After 10 minutes, when the leaves are soaked and soggy, she removes them and drinks the lettuce tea. By the end of the video she’s visibly drowsy and ready to crash. Does this hold water?
Here’s the no. Dr. Charlotte Norton of the Slimming Clinic told Tyla.com that yeah, there are some properties in lettuce that will help you fall asleep, such as lactucarium, which is prominent in romaine. But you would need a massive amount of lettuce to get any effect. The TikTok video, she said, is an example of the placebo effect.
Brains get a rise out of Viagra
A lot of medications are used off label. Antidepressants for COVID have taken the cake recently, but here’s a new one: Viagra for Alzheimer’s disease.
Although there’s no definite link yet between the two, neuron models derived from induced pluripotent stem cells from patients with Alzheimer’s suggest that sildenafil increases neurite growth and decreases phospho-tau expression, Jiansong Fang, PhD, of the Cleveland Clinic, and associates said in Nature Aging.
Their research is an attempt to find untapped sources of new treatments among existing drugs. They began the search with 1,600 approved drugs and focused on those that target the buildup of beta amyloid and tau proteins in the brain, according to the Daily Beast.
Since sildenafil is obviously for men, more research will need to be done on how this drug affects women. Don’t start stocking up just yet.
Omicron is not a social-distancing robot
COVID, safe to say, has not been your typical, run-of-the-mill pandemic. People have protested social distancing. People have protested lockdowns. People have protested mask mandates. People have protested vaccine mandates. People have protested people protesting vaccine mandates.
Someone used a fake arm to get a COVID vaccine card. People have tried to reverse their COVID vaccinations. People had COVID contamination parties.
The common denominator? People. Humans. Maybe what we need is a nonhuman intervention. To fight COVID, we need a hero. A robotic hero.
And where can we find such a hero? The University of Maryland, of course, where computer scientists and engineers are working on an autonomous mobile robot to enforce indoor social-distancing rules.
Their robot can detect lapses in social distancing using cameras, both thermal and visual, along with a LiDAR (Light Detection and Ranging) sensor. It then sorts the offenders into various groups depending on whether they are standing still or moving and predicts their future movement using a state-of-the-art hybrid collision avoidance method known as Frozone, Adarsh Jagan Sathyamoorthy and associates explained in PLOS One.
“Once it reaches the breach, the robot encourages people to move apart via text that appears on a mounted display,” ScienceDaily said.
Maybe you were expecting a Terminator-type robot coming to enforce social distancing requirements rather than a simple text message. Let’s just hope that all COVID guidelines are followed, including social distancing, so the pandemic will finally end and won’t “be back.”
A nose for the tooth
Have you ever had a stuffy nose that just wouldn’t go away? Those irritating head colds have nothing on the stuffy nose a man in New York recently had to go through. A stuffy nose to top all stuffy noses. One stuffy nose to rule them all, as it were.
This man went to a Mount Sinai clinic with difficulty breathing through his right nostril, a problem that had been going on for years. Let us repeat that: A stuffy nose that lasted for years. The exam revealed a white mass jutting through the back of the septum and a CT scan confirmed the diagnosis. Perhaps you’ve already guessed, since the headline does give things away. Yes, this man had a tooth growing into his nose.
The problem was a half-inch-long ectopic tooth. Ectopic teeth are rare, occurring in less than 1% of people, but an ectopic tooth growing backward into the nasal cavity? Well, that’s so uncommon that this man got a case report in the New England Journal of Medicine.
This story does have a happy ending. Not all ectopic teeth need to be treated, but this one really did have to go. The offending tooth was surgically removed and, at a 3-month follow-up, the stuffy nose issue was completely resolved. So our friend gets the best of both worlds: His issue gets cured and he gets a case report in a major medical publication. If that’s not living the dream, we don’t know what is, and that’s the tooth.
Lettuce recommend you a sleep aid
Lettuce is great for many things. The star in a salad? Of course. The fresh element in a BLT? Yep. A sleep aid? According to a TikTok hack with almost 5 million views, the pinch hitter in a sandwich is switching leagues to be used like a tea for faster sleep. But, does it really work? Researchers say yes and no, according to a recent report at Tyla.com.
Studies conducted in 2013 and 2017 pointed toward a compound called lactucin, which is found in the plant’s n-butanol fraction. In the 2013 study, mice that received n-butanol fraction fell asleep faster and stayed asleep longer. In 2017, researchers found that lettuce made mice sleep longer and helped protect against cell inflammation and damage.
OK, so it works on mice. But what about humans? In the TikTok video, user Shapla Hoque pours hot water on a few lettuce leaves in a mug with a peppermint tea bag (for flavor). After 10 minutes, when the leaves are soaked and soggy, she removes them and drinks the lettuce tea. By the end of the video she’s visibly drowsy and ready to crash. Does this hold water?
Here’s the no. Dr. Charlotte Norton of the Slimming Clinic told Tyla.com that yeah, there are some properties in lettuce that will help you fall asleep, such as lactucarium, which is prominent in romaine. But you would need a massive amount of lettuce to get any effect. The TikTok video, she said, is an example of the placebo effect.
Brains get a rise out of Viagra
A lot of medications are used off label. Antidepressants for COVID have taken the cake recently, but here’s a new one: Viagra for Alzheimer’s disease.
Although there’s no definite link yet between the two, neuron models derived from induced pluripotent stem cells from patients with Alzheimer’s suggest that sildenafil increases neurite growth and decreases phospho-tau expression, Jiansong Fang, PhD, of the Cleveland Clinic, and associates said in Nature Aging.
Their research is an attempt to find untapped sources of new treatments among existing drugs. They began the search with 1,600 approved drugs and focused on those that target the buildup of beta amyloid and tau proteins in the brain, according to the Daily Beast.
Since sildenafil is obviously for men, more research will need to be done on how this drug affects women. Don’t start stocking up just yet.
Omicron is not a social-distancing robot
COVID, safe to say, has not been your typical, run-of-the-mill pandemic. People have protested social distancing. People have protested lockdowns. People have protested mask mandates. People have protested vaccine mandates. People have protested people protesting vaccine mandates.
Someone used a fake arm to get a COVID vaccine card. People have tried to reverse their COVID vaccinations. People had COVID contamination parties.
The common denominator? People. Humans. Maybe what we need is a nonhuman intervention. To fight COVID, we need a hero. A robotic hero.
And where can we find such a hero? The University of Maryland, of course, where computer scientists and engineers are working on an autonomous mobile robot to enforce indoor social-distancing rules.
Their robot can detect lapses in social distancing using cameras, both thermal and visual, along with a LiDAR (Light Detection and Ranging) sensor. It then sorts the offenders into various groups depending on whether they are standing still or moving and predicts their future movement using a state-of-the-art hybrid collision avoidance method known as Frozone, Adarsh Jagan Sathyamoorthy and associates explained in PLOS One.
“Once it reaches the breach, the robot encourages people to move apart via text that appears on a mounted display,” ScienceDaily said.
Maybe you were expecting a Terminator-type robot coming to enforce social distancing requirements rather than a simple text message. Let’s just hope that all COVID guidelines are followed, including social distancing, so the pandemic will finally end and won’t “be back.”
A nose for the tooth
Have you ever had a stuffy nose that just wouldn’t go away? Those irritating head colds have nothing on the stuffy nose a man in New York recently had to go through. A stuffy nose to top all stuffy noses. One stuffy nose to rule them all, as it were.
This man went to a Mount Sinai clinic with difficulty breathing through his right nostril, a problem that had been going on for years. Let us repeat that: A stuffy nose that lasted for years. The exam revealed a white mass jutting through the back of the septum and a CT scan confirmed the diagnosis. Perhaps you’ve already guessed, since the headline does give things away. Yes, this man had a tooth growing into his nose.
The problem was a half-inch-long ectopic tooth. Ectopic teeth are rare, occurring in less than 1% of people, but an ectopic tooth growing backward into the nasal cavity? Well, that’s so uncommon that this man got a case report in the New England Journal of Medicine.
This story does have a happy ending. Not all ectopic teeth need to be treated, but this one really did have to go. The offending tooth was surgically removed and, at a 3-month follow-up, the stuffy nose issue was completely resolved. So our friend gets the best of both worlds: His issue gets cured and he gets a case report in a major medical publication. If that’s not living the dream, we don’t know what is, and that’s the tooth.
Lettuce recommend you a sleep aid
Lettuce is great for many things. The star in a salad? Of course. The fresh element in a BLT? Yep. A sleep aid? According to a TikTok hack with almost 5 million views, the pinch hitter in a sandwich is switching leagues to be used like a tea for faster sleep. But, does it really work? Researchers say yes and no, according to a recent report at Tyla.com.
Studies conducted in 2013 and 2017 pointed toward a compound called lactucin, which is found in the plant’s n-butanol fraction. In the 2013 study, mice that received n-butanol fraction fell asleep faster and stayed asleep longer. In 2017, researchers found that lettuce made mice sleep longer and helped protect against cell inflammation and damage.
OK, so it works on mice. But what about humans? In the TikTok video, user Shapla Hoque pours hot water on a few lettuce leaves in a mug with a peppermint tea bag (for flavor). After 10 minutes, when the leaves are soaked and soggy, she removes them and drinks the lettuce tea. By the end of the video she’s visibly drowsy and ready to crash. Does this hold water?
Here’s the no. Dr. Charlotte Norton of the Slimming Clinic told Tyla.com that yeah, there are some properties in lettuce that will help you fall asleep, such as lactucarium, which is prominent in romaine. But you would need a massive amount of lettuce to get any effect. The TikTok video, she said, is an example of the placebo effect.
Brains get a rise out of Viagra
A lot of medications are used off label. Antidepressants for COVID have taken the cake recently, but here’s a new one: Viagra for Alzheimer’s disease.
Although there’s no definite link yet between the two, neuron models derived from induced pluripotent stem cells from patients with Alzheimer’s suggest that sildenafil increases neurite growth and decreases phospho-tau expression, Jiansong Fang, PhD, of the Cleveland Clinic, and associates said in Nature Aging.
Their research is an attempt to find untapped sources of new treatments among existing drugs. They began the search with 1,600 approved drugs and focused on those that target the buildup of beta amyloid and tau proteins in the brain, according to the Daily Beast.
Since sildenafil is obviously for men, more research will need to be done on how this drug affects women. Don’t start stocking up just yet.
Omicron is not a social-distancing robot
COVID, safe to say, has not been your typical, run-of-the-mill pandemic. People have protested social distancing. People have protested lockdowns. People have protested mask mandates. People have protested vaccine mandates. People have protested people protesting vaccine mandates.
Someone used a fake arm to get a COVID vaccine card. People have tried to reverse their COVID vaccinations. People had COVID contamination parties.
The common denominator? People. Humans. Maybe what we need is a nonhuman intervention. To fight COVID, we need a hero. A robotic hero.
And where can we find such a hero? The University of Maryland, of course, where computer scientists and engineers are working on an autonomous mobile robot to enforce indoor social-distancing rules.
Their robot can detect lapses in social distancing using cameras, both thermal and visual, along with a LiDAR (Light Detection and Ranging) sensor. It then sorts the offenders into various groups depending on whether they are standing still or moving and predicts their future movement using a state-of-the-art hybrid collision avoidance method known as Frozone, Adarsh Jagan Sathyamoorthy and associates explained in PLOS One.
“Once it reaches the breach, the robot encourages people to move apart via text that appears on a mounted display,” ScienceDaily said.
Maybe you were expecting a Terminator-type robot coming to enforce social distancing requirements rather than a simple text message. Let’s just hope that all COVID guidelines are followed, including social distancing, so the pandemic will finally end and won’t “be back.”
Could Viagra help prevent Alzheimer’s?
published in the journal Nature Aging.
Patients who used the drug sildenafil, the generic name for Viagra, were 69% less likely to develop the disease than were nonusers.
“Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate,” Feixiong Cheng, PhD, the lead study author in the Cleveland Clinic’s Genomic Medicine Institute, said in a statement.
“Notably, we found that sildenafil use reduced the likelihood of Alzheimer’s in individuals with coronary artery disease, hypertension, and type 2 diabetes, all of which are comorbidities significantly associated with risk of the disease, as well as in those without,” he said.
Alzheimer’s, which is the most common form of age-related dementia, affects hundreds of millions of people worldwide. The disease is expected to affect nearly 14 million Americans by 2050. There is no approved treatment for it.
