Alzheimer’s research is plagued with misconduct and fraud, undermining the progress toward understanding and treating the disease, say investigators who endeavor to expose errors and misleading practices.

The book is yet to be closed, for instance, on whether a 2006 paper by Sylvain Lesne positing amyloid as a major cause of Alzheimer’s was based on fraudulent data. Suspicions about the paper were first raised in late 2021 by Matthew Schrag, MD, PhD, an assistant professor of neurology at Vanderbilt University Medical Center, Nashville, Tennessee.

Dr. Schrag also queried the work of a City University of New York (CUNY) researcher who proposed PT-125 (now simufilam) as a potential anti-amyloid for Alzheimer’s disease. Even though CUNY recently found “egregious” and potentially deliberate misconduct by that researcher, Cassava Sciences is continuing phase 3 trials of simufilam.

Now questions are being raised about work from the lab of Berislav V. Zlokovic, PhD, a prominent neuroscientist at the University of Southern California (USC), Los Angeles, California, and also about studies conducted under the aegis of Domenico Pratico, MD, the director of the Alzheimer’s Center at Temple University in Philadelphia, Pennsylvania.

Alzheimer’s has been a notoriously hard puzzle to solve. Despite decades of research, there are still no effective therapies and disparate theories about potential causes.

Dr. Schrag said he wouldn’t “attribute all the ills in this field” to misconduct, but it “is absolutely a part of the equation.” Some of the papers flagged for integrity issues “have been hugely influential,” he said in an interview. “Some of the labs that we’re talking about have really shaped how we’ve thought about this disease,” he said. “It’s hard to un-ring the bell.”

The fallout from fraud has a wide impact. Taxpayer dollars are wasted in the creation of the fraud and in attempts to replicate the failed experiment. Grad students — the workhorses of labs — waste time trying to repeat studies or may be bullied or intimidated into misconduct, said Elisabeth Bik, PhD, a former Stanford microbiologist who is now a full-time fraud investigator.

And there’s potential harm to patients. “There’s a lot of false hope being given to these people and their families,” Dr. Bik said in an interview.
 

Alzheimer’s Tempts With Big Rewards

There are big rewards for those who publish important papers on Alzheimer’s: More grants, publication in higher-impact journals, larger labs, and potentially, personal enrichment from commercialization of therapies.

“I can see that people are driven to cut corners or even to make up results, or even anything in between, to reach that goal,” said Dr. Bik.

It’s unclear whether misconduct and fraud are on the rise or just being detected more frequently.

“It’s very hard to say,” said Mike Rossner, PhD, president of Image Data Integrity. Institutions hire Dr. Rossner to help ferret out research integrity issues. He told this news organization that it’s likely detection is on the rise, given the increasing number of sleuths like Dr. Bik.

In 2002, Dr. Rossner began to screen all images submitted to the Journal of Clinical Biology in response to the new phenomenon of digital images and the advent of PhotoShop. “Very early on, we started to see problems in digital images that we would not have seen on a glossy printout,” Dr. Rossner said of his time as managing editor of the journal.

From 2002 to 2014, at least 25% of papers had an image that violated guidelines that prohibited the removal of spots or other blemishes (called “beautification”) with PhotoShop, which did not necessarily indicate fraud. They withdrew acceptance for 1% of papers because of image manipulations that affected data interpretation.

Dr. Bik noted that even if there is not a greater percentage of fraudulent papers in Alzheimer’s, “it would still be in absolute numbers a lot of papers that could be fraudulent,” given that Alzheimer’s research is well-funded with federal agencies alone providing $3.7 billion a year.

Images Key to Spotting Issues

Investigative sleuths often use the online forum PubPeer to initially raise questions about papers. The format gives the original authors a chance to comment on or defend their work. While some critiques are about data, most hone in on alleged duplications or manipulations of images, primarily by Western Blots.

The images are key, because “the images are the data,” said Dr. Rossner. “The words are the author’s interpretation of what they see in the images,” he said.

It’s also easier to spot a problem in an image. The raw data or an investigator’s notebooks aren’t needed, and there are artificial intelligence-driven software programs such as Proofig and Image Twin that help investigators spot duplicated images or cases in which an image might have been flipped or otherwise manipulated to make results look better.

Science recently announced that it would be using Proofig to screen images in all papers submitted to its six journals.

Using a screening tool is better than nothing, said Dr. Rossner who still relies on visual inspection, employing contrast or other features in PhotoShop to spot inconsistencies or duplications. But “none of those companies have disclosed how effective they are relative to visual screening, and that to me is very problematic,” he said.

“The tools are not going to catch everything,” said Dr. Bik.

Dr. Schrag agreed. “One of the things that we’re worried about is that a lot of the journals will simply adopt these tools as a screener and assume that that’s going to de-risk their publication portfolio,” he said, noting the high rate of misses.

Artificial Intelligence a Growing Concern

Artificial intelligence (AI) may also accelerate the amount of fraud and add to the difficulty of ferreting it out, said the investigators.

“I’m very worried about AI,” said Dr. Bik. Although AI-generated images and content may be rudimentary today, “next year it’s going to be much better,” she said. Going forward, it may be hard to distinguish between a real dataset and one that has been generated by AI, she said.

“The more closely AI can mimic authentic content, the more difficult it will be for publications to detect intentionally fraudulent submissions,” wrote Dror Kolodkin-Gal, PhD, the founder of Proofig, in an article for the Council of Science Editors.

Dr. Kolodkin-Gal said that AI may be especially prone to misuse by paper mills. Those operations submit fake or shoddy manuscripts to a journal on behalf of researchers seeking publication who pay the mills a fee. The Committee on Publication Ethics reported in 2022 that 2%-46% of papers submitted to journals may be from paper mills.

While it’s unclear whether AI is having any impact now, Dr. Rossner said, “I think I can be pretty confident in saying it is going to be a growing problem” as the tools become more sophisticated.

He sees parallels with the rise of PhotoShop and cites data from the National Institute of Health’s Office of Research Integrity (ORI) showing that in 1990, when PhotoShop was still new, 2% of cases referred to ORI involved image manipulation. By 2007, 70% of cases had image manipulation issues.

Journals, Institutions Need to Step Up More

Fraud may continue apace in part because investigations drag on for years, and in many cases, with a lack of consequences for the perpetrators, said the investigators. And, they say, journals and institutions haven’t devoted enough resources to prevent or investigate misconduct.

“A lot of editors did not even want to investigate because they just didn’t want to believe that there could be fraud in science,” said Dr. Bik of her experiences. “I hope that by now most journals at least should have realized that some proportion of the manuscripts that get sent to their journals is going to be fraud,” she said.

“The bulk of the journals seem like they don’t want to be bothered by this,” agreed Dr. Schrag, adding that “some have gone to great lengths to try to discourage people from bringing forward complaints.”

A big issue is that journals “don’t answer to any higher authority,” said Dr. Schrag. He believes that journals that repeatedly refuse to address integrity issues should be barred from publishing research produced with funds from the National Institutes of Health.

All the investigators said institutions and journals should hire forensic investigators. Relying on unpaid peer reviewers or editors to root out fraud is unrealistic, they said.

“You want to have specialized people with experience and be paid to do that as a full-time job,” said Dr. Bik, who is funded by speaking engagements and receives about $2300 a month through donations to her Patreon account.

Once a potential integrity issue is flagged, there is “an incredible conflict of interest in how these investigations are run,” said Dr. Schrag. “Institutions are asked to investigate their own faculty; they’re asked to investigate themselves.” That “creates the disincentive to move expeditiously,” said Dr. Schrag.

With the space of time, people who have committed fraud can throw out notebooks, delete data from servers, or even PhotoShop original photos so they match the manipulated ones that were submitted, Dr. Bik said.

Institutions could show they are serious about fraud by offering a “central, systematic universal screening of all image data going out of their institutions before submission to a journal,” said Dr. Rossner. But he knows only of a handful that do so. “I think research integrity offices have historically been very reactive, and they need to pivot and become proactive,” said Dr. Rossner.

Dr. Schrag wants to see stronger values within the research enterprise. “You have to build a culture where it’s absolutely anathema at a core level to violate these standards of research integrity,” he said. “We have this notion that we can push the process along faster and get to a grant and get to a paper and get to some short-term goal,” he said. “But the long-term goal in most of these cases is to cure a disease or to understand some biological mysteries. There’s no shortcut to getting there,” said Dr. Schrag.

There have been some high-profile consequences for research integrity failures, such as the 2023 resignation of Stanford University President Marc Tessier-Lavigne in the wake of findings that members of his lab — but not Tessier-Lavigne — engaged in data manipulation.

The process is often opaque, with investigations done in secrecy. “Consequences are not usually revealed, either,” said Dr. Rossner.

Dr. Schrag acknowledges it’s a tough balancing act for institutions to root out bad actors while also ensuring there’s no harm to those who may simply have operated in error.

“But it doesn’t serve anyone’s interest including the people who are accused, in dragging these things out for 5, 6, 8, or 10 years,” he said.

Lesne and Cassava: The Long and Winding Road

The investigations into the Lesne papers and the work underpinning Cassava Sciences’ therapy point to the difficulty of policing integrity and the potential fallout.

Lesne’s signature paper published in Nature in 2006 has been cited some 2300 times and is the fourth most-accessed article of 81,612 articles of a similar age in all journals tracked by Altimetrics.

Dr. Schrag, Dr. Bik, and others wrote to multiple journals asking them to investigate some 25 papers related to simufilam, including a 2012 Journal of Clinical Investigation article by Hoau-Yan Wang, PhD, the CUNY scientist whose work on simufilam has been questioned.

JCI Editor Elizabeth McNally pushed back stating in an editorial in 2022 that they, as whistleblowers, had potential conflicts and that they could be assisting short sellers who were seeking to profit by depressing Cassava’s stock price. Indeed, Dr. Schrag was initially hired by a law firm that was representing short sellers. Ms. McNally said that JCI would start requiring disclosures by whistleblowers.

Dr. Bik urged CUNY to investigate Dr. Wang in 2021 but was rebuffed. Then, in November 2023, a copy of CUNY’s final report on the Wang inquiry was leaked to Science. The university reported that Dr. Wang did not provide any original data or notebooks and that it found “long-standing and egregious misconduct in data management and record keeping by Dr. Wang,” wrote Dr. Bik in a blog post summarizing the investigation.

As of late 2023, 42 papers by Dr. Wang have earned PubPeer posts, seven have been retracted, and five have been marked with an Expression of Concern, wrote Dr. Bik.

Some have called for Cassava to stop its phase 3 studies of simufilam, but the company is proceeding, announcing in November 2023 that they have completed enrollment.

Misconduct Queries Underway at USC and Temple

Meanwhile, Dr. Schrag and Dr. Bik continue sleuthing. They are among a small group of whistleblowers who have filed a complaint with NIH about irregularities in the Zlokovic lab at USC. They allege that images were manipulated in dozens of papers, including some that inform the development of a stroke drug in phase 2 trials.

The inquiry goes well beyond stroke, said Dr. Schrag. Dr. Zlokovic “is one of the most influential scientists on Alzheimer’s scientists in the country,” Dr. Schrag said. The USC scientist is a leader on blood-brain barrier research.

USC is investigating “at some level,” he said. In a statement to this news organization, USC said that it “takes any allegations about research integrity very seriously.” The statement added, “Consistent with federal regulations and USC policies, this review must be kept confidential. As a result, we are unable to provide any further information.”

Mu Yang, PhD, assistant professor of neurobiology at Columbia University Medical Center in New York City, is also working on the Zlokovic investigation.

She calls herself an “accidental sleuth” who fell into the hobby after a graduate student asked her to help replicate a study by Temple University, Philadelphia, Pennsylvania, researcher Dominco Pratico, MD, of Alzheimer’s-like phenotype mice in the Morris Water Maze test. Dr. Yang, who runs the “behavior core” at Columbia — teaching and advising on how to run assays and collect and report data — could see right away that the Pratico data were “too perfect.”

She enlisted maze inventor Richard Morris to join her in a letter of concern to the journals that published Dr. Pratico’s work, all under the aegis of Springer Nature.

The publisher’s integrity team has since retracted four Pratico papers. Three were because of image abnormalities pointed out by Dr. Bik, who worked with Dr. Yang. One was because of “self-plagiarism.”

“The official retraction notes didn’t mention anything about data abnormality being a concern,” said Dr. Yang who says that questionable data is harder to prove than an image duplication or manipulation. And the papers remain available, although dozens of Practico papers have been flagged on PubPeer.

To Dr. Yang, images are the canary in the coalmine. “People don’t just fake western blots but then give real behavior data or give you fake behavior data but give you the most authentic Western Blots,” she said.

Dr. Pratico has now sued a graduate student who was a coauthor on the papers, according to the Philadelphia Inquirer.

The NIH’s ORI has requested that Temple University conduct an investigation, Dr. Yang said.

In a statement to this news organization, Temple said it “does not comment on internal investigations or personnel issues,” but that “allegations of research misconduct are reviewed and investigated centrally through Temple’s Office of the Vice President for Research in accordance with university policy and applicable federal regulations.”

A version of this article appeared on Medscape.com.

Alzheimer’s research is plagued with misconduct and fraud, undermining the progress toward understanding and treating the disease, say investigators who endeavor to expose errors and misleading practices.

The book is yet to be closed, for instance, on whether a 2006 paper by Sylvain Lesne positing amyloid as a major cause of Alzheimer’s was based on fraudulent data. Suspicions about the paper were first raised in late 2021 by Matthew Schrag, MD, PhD, an assistant professor of neurology at Vanderbilt University Medical Center, Nashville, Tennessee.

Dr. Schrag also queried the work of a City University of New York (CUNY) researcher who proposed PT-125 (now simufilam) as a potential anti-amyloid for Alzheimer’s disease. Even though CUNY recently found “egregious” and potentially deliberate misconduct by that researcher, Cassava Sciences is continuing phase 3 trials of simufilam.

Now questions are being raised about work from the lab of Berislav V. Zlokovic, PhD, a prominent neuroscientist at the University of Southern California (USC), Los Angeles, California, and also about studies conducted under the aegis of Domenico Pratico, MD, the director of the Alzheimer’s Center at Temple University in Philadelphia, Pennsylvania.

Alzheimer’s has been a notoriously hard puzzle to solve. Despite decades of research, there are still no effective therapies and disparate theories about potential causes.

Dr. Schrag said he wouldn’t “attribute all the ills in this field” to misconduct, but it “is absolutely a part of the equation.” Some of the papers flagged for integrity issues “have been hugely influential,” he said in an interview. “Some of the labs that we’re talking about have really shaped how we’ve thought about this disease,” he said. “It’s hard to un-ring the bell.”

The fallout from fraud has a wide impact. Taxpayer dollars are wasted in the creation of the fraud and in attempts to replicate the failed experiment. Grad students — the workhorses of labs — waste time trying to repeat studies or may be bullied or intimidated into misconduct, said Elisabeth Bik, PhD, a former Stanford microbiologist who is now a full-time fraud investigator.

And there’s potential harm to patients. “There’s a lot of false hope being given to these people and their families,” Dr. Bik said in an interview.
 

Alzheimer’s Tempts With Big Rewards

There are big rewards for those who publish important papers on Alzheimer’s: More grants, publication in higher-impact journals, larger labs, and potentially, personal enrichment from commercialization of therapies.

“I can see that people are driven to cut corners or even to make up results, or even anything in between, to reach that goal,” said Dr. Bik.

It’s unclear whether misconduct and fraud are on the rise or just being detected more frequently.

