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What are the clinical implications of recent skin dysbiosis discoveries?
NEW ORLEANS – .
“There’s still a lot for us to learn,” Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said at the annual meeting of the American Academy of Dermatology. “Multiple factors contribute to the variability in the skin microbiota, including age, sex, environment, immune system, host genotype, lifestyle, and pathobiology. The question becomes, when do these factors or impacts on the microbiota become clinically significant?”
According to Dr. Friedman, there are 10 times more bacteria cells than human cells in the human body, “but it’s not a fight to the finish; it’s not us versus them,” he said. “Together, we are a super organism.” There are also more than 500 species of bacteria on human skin excluding viruses and fungi, and each person carries up to 5 pounds of bacteria, which is akin to finding a new organ in the body.
“What’s so unique is that we each have our own bacterial fingerprint,” he said. “Whoever is sitting next to you? Their microbiota makeup is different than yours.”
Beyond genetics and environment, activities that can contribute to alterations in skin flora or skin dysbiosis include topical application of steroids, antibiotics, retinoids, harsh soaps, chemical and physical exfoliants, and resurfacing techniques. “With anything we apply or do to the skin, we are literally changing the home of many microorganisms, for good or bad,” he said.
In the realm of atopic dermatitis (AD), Staphylococcus aureus has been implicated as an offender in the pathophysiology of the disease. “It’s not about one single species of Staphylococcus, though,” said Dr. Friedman, who also is director of translational research at George Washington University. “We’re finding out that, depending on the severity of disease, Staph. epidermis may be part of the problem as opposed to it just being about Staph. aureus. Furthermore, and more importantly, these changes in the microbiota, specifically a decrease in microbial diversity, has been shown to precede a disease flare, highlighting the central role of maintaining microbial diversity and by definition, supporting the living barrier in our management of AD.”
With this in mind, researchers in one study used high-throughput sequencing to evaluate the microbial communities associated with affected and unaffected skin of 49 patients with AD before and after emollient treatment. Following 84 days of emollient application, clinical symptoms of AD improved in 72% of the study population and Stenotrophomonas species were significantly more abundant among responders.
Prebiotics, probiotics
“Our treatments certainly can positively impact the microbiota, as we have seen even recently with some of our new targeted therapies, but we can also directly provide support,” he continued. Prebiotics, which he defined as supplements or foods that contain a nondigestible ingredient that selectively stimulates the growth and/or activity of indigenous bacteria, can be found in many over-the-counter moisturizers.
For example, colloidal oatmeal has been found to support the growth of S. epidermidis and enhance the production of lactic acid. “We really don’t know much about what these induced changes mean from a clinical perspective; that has yet to be elucidated,” Dr. Friedman said.
In light of the recent attention to the early application of moisturizers in infants at high risk of developing AD in an effort to prevent or limit AD, “maybe part of this has to do with applying something that’s nurturing an evolving microbiota,” Dr. Friedman noted. “It’s something to think about.”
Yet another area of study involves the use of probiotics, which Dr. Friedman defined as supplements or foods that contain viable microorganisms that alter the microflora of the host. In a first-of-its-kind trial, researchers evaluated the safety and efficacy of self-administered topical Roseomonas mucosa in 10 adults and 5 children with AD. No adverse events or treatment complications were observed, and the topical R. mucosa was associated with significant decreases in measures of disease severity, topical steroid requirement, and S. aureus burden
In a more recent randomized trial of 11 patients with AD, Richard L. Gallo, MD, PhD, chair of dermatology, University of California, San Diego, and colleagues found that application of a personalized topical cream formulated from coagulase-negative Staphylococcus with antimicrobial activity against S. aureus reduced colonization of S. aureus and improved disease severity.
And in another randomized, controlled trial, Italian researchers enrolled 80 adults with mild to severe AD to receive a placebo or a supplement that was a mixture of lactobacilli for 56 days. They found that adults in the treatment arm showed an improvement in skin smoothness, skin moisturization, self-perception, and a decrease in the SCORing Atopic Dermatitis (SCORAD) index as well as in levels of inflammatory markers associated with AD.
Dr. Friedman also discussed postbiotics, nonviable bacterial products or metabolic byproducts from probiotic microorganisms that have biologic activity in the host. In one trial, French researchers enrolled 75 people with AD who ranged in age from 6 to 70 years to receive a cream containing a 5% lysate of the nonpathogenic bacteria Vitreoscilla filiformis, or a vehicle cream for 30 days. They found that compared with the vehicle, V. filiformis lysate significantly decreased SCORAD levels and pruritus; active cream was shown to significantly decrease loss of sleep from day 0 to day 29.
Dr. Friedman characterized these novel approaches to AD as “an exciting area, one we need to pay attention to. But what I really want to know is, aside from these purposefully made and marketed products that have pre- and postprobiotics, is there a difference with some of the products we use already? My assumption is that there is, but we need to see that data.”
Dr. Friedman disclosed that he is a consultant and/or advisory board member for Medscape/SanovaWorks, Oakstone Institute, L’Oréal, La Roche Posay, Galderma, Aveeno, Ortho Dermatologic, Microcures, Pfizer, Novartis, Lilly, Hoth Therapeutics, Zylo Therapeutics, BMS, Vial, Janssen, Novocure, Dermavant, Regeneron/Sanofi, and Incyte. He has also received grants from Pfizer, the Dermatology Foundation, Lilly, Janssen, Incyte, and Galderma.
NEW ORLEANS – .
“There’s still a lot for us to learn,” Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said at the annual meeting of the American Academy of Dermatology. “Multiple factors contribute to the variability in the skin microbiota, including age, sex, environment, immune system, host genotype, lifestyle, and pathobiology. The question becomes, when do these factors or impacts on the microbiota become clinically significant?”
According to Dr. Friedman, there are 10 times more bacteria cells than human cells in the human body, “but it’s not a fight to the finish; it’s not us versus them,” he said. “Together, we are a super organism.” There are also more than 500 species of bacteria on human skin excluding viruses and fungi, and each person carries up to 5 pounds of bacteria, which is akin to finding a new organ in the body.
“What’s so unique is that we each have our own bacterial fingerprint,” he said. “Whoever is sitting next to you? Their microbiota makeup is different than yours.”
Beyond genetics and environment, activities that can contribute to alterations in skin flora or skin dysbiosis include topical application of steroids, antibiotics, retinoids, harsh soaps, chemical and physical exfoliants, and resurfacing techniques. “With anything we apply or do to the skin, we are literally changing the home of many microorganisms, for good or bad,” he said.
In the realm of atopic dermatitis (AD), Staphylococcus aureus has been implicated as an offender in the pathophysiology of the disease. “It’s not about one single species of Staphylococcus, though,” said Dr. Friedman, who also is director of translational research at George Washington University. “We’re finding out that, depending on the severity of disease, Staph. epidermis may be part of the problem as opposed to it just being about Staph. aureus. Furthermore, and more importantly, these changes in the microbiota, specifically a decrease in microbial diversity, has been shown to precede a disease flare, highlighting the central role of maintaining microbial diversity and by definition, supporting the living barrier in our management of AD.”
With this in mind, researchers in one study used high-throughput sequencing to evaluate the microbial communities associated with affected and unaffected skin of 49 patients with AD before and after emollient treatment. Following 84 days of emollient application, clinical symptoms of AD improved in 72% of the study population and Stenotrophomonas species were significantly more abundant among responders.
Prebiotics, probiotics
“Our treatments certainly can positively impact the microbiota, as we have seen even recently with some of our new targeted therapies, but we can also directly provide support,” he continued. Prebiotics, which he defined as supplements or foods that contain a nondigestible ingredient that selectively stimulates the growth and/or activity of indigenous bacteria, can be found in many over-the-counter moisturizers.
For example, colloidal oatmeal has been found to support the growth of S. epidermidis and enhance the production of lactic acid. “We really don’t know much about what these induced changes mean from a clinical perspective; that has yet to be elucidated,” Dr. Friedman said.
In light of the recent attention to the early application of moisturizers in infants at high risk of developing AD in an effort to prevent or limit AD, “maybe part of this has to do with applying something that’s nurturing an evolving microbiota,” Dr. Friedman noted. “It’s something to think about.”
Yet another area of study involves the use of probiotics, which Dr. Friedman defined as supplements or foods that contain viable microorganisms that alter the microflora of the host. In a first-of-its-kind trial, researchers evaluated the safety and efficacy of self-administered topical Roseomonas mucosa in 10 adults and 5 children with AD. No adverse events or treatment complications were observed, and the topical R. mucosa was associated with significant decreases in measures of disease severity, topical steroid requirement, and S. aureus burden
In a more recent randomized trial of 11 patients with AD, Richard L. Gallo, MD, PhD, chair of dermatology, University of California, San Diego, and colleagues found that application of a personalized topical cream formulated from coagulase-negative Staphylococcus with antimicrobial activity against S. aureus reduced colonization of S. aureus and improved disease severity.
And in another randomized, controlled trial, Italian researchers enrolled 80 adults with mild to severe AD to receive a placebo or a supplement that was a mixture of lactobacilli for 56 days. They found that adults in the treatment arm showed an improvement in skin smoothness, skin moisturization, self-perception, and a decrease in the SCORing Atopic Dermatitis (SCORAD) index as well as in levels of inflammatory markers associated with AD.
Dr. Friedman also discussed postbiotics, nonviable bacterial products or metabolic byproducts from probiotic microorganisms that have biologic activity in the host. In one trial, French researchers enrolled 75 people with AD who ranged in age from 6 to 70 years to receive a cream containing a 5% lysate of the nonpathogenic bacteria Vitreoscilla filiformis, or a vehicle cream for 30 days. They found that compared with the vehicle, V. filiformis lysate significantly decreased SCORAD levels and pruritus; active cream was shown to significantly decrease loss of sleep from day 0 to day 29.
Dr. Friedman characterized these novel approaches to AD as “an exciting area, one we need to pay attention to. But what I really want to know is, aside from these purposefully made and marketed products that have pre- and postprobiotics, is there a difference with some of the products we use already? My assumption is that there is, but we need to see that data.”
Dr. Friedman disclosed that he is a consultant and/or advisory board member for Medscape/SanovaWorks, Oakstone Institute, L’Oréal, La Roche Posay, Galderma, Aveeno, Ortho Dermatologic, Microcures, Pfizer, Novartis, Lilly, Hoth Therapeutics, Zylo Therapeutics, BMS, Vial, Janssen, Novocure, Dermavant, Regeneron/Sanofi, and Incyte. He has also received grants from Pfizer, the Dermatology Foundation, Lilly, Janssen, Incyte, and Galderma.
NEW ORLEANS – .
“There’s still a lot for us to learn,” Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said at the annual meeting of the American Academy of Dermatology. “Multiple factors contribute to the variability in the skin microbiota, including age, sex, environment, immune system, host genotype, lifestyle, and pathobiology. The question becomes, when do these factors or impacts on the microbiota become clinically significant?”
According to Dr. Friedman, there are 10 times more bacteria cells than human cells in the human body, “but it’s not a fight to the finish; it’s not us versus them,” he said. “Together, we are a super organism.” There are also more than 500 species of bacteria on human skin excluding viruses and fungi, and each person carries up to 5 pounds of bacteria, which is akin to finding a new organ in the body.
“What’s so unique is that we each have our own bacterial fingerprint,” he said. “Whoever is sitting next to you? Their microbiota makeup is different than yours.”
Beyond genetics and environment, activities that can contribute to alterations in skin flora or skin dysbiosis include topical application of steroids, antibiotics, retinoids, harsh soaps, chemical and physical exfoliants, and resurfacing techniques. “With anything we apply or do to the skin, we are literally changing the home of many microorganisms, for good or bad,” he said.