Dr. Cheng and colleagues at the Cleveland Clinic used a large gene-mapping network to analyze whether more than 1,600 Food and Drug Administration–approved drugs could work against Alzheimer’s. They gave higher scores to drugs that target both amyloid and tau proteins in the brain, which are two hallmarks of the disease. Sildenafil appeared at the top of the list.
Then the researchers used a database of health insurance claims for more than 7 million people in the U.S. to understand the relationship between sildenafil and Alzheimer’s disease outcomes. They compared sildenafil users to nonusers and found that those who used the drug were 69% less likely to have the neurodegenerative disease, even after 6 years of follow-up.
After that, the research team came up with a lab model that showed the sildenafil increased brain cell growth and targeted tau proteins. The lab model could indicate how the drug influences disease-related brain changes.
But Dr. Cheng cautioned against drawing strong conclusions. The study doesn’t demonstrate a causal relationship between sildenafil and Alzheimer’s disease. Researchers will need to conduct clinical trials with a placebo control to see how well the drug works.
Other researchers said the findings offer a new avenue for research but don’t yet provide solid answers.
“Being able to repurpose a drug already licensed for health conditions could help speed up the drug discovery process and bring about life-changing dementia treatments sooner,” Susan Kohlhaas, PhD, director of research at Alzheimer’s Research UK, told the Science Media Centre.
“Importantly, this research doesn’t prove that sildenafil is responsible for reducing dementia risk, or that it slows or stops the disease,” she continued. “If you want to discuss any treatments you are receiving, the first port of call is to speak to your doctor.”
And doctors won’t likely recommend it as a treatment just yet either.
“While these data are interesting scientifically, based on this study, I would not rush out to start taking sildenafil as a prevention for Alzheimer’s disease,” Tara Spires-Jones, PhD, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, told the Science Media Centre.
A version of this article first appeared on WebMD.com.
published in the journal Nature Aging.
Patients who used the drug sildenafil, the generic name for Viagra, were 69% less likely to develop the disease than were nonusers.
“Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate,” Feixiong Cheng, PhD, the lead study author in the Cleveland Clinic’s Genomic Medicine Institute, said in a statement.
“Notably, we found that sildenafil use reduced the likelihood of Alzheimer’s in individuals with coronary artery disease, hypertension, and type 2 diabetes, all of which are comorbidities significantly associated with risk of the disease, as well as in those without,” he said.
Alzheimer’s, which is the most common form of age-related dementia, affects hundreds of millions of people worldwide. The disease is expected to affect nearly 14 million Americans by 2050. There is no approved treatment for it.
Dr. Cheng and colleagues at the Cleveland Clinic used a large gene-mapping network to analyze whether more than 1,600 Food and Drug Administration–approved drugs could work against Alzheimer’s. They gave higher scores to drugs that target both amyloid and tau proteins in the brain, which are two hallmarks of the disease. Sildenafil appeared at the top of the list.
Then the researchers used a database of health insurance claims for more than 7 million people in the U.S. to understand the relationship between sildenafil and Alzheimer’s disease outcomes. They compared sildenafil users to nonusers and found that those who used the drug were 69% less likely to have the neurodegenerative disease, even after 6 years of follow-up.
After that, the research team came up with a lab model that showed the sildenafil increased brain cell growth and targeted tau proteins. The lab model could indicate how the drug influences disease-related brain changes.
But Dr. Cheng cautioned against drawing strong conclusions. The study doesn’t demonstrate a causal relationship between sildenafil and Alzheimer’s disease. Researchers will need to conduct clinical trials with a placebo control to see how well the drug works.
Other researchers said the findings offer a new avenue for research but don’t yet provide solid answers.
“Being able to repurpose a drug already licensed for health conditions could help speed up the drug discovery process and bring about life-changing dementia treatments sooner,” Susan Kohlhaas, PhD, director of research at Alzheimer’s Research UK, told the Science Media Centre.
“Importantly, this research doesn’t prove that sildenafil is responsible for reducing dementia risk, or that it slows or stops the disease,” she continued. “If you want to discuss any treatments you are receiving, the first port of call is to speak to your doctor.”
And doctors won’t likely recommend it as a treatment just yet either.
“While these data are interesting scientifically, based on this study, I would not rush out to start taking sildenafil as a prevention for Alzheimer’s disease,” Tara Spires-Jones, PhD, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, told the Science Media Centre.
A version of this article first appeared on WebMD.com.
published in the journal Nature Aging.
Patients who used the drug sildenafil, the generic name for Viagra, were 69% less likely to develop the disease than were nonusers.
“Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate,” Feixiong Cheng, PhD, the lead study author in the Cleveland Clinic’s Genomic Medicine Institute, said in a statement.
“Notably, we found that sildenafil use reduced the likelihood of Alzheimer’s in individuals with coronary artery disease, hypertension, and type 2 diabetes, all of which are comorbidities significantly associated with risk of the disease, as well as in those without,” he said.
Alzheimer’s, which is the most common form of age-related dementia, affects hundreds of millions of people worldwide. The disease is expected to affect nearly 14 million Americans by 2050. There is no approved treatment for it.
Dr. Cheng and colleagues at the Cleveland Clinic used a large gene-mapping network to analyze whether more than 1,600 Food and Drug Administration–approved drugs could work against Alzheimer’s. They gave higher scores to drugs that target both amyloid and tau proteins in the brain, which are two hallmarks of the disease. Sildenafil appeared at the top of the list.
Then the researchers used a database of health insurance claims for more than 7 million people in the U.S. to understand the relationship between sildenafil and Alzheimer’s disease outcomes. They compared sildenafil users to nonusers and found that those who used the drug were 69% less likely to have the neurodegenerative disease, even after 6 years of follow-up.
After that, the research team came up with a lab model that showed the sildenafil increased brain cell growth and targeted tau proteins. The lab model could indicate how the drug influences disease-related brain changes.
But Dr. Cheng cautioned against drawing strong conclusions. The study doesn’t demonstrate a causal relationship between sildenafil and Alzheimer’s disease. Researchers will need to conduct clinical trials with a placebo control to see how well the drug works.
Other researchers said the findings offer a new avenue for research but don’t yet provide solid answers.
“Being able to repurpose a drug already licensed for health conditions could help speed up the drug discovery process and bring about life-changing dementia treatments sooner,” Susan Kohlhaas, PhD, director of research at Alzheimer’s Research UK, told the Science Media Centre.
“Importantly, this research doesn’t prove that sildenafil is responsible for reducing dementia risk, or that it slows or stops the disease,” she continued. “If you want to discuss any treatments you are receiving, the first port of call is to speak to your doctor.”
And doctors won’t likely recommend it as a treatment just yet either.
“While these data are interesting scientifically, based on this study, I would not rush out to start taking sildenafil as a prevention for Alzheimer’s disease,” Tara Spires-Jones, PhD, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, told the Science Media Centre.
A version of this article first appeared on WebMD.com.
FROM NATURE AGING
Higher resting heart rate tied to increased dementia risk
independent of the presence of cardiovascular disease (CVD) risk factors, new research shows.
“RHR is easy to measure and might be used to identify older people potentially at high risk of dementia and cognitive decline for early interventions,” Yume Imahori, MD, PhD, with the Aging Research Center, Karolinska Institutet, Stockholm, said in an interview.
“Health care professionals should be aware of potential cognitive consequences associated with elevated RHR in older people and may advise older people with high RHR to have a follow-up assessment of cognitive function,” Dr. Imahori said.
The study was published online Dec. 3, 2021, in Alzheimer’s & Dementia.
Heart-brain connection
The findings are based on 2,147 adults (62% women) aged 60 years and older (mean age, 70.6 years) from the population-based Swedish National Aging and Care in Kungsholmen (SNAC-K) study. All were free of dementia at baseline and were followed regularly from 2001-2004 to 2013-2016.
The average RHR at baseline was 65.7 bpm. Individuals in higher RHR groups were older, less educated, and were more likely to be smokers and sedentary and to have hypertension. There were no differences among RHR groups in the prevalence of CVD at baseline.
During a median follow-up of 11.4 years, 289 participants were diagnosed with dementia.
In the fully adjusted model, participants with RHR of 80 bpm or higher had a 55% increased risk of developing dementia, compared with peers with lower RHR of 60 to 69 bpm (hazard ratio, 1.55; 95% CI, 1.06-2.27).
“This association was not due to underlying cardiovascular diseases such as atrial fibrillation and heart failure, which is important because elevated RHR is often related to heart disease,” Dr. Imahori said in an interview.
Regarding cognitive function, Mini-Mental State Examination scores declined over time during the follow-up period in all RHR groups, but participants with RHR 70-79 and 80+ bpm had a greater decline, compared with those with lower RHR of 60-69 bpm.
Dr. Imahori said these findings are in line with data from the U.S. Atherosclerosis Risk in Communities study linking elevated RHR of 80+ bpm in midlife to dementia and cognitive decline in late life.
Public health implications
Reached for comment, Claire Sexton, DPhil, Alzheimer’s Association director of scientific programs and outreach, said this study adds to the “growing body of research showing the health of the heart and brain are closely connected. However, this study only shows a correlation between resting heart rate and cognition, not causation. More research is needed.
“Evidence shows that other risk factors for cardiovascular disease and stroke – obesity, high blood pressure, and diabetes – negatively impact your cognitive health,” Dr. Sexton said in an interview.
“The Alzheimer’s Association believes the conversation about heart health management is something everyone should be having with their doctor,” she said.
“There are things you can do today to lower your risk for cardiovascular disease, including regular exercise and maintaining a healthy diet. Improving your heart health is an important step to maintaining your brain health as you age,” Dr. Sexton added.
SNAC-K is supported by the Swedish Ministry of Health and Social Affairs and the participating county councils and municipalities and in part by additional grants from the Swedish Research Council and the Swedish Research Council for Health, Working Life and Welfare. Dr. Imahori and Dr. Sexton disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
independent of the presence of cardiovascular disease (CVD) risk factors, new research shows.
“RHR is easy to measure and might be used to identify older people potentially at high risk of dementia and cognitive decline for early interventions,” Yume Imahori, MD, PhD, with the Aging Research Center, Karolinska Institutet, Stockholm, said in an interview.
“Health care professionals should be aware of potential cognitive consequences associated with elevated RHR in older people and may advise older people with high RHR to have a follow-up assessment of cognitive function,” Dr. Imahori said.
The study was published online Dec. 3, 2021, in Alzheimer’s & Dementia.
Heart-brain connection
The findings are based on 2,147 adults (62% women) aged 60 years and older (mean age, 70.6 years) from the population-based Swedish National Aging and Care in Kungsholmen (SNAC-K) study. All were free of dementia at baseline and were followed regularly from 2001-2004 to 2013-2016.
The average RHR at baseline was 65.7 bpm. Individuals in higher RHR groups were older, less educated, and were more likely to be smokers and sedentary and to have hypertension. There were no differences among RHR groups in the prevalence of CVD at baseline.
During a median follow-up of 11.4 years, 289 participants were diagnosed with dementia.
In the fully adjusted model, participants with RHR of 80 bpm or higher had a 55% increased risk of developing dementia, compared with peers with lower RHR of 60 to 69 bpm (hazard ratio, 1.55; 95% CI, 1.06-2.27).
“This association was not due to underlying cardiovascular diseases such as atrial fibrillation and heart failure, which is important because elevated RHR is often related to heart disease,” Dr. Imahori said in an interview.
Regarding cognitive function, Mini-Mental State Examination scores declined over time during the follow-up period in all RHR groups, but participants with RHR 70-79 and 80+ bpm had a greater decline, compared with those with lower RHR of 60-69 bpm.
Dr. Imahori said these findings are in line with data from the U.S. Atherosclerosis Risk in Communities study linking elevated RHR of 80+ bpm in midlife to dementia and cognitive decline in late life.
Public health implications
Reached for comment, Claire Sexton, DPhil, Alzheimer’s Association director of scientific programs and outreach, said this study adds to the “growing body of research showing the health of the heart and brain are closely connected. However, this study only shows a correlation between resting heart rate and cognition, not causation. More research is needed.
“Evidence shows that other risk factors for cardiovascular disease and stroke – obesity, high blood pressure, and diabetes – negatively impact your cognitive health,” Dr. Sexton said in an interview.
“The Alzheimer’s Association believes the conversation about heart health management is something everyone should be having with their doctor,” she said.
“There are things you can do today to lower your risk for cardiovascular disease, including regular exercise and maintaining a healthy diet. Improving your heart health is an important step to maintaining your brain health as you age,” Dr. Sexton added.