“It’s very hard to say,” said Mike Rossner, PhD, president of Image Data Integrity. Institutions hire Dr. Rossner to help ferret out research integrity issues. He told this news organization that it’s likely detection is on the rise, given the increasing number of sleuths like Dr. Bik.

In 2002, Dr. Rossner began to screen all images submitted to the Journal of Clinical Biology in response to the new phenomenon of digital images and the advent of PhotoShop. “Very early on, we started to see problems in digital images that we would not have seen on a glossy printout,” Dr. Rossner said of his time as managing editor of the journal.

From 2002 to 2014, at least 25% of papers had an image that violated guidelines that prohibited the removal of spots or other blemishes (called “beautification”) with PhotoShop, which did not necessarily indicate fraud. They withdrew acceptance for 1% of papers because of image manipulations that affected data interpretation.

Dr. Bik noted that even if there is not a greater percentage of fraudulent papers in Alzheimer’s, “it would still be in absolute numbers a lot of papers that could be fraudulent,” given that Alzheimer’s research is well-funded with federal agencies alone providing $3.7 billion a year.

Images Key to Spotting Issues

Investigative sleuths often use the online forum PubPeer to initially raise questions about papers. The format gives the original authors a chance to comment on or defend their work. While some critiques are about data, most hone in on alleged duplications or manipulations of images, primarily by Western Blots.

The images are key, because “the images are the data,” said Dr. Rossner. “The words are the author’s interpretation of what they see in the images,” he said.

It’s also easier to spot a problem in an image. The raw data or an investigator’s notebooks aren’t needed, and there are artificial intelligence-driven software programs such as Proofig and Image Twin that help investigators spot duplicated images or cases in which an image might have been flipped or otherwise manipulated to make results look better.

Science recently announced that it would be using Proofig to screen images in all papers submitted to its six journals.

Using a screening tool is better than nothing, said Dr. Rossner who still relies on visual inspection, employing contrast or other features in PhotoShop to spot inconsistencies or duplications. But “none of those companies have disclosed how effective they are relative to visual screening, and that to me is very problematic,” he said.

“The tools are not going to catch everything,” said Dr. Bik.

Dr. Schrag agreed. “One of the things that we’re worried about is that a lot of the journals will simply adopt these tools as a screener and assume that that’s going to de-risk their publication portfolio,” he said, noting the high rate of misses.

Artificial Intelligence a Growing Concern

Artificial intelligence (AI) may also accelerate the amount of fraud and add to the difficulty of ferreting it out, said the investigators.

“I’m very worried about AI,” said Dr. Bik. Although AI-generated images and content may be rudimentary today, “next year it’s going to be much better,” she said. Going forward, it may be hard to distinguish between a real dataset and one that has been generated by AI, she said.

“The more closely AI can mimic authentic content, the more difficult it will be for publications to detect intentionally fraudulent submissions,” wrote Dror Kolodkin-Gal, PhD, the founder of Proofig, in an article for the Council of Science Editors.

Dr. Kolodkin-Gal said that AI may be especially prone to misuse by paper mills. Those operations submit fake or shoddy manuscripts to a journal on behalf of researchers seeking publication who pay the mills a fee. The Committee on Publication Ethics reported in 2022 that 2%-46% of papers submitted to journals may be from paper mills.

While it’s unclear whether AI is having any impact now, Dr. Rossner said, “I think I can be pretty confident in saying it is going to be a growing problem” as the tools become more sophisticated.

He sees parallels with the rise of PhotoShop and cites data from the National Institute of Health’s Office of Research Integrity (ORI) showing that in 1990, when PhotoShop was still new, 2% of cases referred to ORI involved image manipulation. By 2007, 70% of cases had image manipulation issues.

Journals, Institutions Need to Step Up More

Fraud may continue apace in part because investigations drag on for years, and in many cases, with a lack of consequences for the perpetrators, said the investigators. And, they say, journals and institutions haven’t devoted enough resources to prevent or investigate misconduct.

“A lot of editors did not even want to investigate because they just didn’t want to believe that there could be fraud in science,” said Dr. Bik of her experiences. “I hope that by now most journals at least should have realized that some proportion of the manuscripts that get sent to their journals is going to be fraud,” she said.

“The bulk of the journals seem like they don’t want to be bothered by this,” agreed Dr. Schrag, adding that “some have gone to great lengths to try to discourage people from bringing forward complaints.”

A big issue is that journals “don’t answer to any higher authority,” said Dr. Schrag. He believes that journals that repeatedly refuse to address integrity issues should be barred from publishing research produced with funds from the National Institutes of Health.

All the investigators said institutions and journals should hire forensic investigators. Relying on unpaid peer reviewers or editors to root out fraud is unrealistic, they said.

“You want to have specialized people with experience and be paid to do that as a full-time job,” said Dr. Bik, who is funded by speaking engagements and receives about $2300 a month through donations to her Patreon account.

Once a potential integrity issue is flagged, there is “an incredible conflict of interest in how these investigations are run,” said Dr. Schrag. “Institutions are asked to investigate their own faculty; they’re asked to investigate themselves.” That “creates the disincentive to move expeditiously,” said Dr. Schrag.

With the space of time, people who have committed fraud can throw out notebooks, delete data from servers, or even PhotoShop original photos so they match the manipulated ones that were submitted, Dr. Bik said.

Institutions could show they are serious about fraud by offering a “central, systematic universal screening of all image data going out of their institutions before submission to a journal,” said Dr. Rossner. But he knows only of a handful that do so. “I think research integrity offices have historically been very reactive, and they need to pivot and become proactive,” said Dr. Rossner.

Dr. Schrag wants to see stronger values within the research enterprise. “You have to build a culture where it’s absolutely anathema at a core level to violate these standards of research integrity,” he said. “We have this notion that we can push the process along faster and get to a grant and get to a paper and get to some short-term goal,” he said. “But the long-term goal in most of these cases is to cure a disease or to understand some biological mysteries. There’s no shortcut to getting there,” said Dr. Schrag.

There have been some high-profile consequences for research integrity failures, such as the 2023 resignation of Stanford University President Marc Tessier-Lavigne in the wake of findings that members of his lab — but not Tessier-Lavigne — engaged in data manipulation.

The process is often opaque, with investigations done in secrecy. “Consequences are not usually revealed, either,” said Dr. Rossner.

Dr. Schrag acknowledges it’s a tough balancing act for institutions to root out bad actors while also ensuring there’s no harm to those who may simply have operated in error.

“But it doesn’t serve anyone’s interest including the people who are accused, in dragging these things out for 5, 6, 8, or 10 years,” he said.

Lesne and Cassava: The Long and Winding Road

The investigations into the Lesne papers and the work underpinning Cassava Sciences’ therapy point to the difficulty of policing integrity and the potential fallout.

Lesne’s signature paper published in Nature in 2006 has been cited some 2300 times and is the fourth most-accessed article of 81,612 articles of a similar age in all journals tracked by Altimetrics.

Dr. Schrag, Dr. Bik, and others wrote to multiple journals asking them to investigate some 25 papers related to simufilam, including a 2012 Journal of Clinical Investigation article by Hoau-Yan Wang, PhD, the CUNY scientist whose work on simufilam has been questioned.

JCI Editor Elizabeth McNally pushed back stating in an editorial in 2022 that they, as whistleblowers, had potential conflicts and that they could be assisting short sellers who were seeking to profit by depressing Cassava’s stock price. Indeed, Dr. Schrag was initially hired by a law firm that was representing short sellers. Ms. McNally said that JCI would start requiring disclosures by whistleblowers.

Dr. Bik urged CUNY to investigate Dr. Wang in 2021 but was rebuffed. Then, in November 2023, a copy of CUNY’s final report on the Wang inquiry was leaked to Science. The university reported that Dr. Wang did not provide any original data or notebooks and that it found “long-standing and egregious misconduct in data management and record keeping by Dr. Wang,” wrote Dr. Bik in a blog post summarizing the investigation.

As of late 2023, 42 papers by Dr. Wang have earned PubPeer posts, seven have been retracted, and five have been marked with an Expression of Concern, wrote Dr. Bik.

Some have called for Cassava to stop its phase 3 studies of simufilam, but the company is proceeding, announcing in November 2023 that they have completed enrollment.

Misconduct Queries Underway at USC and Temple

Meanwhile, Dr. Schrag and Dr. Bik continue sleuthing. They are among a small group of whistleblowers who have filed a complaint with NIH about irregularities in the Zlokovic lab at USC. They allege that images were manipulated in dozens of papers, including some that inform the development of a stroke drug in phase 2 trials.

The inquiry goes well beyond stroke, said Dr. Schrag. Dr. Zlokovic “is one of the most influential scientists on Alzheimer’s scientists in the country,” Dr. Schrag said. The USC scientist is a leader on blood-brain barrier research.

USC is investigating “at some level,” he said. In a statement to this news organization, USC said that it “takes any allegations about research integrity very seriously.” The statement added, “Consistent with federal regulations and USC policies, this review must be kept confidential. As a result, we are unable to provide any further information.”

Mu Yang, PhD, assistant professor of neurobiology at Columbia University Medical Center in New York City, is also working on the Zlokovic investigation.

She calls herself an “accidental sleuth” who fell into the hobby after a graduate student asked her to help replicate a study by Temple University, Philadelphia, Pennsylvania, researcher Dominco Pratico, MD, of Alzheimer’s-like phenotype mice in the Morris Water Maze test. Dr. Yang, who runs the “behavior core” at Columbia — teaching and advising on how to run assays and collect and report data — could see right away that the Pratico data were “too perfect.”

She enlisted maze inventor Richard Morris to join her in a letter of concern to the journals that published Dr. Pratico’s work, all under the aegis of Springer Nature.

The publisher’s integrity team has since retracted four Pratico papers. Three were because of image abnormalities pointed out by Dr. Bik, who worked with Dr. Yang. One was because of “self-plagiarism.”

“The official retraction notes didn’t mention anything about data abnormality being a concern,” said Dr. Yang who says that questionable data is harder to prove than an image duplication or manipulation. And the papers remain available, although dozens of Practico papers have been flagged on PubPeer.

To Dr. Yang, images are the canary in the coalmine. “People don’t just fake western blots but then give real behavior data or give you fake behavior data but give you the most authentic Western Blots,” she said.

Dr. Pratico has now sued a graduate student who was a coauthor on the papers, according to the Philadelphia Inquirer.

The NIH’s ORI has requested that Temple University conduct an investigation, Dr. Yang said.

In a statement to this news organization, Temple said it “does not comment on internal investigations or personnel issues,” but that “allegations of research misconduct are reviewed and investigated centrally through Temple’s Office of the Vice President for Research in accordance with university policy and applicable federal regulations.”

A version of this article appeared on Medscape.com.

Alzheimer’s research is plagued with misconduct and fraud, undermining the progress toward understanding and treating the disease, say investigators who endeavor to expose errors and misleading practices.

The book is yet to be closed, for instance, on whether a 2006 paper by Sylvain Lesne positing amyloid as a major cause of Alzheimer’s was based on fraudulent data. Suspicions about the paper were first raised in late 2021 by Matthew Schrag, MD, PhD, an assistant professor of neurology at Vanderbilt University Medical Center, Nashville, Tennessee.

Dr. Schrag also queried the work of a City University of New York (CUNY) researcher who proposed PT-125 (now simufilam) as a potential anti-amyloid for Alzheimer’s disease. Even though CUNY recently found “egregious” and potentially deliberate misconduct by that researcher, Cassava Sciences is continuing phase 3 trials of simufilam.

Now questions are being raised about work from the lab of Berislav V. Zlokovic, PhD, a prominent neuroscientist at the University of Southern California (USC), Los Angeles, California, and also about studies conducted under the aegis of Domenico Pratico, MD, the director of the Alzheimer’s Center at Temple University in Philadelphia, Pennsylvania.

Alzheimer’s has been a notoriously hard puzzle to solve. Despite decades of research, there are still no effective therapies and disparate theories about potential causes.

Dr. Schrag said he wouldn’t “attribute all the ills in this field” to misconduct, but it “is absolutely a part of the equation.” Some of the papers flagged for integrity issues “have been hugely influential,” he said in an interview. “Some of the labs that we’re talking about have really shaped how we’ve thought about this disease,” he said. “It’s hard to un-ring the bell.”

The fallout from fraud has a wide impact. Taxpayer dollars are wasted in the creation of the fraud and in attempts to replicate the failed experiment. Grad students — the workhorses of labs — waste time trying to repeat studies or may be bullied or intimidated into misconduct, said Elisabeth Bik, PhD, a former Stanford microbiologist who is now a full-time fraud investigator.

And there’s potential harm to patients. “There’s a lot of false hope being given to these people and their families,” Dr. Bik said in an interview.
 

Alzheimer’s Tempts With Big Rewards

There are big rewards for those who publish important papers on Alzheimer’s: More grants, publication in higher-impact journals, larger labs, and potentially, personal enrichment from commercialization of therapies.

“I can see that people are driven to cut corners or even to make up results, or even anything in between, to reach that goal,” said Dr. Bik.

It’s unclear whether misconduct and fraud are on the rise or just being detected more frequently.

“It’s very hard to say,” said Mike Rossner, PhD, president of Image Data Integrity. Institutions hire Dr. Rossner to help ferret out research integrity issues. He told this news organization that it’s likely detection is on the rise, given the increasing number of sleuths like Dr. Bik.

In 2002, Dr. Rossner began to screen all images submitted to the Journal of Clinical Biology in response to the new phenomenon of digital images and the advent of PhotoShop. “Very early on, we started to see problems in digital images that we would not have seen on a glossy printout,” Dr. Rossner said of his time as managing editor of the journal.

From 2002 to 2014, at least 25% of papers had an image that violated guidelines that prohibited the removal of spots or other blemishes (called “beautification”) with PhotoShop, which did not necessarily indicate fraud. They withdrew acceptance for 1% of papers because of image manipulations that affected data interpretation.

Dr. Bik noted that even if there is not a greater percentage of fraudulent papers in Alzheimer’s, “it would still be in absolute numbers a lot of papers that could be fraudulent,” given that Alzheimer’s research is well-funded with federal agencies alone providing $3.7 billion a year.

Images Key to Spotting Issues

Investigative sleuths often use the online forum PubPeer to initially raise questions about papers. The format gives the original authors a chance to comment on or defend their work. While some critiques are about data, most hone in on alleged duplications or manipulations of images, primarily by Western Blots.

The images are key, because “the images are the data,” said Dr. Rossner. “The words are the author’s interpretation of what they see in the images,” he said.

It’s also easier to spot a problem in an image. The raw data or an investigator’s notebooks aren’t needed, and there are artificial intelligence-driven software programs such as Proofig and Image Twin that help investigators spot duplicated images or cases in which an image might have been flipped or otherwise manipulated to make results look better.

Science recently announced that it would be using Proofig to screen images in all papers submitted to its six journals.

Using a screening tool is better than nothing, said Dr. Rossner who still relies on visual inspection, employing contrast or other features in PhotoShop to spot inconsistencies or duplications. But “none of those companies have disclosed how effective they are relative to visual screening, and that to me is very problematic,” he said.

“The tools are not going to catch everything,” said Dr. Bik.

Dr. Schrag agreed. “One of the things that we’re worried about is that a lot of the journals will simply adopt these tools as a screener and assume that that’s going to de-risk their publication portfolio,” he said, noting the high rate of misses.

Artificial Intelligence a Growing Concern

Artificial intelligence (AI) may also accelerate the amount of fraud and add to the difficulty of ferreting it out, said the investigators.