In the realm of atopic dermatitis (AD), Staphylococcus aureus has been implicated as an offender in the pathophysiology of the disease. “It’s not about one single species of Staphylococcus, though,” said Dr. Friedman, who also is director of translational research at George Washington University. “We’re finding out that, depending on the severity of disease, Staph. epidermis may be part of the problem as opposed to it just being about Staph. aureus. Furthermore, and more importantly, these changes in the microbiota, specifically a decrease in microbial diversity, has been shown to precede a disease flare, highlighting the central role of maintaining microbial diversity and by definition, supporting the living barrier in our management of AD.”
With this in mind, researchers in one study used high-throughput sequencing to evaluate the microbial communities associated with affected and unaffected skin of 49 patients with AD before and after emollient treatment. Following 84 days of emollient application, clinical symptoms of AD improved in 72% of the study population and Stenotrophomonas species were significantly more abundant among responders.
Prebiotics, probiotics
“Our treatments certainly can positively impact the microbiota, as we have seen even recently with some of our new targeted therapies, but we can also directly provide support,” he continued. Prebiotics, which he defined as supplements or foods that contain a nondigestible ingredient that selectively stimulates the growth and/or activity of indigenous bacteria, can be found in many over-the-counter moisturizers.
For example, colloidal oatmeal has been found to support the growth of S. epidermidis and enhance the production of lactic acid. “We really don’t know much about what these induced changes mean from a clinical perspective; that has yet to be elucidated,” Dr. Friedman said.
In light of the recent attention to the early application of moisturizers in infants at high risk of developing AD in an effort to prevent or limit AD, “maybe part of this has to do with applying something that’s nurturing an evolving microbiota,” Dr. Friedman noted. “It’s something to think about.”
Yet another area of study involves the use of probiotics, which Dr. Friedman defined as supplements or foods that contain viable microorganisms that alter the microflora of the host. In a first-of-its-kind trial, researchers evaluated the safety and efficacy of self-administered topical Roseomonas mucosa in 10 adults and 5 children with AD. No adverse events or treatment complications were observed, and the topical R. mucosa was associated with significant decreases in measures of disease severity, topical steroid requirement, and S. aureus burden
In a more recent randomized trial of 11 patients with AD, Richard L. Gallo, MD, PhD, chair of dermatology, University of California, San Diego, and colleagues found that application of a personalized topical cream formulated from coagulase-negative Staphylococcus with antimicrobial activity against S. aureus reduced colonization of S. aureus and improved disease severity.
And in another randomized, controlled trial, Italian researchers enrolled 80 adults with mild to severe AD to receive a placebo or a supplement that was a mixture of lactobacilli for 56 days. They found that adults in the treatment arm showed an improvement in skin smoothness, skin moisturization, self-perception, and a decrease in the SCORing Atopic Dermatitis (SCORAD) index as well as in levels of inflammatory markers associated with AD.
Dr. Friedman also discussed postbiotics, nonviable bacterial products or metabolic byproducts from probiotic microorganisms that have biologic activity in the host. In one trial, French researchers enrolled 75 people with AD who ranged in age from 6 to 70 years to receive a cream containing a 5% lysate of the nonpathogenic bacteria Vitreoscilla filiformis, or a vehicle cream for 30 days. They found that compared with the vehicle, V. filiformis lysate significantly decreased SCORAD levels and pruritus; active cream was shown to significantly decrease loss of sleep from day 0 to day 29.
Dr. Friedman characterized these novel approaches to AD as “an exciting area, one we need to pay attention to. But what I really want to know is, aside from these purposefully made and marketed products that have pre- and postprobiotics, is there a difference with some of the products we use already? My assumption is that there is, but we need to see that data.”
Dr. Friedman disclosed that he is a consultant and/or advisory board member for Medscape/SanovaWorks, Oakstone Institute, L’Oréal, La Roche Posay, Galderma, Aveeno, Ortho Dermatologic, Microcures, Pfizer, Novartis, Lilly, Hoth Therapeutics, Zylo Therapeutics, BMS, Vial, Janssen, Novocure, Dermavant, Regeneron/Sanofi, and Incyte. He has also received grants from Pfizer, the Dermatology Foundation, Lilly, Janssen, Incyte, and Galderma.
AT AAD 2023
AGA guidelines, CPUs lead education at DDW® 2023
Below is a sampling of AGA’s invited-speaker sessions we’re excited about this year for clinical practitioners. To view other AGA program highlights, check out the DDW Preliminary Program.
- Guidelines Highlights 2023
- Clinical Practice Updates: Battle of the Heavyweights
- AGA Clinical Symposium
- Case Studies in Measuring Care and Improving Quality
- Optimizing Your GI Practice: Guidelines, Quality and Delivery
- AGA Postgraduate Course ($)
- Surviving the First Years in Clinical Practice: Roundtable With the Experts
Below is a sampling of AGA’s invited-speaker sessions we’re excited about this year for clinical practitioners. To view other AGA program highlights, check out the DDW Preliminary Program.
- Guidelines Highlights 2023
- Clinical Practice Updates: Battle of the Heavyweights
- AGA Clinical Symposium
- Case Studies in Measuring Care and Improving Quality
- Optimizing Your GI Practice: Guidelines, Quality and Delivery
- AGA Postgraduate Course ($)
- Surviving the First Years in Clinical Practice: Roundtable With the Experts
Below is a sampling of AGA’s invited-speaker sessions we’re excited about this year for clinical practitioners. To view other AGA program highlights, check out the DDW Preliminary Program.
- Guidelines Highlights 2023
- Clinical Practice Updates: Battle of the Heavyweights
- AGA Clinical Symposium
- Case Studies in Measuring Care and Improving Quality
- Optimizing Your GI Practice: Guidelines, Quality and Delivery
- AGA Postgraduate Course ($)
- Surviving the First Years in Clinical Practice: Roundtable With the Experts
Protect the next generation of GI investigators
Investing in research is the only way we will identify new diagnostics and treatments. However, at this time of unparalleled scientific and clinical opportunity, promising early stage investigators are leaving the field because of the instability of federal research funding.
Fortunately, the AGA Research Foundation has a proven track record of funding young investigators whose work advances the field of gastroenterology and hepatology.
Help the AGA build a community of investigators through the AGA Research Foundation.
Your donation to the AGA Research Foundation can fund future success stories by keeping young scientists working to advance our understanding of digestive diseases.
Donate today to help protect the GI research pipeline. Make a tax-deductible donation at www.foundation.gastro.org.
Investing in research is the only way we will identify new diagnostics and treatments. However, at this time of unparalleled scientific and clinical opportunity, promising early stage investigators are leaving the field because of the instability of federal research funding.
Fortunately, the AGA Research Foundation has a proven track record of funding young investigators whose work advances the field of gastroenterology and hepatology.
Help the AGA build a community of investigators through the AGA Research Foundation.
Your donation to the AGA Research Foundation can fund future success stories by keeping young scientists working to advance our understanding of digestive diseases.
Donate today to help protect the GI research pipeline. Make a tax-deductible donation at www.foundation.gastro.org.
Investing in research is the only way we will identify new diagnostics and treatments. However, at this time of unparalleled scientific and clinical opportunity, promising early stage investigators are leaving the field because of the instability of federal research funding.
Fortunately, the AGA Research Foundation has a proven track record of funding young investigators whose work advances the field of gastroenterology and hepatology.
Help the AGA build a community of investigators through the AGA Research Foundation.
Your donation to the AGA Research Foundation can fund future success stories by keeping young scientists working to advance our understanding of digestive diseases.
Donate today to help protect the GI research pipeline. Make a tax-deductible donation at www.foundation.gastro.org.
Picking up the premotor symptoms of Parkinson’s
This transcript has been edited for clarity.
Matthew F. Watto, MD: Welcome back to The Curbsiders. We had a great discussion on Parkinson’s Disease for Primary Care with Dr. Albert Hung. Paul, this was something that really made me nervous. I didn’t have a lot of comfort with it. But he taught us a lot of tips about how to recognize Parkinson’s.
I hadn’t been as aware of the premotor symptoms: constipation, hyposmia (loss of sense of smell), and rapid eye movement sleep behavior disorder. If patients have those early on and they aren’t explained by other things (especially the REM sleep behavior disorder), you should really key in because those patients are at risk of developing Parkinson’s years down the line. Those symptoms could present first, which just kind of blew my mind.
What tips do you have about how to recognize Parkinson’s? Do you want to talk about the physical exam?
Paul N. Williams, MD: You know I love the physical exam stuff, so I’m happy to talk about that.
You were deeply upset that cogwheel rigidity was not pathognomonic for Parkinson’s, but you made the point – and our guest agreed – that asymmetry tends to be the key here. And I really appreciated the point about reemergent tremor. This is this idea of a resting tremor. If someone has more parkinsonian features, you might see an intention tremor with essential tremor. If they reach out, it might seem steady at first, but if they hold long enough, then the tremor may kind of reemerge. I thought that was a neat distinction.
And this idea of cogwheel rigidity is a combination of some of the cardinal features of Parkinson’s – it’s a little bit of tremor and a little bit of rigidity too. There’s a baseline increase in tone, and then the tremor is superimposed on top of that. When you’re feeling cogwheeling, that’s actually what you’re feeling on examination. Parkinson’s, with all of its physical exam findings has always fascinated me.
Dr. Watto: He also told us about some red flags.
With classic idiopathic parkinsonism, there’s asymmetric involvement of the tremor. So red flags include a symmetric tremor, which might be something other than idiopathic parkinsonism. He also mentioned that one of the reasons you may want to get imaging (which is not always necessary if someone has a classic presentation), is if you see lower body–predominant symptoms of parkinsonism. These patients have rigidity or slowness of movement in their legs, but their upper bodies are not affected. They don’t have masked facies or the tremor in their hands. You might get an MRI in that case because that could be presentation of vascular dementia or vascular disease in the brain or even normal pressure hydrocephalus, which is a treatable condition. That would be one reason to get imaging.
What if the patient was exposed to a drug like a dopamine antagonist? They will get better in a couple of days, right?
Dr. Williams: This was a really fascinating point because we typically think if a patient’s symptoms are related to a drug exposure – in this case, drug-induced parkinsonism – we can just stop the medication and the symptoms will disappear in a couple of days as the drug leaves the system. But as it turns out, it might take much longer. A mistake that Dr Hung often sees is that the clinician stops the possibly offending agent, but when they don’t see an immediate relief of symptoms, they assume the drug wasn’t causing them. You really have to give the patient a fair shot off the medication to experience recovery because those symptoms can last weeks or even months after the drug is discontinued.
Dr. Watto: Dr Hung looks at the patient’s problem list and asks whether is there any reason this patient might have been exposed to one of these medications?
We’re not going to get too much into specific Parkinson’s treatment, but I was glad to hear that exercise actually improves mobility and may even have some neuroprotective effects. He mentioned ongoing trials looking at that. We always love an excuse to tell patients that they should be moving around more and being physically active.
Dr. Williams: That was one of the more shocking things I learned, that exercise might actually be good for you. That will deeply inform my practice. Many of the treatments that we use for Parkinson’s only address symptoms. They don’t address progression or fix anything, but exercise can help with that.
Dr. Watto: Paul, the last question I wanted to ask you is about our role in primary care. Patients with Parkinson’s have autonomic symptoms. They have neurocognitive symptoms. What is our role in that as primary care physicians?
Dr. Williams: Myriad symptoms can accompany Parkinson’s, and we have experience with most of them. We should all feel fairly comfortable dealing with constipation, which can be a very bothersome symptom. And we can use our full arsenal for symptoms such as depression, anxiety, and even apathy – the anhedonia, which apparently can be the predominant feature. We do have the tools to address these problems.