SNAC-K is supported by the Swedish Ministry of Health and Social Affairs and the participating county councils and municipalities and in part by additional grants from the Swedish Research Council and the Swedish Research Council for Health, Working Life and Welfare. Dr. Imahori and Dr. Sexton disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
independent of the presence of cardiovascular disease (CVD) risk factors, new research shows.
“RHR is easy to measure and might be used to identify older people potentially at high risk of dementia and cognitive decline for early interventions,” Yume Imahori, MD, PhD, with the Aging Research Center, Karolinska Institutet, Stockholm, said in an interview.
“Health care professionals should be aware of potential cognitive consequences associated with elevated RHR in older people and may advise older people with high RHR to have a follow-up assessment of cognitive function,” Dr. Imahori said.
The study was published online Dec. 3, 2021, in Alzheimer’s & Dementia.
Heart-brain connection
The findings are based on 2,147 adults (62% women) aged 60 years and older (mean age, 70.6 years) from the population-based Swedish National Aging and Care in Kungsholmen (SNAC-K) study. All were free of dementia at baseline and were followed regularly from 2001-2004 to 2013-2016.
The average RHR at baseline was 65.7 bpm. Individuals in higher RHR groups were older, less educated, and were more likely to be smokers and sedentary and to have hypertension. There were no differences among RHR groups in the prevalence of CVD at baseline.
During a median follow-up of 11.4 years, 289 participants were diagnosed with dementia.
In the fully adjusted model, participants with RHR of 80 bpm or higher had a 55% increased risk of developing dementia, compared with peers with lower RHR of 60 to 69 bpm (hazard ratio, 1.55; 95% CI, 1.06-2.27).
“This association was not due to underlying cardiovascular diseases such as atrial fibrillation and heart failure, which is important because elevated RHR is often related to heart disease,” Dr. Imahori said in an interview.
Regarding cognitive function, Mini-Mental State Examination scores declined over time during the follow-up period in all RHR groups, but participants with RHR 70-79 and 80+ bpm had a greater decline, compared with those with lower RHR of 60-69 bpm.
Dr. Imahori said these findings are in line with data from the U.S. Atherosclerosis Risk in Communities study linking elevated RHR of 80+ bpm in midlife to dementia and cognitive decline in late life.
Public health implications
Reached for comment, Claire Sexton, DPhil, Alzheimer’s Association director of scientific programs and outreach, said this study adds to the “growing body of research showing the health of the heart and brain are closely connected. However, this study only shows a correlation between resting heart rate and cognition, not causation. More research is needed.
“Evidence shows that other risk factors for cardiovascular disease and stroke – obesity, high blood pressure, and diabetes – negatively impact your cognitive health,” Dr. Sexton said in an interview.
“The Alzheimer’s Association believes the conversation about heart health management is something everyone should be having with their doctor,” she said.
“There are things you can do today to lower your risk for cardiovascular disease, including regular exercise and maintaining a healthy diet. Improving your heart health is an important step to maintaining your brain health as you age,” Dr. Sexton added.
SNAC-K is supported by the Swedish Ministry of Health and Social Affairs and the participating county councils and municipalities and in part by additional grants from the Swedish Research Council and the Swedish Research Council for Health, Working Life and Welfare. Dr. Imahori and Dr. Sexton disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ALZHEIMER’S & DEMENTIA
OSA linked to white-matter hyperintensities
Individuals diagnosed with obstructive sleep apnea (OSA) have higher volumes of white-matter hyperintensities (WMHs), according to a new analysis of data from the SHIP-Trend-0 cohort in Western Pomerania, Germany, which is part of the Study of Health In Pomerania. The association was true for individual measures of OSA, including apnea-hypopnea index (AHI) and oxygen desaturation index (ODI).
WMHs are often seen on MRI in older people and in patients with stroke or dementia, and they may be an indicator of cerebral small-vessel disease. They are linked to greater risk of abnormal gait, worsening balance, depression, cognitive decline, dementia, stroke, and death. Suggested mechanisms for harms from WMHs include ischemia, hypoxia, hypoperfusion, inflammation, and demyelination.
WMHs have been linked to vascular risk factors like smoking, diabetes, and hypertension. Brain pathology studies have found loss of myelin, axonal loss, and scarring close to WMHs.
Although a few studies have looked for associations between WMHs and OSA, they have yielded inconsistent results. The new work employed highly standardized data collection and more complete covariate adjustment. The results, published in JAMA Network Open, suggest a novel, and potentially treatable, pathological WMH mechanism, according to the authors.
“This is an important study. It has strong methodology. The automated analysis of WMH in a large population-based cohort helps to eliminate several biases that can occur in this type of assessment. The data analysis was massive, with adequate control of all potential confounders and testing for interactions. This generated robust results,” said Diego Z. Carvalho, MD, who was asked to comment on the findings. Dr. Carvalho is an assistant professor of neurology at the Center for Sleep Medicine at the Mayo Clinic, Rochester, Minn.
Worse apnea, worse hyperintensity
“The association varies according to the degree of apnea severity, so mild OSA is probably not associated with increased WMH, while severe OSA is mostly likely driving most of the associations,” said Dr. Carvalho.
If a causal mechanism were to be proven, it would “bring a stronger call for treatment of severe OSA patients, particularly those with increased risk for small-vessel disease, [such as] patients with metabolic syndrome. Likewise, patients with severe OSA would be the best candidates for therapeutic trials with [continuous positive airway pressure] with or without possible adjunctive neuroprotective treatment for halting or slowing down WMH progression,” said Dr. Carvalho.
Stuart McCarter, MD, who is an instructor of neurology at the Center for Sleep Medicine at the Mayo Clinic, Rochester, Minn., also found the results interesting but pointed out that much more work needs to be done. “While they found a relationship between OSA as well as OSA severity and WMH despite adjusting for other known confounders, it is unlikely that it is as simple as OSA is the main causal factor for WMH, given the complex relationship between OSA, hypertension, and metabolic syndrome. However, this data does highlight the importance of considering OSA in addition to other more traditional risk factors when considering modifiable risk factors for brain aging,” said Dr. McCarter. The study cohort was mostly of White European ancestry, so more work also needs to be done in other racial groups.
The study underlines the importance of screening among individuals with cognitive impairment. “If OSA represents a modifiable risk factor for WMH and associated cognitive decline, then it would represent one of the few potentially treatable etiologies, or at least contributors of cognitive impairment,” said Dr. McCarter.
The SHIP-Trend-0 cohort is drawn from adults in Western Pomerania. The researchers analyzed data from 529 patients who had WMH and for whom intracranial volume data were available. Each member of the cohort also underwent polysomnography.
Based on AHI criteria, 24% of the overall sample had mild OSA, 10% had moderate OSA, and 6% had severe OSA.
After adjustment for sex, age, intracranial volume, and body weight, WMH volume was associated with AHI (beta = 0.024; P < .001) and ODI (beta = 0.033; P < .001). WMH counts were also associated with AHI (beta = 0.008; P = .01) and ODI (beta = 0.011; P = .02).
The effect size increased with greater OSA severity, as measured by AHI for both WMH volume (beta = 0.312, 0.480, and 1.255 for mild, moderate, and severe OSA, respectively) and WMH count (beta = 0.129, 0.107, and 0.419). The ODI regression models showed similar associations for WMH volume (beta = 0.426, 1.030, and 1.130) and WMH count (beta = 0.141, 0.315, and 0.538).
Dr. Carvalho and Dr. McCarter disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Individuals diagnosed with obstructive sleep apnea (OSA) have higher volumes of white-matter hyperintensities (WMHs), according to a new analysis of data from the SHIP-Trend-0 cohort in Western Pomerania, Germany, which is part of the Study of Health In Pomerania. The association was true for individual measures of OSA, including apnea-hypopnea index (AHI) and oxygen desaturation index (ODI).
WMHs are often seen on MRI in older people and in patients with stroke or dementia, and they may be an indicator of cerebral small-vessel disease. They are linked to greater risk of abnormal gait, worsening balance, depression, cognitive decline, dementia, stroke, and death. Suggested mechanisms for harms from WMHs include ischemia, hypoxia, hypoperfusion, inflammation, and demyelination.
WMHs have been linked to vascular risk factors like smoking, diabetes, and hypertension. Brain pathology studies have found loss of myelin, axonal loss, and scarring close to WMHs.
Although a few studies have looked for associations between WMHs and OSA, they have yielded inconsistent results. The new work employed highly standardized data collection and more complete covariate adjustment. The results, published in JAMA Network Open, suggest a novel, and potentially treatable, pathological WMH mechanism, according to the authors.
“This is an important study. It has strong methodology. The automated analysis of WMH in a large population-based cohort helps to eliminate several biases that can occur in this type of assessment. The data analysis was massive, with adequate control of all potential confounders and testing for interactions. This generated robust results,” said Diego Z. Carvalho, MD, who was asked to comment on the findings. Dr. Carvalho is an assistant professor of neurology at the Center for Sleep Medicine at the Mayo Clinic, Rochester, Minn.
Worse apnea, worse hyperintensity
“The association varies according to the degree of apnea severity, so mild OSA is probably not associated with increased WMH, while severe OSA is mostly likely driving most of the associations,” said Dr. Carvalho.
If a causal mechanism were to be proven, it would “bring a stronger call for treatment of severe OSA patients, particularly those with increased risk for small-vessel disease, [such as] patients with metabolic syndrome. Likewise, patients with severe OSA would be the best candidates for therapeutic trials with [continuous positive airway pressure] with or without possible adjunctive neuroprotective treatment for halting or slowing down WMH progression,” said Dr. Carvalho.
Stuart McCarter, MD, who is an instructor of neurology at the Center for Sleep Medicine at the Mayo Clinic, Rochester, Minn., also found the results interesting but pointed out that much more work needs to be done. “While they found a relationship between OSA as well as OSA severity and WMH despite adjusting for other known confounders, it is unlikely that it is as simple as OSA is the main causal factor for WMH, given the complex relationship between OSA, hypertension, and metabolic syndrome. However, this data does highlight the importance of considering OSA in addition to other more traditional risk factors when considering modifiable risk factors for brain aging,” said Dr. McCarter. The study cohort was mostly of White European ancestry, so more work also needs to be done in other racial groups.
The study underlines the importance of screening among individuals with cognitive impairment. “If OSA represents a modifiable risk factor for WMH and associated cognitive decline, then it would represent one of the few potentially treatable etiologies, or at least contributors of cognitive impairment,” said Dr. McCarter.
The SHIP-Trend-0 cohort is drawn from adults in Western Pomerania. The researchers analyzed data from 529 patients who had WMH and for whom intracranial volume data were available. Each member of the cohort also underwent polysomnography.
Based on AHI criteria, 24% of the overall sample had mild OSA, 10% had moderate OSA, and 6% had severe OSA.
After adjustment for sex, age, intracranial volume, and body weight, WMH volume was associated with AHI (beta = 0.024; P < .001) and ODI (beta = 0.033; P < .001). WMH counts were also associated with AHI (beta = 0.008; P = .01) and ODI (beta = 0.011; P = .02).
The effect size increased with greater OSA severity, as measured by AHI for both WMH volume (beta = 0.312, 0.480, and 1.255 for mild, moderate, and severe OSA, respectively) and WMH count (beta = 0.129, 0.107, and 0.419). The ODI regression models showed similar associations for WMH volume (beta = 0.426, 1.030, and 1.130) and WMH count (beta = 0.141, 0.315, and 0.538).
Dr. Carvalho and Dr. McCarter disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Individuals diagnosed with obstructive sleep apnea (OSA) have higher volumes of white-matter hyperintensities (WMHs), according to a new analysis of data from the SHIP-Trend-0 cohort in Western Pomerania, Germany, which is part of the Study of Health In Pomerania. The association was true for individual measures of OSA, including apnea-hypopnea index (AHI) and oxygen desaturation index (ODI).
WMHs are often seen on MRI in older people and in patients with stroke or dementia, and they may be an indicator of cerebral small-vessel disease. They are linked to greater risk of abnormal gait, worsening balance, depression, cognitive decline, dementia, stroke, and death. Suggested mechanisms for harms from WMHs include ischemia, hypoxia, hypoperfusion, inflammation, and demyelination.
WMHs have been linked to vascular risk factors like smoking, diabetes, and hypertension. Brain pathology studies have found loss of myelin, axonal loss, and scarring close to WMHs.