“I’m very worried about AI,” said Dr. Bik. Although AI-generated images and content may be rudimentary today, “next year it’s going to be much better,” she said. Going forward, it may be hard to distinguish between a real dataset and one that has been generated by AI, she said.

“The more closely AI can mimic authentic content, the more difficult it will be for publications to detect intentionally fraudulent submissions,” wrote Dror Kolodkin-Gal, PhD, the founder of Proofig, in an article for the Council of Science Editors.

Dr. Kolodkin-Gal said that AI may be especially prone to misuse by paper mills. Those operations submit fake or shoddy manuscripts to a journal on behalf of researchers seeking publication who pay the mills a fee. The Committee on Publication Ethics reported in 2022 that 2%-46% of papers submitted to journals may be from paper mills.

While it’s unclear whether AI is having any impact now, Dr. Rossner said, “I think I can be pretty confident in saying it is going to be a growing problem” as the tools become more sophisticated.

He sees parallels with the rise of PhotoShop and cites data from the National Institute of Health’s Office of Research Integrity (ORI) showing that in 1990, when PhotoShop was still new, 2% of cases referred to ORI involved image manipulation. By 2007, 70% of cases had image manipulation issues.

Journals, Institutions Need to Step Up More

Fraud may continue apace in part because investigations drag on for years, and in many cases, with a lack of consequences for the perpetrators, said the investigators. And, they say, journals and institutions haven’t devoted enough resources to prevent or investigate misconduct.

“A lot of editors did not even want to investigate because they just didn’t want to believe that there could be fraud in science,” said Dr. Bik of her experiences. “I hope that by now most journals at least should have realized that some proportion of the manuscripts that get sent to their journals is going to be fraud,” she said.

“The bulk of the journals seem like they don’t want to be bothered by this,” agreed Dr. Schrag, adding that “some have gone to great lengths to try to discourage people from bringing forward complaints.”

A big issue is that journals “don’t answer to any higher authority,” said Dr. Schrag. He believes that journals that repeatedly refuse to address integrity issues should be barred from publishing research produced with funds from the National Institutes of Health.

All the investigators said institutions and journals should hire forensic investigators. Relying on unpaid peer reviewers or editors to root out fraud is unrealistic, they said.

“You want to have specialized people with experience and be paid to do that as a full-time job,” said Dr. Bik, who is funded by speaking engagements and receives about $2300 a month through donations to her Patreon account.

Once a potential integrity issue is flagged, there is “an incredible conflict of interest in how these investigations are run,” said Dr. Schrag. “Institutions are asked to investigate their own faculty; they’re asked to investigate themselves.” That “creates the disincentive to move expeditiously,” said Dr. Schrag.

With the space of time, people who have committed fraud can throw out notebooks, delete data from servers, or even PhotoShop original photos so they match the manipulated ones that were submitted, Dr. Bik said.

Institutions could show they are serious about fraud by offering a “central, systematic universal screening of all image data going out of their institutions before submission to a journal,” said Dr. Rossner. But he knows only of a handful that do so. “I think research integrity offices have historically been very reactive, and they need to pivot and become proactive,” said Dr. Rossner.

Dr. Schrag wants to see stronger values within the research enterprise. “You have to build a culture where it’s absolutely anathema at a core level to violate these standards of research integrity,” he said. “We have this notion that we can push the process along faster and get to a grant and get to a paper and get to some short-term goal,” he said. “But the long-term goal in most of these cases is to cure a disease or to understand some biological mysteries. There’s no shortcut to getting there,” said Dr. Schrag.

There have been some high-profile consequences for research integrity failures, such as the 2023 resignation of Stanford University President Marc Tessier-Lavigne in the wake of findings that members of his lab — but not Tessier-Lavigne — engaged in data manipulation.

The process is often opaque, with investigations done in secrecy. “Consequences are not usually revealed, either,” said Dr. Rossner.

Dr. Schrag acknowledges it’s a tough balancing act for institutions to root out bad actors while also ensuring there’s no harm to those who may simply have operated in error.

“But it doesn’t serve anyone’s interest including the people who are accused, in dragging these things out for 5, 6, 8, or 10 years,” he said.

Lesne and Cassava: The Long and Winding Road

The investigations into the Lesne papers and the work underpinning Cassava Sciences’ therapy point to the difficulty of policing integrity and the potential fallout.

Lesne’s signature paper published in Nature in 2006 has been cited some 2300 times and is the fourth most-accessed article of 81,612 articles of a similar age in all journals tracked by Altimetrics.

Dr. Schrag, Dr. Bik, and others wrote to multiple journals asking them to investigate some 25 papers related to simufilam, including a 2012 Journal of Clinical Investigation article by Hoau-Yan Wang, PhD, the CUNY scientist whose work on simufilam has been questioned.

JCI Editor Elizabeth McNally pushed back stating in an editorial in 2022 that they, as whistleblowers, had potential conflicts and that they could be assisting short sellers who were seeking to profit by depressing Cassava’s stock price. Indeed, Dr. Schrag was initially hired by a law firm that was representing short sellers. Ms. McNally said that JCI would start requiring disclosures by whistleblowers.

Dr. Bik urged CUNY to investigate Dr. Wang in 2021 but was rebuffed. Then, in November 2023, a copy of CUNY’s final report on the Wang inquiry was leaked to Science. The university reported that Dr. Wang did not provide any original data or notebooks and that it found “long-standing and egregious misconduct in data management and record keeping by Dr. Wang,” wrote Dr. Bik in a blog post summarizing the investigation.

As of late 2023, 42 papers by Dr. Wang have earned PubPeer posts, seven have been retracted, and five have been marked with an Expression of Concern, wrote Dr. Bik.

Some have called for Cassava to stop its phase 3 studies of simufilam, but the company is proceeding, announcing in November 2023 that they have completed enrollment.

Misconduct Queries Underway at USC and Temple

Meanwhile, Dr. Schrag and Dr. Bik continue sleuthing. They are among a small group of whistleblowers who have filed a complaint with NIH about irregularities in the Zlokovic lab at USC. They allege that images were manipulated in dozens of papers, including some that inform the development of a stroke drug in phase 2 trials.

The inquiry goes well beyond stroke, said Dr. Schrag. Dr. Zlokovic “is one of the most influential scientists on Alzheimer’s scientists in the country,” Dr. Schrag said. The USC scientist is a leader on blood-brain barrier research.

USC is investigating “at some level,” he said. In a statement to this news organization, USC said that it “takes any allegations about research integrity very seriously.” The statement added, “Consistent with federal regulations and USC policies, this review must be kept confidential. As a result, we are unable to provide any further information.”

Mu Yang, PhD, assistant professor of neurobiology at Columbia University Medical Center in New York City, is also working on the Zlokovic investigation.

She calls herself an “accidental sleuth” who fell into the hobby after a graduate student asked her to help replicate a study by Temple University, Philadelphia, Pennsylvania, researcher Dominco Pratico, MD, of Alzheimer’s-like phenotype mice in the Morris Water Maze test. Dr. Yang, who runs the “behavior core” at Columbia — teaching and advising on how to run assays and collect and report data — could see right away that the Pratico data were “too perfect.”

She enlisted maze inventor Richard Morris to join her in a letter of concern to the journals that published Dr. Pratico’s work, all under the aegis of Springer Nature.

The publisher’s integrity team has since retracted four Pratico papers. Three were because of image abnormalities pointed out by Dr. Bik, who worked with Dr. Yang. One was because of “self-plagiarism.”

“The official retraction notes didn’t mention anything about data abnormality being a concern,” said Dr. Yang who says that questionable data is harder to prove than an image duplication or manipulation. And the papers remain available, although dozens of Practico papers have been flagged on PubPeer.

To Dr. Yang, images are the canary in the coalmine. “People don’t just fake western blots but then give real behavior data or give you fake behavior data but give you the most authentic Western Blots,” she said.

Dr. Pratico has now sued a graduate student who was a coauthor on the papers, according to the Philadelphia Inquirer.

The NIH’s ORI has requested that Temple University conduct an investigation, Dr. Yang said.

In a statement to this news organization, Temple said it “does not comment on internal investigations or personnel issues,” but that “allegations of research misconduct are reviewed and investigated centrally through Temple’s Office of the Vice President for Research in accordance with university policy and applicable federal regulations.”

A version of this article appeared on Medscape.com.

TOPLINE:

The remission period of type 1 diabetes (T1D) can be prolonged with high-dose ergocalciferol (a vitamin D analog), by preserving the function of insulin-producing beta cells in newly diagnosed patients.

METHODOLOGY:

• Beta cells may retain approximately 30%-50% function at the time of T1D diagnosis and continue producing insulin for months or years. Preserving beta-cell function early on can extend this remission period and improve long-term glycemic control.
• Researchers conducted a secondary post hoc analysis of a randomized clinical trial looking at residual beta function and vitamin D supplementation in 36 youths (age, 10-21 years; mean age, 13.5 years; 33.3% women) with recently diagnosed T1D.
• Participants were randomly assigned to receive vitamin D (50,000 international units) or placebo every week for 2 months and then biweekly for 10 months.
• Mixed-meal tolerance tests were performed after overnight fasting at 0, 3, 6, 9, and 12 months, and blood draws were obtained 30 minutes and 90 minutes for post-meal C-peptide and glucose estimations.
• The fasting proinsulin to C-peptide ratio (PI:C) and the percentage change in the area under the curve of C-peptide from baseline (%ΔAUC) were calculated to test the effect of vitamin D on beta-cell function.

TAKEAWAY: 

• Vitamin D supplementation improved the insulin secretion capacity of beta cells, as observed by the decrease in the mean fasting PI:C ratio compared with placebo (−0.0009 vs 0.0011; P =.01).
• The reduction in %ΔAUC of C-peptide was notably slower with vitamin D than placebo (−2.8% vs −4.7%; P =.03), indicating a longer delay in the loss of C-peptide.

IN PRACTICE:

“It is exciting to know that vitamin D could protect the beta cells of the pancreas and increase the natural production of good and functional insulin in these patients. This, in turn, prolongs the honeymoon phase of type 1 diabetes and leads to reduced long-term complications of this disease,” Benjamin Udoka Nwosu, MD, Northwell Health, Division of Endocrinology, Department of Pediatrics, Cohen Children’s Medical Center, New Hyde Park, New York, the principal author, said in a press release.

SOURCE:

The study was published online in JAMA Network Open.

LIMITATIONS:

It was a single-center study.

DISCLOSURES:

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The authors did not report any conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

The remission period of type 1 diabetes (T1D) can be prolonged with high-dose ergocalciferol (a vitamin D analog), by preserving the function of insulin-producing beta cells in newly diagnosed patients.

METHODOLOGY:

• Beta cells may retain approximately 30%-50% function at the time of T1D diagnosis and continue producing insulin for months or years. Preserving beta-cell function early on can extend this remission period and improve long-term glycemic control.
• Researchers conducted a secondary post hoc analysis of a randomized clinical trial looking at residual beta function and vitamin D supplementation in 36 youths (age, 10-21 years; mean age, 13.5 years; 33.3% women) with recently diagnosed T1D.
• Participants were randomly assigned to receive vitamin D (50,000 international units) or placebo every week for 2 months and then biweekly for 10 months.
• Mixed-meal tolerance tests were performed after overnight fasting at 0, 3, 6, 9, and 12 months, and blood draws were obtained 30 minutes and 90 minutes for post-meal C-peptide and glucose estimations.
• The fasting proinsulin to C-peptide ratio (PI:C) and the percentage change in the area under the curve of C-peptide from baseline (%ΔAUC) were calculated to test the effect of vitamin D on beta-cell function.

TAKEAWAY: 

• Vitamin D supplementation improved the insulin secretion capacity of beta cells, as observed by the decrease in the mean fasting PI:C ratio compared with placebo (−0.0009 vs 0.0011; P =.01).
• The reduction in %ΔAUC of C-peptide was notably slower with vitamin D than placebo (−2.8% vs −4.7%; P =.03), indicating a longer delay in the loss of C-peptide.

IN PRACTICE:

“It is exciting to know that vitamin D could protect the beta cells of the pancreas and increase the natural production of good and functional insulin in these patients. This, in turn, prolongs the honeymoon phase of type 1 diabetes and leads to reduced long-term complications of this disease,” Benjamin Udoka Nwosu, MD, Northwell Health, Division of Endocrinology, Department of Pediatrics, Cohen Children’s Medical Center, New Hyde Park, New York, the principal author, said in a press release.

SOURCE:

The study was published online in JAMA Network Open.

LIMITATIONS:

It was a single-center study.

DISCLOSURES:

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The authors did not report any conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

The remission period of type 1 diabetes (T1D) can be prolonged with high-dose ergocalciferol (a vitamin D analog), by preserving the function of insulin-producing beta cells in newly diagnosed patients.

METHODOLOGY:

• Beta cells may retain approximately 30%-50% function at the time of T1D diagnosis and continue producing insulin for months or years. Preserving beta-cell function early on can extend this remission period and improve long-term glycemic control.
• Researchers conducted a secondary post hoc analysis of a randomized clinical trial looking at residual beta function and vitamin D supplementation in 36 youths (age, 10-21 years; mean age, 13.5 years; 33.3% women) with recently diagnosed T1D.
• Participants were randomly assigned to receive vitamin D (50,000 international units) or placebo every week for 2 months and then biweekly for 10 months.
• Mixed-meal tolerance tests were performed after overnight fasting at 0, 3, 6, 9, and 12 months, and blood draws were obtained 30 minutes and 90 minutes for post-meal C-peptide and glucose estimations.
• The fasting proinsulin to C-peptide ratio (PI:C) and the percentage change in the area under the curve of C-peptide from baseline (%ΔAUC) were calculated to test the effect of vitamin D on beta-cell function.

TAKEAWAY: 

• Vitamin D supplementation improved the insulin secretion capacity of beta cells, as observed by the decrease in the mean fasting PI:C ratio compared with placebo (−0.0009 vs 0.0011; P =.01).
• The reduction in %ΔAUC of C-peptide was notably slower with vitamin D than placebo (−2.8% vs −4.7%; P =.03), indicating a longer delay in the loss of C-peptide.

IN PRACTICE:

“It is exciting to know that vitamin D could protect the beta cells of the pancreas and increase the natural production of good and functional insulin in these patients. This, in turn, prolongs the honeymoon phase of type 1 diabetes and leads to reduced long-term complications of this disease,” Benjamin Udoka Nwosu, MD, Northwell Health, Division of Endocrinology, Department of Pediatrics, Cohen Children’s Medical Center, New Hyde Park, New York, the principal author, said in a press release.

SOURCE:

The study was published online in JAMA Network Open.

LIMITATIONS:

It was a single-center study.

DISCLOSURES:

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The authors did not report any conflicts of interest.

A version of this article appeared on Medscape.com.

Working with medically trained service dogs is associated with a 31% reduction in seizures compared with usual care in treatment-resistant epilepsy, a new study showed.

Investigators speculate that the dogs may ease participants’ stress, leading to a decrease in seizure frequency, although they note this relationship warrants more study.

“Despite the development of numerous antiseizure medications over the past 15 years, up to 30% of people with epilepsy experience persistent seizures,” study author Valérie van Hezik-Wester, MSc, of Erasmus University Rotterdam, Rotterdam, the Netherlands, said in a press release.

The unpredictable nature of seizures is one of the most disabling aspects of epilepsy, Ms. Hezik-Wester added. Seizure dogs are trained to recognize seizures and respond when they occur.

“The tasks that these dogs perform, along with their companionship, may reduce seizure-related anxiety, also potentially reducing seizures caused by stress, the most common trigger for seizures,” she said.