This might be a situation where we might reach for bupropion or a tricyclic antidepressant, which might not be your initial choice for a patient with a possibly annoying mood disorder. But for someone with Parkinson’s disease, this actually may be very helpful. We know how to manage a lot of the symptoms that come along with Parkinson’s that are not just the motor symptoms, and we should take ownership of those things.
Dr. Watto: You can hear the rest of this podcast here. This has been another episode of The Curbsiders bringing you a little knowledge food for your brain hole. Until next time, I’ve been Dr Matthew Frank Watto.
Dr. Williams: And I’m Dr Paul Nelson Williams.
Dr. Watto is a clinical assistant professor, department of medicine, at the University of Pennsylvania, Philadelphia. Dr. Williams is Associate Professor of Clinical Medicine, Department of General Internal Medicine, at Temple University, Philadelphia. Neither Dr. Watto nor Dr. Williams reported any relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Matthew F. Watto, MD: Welcome back to The Curbsiders. We had a great discussion on Parkinson’s Disease for Primary Care with Dr. Albert Hung. Paul, this was something that really made me nervous. I didn’t have a lot of comfort with it. But he taught us a lot of tips about how to recognize Parkinson’s.
I hadn’t been as aware of the premotor symptoms: constipation, hyposmia (loss of sense of smell), and rapid eye movement sleep behavior disorder. If patients have those early on and they aren’t explained by other things (especially the REM sleep behavior disorder), you should really key in because those patients are at risk of developing Parkinson’s years down the line. Those symptoms could present first, which just kind of blew my mind.
What tips do you have about how to recognize Parkinson’s? Do you want to talk about the physical exam?
Paul N. Williams, MD: You know I love the physical exam stuff, so I’m happy to talk about that.
You were deeply upset that cogwheel rigidity was not pathognomonic for Parkinson’s, but you made the point – and our guest agreed – that asymmetry tends to be the key here. And I really appreciated the point about reemergent tremor. This is this idea of a resting tremor. If someone has more parkinsonian features, you might see an intention tremor with essential tremor. If they reach out, it might seem steady at first, but if they hold long enough, then the tremor may kind of reemerge. I thought that was a neat distinction.
And this idea of cogwheel rigidity is a combination of some of the cardinal features of Parkinson’s – it’s a little bit of tremor and a little bit of rigidity too. There’s a baseline increase in tone, and then the tremor is superimposed on top of that. When you’re feeling cogwheeling, that’s actually what you’re feeling on examination. Parkinson’s, with all of its physical exam findings has always fascinated me.
Dr. Watto: He also told us about some red flags.
With classic idiopathic parkinsonism, there’s asymmetric involvement of the tremor. So red flags include a symmetric tremor, which might be something other than idiopathic parkinsonism. He also mentioned that one of the reasons you may want to get imaging (which is not always necessary if someone has a classic presentation), is if you see lower body–predominant symptoms of parkinsonism. These patients have rigidity or slowness of movement in their legs, but their upper bodies are not affected. They don’t have masked facies or the tremor in their hands. You might get an MRI in that case because that could be presentation of vascular dementia or vascular disease in the brain or even normal pressure hydrocephalus, which is a treatable condition. That would be one reason to get imaging.
What if the patient was exposed to a drug like a dopamine antagonist? They will get better in a couple of days, right?
Dr. Williams: This was a really fascinating point because we typically think if a patient’s symptoms are related to a drug exposure – in this case, drug-induced parkinsonism – we can just stop the medication and the symptoms will disappear in a couple of days as the drug leaves the system. But as it turns out, it might take much longer. A mistake that Dr Hung often sees is that the clinician stops the possibly offending agent, but when they don’t see an immediate relief of symptoms, they assume the drug wasn’t causing them. You really have to give the patient a fair shot off the medication to experience recovery because those symptoms can last weeks or even months after the drug is discontinued.
Dr. Watto: Dr Hung looks at the patient’s problem list and asks whether is there any reason this patient might have been exposed to one of these medications?
We’re not going to get too much into specific Parkinson’s treatment, but I was glad to hear that exercise actually improves mobility and may even have some neuroprotective effects. He mentioned ongoing trials looking at that. We always love an excuse to tell patients that they should be moving around more and being physically active.
Dr. Williams: That was one of the more shocking things I learned, that exercise might actually be good for you. That will deeply inform my practice. Many of the treatments that we use for Parkinson’s only address symptoms. They don’t address progression or fix anything, but exercise can help with that.
Dr. Watto: Paul, the last question I wanted to ask you is about our role in primary care. Patients with Parkinson’s have autonomic symptoms. They have neurocognitive symptoms. What is our role in that as primary care physicians?
Dr. Williams: Myriad symptoms can accompany Parkinson’s, and we have experience with most of them. We should all feel fairly comfortable dealing with constipation, which can be a very bothersome symptom. And we can use our full arsenal for symptoms such as depression, anxiety, and even apathy – the anhedonia, which apparently can be the predominant feature. We do have the tools to address these problems.
This might be a situation where we might reach for bupropion or a tricyclic antidepressant, which might not be your initial choice for a patient with a possibly annoying mood disorder. But for someone with Parkinson’s disease, this actually may be very helpful. We know how to manage a lot of the symptoms that come along with Parkinson’s that are not just the motor symptoms, and we should take ownership of those things.
Dr. Watto: You can hear the rest of this podcast here. This has been another episode of The Curbsiders bringing you a little knowledge food for your brain hole. Until next time, I’ve been Dr Matthew Frank Watto.
Dr. Williams: And I’m Dr Paul Nelson Williams.
Dr. Watto is a clinical assistant professor, department of medicine, at the University of Pennsylvania, Philadelphia. Dr. Williams is Associate Professor of Clinical Medicine, Department of General Internal Medicine, at Temple University, Philadelphia. Neither Dr. Watto nor Dr. Williams reported any relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Matthew F. Watto, MD: Welcome back to The Curbsiders. We had a great discussion on Parkinson’s Disease for Primary Care with Dr. Albert Hung. Paul, this was something that really made me nervous. I didn’t have a lot of comfort with it. But he taught us a lot of tips about how to recognize Parkinson’s.
I hadn’t been as aware of the premotor symptoms: constipation, hyposmia (loss of sense of smell), and rapid eye movement sleep behavior disorder. If patients have those early on and they aren’t explained by other things (especially the REM sleep behavior disorder), you should really key in because those patients are at risk of developing Parkinson’s years down the line. Those symptoms could present first, which just kind of blew my mind.
What tips do you have about how to recognize Parkinson’s? Do you want to talk about the physical exam?
Paul N. Williams, MD: You know I love the physical exam stuff, so I’m happy to talk about that.
You were deeply upset that cogwheel rigidity was not pathognomonic for Parkinson’s, but you made the point – and our guest agreed – that asymmetry tends to be the key here. And I really appreciated the point about reemergent tremor. This is this idea of a resting tremor. If someone has more parkinsonian features, you might see an intention tremor with essential tremor. If they reach out, it might seem steady at first, but if they hold long enough, then the tremor may kind of reemerge. I thought that was a neat distinction.
And this idea of cogwheel rigidity is a combination of some of the cardinal features of Parkinson’s – it’s a little bit of tremor and a little bit of rigidity too. There’s a baseline increase in tone, and then the tremor is superimposed on top of that. When you’re feeling cogwheeling, that’s actually what you’re feeling on examination. Parkinson’s, with all of its physical exam findings has always fascinated me.
Dr. Watto: He also told us about some red flags.
With classic idiopathic parkinsonism, there’s asymmetric involvement of the tremor. So red flags include a symmetric tremor, which might be something other than idiopathic parkinsonism. He also mentioned that one of the reasons you may want to get imaging (which is not always necessary if someone has a classic presentation), is if you see lower body–predominant symptoms of parkinsonism. These patients have rigidity or slowness of movement in their legs, but their upper bodies are not affected. They don’t have masked facies or the tremor in their hands. You might get an MRI in that case because that could be presentation of vascular dementia or vascular disease in the brain or even normal pressure hydrocephalus, which is a treatable condition. That would be one reason to get imaging.
What if the patient was exposed to a drug like a dopamine antagonist? They will get better in a couple of days, right?
Dr. Williams: This was a really fascinating point because we typically think if a patient’s symptoms are related to a drug exposure – in this case, drug-induced parkinsonism – we can just stop the medication and the symptoms will disappear in a couple of days as the drug leaves the system. But as it turns out, it might take much longer. A mistake that Dr Hung often sees is that the clinician stops the possibly offending agent, but when they don’t see an immediate relief of symptoms, they assume the drug wasn’t causing them. You really have to give the patient a fair shot off the medication to experience recovery because those symptoms can last weeks or even months after the drug is discontinued.
Dr. Watto: Dr Hung looks at the patient’s problem list and asks whether is there any reason this patient might have been exposed to one of these medications?
We’re not going to get too much into specific Parkinson’s treatment, but I was glad to hear that exercise actually improves mobility and may even have some neuroprotective effects. He mentioned ongoing trials looking at that. We always love an excuse to tell patients that they should be moving around more and being physically active.
Dr. Williams: That was one of the more shocking things I learned, that exercise might actually be good for you. That will deeply inform my practice. Many of the treatments that we use for Parkinson’s only address symptoms. They don’t address progression or fix anything, but exercise can help with that.
Dr. Watto: Paul, the last question I wanted to ask you is about our role in primary care. Patients with Parkinson’s have autonomic symptoms. They have neurocognitive symptoms. What is our role in that as primary care physicians?
Dr. Williams: Myriad symptoms can accompany Parkinson’s, and we have experience with most of them. We should all feel fairly comfortable dealing with constipation, which can be a very bothersome symptom. And we can use our full arsenal for symptoms such as depression, anxiety, and even apathy – the anhedonia, which apparently can be the predominant feature. We do have the tools to address these problems.
This might be a situation where we might reach for bupropion or a tricyclic antidepressant, which might not be your initial choice for a patient with a possibly annoying mood disorder. But for someone with Parkinson’s disease, this actually may be very helpful. We know how to manage a lot of the symptoms that come along with Parkinson’s that are not just the motor symptoms, and we should take ownership of those things.
Dr. Watto: You can hear the rest of this podcast here. This has been another episode of The Curbsiders bringing you a little knowledge food for your brain hole. Until next time, I’ve been Dr Matthew Frank Watto.
Dr. Williams: And I’m Dr Paul Nelson Williams.
Dr. Watto is a clinical assistant professor, department of medicine, at the University of Pennsylvania, Philadelphia. Dr. Williams is Associate Professor of Clinical Medicine, Department of General Internal Medicine, at Temple University, Philadelphia. Neither Dr. Watto nor Dr. Williams reported any relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Reforming prior authorization remains AGA’s top policy priority
Reforming prior authorization polices to reduce red tape for physicians and help patients get the care they need in a timely manner is the AGA’s number one policy priority as it impacts every gastroenterologist regardless of practice setting. We have seen an increase in prior authorization policies from every major insurer. The most recent prior authorization program to impact gastroenterologists was announced by UnitedHealthcare (UHC) in March for implementation on June 1, 2023 and will require prior authorization for most colonoscopy and upper GI endoscopy procedures with the exception of screening colonoscopy.1 This policy is a step back at a time when payers should be developing innovative policies in collaboration with health care providers to improve patient care.
UHC’s GI prior authorization policy
AGA met with UHC in March to discuss their plan to require prior authorization for most GI endoscopy procedures. We stressed how this change will cause care delays for high-risk individuals, deter patients from undergoing medically recommended procedures, exacerbate existing sociodemographic disparities in care and outcomes, and add unnecessary paperwork burden to physicians who have mounting rates of burnout.