Although a few studies have looked for associations between WMHs and OSA, they have yielded inconsistent results. The new work employed highly standardized data collection and more complete covariate adjustment. The results, published in JAMA Network Open, suggest a novel, and potentially treatable, pathological WMH mechanism, according to the authors.
“This is an important study. It has strong methodology. The automated analysis of WMH in a large population-based cohort helps to eliminate several biases that can occur in this type of assessment. The data analysis was massive, with adequate control of all potential confounders and testing for interactions. This generated robust results,” said Diego Z. Carvalho, MD, who was asked to comment on the findings. Dr. Carvalho is an assistant professor of neurology at the Center for Sleep Medicine at the Mayo Clinic, Rochester, Minn.
Worse apnea, worse hyperintensity
“The association varies according to the degree of apnea severity, so mild OSA is probably not associated with increased WMH, while severe OSA is mostly likely driving most of the associations,” said Dr. Carvalho.
If a causal mechanism were to be proven, it would “bring a stronger call for treatment of severe OSA patients, particularly those with increased risk for small-vessel disease, [such as] patients with metabolic syndrome. Likewise, patients with severe OSA would be the best candidates for therapeutic trials with [continuous positive airway pressure] with or without possible adjunctive neuroprotective treatment for halting or slowing down WMH progression,” said Dr. Carvalho.
Stuart McCarter, MD, who is an instructor of neurology at the Center for Sleep Medicine at the Mayo Clinic, Rochester, Minn., also found the results interesting but pointed out that much more work needs to be done. “While they found a relationship between OSA as well as OSA severity and WMH despite adjusting for other known confounders, it is unlikely that it is as simple as OSA is the main causal factor for WMH, given the complex relationship between OSA, hypertension, and metabolic syndrome. However, this data does highlight the importance of considering OSA in addition to other more traditional risk factors when considering modifiable risk factors for brain aging,” said Dr. McCarter. The study cohort was mostly of White European ancestry, so more work also needs to be done in other racial groups.
The study underlines the importance of screening among individuals with cognitive impairment. “If OSA represents a modifiable risk factor for WMH and associated cognitive decline, then it would represent one of the few potentially treatable etiologies, or at least contributors of cognitive impairment,” said Dr. McCarter.
The SHIP-Trend-0 cohort is drawn from adults in Western Pomerania. The researchers analyzed data from 529 patients who had WMH and for whom intracranial volume data were available. Each member of the cohort also underwent polysomnography.
Based on AHI criteria, 24% of the overall sample had mild OSA, 10% had moderate OSA, and 6% had severe OSA.
After adjustment for sex, age, intracranial volume, and body weight, WMH volume was associated with AHI (beta = 0.024; P < .001) and ODI (beta = 0.033; P < .001). WMH counts were also associated with AHI (beta = 0.008; P = .01) and ODI (beta = 0.011; P = .02).
The effect size increased with greater OSA severity, as measured by AHI for both WMH volume (beta = 0.312, 0.480, and 1.255 for mild, moderate, and severe OSA, respectively) and WMH count (beta = 0.129, 0.107, and 0.419). The ODI regression models showed similar associations for WMH volume (beta = 0.426, 1.030, and 1.130) and WMH count (beta = 0.141, 0.315, and 0.538).
Dr. Carvalho and Dr. McCarter disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Microbleeds, age contribute to ARIA risk with aducanumab
Though primary efficacy results have yet to be published,
Amyloid-related imaging abnormalities, or ARIA, have been seen linked to a variety of experimental amyloid-lowering treatments for Alzheimer’s disease. The abnormalities include brain bleeding (ARIA-H) and brain edema (ARIA-E), detected on magnetic resonance imaging.
Safety findings
In a study published Nov. 22 in JAMA Neurology, Stephen Salloway, MD, director of neurology and the memory and aging program at Butler Hospital and the Martin M. Zucker Professor of Psychiatry and Human Behavior and Professor of Neurology at the Warren Alpert Medical School of Brown University in Providence, R.I., and his colleagues, reported that 41% of 1,029 patients in the high-dose (10 mg/kg) treatment groups of aducanumab (Aduhelm, Biogen) developed ARIA.
Thirty-five percent of the high-dose patients (n = 362) developed ARIA-E, and 94 had symptoms, with headache the most commonly reported, followed by confusion. ARIA-E occurred only sporadically in the placebo groups, while ARIA-H was more common. Microbleeds were seen in 19% of the high-dose patients compared with 6.6% in the placebo group, while superficial siderosis occurred in about 15%, versus 2.2% on placebo. Most of the ARIA-E events occurred during the first eight doses of the infusion treatment. People with one or more copies of the APOE4 genetic variant saw higher risk of ARIA-E associated with treatment compared with noncarriers (hazard ratio [HR] 2.5; 95% confidence interval [CI], 1.90-3.20). Evidence of brain micro-hemorrhages at baseline was associated with higher risk of ARIA-E (HR 1.7; 95% CI, 1.31-2.27) compared with patients without MRI evidence of brain bleeds in the year before treatment began.
Older age independently increased risk of ARIA-H, with a risk that was seen increasing 6% with each additional year of age.
The identically designed EMERGE and ENGAGE trials of aducanumab enrolled nearly 3,300 patients worldwide (mean age 70.4, 52% female). Participants were screened to include only those with amyloid-positive mild cognitive impairment (81% of the cohort) or mild Alzheimer’s dementia. Both trials were halted early after a futility analysis concluded that treatment was unlikely to result in benefit.
A post hoc analysis later determined that patients in one trial, EMERGE, showed slight clinical benefit on follow-up in the high-dose group only. The Food and Drug Administration approved the drug in July 2021 on the basis of that finding, overriding the consensus of its independent advisory committee, which was not persuaded. Since then the drug has become synonymous with controversy, not aided by its high list price of more than $50,000 per year, with many insurers and large health care systems refusing to deliver it. The recent reported death of a woman participating in an open-label extension trial of aducanumab, who was admitted to the hospital with brain swelling, has added to safety concerns.
Brain bleeds and age affect risk
In an interview with MDedge Neurology, neurologist Madhav Thambisetty, MD, PhD, a senior investigator with the National Institute on Aging in Baltimore, and a member of the FDA advisory committee that recommended against approval for aducanumab, said that while physicians are aware that APOE4 carriers face higher risks of treatment-related complications, the new safety findings offer additional guidance on patient selection.
“The older you are the greater your risk of ARIA, and the more micro-hemorrhages you have at baseline the greater your risk. Those are important findings that were not previously well publicized before,” Dr. Thambisetty said.
In the EMERGE and ENGAGE trials, Dr. Thambisetty pointed out, patients with four or more micro-hemorrhages at baseline were excluded. The new findings reveal that even a small number of bleeds at baseline can contribute to ARIA risk.
“Patients in real-world clinical practice are going to be very different from the tightly controlled, well-screened participants who were enrolled in these trials. Microbleeds are very common in Alzheimer’s patients, occurring in 18-32%. Now that these findings are available, it’s important for a practicing physician to obtain a baseline MRI scan and really pay attention to microbleeds, because that will affect treatment decisions.”
Additional concerns
Dr. Thambisetty cautioned that the new results made no mention of another important safety outcome: loss of brain volume associated with treatment.
Changes in brain volume have been seen associated with other amyloid-lowering treatments, though the reasons for this are poorly understood. Participants in EMERGE and ENGAGE “received numerous MRI scans,” Dr. Thambisetty said. “This was one of the strengths of the trials. Thanks to an open-label extension we now have more than 2 years of MRI data from meticulously monitored patients, and there has been no mention of brain volume changes despite this being a prespecified outcome. This, for me, is one of the glaring omissions of this paper, and the fact that it’s not even mentioned is really worrisome.”
The sponsor of the aducanumab trials, Biogen, has yet to publish efficacy findings in a peer-reviewed journal, instead presenting them piecemeal at conferences.
“The current paper was a secondary analysis,” Dr. Thambisetty said. “The authors say the primary analysis will be published elsewhere. I think it’s important to reflect upon the fact that these clinical trials enrolled more than 3,000 participants at more than 300 trial centers in 20 countries. We now have an approved drug that’s commercially available. And yet we don’t have a single peer-reviewed publication discussing the efficacy data. None of this is in the interest of our patients, or in advancing the science.”
The EMERGE and ENGAGE trials were funded by Biogen. Eight of the current paper’s 14 authors are Biogen employees. Dr. Salloway, the lead author, disclosed financial support from Biogen and other manufacturers, as did two of his coauthors. Dr. Thambisetty disclosed no financial conflicts of interest.
Though primary efficacy results have yet to be published,
Amyloid-related imaging abnormalities, or ARIA, have been seen linked to a variety of experimental amyloid-lowering treatments for Alzheimer’s disease. The abnormalities include brain bleeding (ARIA-H) and brain edema (ARIA-E), detected on magnetic resonance imaging.
Safety findings
In a study published Nov. 22 in JAMA Neurology, Stephen Salloway, MD, director of neurology and the memory and aging program at Butler Hospital and the Martin M. Zucker Professor of Psychiatry and Human Behavior and Professor of Neurology at the Warren Alpert Medical School of Brown University in Providence, R.I., and his colleagues, reported that 41% of 1,029 patients in the high-dose (10 mg/kg) treatment groups of aducanumab (Aduhelm, Biogen) developed ARIA.
Thirty-five percent of the high-dose patients (n = 362) developed ARIA-E, and 94 had symptoms, with headache the most commonly reported, followed by confusion. ARIA-E occurred only sporadically in the placebo groups, while ARIA-H was more common. Microbleeds were seen in 19% of the high-dose patients compared with 6.6% in the placebo group, while superficial siderosis occurred in about 15%, versus 2.2% on placebo. Most of the ARIA-E events occurred during the first eight doses of the infusion treatment. People with one or more copies of the APOE4 genetic variant saw higher risk of ARIA-E associated with treatment compared with noncarriers (hazard ratio [HR] 2.5; 95% confidence interval [CI], 1.90-3.20). Evidence of brain micro-hemorrhages at baseline was associated with higher risk of ARIA-E (HR 1.7; 95% CI, 1.31-2.27) compared with patients without MRI evidence of brain bleeds in the year before treatment began.
Older age independently increased risk of ARIA-H, with a risk that was seen increasing 6% with each additional year of age.
The identically designed EMERGE and ENGAGE trials of aducanumab enrolled nearly 3,300 patients worldwide (mean age 70.4, 52% female). Participants were screened to include only those with amyloid-positive mild cognitive impairment (81% of the cohort) or mild Alzheimer’s dementia. Both trials were halted early after a futility analysis concluded that treatment was unlikely to result in benefit.
A post hoc analysis later determined that patients in one trial, EMERGE, showed slight clinical benefit on follow-up in the high-dose group only. The Food and Drug Administration approved the drug in July 2021 on the basis of that finding, overriding the consensus of its independent advisory committee, which was not persuaded. Since then the drug has become synonymous with controversy, not aided by its high list price of more than $50,000 per year, with many insurers and large health care systems refusing to deliver it. The recent reported death of a woman participating in an open-label extension trial of aducanumab, who was admitted to the hospital with brain swelling, has added to safety concerns.
Brain bleeds and age affect risk
In an interview with MDedge Neurology, neurologist Madhav Thambisetty, MD, PhD, a senior investigator with the National Institute on Aging in Baltimore, and a member of the FDA advisory committee that recommended against approval for aducanumab, said that while physicians are aware that APOE4 carriers face higher risks of treatment-related complications, the new safety findings offer additional guidance on patient selection.
“The older you are the greater your risk of ARIA, and the more micro-hemorrhages you have at baseline the greater your risk. Those are important findings that were not previously well publicized before,” Dr. Thambisetty said.
In the EMERGE and ENGAGE trials, Dr. Thambisetty pointed out, patients with four or more micro-hemorrhages at baseline were excluded. The new findings reveal that even a small number of bleeds at baseline can contribute to ARIA risk.
“Patients in real-world clinical practice are going to be very different from the tightly controlled, well-screened participants who were enrolled in these trials. Microbleeds are very common in Alzheimer’s patients, occurring in 18-32%. Now that these findings are available, it’s important for a practicing physician to obtain a baseline MRI scan and really pay attention to microbleeds, because that will affect treatment decisions.”
Additional concerns
Dr. Thambisetty cautioned that the new results made no mention of another important safety outcome: loss of brain volume associated with treatment.