The findings were published online in Neurology.
 

Improve Quality of Life

The study included 25 individuals with medically refractory epilepsy who had an average of two or more seizures per week, with seizure characteristics associated with a high risk for injuries or dysfunction. They also had to be able to care for a service dog.

All were observed under usual care, which included antiseizure medications, neurostimulation devices, and other supportive therapies. Participants could then choose to work with a service dog that had completed socialization and obedience training or be assigned a puppy they would train at home.

The median follow-up was 19 months with usual care and 12 months with the intervention. Participants recorded seizure activity in diaries and completed surveys on seizure severity, quality of life, and well-being every 3 months. Daily seizure counts were converted to obtain cumulative seizure frequencies over 28-day periods.

Of the 25 original participants, six discontinued trial participation before the end of follow-up, four of whom left the study due to difficulty with dog care and training.

Participants receiving usual care reported an average of 115 seizures per 28-day period, while those with trained service dogs recorded 73 seizures in the same period, or a 37% difference between groups.

Researchers found that participants had an average of 31% fewer seizures during the past 3 months when they had seizure dogs, with seven participants achieving a 50%-100% reduction in seizures.

The number of seizure-free days increased from an average of 11 days per 28-day period before receiving a service dog to 15 days after working with a dog.

Scores on the EQ-5D-5L, which measures perceived health problems, decreased on average by 2.5% per consecutive 28-day period with the intervention, reflecting an increase in generic health-related quality of life (0.975; 95% CI, 0.954-0.997).

“These findings show that seizure dogs can help people with epilepsy,” said Ms. van Hezik-Wester. “However, we also found that this partnership with seizure dogs might not be the right fit for everyone, as some people discontinued their participation in this program. More research is needed to better understand which people can benefit from working with seizure dogs.”
 

Enhanced Quality of Life

In an accompanying editorial, Amir Mbonde, MB, and Amy Crepeau, MD, of Mayo Clinic in Phoenix, Arizona, noted the findings add to a growing body of work on the effectiveness of service dogs in reducing seizure frequency.

“In addition to improved seizure control, the EPISODE study demonstrated the benefit of seizure dogs in enhancing the quality of life for patients, a crucial component of comprehensive epilepsy care,” they wrote.

In prior studies, seizure dogs have identified an odor that a person emits before a seizure in up to 97% of people, they noted, adding that this ability “offers immense clinical benefits to people with epilepsy, enhancing their independence, social engagement, employment opportunities, self-confidence, and thus quality of life.”

Study limitations include its small sample size and high attrition rate.

The study was funded by the Netherlands Organization for Health Research and Development and Innovatiefonds Zorgverzekeraars.

A version of this article appeared on Medscape.com.

Working with medically trained service dogs is associated with a 31% reduction in seizures compared with usual care in treatment-resistant epilepsy, a new study showed.

Investigators speculate that the dogs may ease participants’ stress, leading to a decrease in seizure frequency, although they note this relationship warrants more study.

“Despite the development of numerous antiseizure medications over the past 15 years, up to 30% of people with epilepsy experience persistent seizures,” study author Valérie van Hezik-Wester, MSc, of Erasmus University Rotterdam, Rotterdam, the Netherlands, said in a press release.

The unpredictable nature of seizures is one of the most disabling aspects of epilepsy, Ms. Hezik-Wester added. Seizure dogs are trained to recognize seizures and respond when they occur.

“The tasks that these dogs perform, along with their companionship, may reduce seizure-related anxiety, also potentially reducing seizures caused by stress, the most common trigger for seizures,” she said.

The findings were published online in Neurology.
 

Improve Quality of Life

The study included 25 individuals with medically refractory epilepsy who had an average of two or more seizures per week, with seizure characteristics associated with a high risk for injuries or dysfunction. They also had to be able to care for a service dog.

All were observed under usual care, which included antiseizure medications, neurostimulation devices, and other supportive therapies. Participants could then choose to work with a service dog that had completed socialization and obedience training or be assigned a puppy they would train at home.

The median follow-up was 19 months with usual care and 12 months with the intervention. Participants recorded seizure activity in diaries and completed surveys on seizure severity, quality of life, and well-being every 3 months. Daily seizure counts were converted to obtain cumulative seizure frequencies over 28-day periods.

Of the 25 original participants, six discontinued trial participation before the end of follow-up, four of whom left the study due to difficulty with dog care and training.

Participants receiving usual care reported an average of 115 seizures per 28-day period, while those with trained service dogs recorded 73 seizures in the same period, or a 37% difference between groups.

Researchers found that participants had an average of 31% fewer seizures during the past 3 months when they had seizure dogs, with seven participants achieving a 50%-100% reduction in seizures.

The number of seizure-free days increased from an average of 11 days per 28-day period before receiving a service dog to 15 days after working with a dog.

Scores on the EQ-5D-5L, which measures perceived health problems, decreased on average by 2.5% per consecutive 28-day period with the intervention, reflecting an increase in generic health-related quality of life (0.975; 95% CI, 0.954-0.997).

“These findings show that seizure dogs can help people with epilepsy,” said Ms. van Hezik-Wester. “However, we also found that this partnership with seizure dogs might not be the right fit for everyone, as some people discontinued their participation in this program. More research is needed to better understand which people can benefit from working with seizure dogs.”
 

Enhanced Quality of Life

In an accompanying editorial, Amir Mbonde, MB, and Amy Crepeau, MD, of Mayo Clinic in Phoenix, Arizona, noted the findings add to a growing body of work on the effectiveness of service dogs in reducing seizure frequency.

“In addition to improved seizure control, the EPISODE study demonstrated the benefit of seizure dogs in enhancing the quality of life for patients, a crucial component of comprehensive epilepsy care,” they wrote.

In prior studies, seizure dogs have identified an odor that a person emits before a seizure in up to 97% of people, they noted, adding that this ability “offers immense clinical benefits to people with epilepsy, enhancing their independence, social engagement, employment opportunities, self-confidence, and thus quality of life.”

Study limitations include its small sample size and high attrition rate.

The study was funded by the Netherlands Organization for Health Research and Development and Innovatiefonds Zorgverzekeraars.

A version of this article appeared on Medscape.com.

Working with medically trained service dogs is associated with a 31% reduction in seizures compared with usual care in treatment-resistant epilepsy, a new study showed.

Investigators speculate that the dogs may ease participants’ stress, leading to a decrease in seizure frequency, although they note this relationship warrants more study.

“Despite the development of numerous antiseizure medications over the past 15 years, up to 30% of people with epilepsy experience persistent seizures,” study author Valérie van Hezik-Wester, MSc, of Erasmus University Rotterdam, Rotterdam, the Netherlands, said in a press release.

The unpredictable nature of seizures is one of the most disabling aspects of epilepsy, Ms. Hezik-Wester added. Seizure dogs are trained to recognize seizures and respond when they occur.

“The tasks that these dogs perform, along with their companionship, may reduce seizure-related anxiety, also potentially reducing seizures caused by stress, the most common trigger for seizures,” she said.

The findings were published online in Neurology.
 

Improve Quality of Life

The study included 25 individuals with medically refractory epilepsy who had an average of two or more seizures per week, with seizure characteristics associated with a high risk for injuries or dysfunction. They also had to be able to care for a service dog.

All were observed under usual care, which included antiseizure medications, neurostimulation devices, and other supportive therapies. Participants could then choose to work with a service dog that had completed socialization and obedience training or be assigned a puppy they would train at home.

The median follow-up was 19 months with usual care and 12 months with the intervention. Participants recorded seizure activity in diaries and completed surveys on seizure severity, quality of life, and well-being every 3 months. Daily seizure counts were converted to obtain cumulative seizure frequencies over 28-day periods.

Of the 25 original participants, six discontinued trial participation before the end of follow-up, four of whom left the study due to difficulty with dog care and training.

Participants receiving usual care reported an average of 115 seizures per 28-day period, while those with trained service dogs recorded 73 seizures in the same period, or a 37% difference between groups.

Researchers found that participants had an average of 31% fewer seizures during the past 3 months when they had seizure dogs, with seven participants achieving a 50%-100% reduction in seizures.

The number of seizure-free days increased from an average of 11 days per 28-day period before receiving a service dog to 15 days after working with a dog.

Scores on the EQ-5D-5L, which measures perceived health problems, decreased on average by 2.5% per consecutive 28-day period with the intervention, reflecting an increase in generic health-related quality of life (0.975; 95% CI, 0.954-0.997).

“These findings show that seizure dogs can help people with epilepsy,” said Ms. van Hezik-Wester. “However, we also found that this partnership with seizure dogs might not be the right fit for everyone, as some people discontinued their participation in this program. More research is needed to better understand which people can benefit from working with seizure dogs.”
 

Enhanced Quality of Life

In an accompanying editorial, Amir Mbonde, MB, and Amy Crepeau, MD, of Mayo Clinic in Phoenix, Arizona, noted the findings add to a growing body of work on the effectiveness of service dogs in reducing seizure frequency.

“In addition to improved seizure control, the EPISODE study demonstrated the benefit of seizure dogs in enhancing the quality of life for patients, a crucial component of comprehensive epilepsy care,” they wrote.

In prior studies, seizure dogs have identified an odor that a person emits before a seizure in up to 97% of people, they noted, adding that this ability “offers immense clinical benefits to people with epilepsy, enhancing their independence, social engagement, employment opportunities, self-confidence, and thus quality of life.”

Study limitations include its small sample size and high attrition rate.

The study was funded by the Netherlands Organization for Health Research and Development and Innovatiefonds Zorgverzekeraars.

A version of this article appeared on Medscape.com.

A new study provides more evidence that sildenafil (Viagra), which is used to treat erectile dsysfuntion (ED), may help protect against Alzheimer’s disease.

The large real-world analysis of patient data from two databases showed a 30%-54% reduced prevalence in Alzheimer’s disease among patients who took sildenafil (Viagra) than those who did not, after adjusting for potential confounding factors.

This observation was further supported by mechanistic studies showing decreased neurotoxic protein levels in brain cells exposed to the phosphodiesterase type 5 inhibitor (PDE5i).

“Our findings provide further weight to repurposing this existing FDA-approved drug as a novel treatment for Alzheimer’s, which is in great need of new therapies,” Feixiong Cheng, PhD, director of the Cleveland Clinic Genome Center, who led the research, said in a news release. 

“We used artificial intelligence to integrate data across multiple domains which all indicated sildenafil’s potential against this devastating neurological disease,” Dr. Cheng noted. 

The study was published online in the Journal of Alzheimer’s Disease.
 

Neuroprotective?

Using real-world patient data from the MarketScan Medicare Supplemental database (2012-2017) and the Clinformatics database (2007-2020), the researchers conducted propensity score-stratified analyses after adjusting for gender, age, race, and comorbidities. 

They searched for all individuals with pharmacy claims for sildenafil or four comparator drugs — bumetanide, furosemide, spironolactone, and nifedipine. Results showed that sildenafil use was associated with reduced likelihood of Alzheimer’s disease relative to the control drugs. 

For example, sildenafil use was associated with a 54% reduced incidence of Alzheimer’s disease in MarketScan (hazard ratio [HR], 0.46; 95% CI, 0.32-0.66) and a 30% reduced prevalence of Alzheimer’s disease in Clinformatics (HR, 0.70; 95% CI, 0.49-1.00) compared with spironolactone.

The findings support a study published earlier this year that found a potential protective effect of PDE5i treatment on Alzheimer’s disease risk.

However, this research and the current study are contradicted by another paper published in Brain Communications in late 2022 which showed no such link between ED meds and reduced Alzheimer’s disease risk.

The investigators also found that sildenafil reduces tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic Alzheimer’s disease patient induced pluripotent stem cell (iPSC)-derived neurons. 

They further demonstrated through RNA-sequencing data analysis that sildenafil specifically targets Alzheimer’s disease related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in Alzheimer’s disease.

“We believe our findings provide the evidence needed for clinical trials to further examine the potential effectiveness of sildenafil in patients with Alzheimer’s disease,” Dr. Cheng said. 

The study was primarily supported by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Cheng had no relevant disclosures. 

A version of this article appeared on Medscape.com.

A new study provides more evidence that sildenafil (Viagra), which is used to treat erectile dsysfuntion (ED), may help protect against Alzheimer’s disease.

The large real-world analysis of patient data from two databases showed a 30%-54% reduced prevalence in Alzheimer’s disease among patients who took sildenafil (Viagra) than those who did not, after adjusting for potential confounding factors.

This observation was further supported by mechanistic studies showing decreased neurotoxic protein levels in brain cells exposed to the phosphodiesterase type 5 inhibitor (PDE5i).

“Our findings provide further weight to repurposing this existing FDA-approved drug as a novel treatment for Alzheimer’s, which is in great need of new therapies,” Feixiong Cheng, PhD, director of the Cleveland Clinic Genome Center, who led the research, said in a news release. 

“We used artificial intelligence to integrate data across multiple domains which all indicated sildenafil’s potential against this devastating neurological disease,” Dr. Cheng noted. 

The study was published online in the Journal of Alzheimer’s Disease.
 

Neuroprotective?

Using real-world patient data from the MarketScan Medicare Supplemental database (2012-2017) and the Clinformatics database (2007-2020), the researchers conducted propensity score-stratified analyses after adjusting for gender, age, race, and comorbidities. 

They searched for all individuals with pharmacy claims for sildenafil or four comparator drugs — bumetanide, furosemide, spironolactone, and nifedipine. Results showed that sildenafil use was associated with reduced likelihood of Alzheimer’s disease relative to the control drugs. 

For example, sildenafil use was associated with a 54% reduced incidence of Alzheimer’s disease in MarketScan (hazard ratio [HR], 0.46; 95% CI, 0.32-0.66) and a 30% reduced prevalence of Alzheimer’s disease in Clinformatics (HR, 0.70; 95% CI, 0.49-1.00) compared with spironolactone.

The findings support a study published earlier this year that found a potential protective effect of PDE5i treatment on Alzheimer’s disease risk.

However, this research and the current study are contradicted by another paper published in Brain Communications in late 2022 which showed no such link between ED meds and reduced Alzheimer’s disease risk.

The investigators also found that sildenafil reduces tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic Alzheimer’s disease patient induced pluripotent stem cell (iPSC)-derived neurons. 

They further demonstrated through RNA-sequencing data analysis that sildenafil specifically targets Alzheimer’s disease related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in Alzheimer’s disease.

“We believe our findings provide the evidence needed for clinical trials to further examine the potential effectiveness of sildenafil in patients with Alzheimer’s disease,” Dr. Cheng said. 

The study was primarily supported by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Cheng had no relevant disclosures. 

A version of this article appeared on Medscape.com.

A new study provides more evidence that sildenafil (Viagra), which is used to treat erectile dsysfuntion (ED), may help protect against Alzheimer’s disease.

The large real-world analysis of patient data from two databases showed a 30%-54% reduced prevalence in Alzheimer’s disease among patients who took sildenafil (Viagra) than those who did not, after adjusting for potential confounding factors.

This observation was further supported by mechanistic studies showing decreased neurotoxic protein levels in brain cells exposed to the phosphodiesterase type 5 inhibitor (PDE5i).

“Our findings provide further weight to repurposing this existing FDA-approved drug as a novel treatment for Alzheimer’s, which is in great need of new therapies,” Feixiong Cheng, PhD, director of the Cleveland Clinic Genome Center, who led the research, said in a news release. 

“We used artificial intelligence to integrate data across multiple domains which all indicated sildenafil’s potential against this devastating neurological disease,” Dr. Cheng noted. 