Linda Lee, MD, medical director of endoscopy at Brigham and Women’s Hospital, Boston, recently spoke of the impact this policy will have on gastroenterologists and their patients. “We all know that requiring prior authorizations really only leads to more bureaucracy within the insurance company, as well as within each health care provider’s practice, because we need people to fill out these prior authorization forms, waste time trying to get through to their 1-800 number to speak with someone who has no clinical knowledge, then be told we need to speak with someone else who actually does have some medical knowledge about why these procedures are necessary.”
However, Dr. Lee stressed that “most importantly, this will lead to poorer patient care with delays in care as we are struggling to wade through the morass of prior authorization while patients are bleeding, not able to swallow, vomiting, and more while waiting for their insurance company to approve their potentially life-saving procedures.”
We were particularly troubled that UHC announced this policy during Colorectal Cancer Awareness Month, given the need to screen more Americans for colorectal cancer which remains the nation’s number two cancer killer. The UHC program would require a PA on surveillance colonoscopy for those patients who have previously had polyps removed and are at a higher risk for developing colorectal cancer.
“We know that patients with high-risk adenomas or advanced sessile serrated lesions have a higher risk of developing colorectal cancer and timely access to the necessary surveillance colonoscopy is critical,” said David Lieberman, MD, past president of the AGA and chair of the AGA Executive Committee on the Screening Continuum.
AGA plans to meet with UHC again to ask them to reconsider this policy, but we need your advocacy now to tell United how this will impact you and your patients.
How you can help stop UHC’s prior authorization program
Write to UHC: Tell UHC how this policy would impact you and your patients. Contact their CEO using our customizable letter2 that outlines the impact of United’s GI endoscopy prior authorization program on gastroenterologists and their patients available on the AGA Advocacy Action Center.
Use social media: Tag United (@UHC) on Twitter and tell them how this burdensome program will cause delays for high-risk individuals, deter patients from seeking treatment, and exacerbate existing disparities in care, all while saddling physicians with even more paperwork. Once you’ve tweeted, tag your colleagues and encourage them to get involved.
AGA is working to reform prior authorization
The AGA has supported federal legislation that would streamline prior authorization processes in Medicare Advantage (MA), the private insurance plans that contract with the Medicare program, given the explosion of these policies over the past several years. The Improving Seniors Timely Access to Care Act, bipartisan, bicameral legislation, would reduce prior authorization burdens by:
- Establishing an electronic prior authorization (ePA) program and require MA plans to adopt ePA capabilities.
- Requiring the Secretary of Health and Human Services to establish a list of items and services eligible for real-time decisions under an MA ePA program.
- Standardizing and streamlining the prior authorization process for routinely approved items and services.
- Ensuring prior authorization requests are reviewed by qualified medical personnel.
- Increasing transparency around MA prior authorization requirements and their use.
- Protecting beneficiaries from any disruptions in care due to prior authorization requirements as they transition between MA plans.
The Centers for Medicare & Medicaid Services (CMS) has also recognized the impact that prior authorization is having on physician wellness and how it is contributing to physician burnout. The agency recently proposed implementing many of the provisions that are outlined in the legislation, and AGA has expressed our support for moving forward with many of their proposals.
Earlier this year, Shivan Mehta, MD, MPH, met with CMS administrator Chiquita Brooks-LaSure and Surgeon General Vivek Murthy, MD, MBA, to express AGA’s support for prior authorization reform and discussed how it impacts how patients with chronic conditions like inflammatory bowel disease maintain continuity of care. He also stressed how prior authorization further exacerbates health inequities since it creates an additional barrier to care when barriers already exist.
AGA is taking a multi-pronged approach to advocating for prior authorization reform and reducing paperwork through legislative advocacy, regulatory advocacy with the CMS, and payer advocacy. We can’t do this alone. Join our AGA Advocacy Center3 and get involved in our AGA Congressional Advocates Program.4The authors have no conflicts to declare.
References
1. UnitedHealthcare (2023 Mar 01) New requirements for gastroenterology services.
2. American Gastroenterological Association (n.d.) AGA Advocacy Action Center. Tell United to Stop New Prior Auth Requirements!
3. American Gastroenterological Association (n.d.) AGA Advocacy Action Center. Advocacy & Policy. Get Involved.
4. American Gastroenterological Association (n.d.) AGA Congressional Advocates Program.
Reforming prior authorization polices to reduce red tape for physicians and help patients get the care they need in a timely manner is the AGA’s number one policy priority as it impacts every gastroenterologist regardless of practice setting. We have seen an increase in prior authorization policies from every major insurer. The most recent prior authorization program to impact gastroenterologists was announced by UnitedHealthcare (UHC) in March for implementation on June 1, 2023 and will require prior authorization for most colonoscopy and upper GI endoscopy procedures with the exception of screening colonoscopy.1 This policy is a step back at a time when payers should be developing innovative policies in collaboration with health care providers to improve patient care.
UHC’s GI prior authorization policy
AGA met with UHC in March to discuss their plan to require prior authorization for most GI endoscopy procedures. We stressed how this change will cause care delays for high-risk individuals, deter patients from undergoing medically recommended procedures, exacerbate existing sociodemographic disparities in care and outcomes, and add unnecessary paperwork burden to physicians who have mounting rates of burnout.
Linda Lee, MD, medical director of endoscopy at Brigham and Women’s Hospital, Boston, recently spoke of the impact this policy will have on gastroenterologists and their patients. “We all know that requiring prior authorizations really only leads to more bureaucracy within the insurance company, as well as within each health care provider’s practice, because we need people to fill out these prior authorization forms, waste time trying to get through to their 1-800 number to speak with someone who has no clinical knowledge, then be told we need to speak with someone else who actually does have some medical knowledge about why these procedures are necessary.”
However, Dr. Lee stressed that “most importantly, this will lead to poorer patient care with delays in care as we are struggling to wade through the morass of prior authorization while patients are bleeding, not able to swallow, vomiting, and more while waiting for their insurance company to approve their potentially life-saving procedures.”
We were particularly troubled that UHC announced this policy during Colorectal Cancer Awareness Month, given the need to screen more Americans for colorectal cancer which remains the nation’s number two cancer killer. The UHC program would require a PA on surveillance colonoscopy for those patients who have previously had polyps removed and are at a higher risk for developing colorectal cancer.
“We know that patients with high-risk adenomas or advanced sessile serrated lesions have a higher risk of developing colorectal cancer and timely access to the necessary surveillance colonoscopy is critical,” said David Lieberman, MD, past president of the AGA and chair of the AGA Executive Committee on the Screening Continuum.
AGA plans to meet with UHC again to ask them to reconsider this policy, but we need your advocacy now to tell United how this will impact you and your patients.
How you can help stop UHC’s prior authorization program
Write to UHC: Tell UHC how this policy would impact you and your patients. Contact their CEO using our customizable letter2 that outlines the impact of United’s GI endoscopy prior authorization program on gastroenterologists and their patients available on the AGA Advocacy Action Center.
Use social media: Tag United (@UHC) on Twitter and tell them how this burdensome program will cause delays for high-risk individuals, deter patients from seeking treatment, and exacerbate existing disparities in care, all while saddling physicians with even more paperwork. Once you’ve tweeted, tag your colleagues and encourage them to get involved.
AGA is working to reform prior authorization
The AGA has supported federal legislation that would streamline prior authorization processes in Medicare Advantage (MA), the private insurance plans that contract with the Medicare program, given the explosion of these policies over the past several years. The Improving Seniors Timely Access to Care Act, bipartisan, bicameral legislation, would reduce prior authorization burdens by:
- Establishing an electronic prior authorization (ePA) program and require MA plans to adopt ePA capabilities.
- Requiring the Secretary of Health and Human Services to establish a list of items and services eligible for real-time decisions under an MA ePA program.
- Standardizing and streamlining the prior authorization process for routinely approved items and services.
- Ensuring prior authorization requests are reviewed by qualified medical personnel.
- Increasing transparency around MA prior authorization requirements and their use.
- Protecting beneficiaries from any disruptions in care due to prior authorization requirements as they transition between MA plans.
The Centers for Medicare & Medicaid Services (CMS) has also recognized the impact that prior authorization is having on physician wellness and how it is contributing to physician burnout. The agency recently proposed implementing many of the provisions that are outlined in the legislation, and AGA has expressed our support for moving forward with many of their proposals.
Earlier this year, Shivan Mehta, MD, MPH, met with CMS administrator Chiquita Brooks-LaSure and Surgeon General Vivek Murthy, MD, MBA, to express AGA’s support for prior authorization reform and discussed how it impacts how patients with chronic conditions like inflammatory bowel disease maintain continuity of care. He also stressed how prior authorization further exacerbates health inequities since it creates an additional barrier to care when barriers already exist.
AGA is taking a multi-pronged approach to advocating for prior authorization reform and reducing paperwork through legislative advocacy, regulatory advocacy with the CMS, and payer advocacy. We can’t do this alone. Join our AGA Advocacy Center3 and get involved in our AGA Congressional Advocates Program.4The authors have no conflicts to declare.
References
1. UnitedHealthcare (2023 Mar 01) New requirements for gastroenterology services.
2. American Gastroenterological Association (n.d.) AGA Advocacy Action Center. Tell United to Stop New Prior Auth Requirements!
3. American Gastroenterological Association (n.d.) AGA Advocacy Action Center. Advocacy & Policy. Get Involved.
4. American Gastroenterological Association (n.d.) AGA Congressional Advocates Program.
Reforming prior authorization polices to reduce red tape for physicians and help patients get the care they need in a timely manner is the AGA’s number one policy priority as it impacts every gastroenterologist regardless of practice setting. We have seen an increase in prior authorization policies from every major insurer. The most recent prior authorization program to impact gastroenterologists was announced by UnitedHealthcare (UHC) in March for implementation on June 1, 2023 and will require prior authorization for most colonoscopy and upper GI endoscopy procedures with the exception of screening colonoscopy.1 This policy is a step back at a time when payers should be developing innovative policies in collaboration with health care providers to improve patient care.
UHC’s GI prior authorization policy
AGA met with UHC in March to discuss their plan to require prior authorization for most GI endoscopy procedures. We stressed how this change will cause care delays for high-risk individuals, deter patients from undergoing medically recommended procedures, exacerbate existing sociodemographic disparities in care and outcomes, and add unnecessary paperwork burden to physicians who have mounting rates of burnout.
Linda Lee, MD, medical director of endoscopy at Brigham and Women’s Hospital, Boston, recently spoke of the impact this policy will have on gastroenterologists and their patients. “We all know that requiring prior authorizations really only leads to more bureaucracy within the insurance company, as well as within each health care provider’s practice, because we need people to fill out these prior authorization forms, waste time trying to get through to their 1-800 number to speak with someone who has no clinical knowledge, then be told we need to speak with someone else who actually does have some medical knowledge about why these procedures are necessary.”
However, Dr. Lee stressed that “most importantly, this will lead to poorer patient care with delays in care as we are struggling to wade through the morass of prior authorization while patients are bleeding, not able to swallow, vomiting, and more while waiting for their insurance company to approve their potentially life-saving procedures.”
We were particularly troubled that UHC announced this policy during Colorectal Cancer Awareness Month, given the need to screen more Americans for colorectal cancer which remains the nation’s number two cancer killer. The UHC program would require a PA on surveillance colonoscopy for those patients who have previously had polyps removed and are at a higher risk for developing colorectal cancer.
“We know that patients with high-risk adenomas or advanced sessile serrated lesions have a higher risk of developing colorectal cancer and timely access to the necessary surveillance colonoscopy is critical,” said David Lieberman, MD, past president of the AGA and chair of the AGA Executive Committee on the Screening Continuum.
AGA plans to meet with UHC again to ask them to reconsider this policy, but we need your advocacy now to tell United how this will impact you and your patients.
How you can help stop UHC’s prior authorization program
Write to UHC: Tell UHC how this policy would impact you and your patients. Contact their CEO using our customizable letter2 that outlines the impact of United’s GI endoscopy prior authorization program on gastroenterologists and their patients available on the AGA Advocacy Action Center.