Changes in brain volume have been seen associated with other amyloid-lowering treatments, though the reasons for this are poorly understood. Participants in EMERGE and ENGAGE “received numerous MRI scans,” Dr. Thambisetty said. “This was one of the strengths of the trials. Thanks to an open-label extension we now have more than 2 years of MRI data from meticulously monitored patients, and there has been no mention of brain volume changes despite this being a prespecified outcome. This, for me, is one of the glaring omissions of this paper, and the fact that it’s not even mentioned is really worrisome.”
The sponsor of the aducanumab trials, Biogen, has yet to publish efficacy findings in a peer-reviewed journal, instead presenting them piecemeal at conferences.
“The current paper was a secondary analysis,” Dr. Thambisetty said. “The authors say the primary analysis will be published elsewhere. I think it’s important to reflect upon the fact that these clinical trials enrolled more than 3,000 participants at more than 300 trial centers in 20 countries. We now have an approved drug that’s commercially available. And yet we don’t have a single peer-reviewed publication discussing the efficacy data. None of this is in the interest of our patients, or in advancing the science.”
The EMERGE and ENGAGE trials were funded by Biogen. Eight of the current paper’s 14 authors are Biogen employees. Dr. Salloway, the lead author, disclosed financial support from Biogen and other manufacturers, as did two of his coauthors. Dr. Thambisetty disclosed no financial conflicts of interest.
Though primary efficacy results have yet to be published,
Amyloid-related imaging abnormalities, or ARIA, have been seen linked to a variety of experimental amyloid-lowering treatments for Alzheimer’s disease. The abnormalities include brain bleeding (ARIA-H) and brain edema (ARIA-E), detected on magnetic resonance imaging.
Safety findings
In a study published Nov. 22 in JAMA Neurology, Stephen Salloway, MD, director of neurology and the memory and aging program at Butler Hospital and the Martin M. Zucker Professor of Psychiatry and Human Behavior and Professor of Neurology at the Warren Alpert Medical School of Brown University in Providence, R.I., and his colleagues, reported that 41% of 1,029 patients in the high-dose (10 mg/kg) treatment groups of aducanumab (Aduhelm, Biogen) developed ARIA.
Thirty-five percent of the high-dose patients (n = 362) developed ARIA-E, and 94 had symptoms, with headache the most commonly reported, followed by confusion. ARIA-E occurred only sporadically in the placebo groups, while ARIA-H was more common. Microbleeds were seen in 19% of the high-dose patients compared with 6.6% in the placebo group, while superficial siderosis occurred in about 15%, versus 2.2% on placebo. Most of the ARIA-E events occurred during the first eight doses of the infusion treatment. People with one or more copies of the APOE4 genetic variant saw higher risk of ARIA-E associated with treatment compared with noncarriers (hazard ratio [HR] 2.5; 95% confidence interval [CI], 1.90-3.20). Evidence of brain micro-hemorrhages at baseline was associated with higher risk of ARIA-E (HR 1.7; 95% CI, 1.31-2.27) compared with patients without MRI evidence of brain bleeds in the year before treatment began.
Older age independently increased risk of ARIA-H, with a risk that was seen increasing 6% with each additional year of age.
The identically designed EMERGE and ENGAGE trials of aducanumab enrolled nearly 3,300 patients worldwide (mean age 70.4, 52% female). Participants were screened to include only those with amyloid-positive mild cognitive impairment (81% of the cohort) or mild Alzheimer’s dementia. Both trials were halted early after a futility analysis concluded that treatment was unlikely to result in benefit.
A post hoc analysis later determined that patients in one trial, EMERGE, showed slight clinical benefit on follow-up in the high-dose group only. The Food and Drug Administration approved the drug in July 2021 on the basis of that finding, overriding the consensus of its independent advisory committee, which was not persuaded. Since then the drug has become synonymous with controversy, not aided by its high list price of more than $50,000 per year, with many insurers and large health care systems refusing to deliver it. The recent reported death of a woman participating in an open-label extension trial of aducanumab, who was admitted to the hospital with brain swelling, has added to safety concerns.
Brain bleeds and age affect risk
In an interview with MDedge Neurology, neurologist Madhav Thambisetty, MD, PhD, a senior investigator with the National Institute on Aging in Baltimore, and a member of the FDA advisory committee that recommended against approval for aducanumab, said that while physicians are aware that APOE4 carriers face higher risks of treatment-related complications, the new safety findings offer additional guidance on patient selection.
“The older you are the greater your risk of ARIA, and the more micro-hemorrhages you have at baseline the greater your risk. Those are important findings that were not previously well publicized before,” Dr. Thambisetty said.
In the EMERGE and ENGAGE trials, Dr. Thambisetty pointed out, patients with four or more micro-hemorrhages at baseline were excluded. The new findings reveal that even a small number of bleeds at baseline can contribute to ARIA risk.
“Patients in real-world clinical practice are going to be very different from the tightly controlled, well-screened participants who were enrolled in these trials. Microbleeds are very common in Alzheimer’s patients, occurring in 18-32%. Now that these findings are available, it’s important for a practicing physician to obtain a baseline MRI scan and really pay attention to microbleeds, because that will affect treatment decisions.”
Additional concerns
Dr. Thambisetty cautioned that the new results made no mention of another important safety outcome: loss of brain volume associated with treatment.
Changes in brain volume have been seen associated with other amyloid-lowering treatments, though the reasons for this are poorly understood. Participants in EMERGE and ENGAGE “received numerous MRI scans,” Dr. Thambisetty said. “This was one of the strengths of the trials. Thanks to an open-label extension we now have more than 2 years of MRI data from meticulously monitored patients, and there has been no mention of brain volume changes despite this being a prespecified outcome. This, for me, is one of the glaring omissions of this paper, and the fact that it’s not even mentioned is really worrisome.”
The sponsor of the aducanumab trials, Biogen, has yet to publish efficacy findings in a peer-reviewed journal, instead presenting them piecemeal at conferences.
“The current paper was a secondary analysis,” Dr. Thambisetty said. “The authors say the primary analysis will be published elsewhere. I think it’s important to reflect upon the fact that these clinical trials enrolled more than 3,000 participants at more than 300 trial centers in 20 countries. We now have an approved drug that’s commercially available. And yet we don’t have a single peer-reviewed publication discussing the efficacy data. None of this is in the interest of our patients, or in advancing the science.”
The EMERGE and ENGAGE trials were funded by Biogen. Eight of the current paper’s 14 authors are Biogen employees. Dr. Salloway, the lead author, disclosed financial support from Biogen and other manufacturers, as did two of his coauthors. Dr. Thambisetty disclosed no financial conflicts of interest.
FROM JAMA NEUROLOGY
New blood test may detect preclinical Alzheimer’s years in advance
, early research suggests.
Analysis of two studies showed the test (AlzoSure Predict), which uses less than 1 ml of blood, had numerous benefits compared with other blood tests that track AD pathology.
“We believe this has the potential to radically improve early stratification and identification of patients for trials 6 years in advance of a diagnosis, which can potentially enable more rapid and efficient approvals of therapies,” Paul Kinnon, CEO of Diadem, the test’s manufacturer, said in an interview.
The findings were presented at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference.
Positive “discovery” results
P53, which is present in both the brain and elsewhere in the body, “is one of the most targeted proteins” for drug development in cancer and other conditions, said Mr. Kinnon.
The current blood test measures a derivative of P53 (U-p53AZ). Previous research suggests this derivative, which affects amyloid and oxidative stress, is also implicated in AD pathogenesis.
Researchers used blood samples from patients aged 60 years and older from the Australia Imaging, Biomarkers, and Lifestyles (AIBL) study who had various levels of cognitive function.
They analyzed samples at multiple timepoints over a 10-year period, “so we know when the marker is most accurate at predicting decline,” Mr. Kinnon said.
The first of two studies was considered a “discovery” study and included blood samples from 224 patients.
Results showed the test predicted decline from mild cognitive impairment (MCI) to AD at the end of 6 years, with an area under the curve (AUC) greater than 90%.
These results are “massive,” said Mr. Kinnon. “It’s the most accurate test I’ve seen anywhere for predicting decline of a patient.”
The test can also accurately classify a patient’s stage of cognition, he added. “Not only does it allow us to predict 6 years in advance, it also tells us if the patient has SMC [subjective memory complaints], MCI, or AD with a 95% certainty,” Mr. Kinnon said.
He noted that test sensitivity was higher than results found from traditional methods that are currently being used. The positive predictive value (PPV) and negative predictive value (NPV), which were at 90% or more, were “absolutely fantastic,” said Mr. Kinnon.
“Better than expected” results
In the second “validation” study, investigators examined samples from a completely different group of 482 patients. The “very compelling” results showed AUCs over 90%, PPVs over 90%, and “very high” NPVs, Mr. Kinnon said.
“These are great data, better than we expected,” he added.
However, he noted the test is “very specific” for decline to AD and not to other dementias.
In addition, Mr. Kinnon noted the test does not monitor levels of amyloid beta or tau, which accumulate at a later stage of AD. “Amyloid and tau tell you you’ve got it. We’re there way before those concentrations become detectable,” he said.
Identifying patients who will progress to AD years before they have symptoms gives them time to make medical decisions. These patients may also try treatments at an earlier stage of the disease, when these therapies are most likely to be helpful, said Mr. Kinnon.
In addition, using the test could speed up the approval of prospective drug treatments for AD. Currently, pharmaceutical companies enroll thousands of patients into a clinical study “and they don’t know which ones will have AD,” Mr. Kinnon noted.
“This test tells you these are the ones who are going to progress and should go into the study, and these are the ones that aren’t. So it makes the studies statistically relevant and accurate,” he said.
Investigators can also use the test to monitor patients during a study instead of relying on expensive PET scans and painful and costly spinal fluid taps, he added.
Previous surveys and market research have shown that neurologists and general practitioners “want a blood test to screen patients early, to help educate and inform patients,” said Mr. Kinnon.
Further results that will include biobank data on more than 1,000 patients in the United States and Europe are due for completion toward the end of this year.
The company is currently in negotiations to bring the product to North America, Europe, and elsewhere. “Our goal is to have it on the market by the middle of next year in multiple regions,” Mr. Kinnon said.
Encouraging, preliminary
Commenting on the findings, Percy Griffin, PhD, MSc, director of scientific engagement at the Alzheimer’s Association, said “it’s exciting” to see development of novel ways for detecting or predicting AD.
“There is an urgent need for simple, inexpensive, noninvasive, and accessible early detection tools for Alzheimer’s, such as a blood test,” he said.
However, Dr. Griffin cautioned the test is still in the early stages of development and has not been tested extensively in large, diverse clinical trials.
In addition, although the test predicts whether a person will progress, it does not predict when the person will progress, he added.
“These preliminary results are encouraging, but further validation is needed before this test can be implemented widely,” he said.
Technologies that facilitate the early detection and intervention before significant loss of brain cells from AD “would be game-changing” for individuals, families, and the healthcare system, Dr. Griffin concluded.
A version of this article first appeared on Medscape.com.
, early research suggests.
Analysis of two studies showed the test (AlzoSure Predict), which uses less than 1 ml of blood, had numerous benefits compared with other blood tests that track AD pathology.
“We believe this has the potential to radically improve early stratification and identification of patients for trials 6 years in advance of a diagnosis, which can potentially enable more rapid and efficient approvals of therapies,” Paul Kinnon, CEO of Diadem, the test’s manufacturer, said in an interview.
The findings were presented at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference.
Positive “discovery” results
P53, which is present in both the brain and elsewhere in the body, “is one of the most targeted proteins” for drug development in cancer and other conditions, said Mr. Kinnon.
The current blood test measures a derivative of P53 (U-p53AZ). Previous research suggests this derivative, which affects amyloid and oxidative stress, is also implicated in AD pathogenesis.
Researchers used blood samples from patients aged 60 years and older from the Australia Imaging, Biomarkers, and Lifestyles (AIBL) study who had various levels of cognitive function.
They analyzed samples at multiple timepoints over a 10-year period, “so we know when the marker is most accurate at predicting decline,” Mr. Kinnon said.
The first of two studies was considered a “discovery” study and included blood samples from 224 patients.
Results showed the test predicted decline from mild cognitive impairment (MCI) to AD at the end of 6 years, with an area under the curve (AUC) greater than 90%.
These results are “massive,” said Mr. Kinnon. “It’s the most accurate test I’ve seen anywhere for predicting decline of a patient.”