The study was published online in the Journal of Alzheimer’s Disease.
 

Neuroprotective?

Using real-world patient data from the MarketScan Medicare Supplemental database (2012-2017) and the Clinformatics database (2007-2020), the researchers conducted propensity score-stratified analyses after adjusting for gender, age, race, and comorbidities. 

They searched for all individuals with pharmacy claims for sildenafil or four comparator drugs — bumetanide, furosemide, spironolactone, and nifedipine. Results showed that sildenafil use was associated with reduced likelihood of Alzheimer’s disease relative to the control drugs. 

For example, sildenafil use was associated with a 54% reduced incidence of Alzheimer’s disease in MarketScan (hazard ratio [HR], 0.46; 95% CI, 0.32-0.66) and a 30% reduced prevalence of Alzheimer’s disease in Clinformatics (HR, 0.70; 95% CI, 0.49-1.00) compared with spironolactone.

The findings support a study published earlier this year that found a potential protective effect of PDE5i treatment on Alzheimer’s disease risk.

However, this research and the current study are contradicted by another paper published in Brain Communications in late 2022 which showed no such link between ED meds and reduced Alzheimer’s disease risk.

The investigators also found that sildenafil reduces tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic Alzheimer’s disease patient induced pluripotent stem cell (iPSC)-derived neurons. 

They further demonstrated through RNA-sequencing data analysis that sildenafil specifically targets Alzheimer’s disease related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in Alzheimer’s disease.

“We believe our findings provide the evidence needed for clinical trials to further examine the potential effectiveness of sildenafil in patients with Alzheimer’s disease,” Dr. Cheng said. 

The study was primarily supported by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Cheng had no relevant disclosures. 

A version of this article appeared on Medscape.com.

WEST PALM BEACH, FLORIDA — Patient-reported outcomes (PROs) define the issues that matter to the patient, but their potential in multiple sclerosis (MS) is likely to remain unfulfilled until barriers, including a lack of incentives, are addressed systematically, according to experts participating in a symposium at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

These barriers include a lack of consensus on how and which PROs to collect, lack of a systematic method of interpreting the meaning of PRO changes, and lack of reimbursement for the time to collect PRO data and enter it into the medical record, according to Robert McBurney, PhD, president of the nonprofit Accelerated Cure Project for Multiple Sclerosis, Washington.
 

Potentially Useful Clinical Information

PROs can identify hidden symptoms of MS as well as provide information on the relative importance of the standard measures of disease progression, such as disability, but at the current time “these are rarely captured or used in shared decision-making to guide treatment,” Dr. McBurney said.

A reasonable analogy can be made between MS and musculoskeletal diseases, such as arthritis, according to Dr. McBurney. In both, not all patients experience the burden of disease in the same way, whether measured with traditional laboratory or imaging evidence of disease activity or by PROs that capture anxiety, depression, and specific impairments affecting activities of daily living.

Yet, the Centers for Medicare and Medicaid Services (CMS) is now mandating the entry of PRO data for the reimbursement of some forms of orthopedic surgery, while MS is lagging behind, according to Dr. McBurney.

The difference between orthopedics and MS is evidence submitted to CMS showing that improvement in PROs matter for patient outcome and well-being. Dr. McBurney argued that the same type of data is lacking for MS.

More well-designed clinical trials are needed to confirm that beneficial effects on PROs can improve patient outcomes, but Dr. McBurney suggested that PRO data from the many MS patient registries might be an easier first step. He reported that 24 of 43 MS registries around the globe are now capturing PRO data.

Unfortunately, the AXON registry, which is managed by the American Academy of Neurology, is not one of them, Dr. McBurney said. This is not an oversight. Dr. McBurney explained that the first effort to add PROs to data collected by AXON was initiated more than 5 years ago, but several complications thwarted the process. A new effort has been recently scheduled.

By developing data showing that PROs matter, AAN “might lead the charge” for establishing the collection of PRO data as a standard of care and eliciting reimbursement from third-party payers for doing so, Dr. McBurney said. Nevertheless, he cautioned that validated methodology for collecting PRO data and identifying clinically meaningful changes in scores will be fundamental to PRO utility.
 

A Path Forward

In the best circumstance, PRO data captured at a patient visit would be analogous to a lab test. Just as blood tests generate data in the context of normative ranges for a dozen or more parameters, the PRO data could be displayed with the same type of context, allowing physicians and patients to see a specific PRO measure displayed against a normative range so results are easily interpreted, according to Dr. McBurney.

But, again, there are barriers. Numerous validated sets of PROs are available with no consensus on which might serve as a standard. While Dr. McBurney singled out the SymptoMScreen tool as one that is already recommended by the MS Data Alliance, a nonprofit organization supported by the European Charcot Foundation to transform real-world MS data into evidence suitable for MS care, he acknowledged it is just one of many options.

“The SymptoMScreen has been used in several clinical studies and it is relatively simple to use,” Dr. McBurney said. Even if there is no single “best” instrument for measuring PROs, a standard might move the process forward.

The president of the European Charcot Foundation, Giancarlo Comi, MD, agreed that PROs are almost certainly coming to the routine management of MS as each of the current barriers described by Dr. McBurney are addressed. He said that PROs are particularly important in managing progressive MS, for which he thinks that traditional biomarkers, such as brain images, are particularly poor at capturing the burden of disease.

“The EMA [European Medicines Agency] and the FDA [Food and Drug Administration] are both very interested in using PROs to evaluate treatments in MS,” he said.

PROs might be incorporated into routine care by clinicians convinced that they help in guiding treatment choices, but Dr. McBurney and Dr. Comi agreed that some approach, including financial incentives, to encourage clinicians to capture and record PROs is probably needed before they are used routinely.

Dr. McBurney reports no potential conflicts of interest. Dr. Comi reports financial relationships with Almirall, Celgene, Genzyme, Hoffman-LaRoche, Janssen, Merck, Novartis, and Sanofi.

WEST PALM BEACH, FLORIDA — Patient-reported outcomes (PROs) define the issues that matter to the patient, but their potential in multiple sclerosis (MS) is likely to remain unfulfilled until barriers, including a lack of incentives, are addressed systematically, according to experts participating in a symposium at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

These barriers include a lack of consensus on how and which PROs to collect, lack of a systematic method of interpreting the meaning of PRO changes, and lack of reimbursement for the time to collect PRO data and enter it into the medical record, according to Robert McBurney, PhD, president of the nonprofit Accelerated Cure Project for Multiple Sclerosis, Washington.
 

Potentially Useful Clinical Information

PROs can identify hidden symptoms of MS as well as provide information on the relative importance of the standard measures of disease progression, such as disability, but at the current time “these are rarely captured or used in shared decision-making to guide treatment,” Dr. McBurney said.

A reasonable analogy can be made between MS and musculoskeletal diseases, such as arthritis, according to Dr. McBurney. In both, not all patients experience the burden of disease in the same way, whether measured with traditional laboratory or imaging evidence of disease activity or by PROs that capture anxiety, depression, and specific impairments affecting activities of daily living.

Yet, the Centers for Medicare and Medicaid Services (CMS) is now mandating the entry of PRO data for the reimbursement of some forms of orthopedic surgery, while MS is lagging behind, according to Dr. McBurney.

The difference between orthopedics and MS is evidence submitted to CMS showing that improvement in PROs matter for patient outcome and well-being. Dr. McBurney argued that the same type of data is lacking for MS.

More well-designed clinical trials are needed to confirm that beneficial effects on PROs can improve patient outcomes, but Dr. McBurney suggested that PRO data from the many MS patient registries might be an easier first step. He reported that 24 of 43 MS registries around the globe are now capturing PRO data.

Unfortunately, the AXON registry, which is managed by the American Academy of Neurology, is not one of them, Dr. McBurney said. This is not an oversight. Dr. McBurney explained that the first effort to add PROs to data collected by AXON was initiated more than 5 years ago, but several complications thwarted the process. A new effort has been recently scheduled.

By developing data showing that PROs matter, AAN “might lead the charge” for establishing the collection of PRO data as a standard of care and eliciting reimbursement from third-party payers for doing so, Dr. McBurney said. Nevertheless, he cautioned that validated methodology for collecting PRO data and identifying clinically meaningful changes in scores will be fundamental to PRO utility.
 

A Path Forward

In the best circumstance, PRO data captured at a patient visit would be analogous to a lab test. Just as blood tests generate data in the context of normative ranges for a dozen or more parameters, the PRO data could be displayed with the same type of context, allowing physicians and patients to see a specific PRO measure displayed against a normative range so results are easily interpreted, according to Dr. McBurney.

But, again, there are barriers. Numerous validated sets of PROs are available with no consensus on which might serve as a standard. While Dr. McBurney singled out the SymptoMScreen tool as one that is already recommended by the MS Data Alliance, a nonprofit organization supported by the European Charcot Foundation to transform real-world MS data into evidence suitable for MS care, he acknowledged it is just one of many options.

“The SymptoMScreen has been used in several clinical studies and it is relatively simple to use,” Dr. McBurney said. Even if there is no single “best” instrument for measuring PROs, a standard might move the process forward.

The president of the European Charcot Foundation, Giancarlo Comi, MD, agreed that PROs are almost certainly coming to the routine management of MS as each of the current barriers described by Dr. McBurney are addressed. He said that PROs are particularly important in managing progressive MS, for which he thinks that traditional biomarkers, such as brain images, are particularly poor at capturing the burden of disease.

“The EMA [European Medicines Agency] and the FDA [Food and Drug Administration] are both very interested in using PROs to evaluate treatments in MS,” he said.

PROs might be incorporated into routine care by clinicians convinced that they help in guiding treatment choices, but Dr. McBurney and Dr. Comi agreed that some approach, including financial incentives, to encourage clinicians to capture and record PROs is probably needed before they are used routinely.

Dr. McBurney reports no potential conflicts of interest. Dr. Comi reports financial relationships with Almirall, Celgene, Genzyme, Hoffman-LaRoche, Janssen, Merck, Novartis, and Sanofi.

WEST PALM BEACH, FLORIDA — Patient-reported outcomes (PROs) define the issues that matter to the patient, but their potential in multiple sclerosis (MS) is likely to remain unfulfilled until barriers, including a lack of incentives, are addressed systematically, according to experts participating in a symposium at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

These barriers include a lack of consensus on how and which PROs to collect, lack of a systematic method of interpreting the meaning of PRO changes, and lack of reimbursement for the time to collect PRO data and enter it into the medical record, according to Robert McBurney, PhD, president of the nonprofit Accelerated Cure Project for Multiple Sclerosis, Washington.
 

Potentially Useful Clinical Information

PROs can identify hidden symptoms of MS as well as provide information on the relative importance of the standard measures of disease progression, such as disability, but at the current time “these are rarely captured or used in shared decision-making to guide treatment,” Dr. McBurney said.

A reasonable analogy can be made between MS and musculoskeletal diseases, such as arthritis, according to Dr. McBurney. In both, not all patients experience the burden of disease in the same way, whether measured with traditional laboratory or imaging evidence of disease activity or by PROs that capture anxiety, depression, and specific impairments affecting activities of daily living.

Yet, the Centers for Medicare and Medicaid Services (CMS) is now mandating the entry of PRO data for the reimbursement of some forms of orthopedic surgery, while MS is lagging behind, according to Dr. McBurney.

The difference between orthopedics and MS is evidence submitted to CMS showing that improvement in PROs matter for patient outcome and well-being. Dr. McBurney argued that the same type of data is lacking for MS.

More well-designed clinical trials are needed to confirm that beneficial effects on PROs can improve patient outcomes, but Dr. McBurney suggested that PRO data from the many MS patient registries might be an easier first step. He reported that 24 of 43 MS registries around the globe are now capturing PRO data.

Unfortunately, the AXON registry, which is managed by the American Academy of Neurology, is not one of them, Dr. McBurney said. This is not an oversight. Dr. McBurney explained that the first effort to add PROs to data collected by AXON was initiated more than 5 years ago, but several complications thwarted the process. A new effort has been recently scheduled.

By developing data showing that PROs matter, AAN “might lead the charge” for establishing the collection of PRO data as a standard of care and eliciting reimbursement from third-party payers for doing so, Dr. McBurney said. Nevertheless, he cautioned that validated methodology for collecting PRO data and identifying clinically meaningful changes in scores will be fundamental to PRO utility.
 

A Path Forward

In the best circumstance, PRO data captured at a patient visit would be analogous to a lab test. Just as blood tests generate data in the context of normative ranges for a dozen or more parameters, the PRO data could be displayed with the same type of context, allowing physicians and patients to see a specific PRO measure displayed against a normative range so results are easily interpreted, according to Dr. McBurney.

But, again, there are barriers. Numerous validated sets of PROs are available with no consensus on which might serve as a standard. While Dr. McBurney singled out the SymptoMScreen tool as one that is already recommended by the MS Data Alliance, a nonprofit organization supported by the European Charcot Foundation to transform real-world MS data into evidence suitable for MS care, he acknowledged it is just one of many options.

“The SymptoMScreen has been used in several clinical studies and it is relatively simple to use,” Dr. McBurney said. Even if there is no single “best” instrument for measuring PROs, a standard might move the process forward.

The president of the European Charcot Foundation, Giancarlo Comi, MD, agreed that PROs are almost certainly coming to the routine management of MS as each of the current barriers described by Dr. McBurney are addressed. He said that PROs are particularly important in managing progressive MS, for which he thinks that traditional biomarkers, such as brain images, are particularly poor at capturing the burden of disease.

“The EMA [European Medicines Agency] and the FDA [Food and Drug Administration] are both very interested in using PROs to evaluate treatments in MS,” he said.

PROs might be incorporated into routine care by clinicians convinced that they help in guiding treatment choices, but Dr. McBurney and Dr. Comi agreed that some approach, including financial incentives, to encourage clinicians to capture and record PROs is probably needed before they are used routinely.

Dr. McBurney reports no potential conflicts of interest. Dr. Comi reports financial relationships with Almirall, Celgene, Genzyme, Hoffman-LaRoche, Janssen, Merck, Novartis, and Sanofi.

WEST PALM BEACH, FLORIDA — When evaluated at 3 or 12 months, serum neurofilament light chain (sNfL) levels were predictive of new or enlarging T2 lesions in patients with multiple sclerosis (MS) regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.

These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.

When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).

These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.

The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
 

Is sNfL Relevant Independent of Treatment?

In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).

Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.

While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.

The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
 

Optimal sNfL Threshold May Not Be Defined

Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.

Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.

However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.

Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — When evaluated at 3 or 12 months, serum neurofilament light chain (sNfL) levels were predictive of new or enlarging T2 lesions in patients with multiple sclerosis (MS) regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.

These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.

When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).

These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.

The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
 

Is sNfL Relevant Independent of Treatment?

In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).

Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.

While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.

The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
 

Optimal sNfL Threshold May Not Be Defined

Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.

Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.

However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.

Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — When evaluated at 3 or 12 months, serum neurofilament light chain (sNfL) levels were predictive of new or enlarging T2 lesions in patients with multiple sclerosis (MS) regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.

These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.

When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).

These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.

The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
 

Is sNfL Relevant Independent of Treatment?

In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).

Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.

While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.

The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
 

Optimal sNfL Threshold May Not Be Defined

Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.

Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.

However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.

Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.

The American Academy of Pediatrics (AAP) has wisely chosen to draw our attention to the distressing statistic that by age 13, 70% of children have dropped out of organized sports.