Use social media: Tag United (@UHC) on Twitter and tell them how this burdensome program will cause delays for high-risk individuals, deter patients from seeking treatment, and exacerbate existing disparities in care, all while saddling physicians with even more paperwork. Once you’ve tweeted, tag your colleagues and encourage them to get involved.
AGA is working to reform prior authorization
The AGA has supported federal legislation that would streamline prior authorization processes in Medicare Advantage (MA), the private insurance plans that contract with the Medicare program, given the explosion of these policies over the past several years. The Improving Seniors Timely Access to Care Act, bipartisan, bicameral legislation, would reduce prior authorization burdens by:
- Establishing an electronic prior authorization (ePA) program and require MA plans to adopt ePA capabilities.
- Requiring the Secretary of Health and Human Services to establish a list of items and services eligible for real-time decisions under an MA ePA program.
- Standardizing and streamlining the prior authorization process for routinely approved items and services.
- Ensuring prior authorization requests are reviewed by qualified medical personnel.
- Increasing transparency around MA prior authorization requirements and their use.
- Protecting beneficiaries from any disruptions in care due to prior authorization requirements as they transition between MA plans.
The Centers for Medicare & Medicaid Services (CMS) has also recognized the impact that prior authorization is having on physician wellness and how it is contributing to physician burnout. The agency recently proposed implementing many of the provisions that are outlined in the legislation, and AGA has expressed our support for moving forward with many of their proposals.
Earlier this year, Shivan Mehta, MD, MPH, met with CMS administrator Chiquita Brooks-LaSure and Surgeon General Vivek Murthy, MD, MBA, to express AGA’s support for prior authorization reform and discussed how it impacts how patients with chronic conditions like inflammatory bowel disease maintain continuity of care. He also stressed how prior authorization further exacerbates health inequities since it creates an additional barrier to care when barriers already exist.
AGA is taking a multi-pronged approach to advocating for prior authorization reform and reducing paperwork through legislative advocacy, regulatory advocacy with the CMS, and payer advocacy. We can’t do this alone. Join our AGA Advocacy Center3 and get involved in our AGA Congressional Advocates Program.4The authors have no conflicts to declare.
References
1. UnitedHealthcare (2023 Mar 01) New requirements for gastroenterology services.
2. American Gastroenterological Association (n.d.) AGA Advocacy Action Center. Tell United to Stop New Prior Auth Requirements!
3. American Gastroenterological Association (n.d.) AGA Advocacy Action Center. Advocacy & Policy. Get Involved.
4. American Gastroenterological Association (n.d.) AGA Congressional Advocates Program.
Spherical heart may predict cardiomyopathy, AFib
A round heart, or left ventricle sphericity, predicted cardiomyopathy and atrial fibrillation (AFib) in a deep learning analysis of MRI images from close to 39,000 participants in the UK Biobank, a new study shows.
An increase of 1 standard deviation in the sphericity index (short axis length/long axis length) was associated with a 47% increased incidence of cardiomyopathy and a 20% increased incidence of AFib, independent of clinical factors and traditional MRI measures.
Furthermore, a genetic analysis suggested a shared architecture between sphericity and nonischemic cardiomyopathy, pointing to NICM as a possible causal factor for left ventricle sphericity among individuals with normal LV size and function.
“Physicians have known the heart gets rounder after heart attacks and as we get older,” David Ouyang, MD, a cardiologist in the Smidt Heart Institute at Cedars-Sinai Medical Center, Los Angeles, and a researcher in the division of artificial intelligence in medicine, said in an interview. “We wanted to see if this sphericity is prognostic of future disease even in healthy individuals.”
Although it is too early to recommend heart shape assessment in healthy asymptomatic people, he said, “physicians should be extra careful and think about treatments when they notice a patient’s heart is particularly round.”
The study was published online March 29 in the journal Med.
Sphericity index key
The investigators hypothesized that there is variation in LV sphericity within the spectrum of normal LV chamber size and systolic function, and that such variation might be a marker of cardiac risk with genetic influences.
To test this hypothesis, they used automated deep-learning segmentation of cardiac MRI data to estimate and analyze the sphericity index in a cohort of 38,897 individuals participating in the UK Biobank.
After adjustment for age at MRI and sex, an increased sphericity index was associated with an increased risk for cardiomyopathy (hazard ratio, 1.57), AFib (HR, 1.35), and heart failure (HR, 1.37).
No significant association was seen with cardiac arrest.
The team then stratified the cohort into quintiles and compared the top 20%, middle 60%, and bottom 20%. The relationship between the sphericity index and risk extended across the distribution; individuals with higher than median sphericity had increased disease incidence, and those with lower than median sphericity had decreased incidence.
Overall, a single standard deviation in the sphericity index was associated with increased risk of cardiomyopathy (HR, 1.47) and of AFib (HR, 1.20), independent of clinical factors and usual MRI measurements.
In a minimally adjusted model, the sphericity index was a predictor of incident cardiomyopathy, AFib, and heart failure.
Adjustment for clinical factors partially attenuated the heart failure association; additional adjustment for MRI measurements fully attenuated that association and partially attenuated the association with AFib.
However, in all adjusted models, the association with cardiomyopathy showed little attenuation.
Furthermore, the team identified four loci associated with sphericity at genomewide significance – PLN, ANGPT1, PDZRN3, and HLA DR/DQ – and Mendelian randomization supported NICM as a cause of LV sphericity.
Looking ahead
“While conventional imaging metrics have significant diagnostic and prognostic value, some of these measurements have been adopted out of convenience or tradition,” the authors noted. “By representing a specific multidimensional remodeling phenotype, sphericity has emerged as a distinct morphologic trait with features not adequately captured by conventional measurements.
“We expect that the search space of potential imaging measurements is vast, and we have only begun to scratch at the surface of disease associations.”
Indeed, Dr. Ouyang said his group is “trying to evaluate the sphericity in echocardiograms or heart ultrasounds, which are more common and cheaper than MRI.”
“The main caveat is translating the information directly to patient care,” Richard C. Becker, MD, director and physician-in-chief of the University of Cincinnati Heart, Lung, and Vascular Institute, said in an interview. “Near-term yield could include using the spherical calculation in routine MRI of the heart, and based on the findings, following patients more closely if there is an abnormal shape. Or performing an MRI and targeted gene testing if there is a family history of cardiomyopathy or [of] an abnormal shape of the heart.”
“Validation of the findings and large-scale evaluation of the genes identified, and how they interact with patient and environmental factors, will be very important,” he added.
Nevertheless, “the study was well done and may serve as a foundation for future research,” Dr. Becker said. “The investigators used several powerful tools, including MRI, genomics, and [artificial intelligence] to draw their conclusions. This is precisely the way that ‘big data’ should be used – in a complementary fashion.”
The study authors and Dr. Becker reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A round heart, or left ventricle sphericity, predicted cardiomyopathy and atrial fibrillation (AFib) in a deep learning analysis of MRI images from close to 39,000 participants in the UK Biobank, a new study shows.
An increase of 1 standard deviation in the sphericity index (short axis length/long axis length) was associated with a 47% increased incidence of cardiomyopathy and a 20% increased incidence of AFib, independent of clinical factors and traditional MRI measures.
Furthermore, a genetic analysis suggested a shared architecture between sphericity and nonischemic cardiomyopathy, pointing to NICM as a possible causal factor for left ventricle sphericity among individuals with normal LV size and function.
“Physicians have known the heart gets rounder after heart attacks and as we get older,” David Ouyang, MD, a cardiologist in the Smidt Heart Institute at Cedars-Sinai Medical Center, Los Angeles, and a researcher in the division of artificial intelligence in medicine, said in an interview. “We wanted to see if this sphericity is prognostic of future disease even in healthy individuals.”
Although it is too early to recommend heart shape assessment in healthy asymptomatic people, he said, “physicians should be extra careful and think about treatments when they notice a patient’s heart is particularly round.”
The study was published online March 29 in the journal Med.
Sphericity index key
The investigators hypothesized that there is variation in LV sphericity within the spectrum of normal LV chamber size and systolic function, and that such variation might be a marker of cardiac risk with genetic influences.
To test this hypothesis, they used automated deep-learning segmentation of cardiac MRI data to estimate and analyze the sphericity index in a cohort of 38,897 individuals participating in the UK Biobank.
After adjustment for age at MRI and sex, an increased sphericity index was associated with an increased risk for cardiomyopathy (hazard ratio, 1.57), AFib (HR, 1.35), and heart failure (HR, 1.37).
No significant association was seen with cardiac arrest.
The team then stratified the cohort into quintiles and compared the top 20%, middle 60%, and bottom 20%. The relationship between the sphericity index and risk extended across the distribution; individuals with higher than median sphericity had increased disease incidence, and those with lower than median sphericity had decreased incidence.
Overall, a single standard deviation in the sphericity index was associated with increased risk of cardiomyopathy (HR, 1.47) and of AFib (HR, 1.20), independent of clinical factors and usual MRI measurements.
In a minimally adjusted model, the sphericity index was a predictor of incident cardiomyopathy, AFib, and heart failure.
Adjustment for clinical factors partially attenuated the heart failure association; additional adjustment for MRI measurements fully attenuated that association and partially attenuated the association with AFib.
However, in all adjusted models, the association with cardiomyopathy showed little attenuation.
Furthermore, the team identified four loci associated with sphericity at genomewide significance – PLN, ANGPT1, PDZRN3, and HLA DR/DQ – and Mendelian randomization supported NICM as a cause of LV sphericity.
Looking ahead
“While conventional imaging metrics have significant diagnostic and prognostic value, some of these measurements have been adopted out of convenience or tradition,” the authors noted. “By representing a specific multidimensional remodeling phenotype, sphericity has emerged as a distinct morphologic trait with features not adequately captured by conventional measurements.
“We expect that the search space of potential imaging measurements is vast, and we have only begun to scratch at the surface of disease associations.”
Indeed, Dr. Ouyang said his group is “trying to evaluate the sphericity in echocardiograms or heart ultrasounds, which are more common and cheaper than MRI.”
“The main caveat is translating the information directly to patient care,” Richard C. Becker, MD, director and physician-in-chief of the University of Cincinnati Heart, Lung, and Vascular Institute, said in an interview. “Near-term yield could include using the spherical calculation in routine MRI of the heart, and based on the findings, following patients more closely if there is an abnormal shape. Or performing an MRI and targeted gene testing if there is a family history of cardiomyopathy or [of] an abnormal shape of the heart.”
“Validation of the findings and large-scale evaluation of the genes identified, and how they interact with patient and environmental factors, will be very important,” he added.
Nevertheless, “the study was well done and may serve as a foundation for future research,” Dr. Becker said. “The investigators used several powerful tools, including MRI, genomics, and [artificial intelligence] to draw their conclusions. This is precisely the way that ‘big data’ should be used – in a complementary fashion.”
The study authors and Dr. Becker reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A round heart, or left ventricle sphericity, predicted cardiomyopathy and atrial fibrillation (AFib) in a deep learning analysis of MRI images from close to 39,000 participants in the UK Biobank, a new study shows.
An increase of 1 standard deviation in the sphericity index (short axis length/long axis length) was associated with a 47% increased incidence of cardiomyopathy and a 20% increased incidence of AFib, independent of clinical factors and traditional MRI measures.
Furthermore, a genetic analysis suggested a shared architecture between sphericity and nonischemic cardiomyopathy, pointing to NICM as a possible causal factor for left ventricle sphericity among individuals with normal LV size and function.
“Physicians have known the heart gets rounder after heart attacks and as we get older,” David Ouyang, MD, a cardiologist in the Smidt Heart Institute at Cedars-Sinai Medical Center, Los Angeles, and a researcher in the division of artificial intelligence in medicine, said in an interview. “We wanted to see if this sphericity is prognostic of future disease even in healthy individuals.”