The test can also accurately classify a patient’s stage of cognition, he added. “Not only does it allow us to predict 6 years in advance, it also tells us if the patient has SMC [subjective memory complaints], MCI, or AD with a 95% certainty,” Mr. Kinnon said.
He noted that test sensitivity was higher than results found from traditional methods that are currently being used. The positive predictive value (PPV) and negative predictive value (NPV), which were at 90% or more, were “absolutely fantastic,” said Mr. Kinnon.
“Better than expected” results
In the second “validation” study, investigators examined samples from a completely different group of 482 patients. The “very compelling” results showed AUCs over 90%, PPVs over 90%, and “very high” NPVs, Mr. Kinnon said.
“These are great data, better than we expected,” he added.
However, he noted the test is “very specific” for decline to AD and not to other dementias.
In addition, Mr. Kinnon noted the test does not monitor levels of amyloid beta or tau, which accumulate at a later stage of AD. “Amyloid and tau tell you you’ve got it. We’re there way before those concentrations become detectable,” he said.
Identifying patients who will progress to AD years before they have symptoms gives them time to make medical decisions. These patients may also try treatments at an earlier stage of the disease, when these therapies are most likely to be helpful, said Mr. Kinnon.
In addition, using the test could speed up the approval of prospective drug treatments for AD. Currently, pharmaceutical companies enroll thousands of patients into a clinical study “and they don’t know which ones will have AD,” Mr. Kinnon noted.
“This test tells you these are the ones who are going to progress and should go into the study, and these are the ones that aren’t. So it makes the studies statistically relevant and accurate,” he said.
Investigators can also use the test to monitor patients during a study instead of relying on expensive PET scans and painful and costly spinal fluid taps, he added.
Previous surveys and market research have shown that neurologists and general practitioners “want a blood test to screen patients early, to help educate and inform patients,” said Mr. Kinnon.
Further results that will include biobank data on more than 1,000 patients in the United States and Europe are due for completion toward the end of this year.
The company is currently in negotiations to bring the product to North America, Europe, and elsewhere. “Our goal is to have it on the market by the middle of next year in multiple regions,” Mr. Kinnon said.
Encouraging, preliminary
Commenting on the findings, Percy Griffin, PhD, MSc, director of scientific engagement at the Alzheimer’s Association, said “it’s exciting” to see development of novel ways for detecting or predicting AD.
“There is an urgent need for simple, inexpensive, noninvasive, and accessible early detection tools for Alzheimer’s, such as a blood test,” he said.
However, Dr. Griffin cautioned the test is still in the early stages of development and has not been tested extensively in large, diverse clinical trials.
In addition, although the test predicts whether a person will progress, it does not predict when the person will progress, he added.
“These preliminary results are encouraging, but further validation is needed before this test can be implemented widely,” he said.
Technologies that facilitate the early detection and intervention before significant loss of brain cells from AD “would be game-changing” for individuals, families, and the healthcare system, Dr. Griffin concluded.
A version of this article first appeared on Medscape.com.
, early research suggests.
Analysis of two studies showed the test (AlzoSure Predict), which uses less than 1 ml of blood, had numerous benefits compared with other blood tests that track AD pathology.
“We believe this has the potential to radically improve early stratification and identification of patients for trials 6 years in advance of a diagnosis, which can potentially enable more rapid and efficient approvals of therapies,” Paul Kinnon, CEO of Diadem, the test’s manufacturer, said in an interview.
The findings were presented at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference.
Positive “discovery” results
P53, which is present in both the brain and elsewhere in the body, “is one of the most targeted proteins” for drug development in cancer and other conditions, said Mr. Kinnon.
The current blood test measures a derivative of P53 (U-p53AZ). Previous research suggests this derivative, which affects amyloid and oxidative stress, is also implicated in AD pathogenesis.
Researchers used blood samples from patients aged 60 years and older from the Australia Imaging, Biomarkers, and Lifestyles (AIBL) study who had various levels of cognitive function.
They analyzed samples at multiple timepoints over a 10-year period, “so we know when the marker is most accurate at predicting decline,” Mr. Kinnon said.
The first of two studies was considered a “discovery” study and included blood samples from 224 patients.
Results showed the test predicted decline from mild cognitive impairment (MCI) to AD at the end of 6 years, with an area under the curve (AUC) greater than 90%.
These results are “massive,” said Mr. Kinnon. “It’s the most accurate test I’ve seen anywhere for predicting decline of a patient.”
The test can also accurately classify a patient’s stage of cognition, he added. “Not only does it allow us to predict 6 years in advance, it also tells us if the patient has SMC [subjective memory complaints], MCI, or AD with a 95% certainty,” Mr. Kinnon said.
He noted that test sensitivity was higher than results found from traditional methods that are currently being used. The positive predictive value (PPV) and negative predictive value (NPV), which were at 90% or more, were “absolutely fantastic,” said Mr. Kinnon.
“Better than expected” results
In the second “validation” study, investigators examined samples from a completely different group of 482 patients. The “very compelling” results showed AUCs over 90%, PPVs over 90%, and “very high” NPVs, Mr. Kinnon said.
“These are great data, better than we expected,” he added.
However, he noted the test is “very specific” for decline to AD and not to other dementias.
In addition, Mr. Kinnon noted the test does not monitor levels of amyloid beta or tau, which accumulate at a later stage of AD. “Amyloid and tau tell you you’ve got it. We’re there way before those concentrations become detectable,” he said.
Identifying patients who will progress to AD years before they have symptoms gives them time to make medical decisions. These patients may also try treatments at an earlier stage of the disease, when these therapies are most likely to be helpful, said Mr. Kinnon.
In addition, using the test could speed up the approval of prospective drug treatments for AD. Currently, pharmaceutical companies enroll thousands of patients into a clinical study “and they don’t know which ones will have AD,” Mr. Kinnon noted.
“This test tells you these are the ones who are going to progress and should go into the study, and these are the ones that aren’t. So it makes the studies statistically relevant and accurate,” he said.
Investigators can also use the test to monitor patients during a study instead of relying on expensive PET scans and painful and costly spinal fluid taps, he added.
Previous surveys and market research have shown that neurologists and general practitioners “want a blood test to screen patients early, to help educate and inform patients,” said Mr. Kinnon.
Further results that will include biobank data on more than 1,000 patients in the United States and Europe are due for completion toward the end of this year.
The company is currently in negotiations to bring the product to North America, Europe, and elsewhere. “Our goal is to have it on the market by the middle of next year in multiple regions,” Mr. Kinnon said.
Encouraging, preliminary
Commenting on the findings, Percy Griffin, PhD, MSc, director of scientific engagement at the Alzheimer’s Association, said “it’s exciting” to see development of novel ways for detecting or predicting AD.
“There is an urgent need for simple, inexpensive, noninvasive, and accessible early detection tools for Alzheimer’s, such as a blood test,” he said.
However, Dr. Griffin cautioned the test is still in the early stages of development and has not been tested extensively in large, diverse clinical trials.
In addition, although the test predicts whether a person will progress, it does not predict when the person will progress, he added.
“These preliminary results are encouraging, but further validation is needed before this test can be implemented widely,” he said.
Technologies that facilitate the early detection and intervention before significant loss of brain cells from AD “would be game-changing” for individuals, families, and the healthcare system, Dr. Griffin concluded.
A version of this article first appeared on Medscape.com.
FROM CTAD21
AAN issues ethical guidance on controversial Alzheimer’s drug
The statement includes ethical considerations and recommendations for informed consent, and the AAN notes that neurologists should ensure that patients understand all of the issues and uncertainties surrounding the use of aducanumab.
“Neurologists and other clinicians want to provide the best care to patients and families, particularly for a disease that is as challenging as Alzheimer’s. We hope that this statement can be a guide for clinicians in communicating with patients and families in order to carefully consider decisions about the use of aducanumab,” said lead author Winston Chiong, MD, PhD, University of California San Francisco Memory and Aging Center, and a member of the AAN’s Ethics, Law, and Humanities Committee.
The statement was published online Nov. 17 in Neurology.
Open, honest communication
The Food and Drug Administration approved the antiamyloid agent aducanumab based on two studies that were both stopped prematurely for futility. In subsequent post hoc analyses of the available data, one of those studies indicated a statistically significant, albeit small, benefit with high-dose aducanumab, while the other study continued to show no benefit.
The clinical importance of the small statistical benefit in the single trial for daily function is unclear, and aducanumab was also associated with brain inflammation and brain bleeds in more than one-third of patients who received the FDA-approved dose, which requires regular brain MRI monitoring.
All of this should be communicated to patients, the AAN advises.
Patients should know that while aducanumab reduces beta-amyloid plaques in the brain that are markers of Alzheimer’s disease, it remains unclear whether this provides any meaningful benefit.
The AAN adds that it is equally important to tell patients and families that aducanumab does not restore cognitive function and that there is insufficient data to offer it to people with moderate or advanced dementia or to those without evidence of beta-amyloid plaques.
It’s important to note that very few participants in the aducanumab trials were Hispanic, Black, or Indigenous.
“Informed consent conversations with patients of populations underrepresented in clinical trials should include disclosure about the absence of safety and efficacy data in these groups,” the authors noted.
‘New territory’ for neurologists
“There are two aspects of aducanumab that are relatively new territory for us as neurologists,” Dr. Chiong said. One is the controversy about the evidence for the drug. “In the statement, we’ve tried to help clinicians communicate the uncertainty over aducanumab’s risks and potential benefits,” Dr. Chiong said. The other is the high cost of the drug and how it will be covered.
Aducanumab has a price tag of $56,000 per year, which does not include the cost of infusing the drug, required repeat imaging, and medical management.
The AAN estimates annual costs of prescribing aducanumab may top $100,000 per year. With Medicare generally covering 80%, patients and families must be told that the full costs of treatment may not be covered.
“Regarding cost, we probably don’t think often enough about what prescribing a drug means for an individual patient’s finances and for the health system,” said Dr. Chiong. “In particular, when patients are in Medicare we might assume their health care costs will be sufficiently covered, but because aducanumab is so expensive its use is likely to impose very significant costs on individual patients as well as to the Medicare program,” Dr. Chiong said.
“It is understandable why a new drug for Alzheimer’s disease generates so much interest, because while its approval has been controversial, it still offers a glimmer of hope to patients and their families,” AAN President Orly Avitzur, MD, said in a news release. “By using ethical principles to create this position statement, the American Academy of Neurology aims to help neurologists and other physicians transparently counsel patients and their families with a goal of providing the highest quality patient-centered care,” Dr. Avitzur said.
This statement was approved by the Ethics, Law, and Humanities Committee, a joint committee of the AAN, American Neurological Association, and Child Neurology Society.
This research had no targeted funding. Dr. Chiong has received personal compensation for serving on the Neuroethics Working Group of the National Institutes of Health BRAIN Initiative, and his institution has received research support from the National Institutes of Health. A complete list of author disclosures is available with the original article.
A version of this article first appeared on Medscape.com.
The statement includes ethical considerations and recommendations for informed consent, and the AAN notes that neurologists should ensure that patients understand all of the issues and uncertainties surrounding the use of aducanumab.
“Neurologists and other clinicians want to provide the best care to patients and families, particularly for a disease that is as challenging as Alzheimer’s. We hope that this statement can be a guide for clinicians in communicating with patients and families in order to carefully consider decisions about the use of aducanumab,” said lead author Winston Chiong, MD, PhD, University of California San Francisco Memory and Aging Center, and a member of the AAN’s Ethics, Law, and Humanities Committee.
The statement was published online Nov. 17 in Neurology.
Open, honest communication
The Food and Drug Administration approved the antiamyloid agent aducanumab based on two studies that were both stopped prematurely for futility. In subsequent post hoc analyses of the available data, one of those studies indicated a statistically significant, albeit small, benefit with high-dose aducanumab, while the other study continued to show no benefit.
The clinical importance of the small statistical benefit in the single trial for daily function is unclear, and aducanumab was also associated with brain inflammation and brain bleeds in more than one-third of patients who received the FDA-approved dose, which requires regular brain MRI monitoring.
All of this should be communicated to patients, the AAN advises.
Patients should know that while aducanumab reduces beta-amyloid plaques in the brain that are markers of Alzheimer’s disease, it remains unclear whether this provides any meaningful benefit.
The AAN adds that it is equally important to tell patients and families that aducanumab does not restore cognitive function and that there is insufficient data to offer it to people with moderate or advanced dementia or to those without evidence of beta-amyloid plaques.