Seventy-five years ago news of this dramatic decline in participation would have received a quizzical shrug because organized youth sports was in its infancy. It consisted primarily of Little League Baseball and for the most part excluded girls. Prior to middle school and high school, children were self-organizing their sports activities – picking their own teams, demarcating their own fields, and making up the rules to fit the conditions. Soccer Dads and Hockey Moms hadn’t been invented. To what extent this attrition from youth sports is contributing to the fact that more than 75% of this country’s adolescents fail to meet even the most lenient activity requirements is unclear. But, it certainly isn’t helping the situation.

Parsing out the contributors to this decline in organized sport should be high on our priority list. In the recent AAP Clinical Report published in Pediatrics (same reference as above) the authors claim “Burnout represents one of the primary reasons for attrition in youth sports.” This statement doesn’t quite agree with my experiences. So, I decided to chase down their reference. It turns out their assertion comes from an article coming out of Australia by eight authors who “brainstormed” 83 unique statements of 61 stakeholders regarding “athlete participation in the high-performance pathway” and concluded “Athlete health was considered the most important athlete retention to address.” While injury and overuse may explain why some elite youth participants drop out and represent a topic for the AAP to address, I’m not sure this paper’s anecdotal conclusion helps us understand the overall decline in youth sports. A broader and deeper discussion can be found in a 2019 AAP Clinical Report that addresses the advantages and pitfalls of youth sports as organized in this country.

How we arrived at this point in which, as the AAP report observes, “Youth sport participation represents the primary route to physical activity” is unclear. One obvious cause is the blossoming of the sedentary entertainment alternatives that has easily overpowered the attraction of self-organized outdoor games. The first attack in this war that we are losing came with affordable color television. Here we must blame ourselves both as parents and pediatricians for not acknowledging the risks and creating some limits. Sadly, the AAP’s initial focus was on content and not on time watched. And, of course, by the time handheld electronic devices arrived the cat was out of the bag.

We also must accept some blame for allowing physical activity to disappear as a meaningful part of the school day. Recesses have been curtailed, leaving free play and all its benefits as an endangered species. Physical education classes have been pared down tragically just as teenagers are making their own choices about how they will spend their time.

We must not underestimate the role that parental anxiety has played in the popularity of organized sport. I’m not sure of the origins of this change, but folks in my cohort recall that our parents let us roam free. As long as we showed up for meals without a policeman in tow, our parents were happy. For some reason parents seem more concerned about risks of their children being outside unmonitored, even in what are clearly safe neighborhoods.

Into this void created by sedentary amusements, limited in-school opportunities for physical activity, and parental anxiety, adult (often parent) organized sports have flourished. Unfortunately, they have too often been over-organized and allowed to morph into a model that mimics professional sports. The myth that to succeed a child must start early, narrow his/her focus and practice, practice, practice has created a situation that is a major contributor to the decline in youth sports participation. This philosophy also contributes to burnout and overuse injuries, but this is primarily among the few and the more elite.

When the child who is already involved in an organized sport sees and believes that he or she hasn’t a chance against the “early bloomers,” that child will quit. Without an appealing alternative, he/she will become sedentary. Further damage is done when children themselves and their parents have witnessed other families heavily invested in professionalized youth programs and decide it doesn’t make sense to even sign up.

In full disclosure, I must say that I have children and grandchildren who have participated in travel teams. Luckily they have not been tempted to seek even more elite programs. They have played at least two or three sports each year and still remain physically active as adults.

I don’t think the answer to the decline in youth sports is to eliminate travel and super-elite teams. The drive to succeed is too strong in some individuals. The answers lie in setting limits on sedentary alternatives, continuing to loudly question the myth of early specialization, and to work harder at offering the broadest range of opportunities that can appeal to children of all skill levels.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

The American Academy of Pediatrics (AAP) has wisely chosen to draw our attention to the distressing statistic that by age 13, 70% of children have dropped out of organized sports.

Seventy-five years ago news of this dramatic decline in participation would have received a quizzical shrug because organized youth sports was in its infancy. It consisted primarily of Little League Baseball and for the most part excluded girls. Prior to middle school and high school, children were self-organizing their sports activities – picking their own teams, demarcating their own fields, and making up the rules to fit the conditions. Soccer Dads and Hockey Moms hadn’t been invented. To what extent this attrition from youth sports is contributing to the fact that more than 75% of this country’s adolescents fail to meet even the most lenient activity requirements is unclear. But, it certainly isn’t helping the situation.

Parsing out the contributors to this decline in organized sport should be high on our priority list. In the recent AAP Clinical Report published in Pediatrics (same reference as above) the authors claim “Burnout represents one of the primary reasons for attrition in youth sports.” This statement doesn’t quite agree with my experiences. So, I decided to chase down their reference. It turns out their assertion comes from an article coming out of Australia by eight authors who “brainstormed” 83 unique statements of 61 stakeholders regarding “athlete participation in the high-performance pathway” and concluded “Athlete health was considered the most important athlete retention to address.” While injury and overuse may explain why some elite youth participants drop out and represent a topic for the AAP to address, I’m not sure this paper’s anecdotal conclusion helps us understand the overall decline in youth sports. A broader and deeper discussion can be found in a 2019 AAP Clinical Report that addresses the advantages and pitfalls of youth sports as organized in this country.

How we arrived at this point in which, as the AAP report observes, “Youth sport participation represents the primary route to physical activity” is unclear. One obvious cause is the blossoming of the sedentary entertainment alternatives that has easily overpowered the attraction of self-organized outdoor games. The first attack in this war that we are losing came with affordable color television. Here we must blame ourselves both as parents and pediatricians for not acknowledging the risks and creating some limits. Sadly, the AAP’s initial focus was on content and not on time watched. And, of course, by the time handheld electronic devices arrived the cat was out of the bag.

We also must accept some blame for allowing physical activity to disappear as a meaningful part of the school day. Recesses have been curtailed, leaving free play and all its benefits as an endangered species. Physical education classes have been pared down tragically just as teenagers are making their own choices about how they will spend their time.

We must not underestimate the role that parental anxiety has played in the popularity of organized sport. I’m not sure of the origins of this change, but folks in my cohort recall that our parents let us roam free. As long as we showed up for meals without a policeman in tow, our parents were happy. For some reason parents seem more concerned about risks of their children being outside unmonitored, even in what are clearly safe neighborhoods.

Into this void created by sedentary amusements, limited in-school opportunities for physical activity, and parental anxiety, adult (often parent) organized sports have flourished. Unfortunately, they have too often been over-organized and allowed to morph into a model that mimics professional sports. The myth that to succeed a child must start early, narrow his/her focus and practice, practice, practice has created a situation that is a major contributor to the decline in youth sports participation. This philosophy also contributes to burnout and overuse injuries, but this is primarily among the few and the more elite.

When the child who is already involved in an organized sport sees and believes that he or she hasn’t a chance against the “early bloomers,” that child will quit. Without an appealing alternative, he/she will become sedentary. Further damage is done when children themselves and their parents have witnessed other families heavily invested in professionalized youth programs and decide it doesn’t make sense to even sign up.

In full disclosure, I must say that I have children and grandchildren who have participated in travel teams. Luckily they have not been tempted to seek even more elite programs. They have played at least two or three sports each year and still remain physically active as adults.

I don’t think the answer to the decline in youth sports is to eliminate travel and super-elite teams. The drive to succeed is too strong in some individuals. The answers lie in setting limits on sedentary alternatives, continuing to loudly question the myth of early specialization, and to work harder at offering the broadest range of opportunities that can appeal to children of all skill levels.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

The American Academy of Pediatrics (AAP) has wisely chosen to draw our attention to the distressing statistic that by age 13, 70% of children have dropped out of organized sports.

Seventy-five years ago news of this dramatic decline in participation would have received a quizzical shrug because organized youth sports was in its infancy. It consisted primarily of Little League Baseball and for the most part excluded girls. Prior to middle school and high school, children were self-organizing their sports activities – picking their own teams, demarcating their own fields, and making up the rules to fit the conditions. Soccer Dads and Hockey Moms hadn’t been invented. To what extent this attrition from youth sports is contributing to the fact that more than 75% of this country’s adolescents fail to meet even the most lenient activity requirements is unclear. But, it certainly isn’t helping the situation.

Parsing out the contributors to this decline in organized sport should be high on our priority list. In the recent AAP Clinical Report published in Pediatrics (same reference as above) the authors claim “Burnout represents one of the primary reasons for attrition in youth sports.” This statement doesn’t quite agree with my experiences. So, I decided to chase down their reference. It turns out their assertion comes from an article coming out of Australia by eight authors who “brainstormed” 83 unique statements of 61 stakeholders regarding “athlete participation in the high-performance pathway” and concluded “Athlete health was considered the most important athlete retention to address.” While injury and overuse may explain why some elite youth participants drop out and represent a topic for the AAP to address, I’m not sure this paper’s anecdotal conclusion helps us understand the overall decline in youth sports. A broader and deeper discussion can be found in a 2019 AAP Clinical Report that addresses the advantages and pitfalls of youth sports as organized in this country.

How we arrived at this point in which, as the AAP report observes, “Youth sport participation represents the primary route to physical activity” is unclear. One obvious cause is the blossoming of the sedentary entertainment alternatives that has easily overpowered the attraction of self-organized outdoor games. The first attack in this war that we are losing came with affordable color television. Here we must blame ourselves both as parents and pediatricians for not acknowledging the risks and creating some limits. Sadly, the AAP’s initial focus was on content and not on time watched. And, of course, by the time handheld electronic devices arrived the cat was out of the bag.

We also must accept some blame for allowing physical activity to disappear as a meaningful part of the school day. Recesses have been curtailed, leaving free play and all its benefits as an endangered species. Physical education classes have been pared down tragically just as teenagers are making their own choices about how they will spend their time.

We must not underestimate the role that parental anxiety has played in the popularity of organized sport. I’m not sure of the origins of this change, but folks in my cohort recall that our parents let us roam free. As long as we showed up for meals without a policeman in tow, our parents were happy. For some reason parents seem more concerned about risks of their children being outside unmonitored, even in what are clearly safe neighborhoods.

Into this void created by sedentary amusements, limited in-school opportunities for physical activity, and parental anxiety, adult (often parent) organized sports have flourished. Unfortunately, they have too often been over-organized and allowed to morph into a model that mimics professional sports. The myth that to succeed a child must start early, narrow his/her focus and practice, practice, practice has created a situation that is a major contributor to the decline in youth sports participation. This philosophy also contributes to burnout and overuse injuries, but this is primarily among the few and the more elite.

When the child who is already involved in an organized sport sees and believes that he or she hasn’t a chance against the “early bloomers,” that child will quit. Without an appealing alternative, he/she will become sedentary. Further damage is done when children themselves and their parents have witnessed other families heavily invested in professionalized youth programs and decide it doesn’t make sense to even sign up.

In full disclosure, I must say that I have children and grandchildren who have participated in travel teams. Luckily they have not been tempted to seek even more elite programs. They have played at least two or three sports each year and still remain physically active as adults.

I don’t think the answer to the decline in youth sports is to eliminate travel and super-elite teams. The drive to succeed is too strong in some individuals. The answers lie in setting limits on sedentary alternatives, continuing to loudly question the myth of early specialization, and to work harder at offering the broadest range of opportunities that can appeal to children of all skill levels.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

Frexalimab (Sanofi), a novel, investigational second-generation inhibitor of the CD40 ligand, significantly reduced disease activity in relapsing multiple sclerosis (MS) and was well tolerated in a phase 2 study.

At week 12, there was an 89% reduction in new gadolinium (Gd)-enhancing T1 brain lesions — a standard measure of active inflammation in MS – in the high-dose frexalimab group and a 79% reduction in the low-dose treatment group compared with placebo, meeting the study’s primary endpoint.

The effects of frexalimab were sustained over time, “especially at the high dose of frexalimab where 96% of patients were free of new active lesions after 24 weeks of treatment,” first author Patrick Vermersch, MD, PhD, University of Lille, CHU Lille, France, said in a news release.

The full results were published online on in The New England Journal of Medicine, following presentation of preliminary data at the Consortium of Multiple Sclerosis Centers 2023 Annual Meeting.
 

‘Unambiguous Benefit’

Frexalimab blocks the costimulatory CD40/CD40L pathway, which regulates both adaptive and innate immune responses, and has been implicated in the pathogenesis of MS.

“Through this unique upstream mechanism of action, frexalimab has the potential to address both acute and chronic neuroinflammation in MS, without causing lymphocyte depletion,” a Sanofi press statement noted.

The phase 2 study enrolled 129 adults (mean age, 36 years; 66% women) with relapsing MS, 30% of whom had Gd-enhancing lesions at baseline.

Participants received 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose; n = 52), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose; n = 51), or matching placebos for each active treatment (n = 12 and n = 14, respectively).

All but four patients completed the 12-week double-blind period and entered the open-label period.

The primary end point was the number of new Gd-enhancing T1-weighted lesions seen on MRI at week 12 relative to week 8.

At week 12, the adjusted mean number of new Gd-enhancing T1 lesions was 0.2 and 0.3 in the high- and low-dose frexalimab groups, respectively, compared with 1.4 in the pooled placebo group.

The rate ratios, as compared with placebo, were 0.11 in the high-dose group and 0.21 in the low-dose group, corresponding to 89% and 79% reductions in the high- and low-dose groups, respectively.

On the secondary endpoint of number of new/enlarging T2-weighted lesions at week 12, rate ratios in the high- and low-dose groups were 0.08 and 0.14, respectively, corresponding to 92% and 86% reduction in the high- and low-dose treatment groups vs placebo.

The effects were sustained over time across both active treatment groups.

Frexalimab also lowered plasma levels of neurofilament light chain, a biomarker of neuroaxonal damage in MS, as well as plasma levels of CXCL13, a biomarker of inflammatory activity.
 

Phase 3 Trials Underway

The authors noted that the trial was too brief and small to draw conclusions regarding clinical outcomes. However, during the 12-week double-blind period, no relapses occurred in the high-dose frexalimab group, whereas relapses occurred in roughly 4% of those in the low-dose frexalimab group and the pooled placebo group.

There was no change from baseline to 12 weeks in median scores on the Expanded Disability Status Scale in any study group.

No serious or severe adverse events or deaths were reported during the double-blind period. There were no thromboembolic events — a concern with first-generation anti–CD40L antibodies.

Depletion of lymphocytes was not observed. More infections were observed with frexalimab than with placebo, but no serious infections occurred during 24 weeks of frexalimab treatment. The most common adverse events were COVID-19 and headache. All cases of COVID-19 were uncomplicated and mild to moderate in severity.

Bolstered by the promising phase 2 data, Sanofi has initiated two phase 3 studies assessing frexalimab in relapsing MS and non-relapsing secondary progressive MS.
 

‘A High Bar for Any New Treatment’

In an accompanying editorial, Stephen L. Hauser, MD, with UCSF Weill Institute for Neurosciences, San Francisco, California, wrote that the results “appear clear, although the clinical significance is uncertain — clear because there was an unambiguous benefit with regard to short-term MRI outcomes in patients who received frexalimab as compared with those who received placebo and because a generally low level of MRI activity persisted during an additional 12-week open-label extension period.”

If the findings hold with longer-term use, Dr. Hauser continued, “it seems likely that there will be a protective effect of frexalimab therapy with regard to relapses of multiple sclerosis.”

Dr. Hauser noted, however, that the “striking clinical benefits and safety profile of the available high-efficacy therapies for relapsing multiple sclerosis create a high bar for any new treatment.”

“In this trial, the MRI outcomes with frexalimab therapy were impressive but appear to be less complete than those with anti-CD20 agents, although trials of different agents cannot be directly compared.”