Although it is too early to recommend heart shape assessment in healthy asymptomatic people, he said, “physicians should be extra careful and think about treatments when they notice a patient’s heart is particularly round.”
The study was published online March 29 in the journal Med.
Sphericity index key
The investigators hypothesized that there is variation in LV sphericity within the spectrum of normal LV chamber size and systolic function, and that such variation might be a marker of cardiac risk with genetic influences.
To test this hypothesis, they used automated deep-learning segmentation of cardiac MRI data to estimate and analyze the sphericity index in a cohort of 38,897 individuals participating in the UK Biobank.
After adjustment for age at MRI and sex, an increased sphericity index was associated with an increased risk for cardiomyopathy (hazard ratio, 1.57), AFib (HR, 1.35), and heart failure (HR, 1.37).
No significant association was seen with cardiac arrest.
The team then stratified the cohort into quintiles and compared the top 20%, middle 60%, and bottom 20%. The relationship between the sphericity index and risk extended across the distribution; individuals with higher than median sphericity had increased disease incidence, and those with lower than median sphericity had decreased incidence.
Overall, a single standard deviation in the sphericity index was associated with increased risk of cardiomyopathy (HR, 1.47) and of AFib (HR, 1.20), independent of clinical factors and usual MRI measurements.
In a minimally adjusted model, the sphericity index was a predictor of incident cardiomyopathy, AFib, and heart failure.
Adjustment for clinical factors partially attenuated the heart failure association; additional adjustment for MRI measurements fully attenuated that association and partially attenuated the association with AFib.
However, in all adjusted models, the association with cardiomyopathy showed little attenuation.
Furthermore, the team identified four loci associated with sphericity at genomewide significance – PLN, ANGPT1, PDZRN3, and HLA DR/DQ – and Mendelian randomization supported NICM as a cause of LV sphericity.
Looking ahead
“While conventional imaging metrics have significant diagnostic and prognostic value, some of these measurements have been adopted out of convenience or tradition,” the authors noted. “By representing a specific multidimensional remodeling phenotype, sphericity has emerged as a distinct morphologic trait with features not adequately captured by conventional measurements.
“We expect that the search space of potential imaging measurements is vast, and we have only begun to scratch at the surface of disease associations.”
Indeed, Dr. Ouyang said his group is “trying to evaluate the sphericity in echocardiograms or heart ultrasounds, which are more common and cheaper than MRI.”
“The main caveat is translating the information directly to patient care,” Richard C. Becker, MD, director and physician-in-chief of the University of Cincinnati Heart, Lung, and Vascular Institute, said in an interview. “Near-term yield could include using the spherical calculation in routine MRI of the heart, and based on the findings, following patients more closely if there is an abnormal shape. Or performing an MRI and targeted gene testing if there is a family history of cardiomyopathy or [of] an abnormal shape of the heart.”
“Validation of the findings and large-scale evaluation of the genes identified, and how they interact with patient and environmental factors, will be very important,” he added.
Nevertheless, “the study was well done and may serve as a foundation for future research,” Dr. Becker said. “The investigators used several powerful tools, including MRI, genomics, and [artificial intelligence] to draw their conclusions. This is precisely the way that ‘big data’ should be used – in a complementary fashion.”
The study authors and Dr. Becker reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM MED
FDA withdraws approval of Makena
The Food and Drug Administration has decided to withdraw approval of Makena and generic versions of the drug, the agency announced April 6.
The medication was approved in 2011 to reduce the risk for preterm birth in women who had previously experienced spontaneous preterm birth. The treatment had been approved under an accelerated pathway that required another trial to confirm clinical benefit.
A postmarketing study did not show clinical benefit, however, and the agency proposed withdrawing the drug, hydroxyprogesterone caproate injection, in 2020. The drug’s sponsor requested a hearing on the decision, and that meeting was held in October 2022.
The FDA commissioner and chief scientist subsequently reviewed submitted reports, comments, and transcripts, and made the decision to withdraw the drug.
“Effective today, Makena and its generics are no longer approved and cannot lawfully be distributed in interstate commerce,” the agency said.
“It is tragic that the scientific research and medical communities have not yet found a treatment shown to be effective in preventing preterm birth and improving neonatal outcomes – particularly in light of the fact that this serious condition has a disparate impact on communities of color, especially Black women,” FDA Commissioner Robert M. Califf, MD, said in a statement.
Risks associated with the drug include thromboembolic disorders, allergic reactions, decreased glucose tolerance, and fluid retention, regulators have noted. The agency acknowledged that some supplies of the product have already been distributed. Patients with questions should talk to their health care provider, the FDA advised.
The Food and Drug Administration has decided to withdraw approval of Makena and generic versions of the drug, the agency announced April 6.
The medication was approved in 2011 to reduce the risk for preterm birth in women who had previously experienced spontaneous preterm birth. The treatment had been approved under an accelerated pathway that required another trial to confirm clinical benefit.
A postmarketing study did not show clinical benefit, however, and the agency proposed withdrawing the drug, hydroxyprogesterone caproate injection, in 2020. The drug’s sponsor requested a hearing on the decision, and that meeting was held in October 2022.
The FDA commissioner and chief scientist subsequently reviewed submitted reports, comments, and transcripts, and made the decision to withdraw the drug.
“Effective today, Makena and its generics are no longer approved and cannot lawfully be distributed in interstate commerce,” the agency said.
“It is tragic that the scientific research and medical communities have not yet found a treatment shown to be effective in preventing preterm birth and improving neonatal outcomes – particularly in light of the fact that this serious condition has a disparate impact on communities of color, especially Black women,” FDA Commissioner Robert M. Califf, MD, said in a statement.
Risks associated with the drug include thromboembolic disorders, allergic reactions, decreased glucose tolerance, and fluid retention, regulators have noted. The agency acknowledged that some supplies of the product have already been distributed. Patients with questions should talk to their health care provider, the FDA advised.
The Food and Drug Administration has decided to withdraw approval of Makena and generic versions of the drug, the agency announced April 6.
The medication was approved in 2011 to reduce the risk for preterm birth in women who had previously experienced spontaneous preterm birth. The treatment had been approved under an accelerated pathway that required another trial to confirm clinical benefit.
A postmarketing study did not show clinical benefit, however, and the agency proposed withdrawing the drug, hydroxyprogesterone caproate injection, in 2020. The drug’s sponsor requested a hearing on the decision, and that meeting was held in October 2022.
The FDA commissioner and chief scientist subsequently reviewed submitted reports, comments, and transcripts, and made the decision to withdraw the drug.
“Effective today, Makena and its generics are no longer approved and cannot lawfully be distributed in interstate commerce,” the agency said.
“It is tragic that the scientific research and medical communities have not yet found a treatment shown to be effective in preventing preterm birth and improving neonatal outcomes – particularly in light of the fact that this serious condition has a disparate impact on communities of color, especially Black women,” FDA Commissioner Robert M. Califf, MD, said in a statement.
Risks associated with the drug include thromboembolic disorders, allergic reactions, decreased glucose tolerance, and fluid retention, regulators have noted. The agency acknowledged that some supplies of the product have already been distributed. Patients with questions should talk to their health care provider, the FDA advised.
Survival improved for some patients with metastatic cancers
Over the past 30 years, more than 80 new systemic therapies for cancer have been approved, and many patients diagnosed with localized disease have benefited with improved progression-free and overall survival. The same can be said for some – but by no means all – patients with metastatic disease at diagnosis, a new study indicates.
comment the authors, led by Marianne Luyendijk, MSc, from the Netherlands Comprehensive Cancer Organization, Utrecht.
The study was published online in the Journal of the National Cancer Institute.
The retrospective study compared survival data of patients with de novo metastatic disease diagnosed from 1989 through 1993 with those of patients diagnosed from 2014 to 2018.
The results show that 5-year survival increased by 15% or more among patients with metastatic gastrointestinal stromal tumors; neuroendocrine tumors; melanoma; and cancers of the prostate, breast, thyroid, and testes.
For patients with other cancers, however, the gains in survival were more modest. For example, over the study period, 5-year survival of patients with metastatic non–small cell lung cancer increased by only 6%, a disappointing finding, given the advent of targeted therapies and immunotherapy during the most recent period, the authors note.
In contrast, there was a 16% improvement in long-term survival of patients with metastatic melanoma, likely owing to the introduction of immune checkpoint inhibitors and targeted therapies, such as tyrosine kinase inhibitors.
The data also showed differences over time in the proportion of patients diagnosed with de novo metastatic disease; some cancers, such as NSCLC and small cell lung cancer, were more frequently diagnosed at late stages in the more recent era, possibly owing to increased screening and the use of technology such as FDG-PET imaging.
On the other end of the spectrum, cancers of the prostate, rectum, uterine cervix, breast, gallbladder, and bile ducts were more likely to be caught at an earlier stage during later years of the study period.
The authors say that among the possible explanations for a less than robust reduction over time in metastatic disease is that new drugs do not always translate into improved survival. They cite a 2017 study showing that among 53 new cancer drugs approved by U.S., European, or Australian drug regulators, fewer than half improved overall survival by at least 3 months, and an additional 26% offered survival advantages that were either shorter than 3 months or of unknown benefit.
“This may also explain why the 1- and 5-year survival rates of some cancers have changed little in the last 30 years,” they write. “Nevertheless, even minor benefits in survival or other outcomes (for example, quality of life) may represent progress in treating patients with metastatic cancer.”
The investigators recommend that to improve understanding of the effect of new therapies on survival of metastatic disease, cancer registries include data on therapies used beyond the first line, as well as comorbidities and quality-of-life measures.
The authors did not report a study funding source. Ms. Luyendijk has disclosed no relevant financial relationships. Several co-authors reported financial relationships with pharmaceutical companies.
A version of this article first appeared on Medscape.com.
Over the past 30 years, more than 80 new systemic therapies for cancer have been approved, and many patients diagnosed with localized disease have benefited with improved progression-free and overall survival. The same can be said for some – but by no means all – patients with metastatic disease at diagnosis, a new study indicates.
comment the authors, led by Marianne Luyendijk, MSc, from the Netherlands Comprehensive Cancer Organization, Utrecht.
The study was published online in the Journal of the National Cancer Institute.
The retrospective study compared survival data of patients with de novo metastatic disease diagnosed from 1989 through 1993 with those of patients diagnosed from 2014 to 2018.
The results show that 5-year survival increased by 15% or more among patients with metastatic gastrointestinal stromal tumors; neuroendocrine tumors; melanoma; and cancers of the prostate, breast, thyroid, and testes.
For patients with other cancers, however, the gains in survival were more modest. For example, over the study period, 5-year survival of patients with metastatic non–small cell lung cancer increased by only 6%, a disappointing finding, given the advent of targeted therapies and immunotherapy during the most recent period, the authors note.
In contrast, there was a 16% improvement in long-term survival of patients with metastatic melanoma, likely owing to the introduction of immune checkpoint inhibitors and targeted therapies, such as tyrosine kinase inhibitors.
The data also showed differences over time in the proportion of patients diagnosed with de novo metastatic disease; some cancers, such as NSCLC and small cell lung cancer, were more frequently diagnosed at late stages in the more recent era, possibly owing to increased screening and the use of technology such as FDG-PET imaging.
On the other end of the spectrum, cancers of the prostate, rectum, uterine cervix, breast, gallbladder, and bile ducts were more likely to be caught at an earlier stage during later years of the study period.
The authors say that among the possible explanations for a less than robust reduction over time in metastatic disease is that new drugs do not always translate into improved survival. They cite a 2017 study showing that among 53 new cancer drugs approved by U.S., European, or Australian drug regulators, fewer than half improved overall survival by at least 3 months, and an additional 26% offered survival advantages that were either shorter than 3 months or of unknown benefit.