It’s important to note that very few participants in the aducanumab trials were Hispanic, Black, or Indigenous.
“Informed consent conversations with patients of populations underrepresented in clinical trials should include disclosure about the absence of safety and efficacy data in these groups,” the authors noted.
‘New territory’ for neurologists
“There are two aspects of aducanumab that are relatively new territory for us as neurologists,” Dr. Chiong said. One is the controversy about the evidence for the drug. “In the statement, we’ve tried to help clinicians communicate the uncertainty over aducanumab’s risks and potential benefits,” Dr. Chiong said. The other is the high cost of the drug and how it will be covered.
Aducanumab has a price tag of $56,000 per year, which does not include the cost of infusing the drug, required repeat imaging, and medical management.
The AAN estimates annual costs of prescribing aducanumab may top $100,000 per year. With Medicare generally covering 80%, patients and families must be told that the full costs of treatment may not be covered.
“Regarding cost, we probably don’t think often enough about what prescribing a drug means for an individual patient’s finances and for the health system,” said Dr. Chiong. “In particular, when patients are in Medicare we might assume their health care costs will be sufficiently covered, but because aducanumab is so expensive its use is likely to impose very significant costs on individual patients as well as to the Medicare program,” Dr. Chiong said.
“It is understandable why a new drug for Alzheimer’s disease generates so much interest, because while its approval has been controversial, it still offers a glimmer of hope to patients and their families,” AAN President Orly Avitzur, MD, said in a news release. “By using ethical principles to create this position statement, the American Academy of Neurology aims to help neurologists and other physicians transparently counsel patients and their families with a goal of providing the highest quality patient-centered care,” Dr. Avitzur said.
This statement was approved by the Ethics, Law, and Humanities Committee, a joint committee of the AAN, American Neurological Association, and Child Neurology Society.
This research had no targeted funding. Dr. Chiong has received personal compensation for serving on the Neuroethics Working Group of the National Institutes of Health BRAIN Initiative, and his institution has received research support from the National Institutes of Health. A complete list of author disclosures is available with the original article.
A version of this article first appeared on Medscape.com.
The statement includes ethical considerations and recommendations for informed consent, and the AAN notes that neurologists should ensure that patients understand all of the issues and uncertainties surrounding the use of aducanumab.
“Neurologists and other clinicians want to provide the best care to patients and families, particularly for a disease that is as challenging as Alzheimer’s. We hope that this statement can be a guide for clinicians in communicating with patients and families in order to carefully consider decisions about the use of aducanumab,” said lead author Winston Chiong, MD, PhD, University of California San Francisco Memory and Aging Center, and a member of the AAN’s Ethics, Law, and Humanities Committee.
The statement was published online Nov. 17 in Neurology.
Open, honest communication
The Food and Drug Administration approved the antiamyloid agent aducanumab based on two studies that were both stopped prematurely for futility. In subsequent post hoc analyses of the available data, one of those studies indicated a statistically significant, albeit small, benefit with high-dose aducanumab, while the other study continued to show no benefit.
The clinical importance of the small statistical benefit in the single trial for daily function is unclear, and aducanumab was also associated with brain inflammation and brain bleeds in more than one-third of patients who received the FDA-approved dose, which requires regular brain MRI monitoring.
All of this should be communicated to patients, the AAN advises.
Patients should know that while aducanumab reduces beta-amyloid plaques in the brain that are markers of Alzheimer’s disease, it remains unclear whether this provides any meaningful benefit.
The AAN adds that it is equally important to tell patients and families that aducanumab does not restore cognitive function and that there is insufficient data to offer it to people with moderate or advanced dementia or to those without evidence of beta-amyloid plaques.
It’s important to note that very few participants in the aducanumab trials were Hispanic, Black, or Indigenous.
“Informed consent conversations with patients of populations underrepresented in clinical trials should include disclosure about the absence of safety and efficacy data in these groups,” the authors noted.
‘New territory’ for neurologists
“There are two aspects of aducanumab that are relatively new territory for us as neurologists,” Dr. Chiong said. One is the controversy about the evidence for the drug. “In the statement, we’ve tried to help clinicians communicate the uncertainty over aducanumab’s risks and potential benefits,” Dr. Chiong said. The other is the high cost of the drug and how it will be covered.
Aducanumab has a price tag of $56,000 per year, which does not include the cost of infusing the drug, required repeat imaging, and medical management.
The AAN estimates annual costs of prescribing aducanumab may top $100,000 per year. With Medicare generally covering 80%, patients and families must be told that the full costs of treatment may not be covered.
“Regarding cost, we probably don’t think often enough about what prescribing a drug means for an individual patient’s finances and for the health system,” said Dr. Chiong. “In particular, when patients are in Medicare we might assume their health care costs will be sufficiently covered, but because aducanumab is so expensive its use is likely to impose very significant costs on individual patients as well as to the Medicare program,” Dr. Chiong said.
“It is understandable why a new drug for Alzheimer’s disease generates so much interest, because while its approval has been controversial, it still offers a glimmer of hope to patients and their families,” AAN President Orly Avitzur, MD, said in a news release. “By using ethical principles to create this position statement, the American Academy of Neurology aims to help neurologists and other physicians transparently counsel patients and their families with a goal of providing the highest quality patient-centered care,” Dr. Avitzur said.
This statement was approved by the Ethics, Law, and Humanities Committee, a joint committee of the AAN, American Neurological Association, and Child Neurology Society.
This research had no targeted funding. Dr. Chiong has received personal compensation for serving on the Neuroethics Working Group of the National Institutes of Health BRAIN Initiative, and his institution has received research support from the National Institutes of Health. A complete list of author disclosures is available with the original article.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
Premenopausal bilateral oophorectomy linked to later cognitive impairment
Women whose ovaries were surgically removed before the age of 46 had a higher risk of mild cognitive impairment (MCI) around 30 years later, compared with those who did not undergo bilateral oophorectomy, according to a population-based linkage study published in JAMA Network Open.
The findings suggest that “physicians treating women with premenopausal bilateral oophorectomy need to be aware of their patients’ risk of cognitive impairment or MCI and should consider implementing treatment-monitoring plans,” noted lead author Walter A. Rocca, MD, MPH, from the division of epidemiology, department of quantitative health sciences, at the Mayo Clinic, Rochester, Minn. and colleagues.
The results may particularly “help women at mean risk levels of ovarian cancer to better evaluate the risk-to-benefit ratio of undergoing bilateral oophorectomy prior to spontaneous menopause for the prevention of ovarian cancer,” they emphasized.
While the link between premenopausal bilateral oophorectomy and higher risk of cognitive impairment has been previously suggested, this new study “contributes valuable new data to a major public health importance issue and addresses a number of important shortcomings of existing literature,” Marios K. Georgakis, MD, PhD, and Eleni T. Petridou, MD, PhD, noted in an accompanying commentary.
“As bilateral oophorectomy is still a common procedure at least in well-resourced countries, the results of these studies should alert clinicians about its potential public health consequences. Given that the abrupt cessation of ovarian hormones might be accompanied by previously underestimated long-term adverse effects, treating physicians proposing the operation should weigh its benefits against potential long-term harmful effects, especially among women without an absolute indication,” noted Dr. Georgakis and Dr. Petridou, respectively from the Center for Genomic Medicine at Massachusetts General Hospital in Boston and the National and Kapodistrian University of Athens.
The case-control cross-sectional study used data from the Mayo Clinic Study of Aging (MCSA), a prospective, population-based study examining risk factors for, as well as prevalence and incidence of cognitive decline and MCI among a representative sample of women in Olmsted County, Minn. It included 2,732 women aged 50-89 years who participated in the MCSA study from 2004 to 2019 and underwent a clinical evaluation and comprehensive cognitive testing including nine tests covering four cognitive domains. Almost all of the subjects (98.4%) were White. The mean age of cognitive evaluation was 74 years – at which time 283 women (10.4%) were diagnosed with MCI (197 with amnestic and 86 with nonamnestic MCI). Data from the Rochester Epidemiology Project medical record–linkage system showed a total of 625 women (22.9%) had a history of bilateral oophorectomy. Among this group, 161 women underwent the procedure both before age 46, and before menopause, with 46 (28.6%) receiving oral conjugated equine estrogen (unopposed) and the remaining 95 (59.0%) receiving no estrogen therapy.
The study found that, compared with women who did not undergo bilateral oophorectomy, those who did so before age 46, but not after this age, had statistically significantly increased odds of MCI (adjusted odds ratio, 2.21; P < .001). When type of MCI was examined, the risk was statistically significant for nonamnestic MCI (aOR, 2.96; P < .001), and amnestic (aOR, 1.87; P =.03). The study also found no evidence that estrogen therapy was associated with decreased risk of MCI among women aged less than 46 years, with an aOR of 2.56 in those who received estrogen therapy and 2.05 in those who did not (P = .01 for both).
Finally, in women who had bilateral oophorectomy before menopause and before age 50, surgical indication for the procedure affected the association with MCI. Indications of either cancer or “no ovarian condition” (i.e., performed at the time of hysterectomy) were associated with no increased risk, whereas there was a statistically significantly increased risk associated with benign indications such as an adnexal mass, cyst or endometriosis (aOR, 2.43; P = .003). “This is important,” noted the commentators, “because in many of those cases removal of both ovaries could be avoided.”
The study also found that, compared with women who had not undergone bilateral oophorectomy, those who had also had increased frequency of cardiovascular risk factors, heart disease, and stroke at the time of their cognitive evaluation. “Additional research is needed to clarify the biological explanation of the association,” the investigators said.
The prevailing hypothesis for why premenopausal bilateral oophorectomy is associated with cognitive decline “is that the abrupt endocrine cessation of exposure to ovarian hormones accelerates the aging process,” the commentators noted. “Most important from a clinical perspective is whether these women would benefit from specific hormone replacement therapy schemes. Observational studies cannot reliably answer this question, and possibly it is time to rethink designing trials in specific groups of women who underwent bilateral oophorectomy before 46 years of age starting treatment immediately thereafter.”
In an interview Dr. Georgakis elaborated on this point, saying that, while the Women’s Health Study clearly showed no benefit of hormone replacement therapy for preventing dementia, it recruited women who were aged 65 years or older and had therefore undergone menopause more than 10-15 years earlier. “A hypothesis suggests that a critical vulnerability window exists shortly after menopause during which hormone replacement therapy might be needed to ameliorate any elevated risk,” he said. “Thus, it might make sense to reconsider a trial focused on this group of premenopausal women, who need to undergo oophorectomy at a young age (<46 years). Early initiation would be important. Unfortunately, such a trial would be difficult to conduct, because these women would need to be followed up for very long periods, as cognitive decline usually does not occur before the age of 65.”
Asked to comment on the study, Meadow Good, DO, an ob.gyn., female pelvic medicine and reconstructive surgeon, and physician adviser for Winnie Palmer Hospital for Women & Babies in Orlando, said this study adds credibility to previous studies showing the cognitive risk associated with premenopausal bilateral oophorectomy. “The literature is now pointing to a need to refrain from elective bilateral oophorectomy in women less than 60,” she said in an interview. “It should not be common that a women receives a bilateral oophorectomy before 60 for benign reasons.”
She added that cognition is not the only think at stake. “Bilateral oophorectomy before the age of 60 has a higher risk of incident heart disease, stroke, lung cancer and total cancers,” she said, citing a prospective cohort study within the Nurses’ Health Study.
Dr. Rocca reported financial support from the Mayo Clinic Research Committee during the conduct of the study. One coauthor reported unrestricted grants from Biogen and consulting fees from Brain Protection outside the submitted work. No other disclosures were reported from the authors. Dr. Georgakis, Dr. Petridou, and Dr. Good reported no conflicts of interest. The study was funded by the National Institute on Aging. It also used resources of the Rochester Epidemiology Project medical record–linkage system, which is supported by the NIA, the Mayo Clinic Research Committee, and user fees. Dr. Rocca was partly funded by the Ralph S. and Beverley E. Caulkins Professorship of Neurodegenerative Diseases Research of the Mayo Clinic.
Women whose ovaries were surgically removed before the age of 46 had a higher risk of mild cognitive impairment (MCI) around 30 years later, compared with those who did not undergo bilateral oophorectomy, according to a population-based linkage study published in JAMA Network Open.