“Even if future studies show frexalimab to be competitive with currently available therapies for relapsing multiple sclerosis, the paramount need is for more effective therapy against progression,” Dr. Hauser wrote.

While the current trial was neither designed nor powered to assess benefits against progressive MS, “progression is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against multiple sclerosis, will need to be defined,” Dr. Hauser concluded.

The study was supported by Sanofi. Disclosures for authors and editorialist are available at NEJM.org.
 

A version of this article first appeared on Medscape.com.

Frexalimab (Sanofi), a novel, investigational second-generation inhibitor of the CD40 ligand, significantly reduced disease activity in relapsing multiple sclerosis (MS) and was well tolerated in a phase 2 study.

At week 12, there was an 89% reduction in new gadolinium (Gd)-enhancing T1 brain lesions — a standard measure of active inflammation in MS – in the high-dose frexalimab group and a 79% reduction in the low-dose treatment group compared with placebo, meeting the study’s primary endpoint.

The effects of frexalimab were sustained over time, “especially at the high dose of frexalimab where 96% of patients were free of new active lesions after 24 weeks of treatment,” first author Patrick Vermersch, MD, PhD, University of Lille, CHU Lille, France, said in a news release.

The full results were published online on in The New England Journal of Medicine, following presentation of preliminary data at the Consortium of Multiple Sclerosis Centers 2023 Annual Meeting.
 

‘Unambiguous Benefit’

Frexalimab blocks the costimulatory CD40/CD40L pathway, which regulates both adaptive and innate immune responses, and has been implicated in the pathogenesis of MS.

“Through this unique upstream mechanism of action, frexalimab has the potential to address both acute and chronic neuroinflammation in MS, without causing lymphocyte depletion,” a Sanofi press statement noted.

The phase 2 study enrolled 129 adults (mean age, 36 years; 66% women) with relapsing MS, 30% of whom had Gd-enhancing lesions at baseline.

Participants received 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose; n = 52), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose; n = 51), or matching placebos for each active treatment (n = 12 and n = 14, respectively).

All but four patients completed the 12-week double-blind period and entered the open-label period.

The primary end point was the number of new Gd-enhancing T1-weighted lesions seen on MRI at week 12 relative to week 8.

At week 12, the adjusted mean number of new Gd-enhancing T1 lesions was 0.2 and 0.3 in the high- and low-dose frexalimab groups, respectively, compared with 1.4 in the pooled placebo group.

The rate ratios, as compared with placebo, were 0.11 in the high-dose group and 0.21 in the low-dose group, corresponding to 89% and 79% reductions in the high- and low-dose groups, respectively.

On the secondary endpoint of number of new/enlarging T2-weighted lesions at week 12, rate ratios in the high- and low-dose groups were 0.08 and 0.14, respectively, corresponding to 92% and 86% reduction in the high- and low-dose treatment groups vs placebo.

The effects were sustained over time across both active treatment groups.

Frexalimab also lowered plasma levels of neurofilament light chain, a biomarker of neuroaxonal damage in MS, as well as plasma levels of CXCL13, a biomarker of inflammatory activity.
 

Phase 3 Trials Underway

The authors noted that the trial was too brief and small to draw conclusions regarding clinical outcomes. However, during the 12-week double-blind period, no relapses occurred in the high-dose frexalimab group, whereas relapses occurred in roughly 4% of those in the low-dose frexalimab group and the pooled placebo group.

There was no change from baseline to 12 weeks in median scores on the Expanded Disability Status Scale in any study group.

No serious or severe adverse events or deaths were reported during the double-blind period. There were no thromboembolic events — a concern with first-generation anti–CD40L antibodies.

Depletion of lymphocytes was not observed. More infections were observed with frexalimab than with placebo, but no serious infections occurred during 24 weeks of frexalimab treatment. The most common adverse events were COVID-19 and headache. All cases of COVID-19 were uncomplicated and mild to moderate in severity.

Bolstered by the promising phase 2 data, Sanofi has initiated two phase 3 studies assessing frexalimab in relapsing MS and non-relapsing secondary progressive MS.
 

‘A High Bar for Any New Treatment’

In an accompanying editorial, Stephen L. Hauser, MD, with UCSF Weill Institute for Neurosciences, San Francisco, California, wrote that the results “appear clear, although the clinical significance is uncertain — clear because there was an unambiguous benefit with regard to short-term MRI outcomes in patients who received frexalimab as compared with those who received placebo and because a generally low level of MRI activity persisted during an additional 12-week open-label extension period.”

If the findings hold with longer-term use, Dr. Hauser continued, “it seems likely that there will be a protective effect of frexalimab therapy with regard to relapses of multiple sclerosis.”

Dr. Hauser noted, however, that the “striking clinical benefits and safety profile of the available high-efficacy therapies for relapsing multiple sclerosis create a high bar for any new treatment.”

“In this trial, the MRI outcomes with frexalimab therapy were impressive but appear to be less complete than those with anti-CD20 agents, although trials of different agents cannot be directly compared.”

“Even if future studies show frexalimab to be competitive with currently available therapies for relapsing multiple sclerosis, the paramount need is for more effective therapy against progression,” Dr. Hauser wrote.

While the current trial was neither designed nor powered to assess benefits against progressive MS, “progression is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against multiple sclerosis, will need to be defined,” Dr. Hauser concluded.

The study was supported by Sanofi. Disclosures for authors and editorialist are available at NEJM.org.
 

A version of this article first appeared on Medscape.com.

Frexalimab (Sanofi), a novel, investigational second-generation inhibitor of the CD40 ligand, significantly reduced disease activity in relapsing multiple sclerosis (MS) and was well tolerated in a phase 2 study.

At week 12, there was an 89% reduction in new gadolinium (Gd)-enhancing T1 brain lesions — a standard measure of active inflammation in MS – in the high-dose frexalimab group and a 79% reduction in the low-dose treatment group compared with placebo, meeting the study’s primary endpoint.

The effects of frexalimab were sustained over time, “especially at the high dose of frexalimab where 96% of patients were free of new active lesions after 24 weeks of treatment,” first author Patrick Vermersch, MD, PhD, University of Lille, CHU Lille, France, said in a news release.

The full results were published online on in The New England Journal of Medicine, following presentation of preliminary data at the Consortium of Multiple Sclerosis Centers 2023 Annual Meeting.
 

‘Unambiguous Benefit’

Frexalimab blocks the costimulatory CD40/CD40L pathway, which regulates both adaptive and innate immune responses, and has been implicated in the pathogenesis of MS.

“Through this unique upstream mechanism of action, frexalimab has the potential to address both acute and chronic neuroinflammation in MS, without causing lymphocyte depletion,” a Sanofi press statement noted.

The phase 2 study enrolled 129 adults (mean age, 36 years; 66% women) with relapsing MS, 30% of whom had Gd-enhancing lesions at baseline.

Participants received 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose; n = 52), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose; n = 51), or matching placebos for each active treatment (n = 12 and n = 14, respectively).

All but four patients completed the 12-week double-blind period and entered the open-label period.

The primary end point was the number of new Gd-enhancing T1-weighted lesions seen on MRI at week 12 relative to week 8.

At week 12, the adjusted mean number of new Gd-enhancing T1 lesions was 0.2 and 0.3 in the high- and low-dose frexalimab groups, respectively, compared with 1.4 in the pooled placebo group.

The rate ratios, as compared with placebo, were 0.11 in the high-dose group and 0.21 in the low-dose group, corresponding to 89% and 79% reductions in the high- and low-dose groups, respectively.

On the secondary endpoint of number of new/enlarging T2-weighted lesions at week 12, rate ratios in the high- and low-dose groups were 0.08 and 0.14, respectively, corresponding to 92% and 86% reduction in the high- and low-dose treatment groups vs placebo.

The effects were sustained over time across both active treatment groups.

Frexalimab also lowered plasma levels of neurofilament light chain, a biomarker of neuroaxonal damage in MS, as well as plasma levels of CXCL13, a biomarker of inflammatory activity.
 

Phase 3 Trials Underway

The authors noted that the trial was too brief and small to draw conclusions regarding clinical outcomes. However, during the 12-week double-blind period, no relapses occurred in the high-dose frexalimab group, whereas relapses occurred in roughly 4% of those in the low-dose frexalimab group and the pooled placebo group.

There was no change from baseline to 12 weeks in median scores on the Expanded Disability Status Scale in any study group.

No serious or severe adverse events or deaths were reported during the double-blind period. There were no thromboembolic events — a concern with first-generation anti–CD40L antibodies.

Depletion of lymphocytes was not observed. More infections were observed with frexalimab than with placebo, but no serious infections occurred during 24 weeks of frexalimab treatment. The most common adverse events were COVID-19 and headache. All cases of COVID-19 were uncomplicated and mild to moderate in severity.

Bolstered by the promising phase 2 data, Sanofi has initiated two phase 3 studies assessing frexalimab in relapsing MS and non-relapsing secondary progressive MS.
 

‘A High Bar for Any New Treatment’

In an accompanying editorial, Stephen L. Hauser, MD, with UCSF Weill Institute for Neurosciences, San Francisco, California, wrote that the results “appear clear, although the clinical significance is uncertain — clear because there was an unambiguous benefit with regard to short-term MRI outcomes in patients who received frexalimab as compared with those who received placebo and because a generally low level of MRI activity persisted during an additional 12-week open-label extension period.”

If the findings hold with longer-term use, Dr. Hauser continued, “it seems likely that there will be a protective effect of frexalimab therapy with regard to relapses of multiple sclerosis.”

Dr. Hauser noted, however, that the “striking clinical benefits and safety profile of the available high-efficacy therapies for relapsing multiple sclerosis create a high bar for any new treatment.”

“In this trial, the MRI outcomes with frexalimab therapy were impressive but appear to be less complete than those with anti-CD20 agents, although trials of different agents cannot be directly compared.”

“Even if future studies show frexalimab to be competitive with currently available therapies for relapsing multiple sclerosis, the paramount need is for more effective therapy against progression,” Dr. Hauser wrote.

While the current trial was neither designed nor powered to assess benefits against progressive MS, “progression is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against multiple sclerosis, will need to be defined,” Dr. Hauser concluded.

The study was supported by Sanofi. Disclosures for authors and editorialist are available at NEJM.org.
 

A version of this article first appeared on Medscape.com.

WEST PALM BEACH, FLORIDA — There is growing confidence that remyelinating agents will be a viable option in the treatment of multiple sclerosis (MS) in the not-too-distant future, according to a summary of the science as well as a late-breaker study presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

In an outline of barriers to remyelinating drugs, including the challenge of delivering well-tolerated therapies into the central nervous system (CNS), Ari J. Green, MD, Chief of the Division of Neuroimmunology and Glial Biology, University of California, San Francisco, spoke specifically about recent progress in drug development.

Ted Bosworth/MDedge News

“The important thing is that once we understand the biology, we can turn barriers into opportunities,” he said as he outlined advances over the 6 years since he led the ReBUILD trial.

“We are thinking of remyelination therapies as something off in the horizon,” said Dr. Green, but “the horizon might be closer than we might imagine.”

The double-blind ReBUILD trial provided the first evidence of activity from a remyelinating drug. In this study, 50 patients with chronic demyelinating optic neuropathy and relapsing-remitting MS were randomized to twice daily doses (5-36 mg) of clemastine fumarate for 90 days followed by placebo for 60 days or to placebo for 60 days followed by active drug for 90 days.
 

Remyelinating Effect Documented at Multiple Sites

The improvement on the primary endpoint of visual evoked potentials was interpreted as evidence that the therapy had a positive remyelinating effect, and Dr. Green said that the result has been reproduced by more than a dozen other centers.

The theoretical benefit is from a favorable effect on myelin-producing stem cells, but Dr. Green emphasized that theoretical benefits are not enough for moving the field forward. Negative trials with a theoretical potential to generate remyelination both preceded and followed ReBUILD. Examples include the RENEW study with the anti-lingo monoclonal antibody opicinumab and the CCMR One study with the non-selective retinoid X receptor agonist bexarotene.

Whether there is benefit or failure, “we need to be able to tell what is going on,” Dr. Green said. The reason is that a negative result is not necessarily due to the absence of a meaningful remyelination. Rather, other variables, such as an insufficient number of axons to remyelinate, might explain a lack of effect.

Citing evidence that remyelination and demyelination are often concurrent events, Dr. Green said that there is an urgent need for tools to objectively quantify myelination in order to document that drugs purported to favorably influence myelin repair are doing so. Surrogate markers are potentially unreliable.

“There is an unfortunate tendency in our field to overinterpret atrophy and neurodegeneration and to use those terms too loosely,” Dr. Green said. He said these terms are not interchangeable.

One basis for excitement is the growing support for the theory that oligodendrocyte progenitor cell (OPC) recruitment is critical to the remyelination process. By activating these cells or blocking inhibitors of their activity, experimental evidence suggests new myelin formation can occur. However, a clinically meaningful benefit might still be dependent on multiple additional factors, including the timing of OPC recruitment, Dr. Green explained.

“We might need to provide drugs with a remyelinating effect very early in the process,” he said.

The progress in understanding the interacting factors that define the biology of remyelination is the basis for new enthusiasm about this field, agreed Véronique Miron, PhD, Chair of the Multiple Sclerosis Research, Barlo MS Center, Toronto. Dr. Miron, professor in the Department of Immunology at the University of Toronto, identified the session on remyelination in which Dr. Green spoke as one of the highlights of this year’s ACTRIMS conference.
 

Late-breaker: Two Remyelinating Drugs with Promise

Consistent with this progress, a late-breaker presentation on two drugs that promote oligodendrocyte formation and remyelination in the experimental setting reinforced the growing array of potential therapeutic targets to generate remyelination. The two drugs, CVL-1001 and CVL-2001, act by inhibiting the cholesterol biosynthesis enzymes sterol 14-demethylase (CYP51) and an emopamil binding protein (EBP).

Multiple studies have suggested that CYP51 and EBP are “key therapeutic targets to promote oligodendrocyte formation,” thereby promoting remyelination, reported Brad T. Lang, PhD, vice president of research for Convelo Therapeutics, Cleveland.

The drugs performed as predicted in animal models, where remyelination was documented, and in promoting human oligodendrocyte formation in human brain organoids. The development of these agents has been accompanied by strategy to measure their activity.

“We established a mechanistic biomarker to assess target engagement in the CNS and periphery to guide the next steps in preclinical and clinical development,” Dr. Lang said.

He called these drugs “first-in-class potential therapies in the field of remyelination.” While he acknowledged that no clinical studies have yet been performed, his late-breaker presentation indicated that many of the criteria identified by Dr. Green, including an ability to penetrate the CNS and a plausible, measurable mechanism of action have been fulfilled.

Dr. Green reported financial relationships with Biogen, Mylan, and Novartis. Dr. Miron reported no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — There is growing confidence that remyelinating agents will be a viable option in the treatment of multiple sclerosis (MS) in the not-too-distant future, according to a summary of the science as well as a late-breaker study presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

In an outline of barriers to remyelinating drugs, including the challenge of delivering well-tolerated therapies into the central nervous system (CNS), Ari J. Green, MD, Chief of the Division of Neuroimmunology and Glial Biology, University of California, San Francisco, spoke specifically about recent progress in drug development.

Ted Bosworth/MDedge News

“The important thing is that once we understand the biology, we can turn barriers into opportunities,” he said as he outlined advances over the 6 years since he led the ReBUILD trial.

“We are thinking of remyelination therapies as something off in the horizon,” said Dr. Green, but “the horizon might be closer than we might imagine.”