“This may also explain why the 1- and 5-year survival rates of some cancers have changed little in the last 30 years,” they write. “Nevertheless, even minor benefits in survival or other outcomes (for example, quality of life) may represent progress in treating patients with metastatic cancer.”
The investigators recommend that to improve understanding of the effect of new therapies on survival of metastatic disease, cancer registries include data on therapies used beyond the first line, as well as comorbidities and quality-of-life measures.
The authors did not report a study funding source. Ms. Luyendijk has disclosed no relevant financial relationships. Several co-authors reported financial relationships with pharmaceutical companies.
A version of this article first appeared on Medscape.com.
Over the past 30 years, more than 80 new systemic therapies for cancer have been approved, and many patients diagnosed with localized disease have benefited with improved progression-free and overall survival. The same can be said for some – but by no means all – patients with metastatic disease at diagnosis, a new study indicates.
comment the authors, led by Marianne Luyendijk, MSc, from the Netherlands Comprehensive Cancer Organization, Utrecht.
The study was published online in the Journal of the National Cancer Institute.
The retrospective study compared survival data of patients with de novo metastatic disease diagnosed from 1989 through 1993 with those of patients diagnosed from 2014 to 2018.
The results show that 5-year survival increased by 15% or more among patients with metastatic gastrointestinal stromal tumors; neuroendocrine tumors; melanoma; and cancers of the prostate, breast, thyroid, and testes.
For patients with other cancers, however, the gains in survival were more modest. For example, over the study period, 5-year survival of patients with metastatic non–small cell lung cancer increased by only 6%, a disappointing finding, given the advent of targeted therapies and immunotherapy during the most recent period, the authors note.
In contrast, there was a 16% improvement in long-term survival of patients with metastatic melanoma, likely owing to the introduction of immune checkpoint inhibitors and targeted therapies, such as tyrosine kinase inhibitors.
The data also showed differences over time in the proportion of patients diagnosed with de novo metastatic disease; some cancers, such as NSCLC and small cell lung cancer, were more frequently diagnosed at late stages in the more recent era, possibly owing to increased screening and the use of technology such as FDG-PET imaging.
On the other end of the spectrum, cancers of the prostate, rectum, uterine cervix, breast, gallbladder, and bile ducts were more likely to be caught at an earlier stage during later years of the study period.
The authors say that among the possible explanations for a less than robust reduction over time in metastatic disease is that new drugs do not always translate into improved survival. They cite a 2017 study showing that among 53 new cancer drugs approved by U.S., European, or Australian drug regulators, fewer than half improved overall survival by at least 3 months, and an additional 26% offered survival advantages that were either shorter than 3 months or of unknown benefit.
“This may also explain why the 1- and 5-year survival rates of some cancers have changed little in the last 30 years,” they write. “Nevertheless, even minor benefits in survival or other outcomes (for example, quality of life) may represent progress in treating patients with metastatic cancer.”
The investigators recommend that to improve understanding of the effect of new therapies on survival of metastatic disease, cancer registries include data on therapies used beyond the first line, as well as comorbidities and quality-of-life measures.
The authors did not report a study funding source. Ms. Luyendijk has disclosed no relevant financial relationships. Several co-authors reported financial relationships with pharmaceutical companies.
A version of this article first appeared on Medscape.com.
FROM JOURNAL OF THE NATIONAL CANCER INSTITUTE
COVID-19 in pregnancy affects growth in child’s first year of life
in a new analysis.
This “exaggerated growth pattern observed among infants with COVID-19 exposure may in some cases be a catch-up response to a prenatal growth deficit,” Mollie W. Ockene and colleagues wrote in a report published recently in the Journal of Clinical Endocrinology & Metabolism.
But given that lower birth weight and accelerated postnatal weight gain are risk factors for cardiometabolic disease, the findings “raise concern” about whether children born to mothers with prenatal COVID-19 go on to develop obesity, diabetes, or cardiovascular disease, senior coauthors Andrea G. Edlow, MD, and Lindsay T. Fourman, MD, of Massachusetts General Hospital, Boston, told this news organization.
Further studies in larger numbers of patients with longer follow-up and detailed assessments are needed, the researchers said, but this points to “a potentially increased cardiometabolic disease risk for the large global population of children with in utero COVID-19 exposure.”
It will be “important for clinicians caring for children with in utero exposure to maternal COVID-19 to be aware of this history,” Dr. Edlow and Dr. Fourman added, “and to view the child’s growth trajectory and metabolic risk factors in a holistic context that includes this prenatal infection exposure.”
COVID-19 vaccination important during and prior to pregnancy
The study also underscores the importance of primary prevention of COVID-19 among women who are contemplating pregnancy or who are already pregnant, the researchers noted, “including the need for widespread implementation of protective measures such as indoor masking and COVID-19 vaccination and boosting during or prior to pregnancy.”
Dr. Edlow and Dr. Fourman added, “Given the disproportionate impact that COVID-19 has had on historically marginalized populations, adverse health outcomes following in utero exposure to maternal COVID-19 may threaten to widen existing disparities in child health.”
On the other hand, although “COVID-19 vaccination rates lagged behind in minority populations following the initial vaccine rollout,” they noted, “these differences have fortunately narrowed over time, particularly for Hispanic individuals, though they do still persist in the Black population,” according to a recent report.
BMI trajectories during first year of life
In utero exposure to COVID-19 has been linked to fetal/neonatal morbidity and mortality, including stillbirth, preterm birth, preeclampsia, and gestational hypertension, but less is known about infant outcomes during the first year of life.
The researchers aimed to compare weight, length, and BMI trajectories over the first year of life in infants with, versus without, in utero exposure to COVID-19.
They identified 149 infants with in utero exposure to COVID-19 and 127 unexposed infants; all were born between March 30, 2020, and May 30, 2021, to mothers who participated in the Mass General Brigham COVID-19 Perinatal Biorepository.
The study excluded infants whose mothers received the vaccine (n = 5) or who had unclear vaccination status during pregnancy (n = 4) to reduce sample heterogeneity.
At the time of the study, few women had received the COVID-19 vaccine because vaccines were approved by the Food and Drug Administration for emergency use in December 2020 and the CDC recommended them for all pregnant women much later, in August 2021.
The researchers examined the weight, length, and BMI of the infants at birth, and at 2, 6, and 12 months, standardized using World Health Organization (WHO) growth charts.
Compared with mothers who did not have COVID-19 during pregnancy, those who had COVID-19 were younger (mean age, 32 vs. 34 years) and had a higher earliest BMI during pregnancy (29 vs. 26 kg/m2) and greater parity (previous births, excluding the index pregnancy, 1.2 vs. 0.9), and they were more likely to be Hispanic or Black and less likely to have private insurance.
Compared with infants exposed to COVID-19 in utero, infants who were not exposed were more likely to be male (47% vs. 55%).
Both infant groups were equally likely to be breastfed (90%).
Compared with the unexposed infants, infants born to mothers with prenatal COVID-19 had lower BMI z-scores at birth (effect size, −0.35; P = .03) and greater gain in BMI z-scores from birth to 12 months (effect size, 0.53; P = .03), but they had similar length at birth and over 12 months, after adjustment for maternal age at delivery, ethnicity, parity, insurance status, and earliest BMI during pregnancy, as well as infant sex, date of birth, and if applicable, history of breastfeeding.
The study received funding from the National Institutes of Health, Harvard Nutrition Obesity Research Center, Boston Area Diabetes Endocrinology Research Centers, American Heart Association, and Simons Foundation. Ms. Ockene has reported no relevant financial relationships. Dr. Edlow has reported being a consultant for Mirvie and receiving research funding from Merck outside the study. Dr. Fourman has reported serving as a consultant and receiving grant funding to her institution from Amryt outside the study. Disclosures for the other authors are listed with the article.
in a new analysis.
This “exaggerated growth pattern observed among infants with COVID-19 exposure may in some cases be a catch-up response to a prenatal growth deficit,” Mollie W. Ockene and colleagues wrote in a report published recently in the Journal of Clinical Endocrinology & Metabolism.
But given that lower birth weight and accelerated postnatal weight gain are risk factors for cardiometabolic disease, the findings “raise concern” about whether children born to mothers with prenatal COVID-19 go on to develop obesity, diabetes, or cardiovascular disease, senior coauthors Andrea G. Edlow, MD, and Lindsay T. Fourman, MD, of Massachusetts General Hospital, Boston, told this news organization.
Further studies in larger numbers of patients with longer follow-up and detailed assessments are needed, the researchers said, but this points to “a potentially increased cardiometabolic disease risk for the large global population of children with in utero COVID-19 exposure.”
It will be “important for clinicians caring for children with in utero exposure to maternal COVID-19 to be aware of this history,” Dr. Edlow and Dr. Fourman added, “and to view the child’s growth trajectory and metabolic risk factors in a holistic context that includes this prenatal infection exposure.”
COVID-19 vaccination important during and prior to pregnancy
The study also underscores the importance of primary prevention of COVID-19 among women who are contemplating pregnancy or who are already pregnant, the researchers noted, “including the need for widespread implementation of protective measures such as indoor masking and COVID-19 vaccination and boosting during or prior to pregnancy.”
Dr. Edlow and Dr. Fourman added, “Given the disproportionate impact that COVID-19 has had on historically marginalized populations, adverse health outcomes following in utero exposure to maternal COVID-19 may threaten to widen existing disparities in child health.”
On the other hand, although “COVID-19 vaccination rates lagged behind in minority populations following the initial vaccine rollout,” they noted, “these differences have fortunately narrowed over time, particularly for Hispanic individuals, though they do still persist in the Black population,” according to a recent report.
BMI trajectories during first year of life
In utero exposure to COVID-19 has been linked to fetal/neonatal morbidity and mortality, including stillbirth, preterm birth, preeclampsia, and gestational hypertension, but less is known about infant outcomes during the first year of life.
The researchers aimed to compare weight, length, and BMI trajectories over the first year of life in infants with, versus without, in utero exposure to COVID-19.
They identified 149 infants with in utero exposure to COVID-19 and 127 unexposed infants; all were born between March 30, 2020, and May 30, 2021, to mothers who participated in the Mass General Brigham COVID-19 Perinatal Biorepository.
The study excluded infants whose mothers received the vaccine (n = 5) or who had unclear vaccination status during pregnancy (n = 4) to reduce sample heterogeneity.
At the time of the study, few women had received the COVID-19 vaccine because vaccines were approved by the Food and Drug Administration for emergency use in December 2020 and the CDC recommended them for all pregnant women much later, in August 2021.
The researchers examined the weight, length, and BMI of the infants at birth, and at 2, 6, and 12 months, standardized using World Health Organization (WHO) growth charts.
Compared with mothers who did not have COVID-19 during pregnancy, those who had COVID-19 were younger (mean age, 32 vs. 34 years) and had a higher earliest BMI during pregnancy (29 vs. 26 kg/m2) and greater parity (previous births, excluding the index pregnancy, 1.2 vs. 0.9), and they were more likely to be Hispanic or Black and less likely to have private insurance.
Compared with infants exposed to COVID-19 in utero, infants who were not exposed were more likely to be male (47% vs. 55%).
Both infant groups were equally likely to be breastfed (90%).
Compared with the unexposed infants, infants born to mothers with prenatal COVID-19 had lower BMI z-scores at birth (effect size, −0.35; P = .03) and greater gain in BMI z-scores from birth to 12 months (effect size, 0.53; P = .03), but they had similar length at birth and over 12 months, after adjustment for maternal age at delivery, ethnicity, parity, insurance status, and earliest BMI during pregnancy, as well as infant sex, date of birth, and if applicable, history of breastfeeding.