The findings suggest that “physicians treating women with premenopausal bilateral oophorectomy need to be aware of their patients’ risk of cognitive impairment or MCI and should consider implementing treatment-monitoring plans,” noted lead author Walter A. Rocca, MD, MPH, from the division of epidemiology, department of quantitative health sciences, at the Mayo Clinic, Rochester, Minn. and colleagues.
The results may particularly “help women at mean risk levels of ovarian cancer to better evaluate the risk-to-benefit ratio of undergoing bilateral oophorectomy prior to spontaneous menopause for the prevention of ovarian cancer,” they emphasized.
While the link between premenopausal bilateral oophorectomy and higher risk of cognitive impairment has been previously suggested, this new study “contributes valuable new data to a major public health importance issue and addresses a number of important shortcomings of existing literature,” Marios K. Georgakis, MD, PhD, and Eleni T. Petridou, MD, PhD, noted in an accompanying commentary.
“As bilateral oophorectomy is still a common procedure at least in well-resourced countries, the results of these studies should alert clinicians about its potential public health consequences. Given that the abrupt cessation of ovarian hormones might be accompanied by previously underestimated long-term adverse effects, treating physicians proposing the operation should weigh its benefits against potential long-term harmful effects, especially among women without an absolute indication,” noted Dr. Georgakis and Dr. Petridou, respectively from the Center for Genomic Medicine at Massachusetts General Hospital in Boston and the National and Kapodistrian University of Athens.
The case-control cross-sectional study used data from the Mayo Clinic Study of Aging (MCSA), a prospective, population-based study examining risk factors for, as well as prevalence and incidence of cognitive decline and MCI among a representative sample of women in Olmsted County, Minn. It included 2,732 women aged 50-89 years who participated in the MCSA study from 2004 to 2019 and underwent a clinical evaluation and comprehensive cognitive testing including nine tests covering four cognitive domains. Almost all of the subjects (98.4%) were White. The mean age of cognitive evaluation was 74 years – at which time 283 women (10.4%) were diagnosed with MCI (197 with amnestic and 86 with nonamnestic MCI). Data from the Rochester Epidemiology Project medical record–linkage system showed a total of 625 women (22.9%) had a history of bilateral oophorectomy. Among this group, 161 women underwent the procedure both before age 46, and before menopause, with 46 (28.6%) receiving oral conjugated equine estrogen (unopposed) and the remaining 95 (59.0%) receiving no estrogen therapy.
The study found that, compared with women who did not undergo bilateral oophorectomy, those who did so before age 46, but not after this age, had statistically significantly increased odds of MCI (adjusted odds ratio, 2.21; P < .001). When type of MCI was examined, the risk was statistically significant for nonamnestic MCI (aOR, 2.96; P < .001), and amnestic (aOR, 1.87; P =.03). The study also found no evidence that estrogen therapy was associated with decreased risk of MCI among women aged less than 46 years, with an aOR of 2.56 in those who received estrogen therapy and 2.05 in those who did not (P = .01 for both).
Finally, in women who had bilateral oophorectomy before menopause and before age 50, surgical indication for the procedure affected the association with MCI. Indications of either cancer or “no ovarian condition” (i.e., performed at the time of hysterectomy) were associated with no increased risk, whereas there was a statistically significantly increased risk associated with benign indications such as an adnexal mass, cyst or endometriosis (aOR, 2.43; P = .003). “This is important,” noted the commentators, “because in many of those cases removal of both ovaries could be avoided.”
The study also found that, compared with women who had not undergone bilateral oophorectomy, those who had also had increased frequency of cardiovascular risk factors, heart disease, and stroke at the time of their cognitive evaluation. “Additional research is needed to clarify the biological explanation of the association,” the investigators said.
The prevailing hypothesis for why premenopausal bilateral oophorectomy is associated with cognitive decline “is that the abrupt endocrine cessation of exposure to ovarian hormones accelerates the aging process,” the commentators noted. “Most important from a clinical perspective is whether these women would benefit from specific hormone replacement therapy schemes. Observational studies cannot reliably answer this question, and possibly it is time to rethink designing trials in specific groups of women who underwent bilateral oophorectomy before 46 years of age starting treatment immediately thereafter.”
In an interview Dr. Georgakis elaborated on this point, saying that, while the Women’s Health Study clearly showed no benefit of hormone replacement therapy for preventing dementia, it recruited women who were aged 65 years or older and had therefore undergone menopause more than 10-15 years earlier. “A hypothesis suggests that a critical vulnerability window exists shortly after menopause during which hormone replacement therapy might be needed to ameliorate any elevated risk,” he said. “Thus, it might make sense to reconsider a trial focused on this group of premenopausal women, who need to undergo oophorectomy at a young age (<46 years). Early initiation would be important. Unfortunately, such a trial would be difficult to conduct, because these women would need to be followed up for very long periods, as cognitive decline usually does not occur before the age of 65.”
Asked to comment on the study, Meadow Good, DO, an ob.gyn., female pelvic medicine and reconstructive surgeon, and physician adviser for Winnie Palmer Hospital for Women & Babies in Orlando, said this study adds credibility to previous studies showing the cognitive risk associated with premenopausal bilateral oophorectomy. “The literature is now pointing to a need to refrain from elective bilateral oophorectomy in women less than 60,” she said in an interview. “It should not be common that a women receives a bilateral oophorectomy before 60 for benign reasons.”
She added that cognition is not the only think at stake. “Bilateral oophorectomy before the age of 60 has a higher risk of incident heart disease, stroke, lung cancer and total cancers,” she said, citing a prospective cohort study within the Nurses’ Health Study.
Dr. Rocca reported financial support from the Mayo Clinic Research Committee during the conduct of the study. One coauthor reported unrestricted grants from Biogen and consulting fees from Brain Protection outside the submitted work. No other disclosures were reported from the authors. Dr. Georgakis, Dr. Petridou, and Dr. Good reported no conflicts of interest. The study was funded by the National Institute on Aging. It also used resources of the Rochester Epidemiology Project medical record–linkage system, which is supported by the NIA, the Mayo Clinic Research Committee, and user fees. Dr. Rocca was partly funded by the Ralph S. and Beverley E. Caulkins Professorship of Neurodegenerative Diseases Research of the Mayo Clinic.
Women whose ovaries were surgically removed before the age of 46 had a higher risk of mild cognitive impairment (MCI) around 30 years later, compared with those who did not undergo bilateral oophorectomy, according to a population-based linkage study published in JAMA Network Open.
The findings suggest that “physicians treating women with premenopausal bilateral oophorectomy need to be aware of their patients’ risk of cognitive impairment or MCI and should consider implementing treatment-monitoring plans,” noted lead author Walter A. Rocca, MD, MPH, from the division of epidemiology, department of quantitative health sciences, at the Mayo Clinic, Rochester, Minn. and colleagues.
The results may particularly “help women at mean risk levels of ovarian cancer to better evaluate the risk-to-benefit ratio of undergoing bilateral oophorectomy prior to spontaneous menopause for the prevention of ovarian cancer,” they emphasized.
While the link between premenopausal bilateral oophorectomy and higher risk of cognitive impairment has been previously suggested, this new study “contributes valuable new data to a major public health importance issue and addresses a number of important shortcomings of existing literature,” Marios K. Georgakis, MD, PhD, and Eleni T. Petridou, MD, PhD, noted in an accompanying commentary.
“As bilateral oophorectomy is still a common procedure at least in well-resourced countries, the results of these studies should alert clinicians about its potential public health consequences. Given that the abrupt cessation of ovarian hormones might be accompanied by previously underestimated long-term adverse effects, treating physicians proposing the operation should weigh its benefits against potential long-term harmful effects, especially among women without an absolute indication,” noted Dr. Georgakis and Dr. Petridou, respectively from the Center for Genomic Medicine at Massachusetts General Hospital in Boston and the National and Kapodistrian University of Athens.
The case-control cross-sectional study used data from the Mayo Clinic Study of Aging (MCSA), a prospective, population-based study examining risk factors for, as well as prevalence and incidence of cognitive decline and MCI among a representative sample of women in Olmsted County, Minn. It included 2,732 women aged 50-89 years who participated in the MCSA study from 2004 to 2019 and underwent a clinical evaluation and comprehensive cognitive testing including nine tests covering four cognitive domains. Almost all of the subjects (98.4%) were White. The mean age of cognitive evaluation was 74 years – at which time 283 women (10.4%) were diagnosed with MCI (197 with amnestic and 86 with nonamnestic MCI). Data from the Rochester Epidemiology Project medical record–linkage system showed a total of 625 women (22.9%) had a history of bilateral oophorectomy. Among this group, 161 women underwent the procedure both before age 46, and before menopause, with 46 (28.6%) receiving oral conjugated equine estrogen (unopposed) and the remaining 95 (59.0%) receiving no estrogen therapy.
The study found that, compared with women who did not undergo bilateral oophorectomy, those who did so before age 46, but not after this age, had statistically significantly increased odds of MCI (adjusted odds ratio, 2.21; P < .001). When type of MCI was examined, the risk was statistically significant for nonamnestic MCI (aOR, 2.96; P < .001), and amnestic (aOR, 1.87; P =.03). The study also found no evidence that estrogen therapy was associated with decreased risk of MCI among women aged less than 46 years, with an aOR of 2.56 in those who received estrogen therapy and 2.05 in those who did not (P = .01 for both).
Finally, in women who had bilateral oophorectomy before menopause and before age 50, surgical indication for the procedure affected the association with MCI. Indications of either cancer or “no ovarian condition” (i.e., performed at the time of hysterectomy) were associated with no increased risk, whereas there was a statistically significantly increased risk associated with benign indications such as an adnexal mass, cyst or endometriosis (aOR, 2.43; P = .003). “This is important,” noted the commentators, “because in many of those cases removal of both ovaries could be avoided.”
The study also found that, compared with women who had not undergone bilateral oophorectomy, those who had also had increased frequency of cardiovascular risk factors, heart disease, and stroke at the time of their cognitive evaluation. “Additional research is needed to clarify the biological explanation of the association,” the investigators said.
The prevailing hypothesis for why premenopausal bilateral oophorectomy is associated with cognitive decline “is that the abrupt endocrine cessation of exposure to ovarian hormones accelerates the aging process,” the commentators noted. “Most important from a clinical perspective is whether these women would benefit from specific hormone replacement therapy schemes. Observational studies cannot reliably answer this question, and possibly it is time to rethink designing trials in specific groups of women who underwent bilateral oophorectomy before 46 years of age starting treatment immediately thereafter.”
In an interview Dr. Georgakis elaborated on this point, saying that, while the Women’s Health Study clearly showed no benefit of hormone replacement therapy for preventing dementia, it recruited women who were aged 65 years or older and had therefore undergone menopause more than 10-15 years earlier. “A hypothesis suggests that a critical vulnerability window exists shortly after menopause during which hormone replacement therapy might be needed to ameliorate any elevated risk,” he said. “Thus, it might make sense to reconsider a trial focused on this group of premenopausal women, who need to undergo oophorectomy at a young age (<46 years). Early initiation would be important. Unfortunately, such a trial would be difficult to conduct, because these women would need to be followed up for very long periods, as cognitive decline usually does not occur before the age of 65.”
Asked to comment on the study, Meadow Good, DO, an ob.gyn., female pelvic medicine and reconstructive surgeon, and physician adviser for Winnie Palmer Hospital for Women & Babies in Orlando, said this study adds credibility to previous studies showing the cognitive risk associated with premenopausal bilateral oophorectomy. “The literature is now pointing to a need to refrain from elective bilateral oophorectomy in women less than 60,” she said in an interview. “It should not be common that a women receives a bilateral oophorectomy before 60 for benign reasons.”
She added that cognition is not the only think at stake. “Bilateral oophorectomy before the age of 60 has a higher risk of incident heart disease, stroke, lung cancer and total cancers,” she said, citing a prospective cohort study within the Nurses’ Health Study.
Dr. Rocca reported financial support from the Mayo Clinic Research Committee during the conduct of the study. One coauthor reported unrestricted grants from Biogen and consulting fees from Brain Protection outside the submitted work. No other disclosures were reported from the authors. Dr. Georgakis, Dr. Petridou, and Dr. Good reported no conflicts of interest. The study was funded by the National Institute on Aging. It also used resources of the Rochester Epidemiology Project medical record–linkage system, which is supported by the NIA, the Mayo Clinic Research Committee, and user fees. Dr. Rocca was partly funded by the Ralph S. and Beverley E. Caulkins Professorship of Neurodegenerative Diseases Research of the Mayo Clinic.
FROM JAMA NETWORK OPEN