The double-blind ReBUILD trial provided the first evidence of activity from a remyelinating drug. In this study, 50 patients with chronic demyelinating optic neuropathy and relapsing-remitting MS were randomized to twice daily doses (5-36 mg) of clemastine fumarate for 90 days followed by placebo for 60 days or to placebo for 60 days followed by active drug for 90 days.
 

Remyelinating Effect Documented at Multiple Sites

The improvement on the primary endpoint of visual evoked potentials was interpreted as evidence that the therapy had a positive remyelinating effect, and Dr. Green said that the result has been reproduced by more than a dozen other centers.

The theoretical benefit is from a favorable effect on myelin-producing stem cells, but Dr. Green emphasized that theoretical benefits are not enough for moving the field forward. Negative trials with a theoretical potential to generate remyelination both preceded and followed ReBUILD. Examples include the RENEW study with the anti-lingo monoclonal antibody opicinumab and the CCMR One study with the non-selective retinoid X receptor agonist bexarotene.

Whether there is benefit or failure, “we need to be able to tell what is going on,” Dr. Green said. The reason is that a negative result is not necessarily due to the absence of a meaningful remyelination. Rather, other variables, such as an insufficient number of axons to remyelinate, might explain a lack of effect.

Citing evidence that remyelination and demyelination are often concurrent events, Dr. Green said that there is an urgent need for tools to objectively quantify myelination in order to document that drugs purported to favorably influence myelin repair are doing so. Surrogate markers are potentially unreliable.

“There is an unfortunate tendency in our field to overinterpret atrophy and neurodegeneration and to use those terms too loosely,” Dr. Green said. He said these terms are not interchangeable.

One basis for excitement is the growing support for the theory that oligodendrocyte progenitor cell (OPC) recruitment is critical to the remyelination process. By activating these cells or blocking inhibitors of their activity, experimental evidence suggests new myelin formation can occur. However, a clinically meaningful benefit might still be dependent on multiple additional factors, including the timing of OPC recruitment, Dr. Green explained.

“We might need to provide drugs with a remyelinating effect very early in the process,” he said.

The progress in understanding the interacting factors that define the biology of remyelination is the basis for new enthusiasm about this field, agreed Véronique Miron, PhD, Chair of the Multiple Sclerosis Research, Barlo MS Center, Toronto. Dr. Miron, professor in the Department of Immunology at the University of Toronto, identified the session on remyelination in which Dr. Green spoke as one of the highlights of this year’s ACTRIMS conference.
 

Late-breaker: Two Remyelinating Drugs with Promise

Consistent with this progress, a late-breaker presentation on two drugs that promote oligodendrocyte formation and remyelination in the experimental setting reinforced the growing array of potential therapeutic targets to generate remyelination. The two drugs, CVL-1001 and CVL-2001, act by inhibiting the cholesterol biosynthesis enzymes sterol 14-demethylase (CYP51) and an emopamil binding protein (EBP).

Multiple studies have suggested that CYP51 and EBP are “key therapeutic targets to promote oligodendrocyte formation,” thereby promoting remyelination, reported Brad T. Lang, PhD, vice president of research for Convelo Therapeutics, Cleveland.

The drugs performed as predicted in animal models, where remyelination was documented, and in promoting human oligodendrocyte formation in human brain organoids. The development of these agents has been accompanied by strategy to measure their activity.

“We established a mechanistic biomarker to assess target engagement in the CNS and periphery to guide the next steps in preclinical and clinical development,” Dr. Lang said.

He called these drugs “first-in-class potential therapies in the field of remyelination.” While he acknowledged that no clinical studies have yet been performed, his late-breaker presentation indicated that many of the criteria identified by Dr. Green, including an ability to penetrate the CNS and a plausible, measurable mechanism of action have been fulfilled.

Dr. Green reported financial relationships with Biogen, Mylan, and Novartis. Dr. Miron reported no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — There is growing confidence that remyelinating agents will be a viable option in the treatment of multiple sclerosis (MS) in the not-too-distant future, according to a summary of the science as well as a late-breaker study presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

In an outline of barriers to remyelinating drugs, including the challenge of delivering well-tolerated therapies into the central nervous system (CNS), Ari J. Green, MD, Chief of the Division of Neuroimmunology and Glial Biology, University of California, San Francisco, spoke specifically about recent progress in drug development.

Ted Bosworth/MDedge News

“The important thing is that once we understand the biology, we can turn barriers into opportunities,” he said as he outlined advances over the 6 years since he led the ReBUILD trial.

“We are thinking of remyelination therapies as something off in the horizon,” said Dr. Green, but “the horizon might be closer than we might imagine.”

The double-blind ReBUILD trial provided the first evidence of activity from a remyelinating drug. In this study, 50 patients with chronic demyelinating optic neuropathy and relapsing-remitting MS were randomized to twice daily doses (5-36 mg) of clemastine fumarate for 90 days followed by placebo for 60 days or to placebo for 60 days followed by active drug for 90 days.
 

Remyelinating Effect Documented at Multiple Sites

The improvement on the primary endpoint of visual evoked potentials was interpreted as evidence that the therapy had a positive remyelinating effect, and Dr. Green said that the result has been reproduced by more than a dozen other centers.

The theoretical benefit is from a favorable effect on myelin-producing stem cells, but Dr. Green emphasized that theoretical benefits are not enough for moving the field forward. Negative trials with a theoretical potential to generate remyelination both preceded and followed ReBUILD. Examples include the RENEW study with the anti-lingo monoclonal antibody opicinumab and the CCMR One study with the non-selective retinoid X receptor agonist bexarotene.

Whether there is benefit or failure, “we need to be able to tell what is going on,” Dr. Green said. The reason is that a negative result is not necessarily due to the absence of a meaningful remyelination. Rather, other variables, such as an insufficient number of axons to remyelinate, might explain a lack of effect.

Citing evidence that remyelination and demyelination are often concurrent events, Dr. Green said that there is an urgent need for tools to objectively quantify myelination in order to document that drugs purported to favorably influence myelin repair are doing so. Surrogate markers are potentially unreliable.

“There is an unfortunate tendency in our field to overinterpret atrophy and neurodegeneration and to use those terms too loosely,” Dr. Green said. He said these terms are not interchangeable.

One basis for excitement is the growing support for the theory that oligodendrocyte progenitor cell (OPC) recruitment is critical to the remyelination process. By activating these cells or blocking inhibitors of their activity, experimental evidence suggests new myelin formation can occur. However, a clinically meaningful benefit might still be dependent on multiple additional factors, including the timing of OPC recruitment, Dr. Green explained.

“We might need to provide drugs with a remyelinating effect very early in the process,” he said.

The progress in understanding the interacting factors that define the biology of remyelination is the basis for new enthusiasm about this field, agreed Véronique Miron, PhD, Chair of the Multiple Sclerosis Research, Barlo MS Center, Toronto. Dr. Miron, professor in the Department of Immunology at the University of Toronto, identified the session on remyelination in which Dr. Green spoke as one of the highlights of this year’s ACTRIMS conference.
 

Late-breaker: Two Remyelinating Drugs with Promise

Consistent with this progress, a late-breaker presentation on two drugs that promote oligodendrocyte formation and remyelination in the experimental setting reinforced the growing array of potential therapeutic targets to generate remyelination. The two drugs, CVL-1001 and CVL-2001, act by inhibiting the cholesterol biosynthesis enzymes sterol 14-demethylase (CYP51) and an emopamil binding protein (EBP).

Multiple studies have suggested that CYP51 and EBP are “key therapeutic targets to promote oligodendrocyte formation,” thereby promoting remyelination, reported Brad T. Lang, PhD, vice president of research for Convelo Therapeutics, Cleveland.

The drugs performed as predicted in animal models, where remyelination was documented, and in promoting human oligodendrocyte formation in human brain organoids. The development of these agents has been accompanied by strategy to measure their activity.

“We established a mechanistic biomarker to assess target engagement in the CNS and periphery to guide the next steps in preclinical and clinical development,” Dr. Lang said.

He called these drugs “first-in-class potential therapies in the field of remyelination.” While he acknowledged that no clinical studies have yet been performed, his late-breaker presentation indicated that many of the criteria identified by Dr. Green, including an ability to penetrate the CNS and a plausible, measurable mechanism of action have been fulfilled.

Dr. Green reported financial relationships with Biogen, Mylan, and Novartis. Dr. Miron reported no potential conflicts of interest.

TOPLINE:

Higher dietary niacin intake is associated with a lower risk for all-cause mortality among people with metabolic dysfunction-associated steatotic liver disease (MASLD), but there is no connection between niacin consumption and cardiovascular disease (CVD) mortality, a recent study suggested.

METHODOLOGY:

• Researchers analyzed data from the National Health and Nutrition Examination Survey (2003-2018) for 4315 adults with MASLD (mean age, 52.5 years; 55%, men; 67%, non-Hispanic White).
• Dietary niacin intake levels were based on two 24-hour dietary recall interviews to report the types and quantities of foods that participants consumed in the 24 hours prior to the interviews.
• Participants were categorized by tertile of dietary niacin intake: Tertile 1 (n = 1440), < 18.4 mg; tertile 2 (n = 1441), 18.5-26.6 mg; and tertile 3 (n = 1434), > 26.7 mg.

TAKEAWAY:

• During a median follow-up of 8.8 years, 566 deaths occurred, of which 197 were attributed to CVD.
• Compared with participants with a niacin intake of 18.4 mg or lower (the lowest tertile), the multivariable-adjusted hazard ratios (HRs) for participants with a niacin intake of 26.7 mg or higher (the highest tertile) were 0.70 for all-cause mortality and 0.65 for CVD mortality.
• For the subgroup with diabetes compared with the reference group (the first tertile), the HR of all-cause mortality in the third tertile was 0.82.
• When the subgroup without diabetes was compared with the reference group, the HR of all-cause mortality in the third tertile was 0.58, suggesting a significant interaction between niacin and diabetes with the risk of all-cause mortality.
• An inverse association between dietary niacin intake and all-cause mortality was seen in sensitivity analyses, when excluding a participant who died within 2 years of follow-up.

IN PRACTICE:

“Higher dietary niacin intake was associated with a lower risk of all-cause mortality,” but not CVD, among individuals with MASLD, and “the dose-response association…needs to be further investigated to determine optimal intake level,” the authors wrote.

SOURCE:

The study, led by Jie Pan, MD, Sun Yat-sen University, Guangzhou, China, was published online in JAMA Network Open.

LIMITATIONS:

Physical activity data were missing and could not be adjusted for. The National Death Index used by the researchers has only “modest” ability to accurately classify CVD mortality, and the dietary data were subject to recall bias.

DISCLOSURES:

One author was supported by a grant from the National Nature Science Foundation of China. No other conflicts of interest were reported.

A version of this article appeared on Medscape.com.

TOPLINE:

Higher dietary niacin intake is associated with a lower risk for all-cause mortality among people with metabolic dysfunction-associated steatotic liver disease (MASLD), but there is no connection between niacin consumption and cardiovascular disease (CVD) mortality, a recent study suggested.

METHODOLOGY:

• Researchers analyzed data from the National Health and Nutrition Examination Survey (2003-2018) for 4315 adults with MASLD (mean age, 52.5 years; 55%, men; 67%, non-Hispanic White).
• Dietary niacin intake levels were based on two 24-hour dietary recall interviews to report the types and quantities of foods that participants consumed in the 24 hours prior to the interviews.
• Participants were categorized by tertile of dietary niacin intake: Tertile 1 (n = 1440), < 18.4 mg; tertile 2 (n = 1441), 18.5-26.6 mg; and tertile 3 (n = 1434), > 26.7 mg.

TAKEAWAY:

• During a median follow-up of 8.8 years, 566 deaths occurred, of which 197 were attributed to CVD.
• Compared with participants with a niacin intake of 18.4 mg or lower (the lowest tertile), the multivariable-adjusted hazard ratios (HRs) for participants with a niacin intake of 26.7 mg or higher (the highest tertile) were 0.70 for all-cause mortality and 0.65 for CVD mortality.
• For the subgroup with diabetes compared with the reference group (the first tertile), the HR of all-cause mortality in the third tertile was 0.82.
• When the subgroup without diabetes was compared with the reference group, the HR of all-cause mortality in the third tertile was 0.58, suggesting a significant interaction between niacin and diabetes with the risk of all-cause mortality.
• An inverse association between dietary niacin intake and all-cause mortality was seen in sensitivity analyses, when excluding a participant who died within 2 years of follow-up.

IN PRACTICE:

“Higher dietary niacin intake was associated with a lower risk of all-cause mortality,” but not CVD, among individuals with MASLD, and “the dose-response association…needs to be further investigated to determine optimal intake level,” the authors wrote.

SOURCE:

The study, led by Jie Pan, MD, Sun Yat-sen University, Guangzhou, China, was published online in JAMA Network Open.

LIMITATIONS:

Physical activity data were missing and could not be adjusted for. The National Death Index used by the researchers has only “modest” ability to accurately classify CVD mortality, and the dietary data were subject to recall bias.

DISCLOSURES:

One author was supported by a grant from the National Nature Science Foundation of China. No other conflicts of interest were reported.

A version of this article appeared on Medscape.com.

TOPLINE:

Higher dietary niacin intake is associated with a lower risk for all-cause mortality among people with metabolic dysfunction-associated steatotic liver disease (MASLD), but there is no connection between niacin consumption and cardiovascular disease (CVD) mortality, a recent study suggested.

METHODOLOGY:

• Researchers analyzed data from the National Health and Nutrition Examination Survey (2003-2018) for 4315 adults with MASLD (mean age, 52.5 years; 55%, men; 67%, non-Hispanic White).
• Dietary niacin intake levels were based on two 24-hour dietary recall interviews to report the types and quantities of foods that participants consumed in the 24 hours prior to the interviews.
• Participants were categorized by tertile of dietary niacin intake: Tertile 1 (n = 1440), < 18.4 mg; tertile 2 (n = 1441), 18.5-26.6 mg; and tertile 3 (n = 1434), > 26.7 mg.

TAKEAWAY:

• During a median follow-up of 8.8 years, 566 deaths occurred, of which 197 were attributed to CVD.
• Compared with participants with a niacin intake of 18.4 mg or lower (the lowest tertile), the multivariable-adjusted hazard ratios (HRs) for participants with a niacin intake of 26.7 mg or higher (the highest tertile) were 0.70 for all-cause mortality and 0.65 for CVD mortality.
• For the subgroup with diabetes compared with the reference group (the first tertile), the HR of all-cause mortality in the third tertile was 0.82.
• When the subgroup without diabetes was compared with the reference group, the HR of all-cause mortality in the third tertile was 0.58, suggesting a significant interaction between niacin and diabetes with the risk of all-cause mortality.
• An inverse association between dietary niacin intake and all-cause mortality was seen in sensitivity analyses, when excluding a participant who died within 2 years of follow-up.

IN PRACTICE:

“Higher dietary niacin intake was associated with a lower risk of all-cause mortality,” but not CVD, among individuals with MASLD, and “the dose-response association…needs to be further investigated to determine optimal intake level,” the authors wrote.

SOURCE:

The study, led by Jie Pan, MD, Sun Yat-sen University, Guangzhou, China, was published online in JAMA Network Open.

LIMITATIONS:

Physical activity data were missing and could not be adjusted for. The National Death Index used by the researchers has only “modest” ability to accurately classify CVD mortality, and the dietary data were subject to recall bias.

DISCLOSURES:

One author was supported by a grant from the National Nature Science Foundation of China. No other conflicts of interest were reported.

A version of this article appeared on Medscape.com.