The study received funding from the National Institutes of Health, Harvard Nutrition Obesity Research Center, Boston Area Diabetes Endocrinology Research Centers, American Heart Association, and Simons Foundation. Ms. Ockene has reported no relevant financial relationships. Dr. Edlow has reported being a consultant for Mirvie and receiving research funding from Merck outside the study. Dr. Fourman has reported serving as a consultant and receiving grant funding to her institution from Amryt outside the study. Disclosures for the other authors are listed with the article.
in a new analysis.
This “exaggerated growth pattern observed among infants with COVID-19 exposure may in some cases be a catch-up response to a prenatal growth deficit,” Mollie W. Ockene and colleagues wrote in a report published recently in the Journal of Clinical Endocrinology & Metabolism.
But given that lower birth weight and accelerated postnatal weight gain are risk factors for cardiometabolic disease, the findings “raise concern” about whether children born to mothers with prenatal COVID-19 go on to develop obesity, diabetes, or cardiovascular disease, senior coauthors Andrea G. Edlow, MD, and Lindsay T. Fourman, MD, of Massachusetts General Hospital, Boston, told this news organization.
Further studies in larger numbers of patients with longer follow-up and detailed assessments are needed, the researchers said, but this points to “a potentially increased cardiometabolic disease risk for the large global population of children with in utero COVID-19 exposure.”
It will be “important for clinicians caring for children with in utero exposure to maternal COVID-19 to be aware of this history,” Dr. Edlow and Dr. Fourman added, “and to view the child’s growth trajectory and metabolic risk factors in a holistic context that includes this prenatal infection exposure.”
COVID-19 vaccination important during and prior to pregnancy
The study also underscores the importance of primary prevention of COVID-19 among women who are contemplating pregnancy or who are already pregnant, the researchers noted, “including the need for widespread implementation of protective measures such as indoor masking and COVID-19 vaccination and boosting during or prior to pregnancy.”
Dr. Edlow and Dr. Fourman added, “Given the disproportionate impact that COVID-19 has had on historically marginalized populations, adverse health outcomes following in utero exposure to maternal COVID-19 may threaten to widen existing disparities in child health.”
On the other hand, although “COVID-19 vaccination rates lagged behind in minority populations following the initial vaccine rollout,” they noted, “these differences have fortunately narrowed over time, particularly for Hispanic individuals, though they do still persist in the Black population,” according to a recent report.
BMI trajectories during first year of life
In utero exposure to COVID-19 has been linked to fetal/neonatal morbidity and mortality, including stillbirth, preterm birth, preeclampsia, and gestational hypertension, but less is known about infant outcomes during the first year of life.
The researchers aimed to compare weight, length, and BMI trajectories over the first year of life in infants with, versus without, in utero exposure to COVID-19.
They identified 149 infants with in utero exposure to COVID-19 and 127 unexposed infants; all were born between March 30, 2020, and May 30, 2021, to mothers who participated in the Mass General Brigham COVID-19 Perinatal Biorepository.
The study excluded infants whose mothers received the vaccine (n = 5) or who had unclear vaccination status during pregnancy (n = 4) to reduce sample heterogeneity.
At the time of the study, few women had received the COVID-19 vaccine because vaccines were approved by the Food and Drug Administration for emergency use in December 2020 and the CDC recommended them for all pregnant women much later, in August 2021.
The researchers examined the weight, length, and BMI of the infants at birth, and at 2, 6, and 12 months, standardized using World Health Organization (WHO) growth charts.
Compared with mothers who did not have COVID-19 during pregnancy, those who had COVID-19 were younger (mean age, 32 vs. 34 years) and had a higher earliest BMI during pregnancy (29 vs. 26 kg/m2) and greater parity (previous births, excluding the index pregnancy, 1.2 vs. 0.9), and they were more likely to be Hispanic or Black and less likely to have private insurance.
Compared with infants exposed to COVID-19 in utero, infants who were not exposed were more likely to be male (47% vs. 55%).
Both infant groups were equally likely to be breastfed (90%).
Compared with the unexposed infants, infants born to mothers with prenatal COVID-19 had lower BMI z-scores at birth (effect size, −0.35; P = .03) and greater gain in BMI z-scores from birth to 12 months (effect size, 0.53; P = .03), but they had similar length at birth and over 12 months, after adjustment for maternal age at delivery, ethnicity, parity, insurance status, and earliest BMI during pregnancy, as well as infant sex, date of birth, and if applicable, history of breastfeeding.
The study received funding from the National Institutes of Health, Harvard Nutrition Obesity Research Center, Boston Area Diabetes Endocrinology Research Centers, American Heart Association, and Simons Foundation. Ms. Ockene has reported no relevant financial relationships. Dr. Edlow has reported being a consultant for Mirvie and receiving research funding from Merck outside the study. Dr. Fourman has reported serving as a consultant and receiving grant funding to her institution from Amryt outside the study. Disclosures for the other authors are listed with the article.
FROM JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Antiamyloids linked to accelerated brain atrophy
a comprehensive meta-analysis of MRI data from clinical trials suggests.
Depending on the anti–amyloid-beta drug class, these agents can accelerate loss of whole brain and hippocampal volume and increase ventricular volume. This has been shown for some of the beta-secretase inhibitors and with several of the antiamyloid monoclonal antibodies, researchers noted.
“These data warrant concern, but we can’t make any firm conclusions yet. It is possible that the finding is not detrimental, but the usual interpretation of this finding is that volume changes are a surrogate for disease progression,” study investigator Scott Ayton, PhD, of the Florey Institute of Neuroscience and Mental Health, University of Melbourne, said in an interview.
“These data should be factored into the decisions by clinicians when they consider prescribing antiamyloid therapies. Like any side effect, clinicians should inform patients regarding the risk of brain atrophy. Patients should be actively monitored for this side effect,” Dr. Ayton said.
The study was published online in Neurology.
Earlier progression from MCI to AD?
Dr. Ayton and colleagues evaluated brain volume changes in 31 clinical trials of anti–amyloid-beta drugs that demonstrated a favorable change in at least one biomarker of pathological amyloid-beta and included detailed MRI data sufficient to assess the volumetric changes in at least one brain region.
A meta-analysis on the highest dose in each trial on the hippocampus, ventricles, and whole brain showed drug-induced acceleration of volume changes that varied by anti–amyloid-beta drug class.
Secretase inhibitors accelerated atrophy in the hippocampus (mean difference –37.1 mcL; –19.6% relative to change in placebo) and whole brain (mean difference –3.3 mL; –21.8% relative to change in placebo), but not ventricles.
Conversely, monoclonal antibodies caused accelerated ventricular enlargement (mean difference +1.3 mL; +23.8% relative to change in placebo), which was driven by the subset of monoclonal antibodies that induce amyloid-related imaging abnormalities (ARIA) (+2.1 mL; +38.7% relative to change in placebo). There was a “striking correlation between ventricular volume and ARIA frequency,” the investigators reported.
The effect of ARIA-inducing monoclonal antibodies on whole brain volume varied, with accelerated whole brain volume loss caused by donanemab (mean difference –4.6 mL; +23% relative to change in placebo) and lecanemab (–5.2 mL; +36.4% relative to change in placebo). This was not observed with aducanumab and bapineuzumab.
Monoclonal antibodies did not cause accelerated volume loss to the hippocampus regardless of whether they caused ARIA.
The researchers also modeled the effect of anti–amyloid-beta drugs on brain volume changes. In this analysis, participants with mild cognitive impairment (MCI) treated with anti–amyloid-beta drugs were projected to have a “material regression” toward brain volumes typical of AD roughly 8 months earlier than untreated peers.
The data, they note, “permit robust conclusions regarding the effect of [anti–amyloid-beta] drug classes on different brain structures, but the lack of individual patient data (which has yet to be released) limits the interpretations of our findings.”
“Questions like which brain regions are impacted by [anti–amyloid-beta] drugs and whether the volume changes are related to ARIA, plaque loss, cognitive/noncognitive outcomes, or clinical factors such as age, sex, and apoE4 genotype can and should be addressed with available data,” said Dr. Ayton.
Dr. Ayton and colleagues called on data safety monitoring boards (DSMBs) for current clinical trials of anti–amyloid-beta drugs to review volumetric data to determine if patient safety is at risk, particularly in patients who develop ARIA.
In addition, they noted ethics boards that approve trials for anti–amyloid-beta drugs “should request that volume changes be actively monitored. Long-term follow-up of brain volumes should be factored into the trial designs to determine if brain atrophy is progressive, particularly in patients who develop ARIA.”
Finally, they added that drug companies that have conducted trials of anti–amyloid-beta drugs should interrogate prior data on brain volume, report the findings, and release the data for researchers to investigate.
“I have been banging on about this for years,” said Dr. Ayton. “Unfortunately, my raising of this issue has not led to any response. The data are not available, and the basic questions haven’t been asked (publicly).”
Commendable research
In an accompanying editorial, Frederik Barkhof, MD, PhD, with Amsterdam University Medical Centers, and David Knopman, MD, with Mayo Clinic Alzheimer’s Disease Research Center, Rochester, Minn., wrote that the investigators should be “commended” for their analysis.
“The reality in 2023 is that the relevance of brain volume reductions in this therapeutic context remains uncertain,” they wrote.
“Longer periods of observation will be needed to know whether the brain volume losses continue at an accelerated rate or if they attenuate or disappear. Ultimately, it’s the clinical outcomes that matter, regardless of the MRI changes,” Barkhof and Knopman concluded.
The research was supported by funds from the Australian National Health & Medical Research Council. Dr. Ayton reported being a consultant for Eisai in the past 3 years. Dr. Barkhof reported serving on the data and safety monitoring board for Prothena and the A45-AHEAD studies; being a steering committee member for Merck, Bayer, and Biogen; and being a consultant for IXICO, Roche, Celltrion, Rewind Therapeutics, and Combinostics. Dr. Knopman reported serving on the DSMB for the Dominantly Inherited Alzheimer Network Treatment Unit study; serving on a DSMB for a tau therapeutic for Biogen; being an investigator for clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. He reported consulting with Roche, Samus Therapeutics, Magellan Health, BioVie, and Alzeca Biosciences.
A version of this article first appeared on Medscape.com.
a comprehensive meta-analysis of MRI data from clinical trials suggests.
Depending on the anti–amyloid-beta drug class, these agents can accelerate loss of whole brain and hippocampal volume and increase ventricular volume. This has been shown for some of the beta-secretase inhibitors and with several of the antiamyloid monoclonal antibodies, researchers noted.
“These data warrant concern, but we can’t make any firm conclusions yet. It is possible that the finding is not detrimental, but the usual interpretation of this finding is that volume changes are a surrogate for disease progression,” study investigator Scott Ayton, PhD, of the Florey Institute of Neuroscience and Mental Health, University of Melbourne, said in an interview.
“These data should be factored into the decisions by clinicians when they consider prescribing antiamyloid therapies. Like any side effect, clinicians should inform patients regarding the risk of brain atrophy. Patients should be actively monitored for this side effect,” Dr. Ayton said.
The study was published online in Neurology.
Earlier progression from MCI to AD?
Dr. Ayton and colleagues evaluated brain volume changes in 31 clinical trials of anti–amyloid-beta drugs that demonstrated a favorable change in at least one biomarker of pathological amyloid-beta and included detailed MRI data sufficient to assess the volumetric changes in at least one brain region.
A meta-analysis on the highest dose in each trial on the hippocampus, ventricles, and whole brain showed drug-induced acceleration of volume changes that varied by anti–amyloid-beta drug class.
Secretase inhibitors accelerated atrophy in the hippocampus (mean difference –37.1 mcL; –19.6% relative to change in placebo) and whole brain (mean difference –3.3 mL; –21.8% relative to change in placebo), but not ventricles.
Conversely, monoclonal antibodies caused accelerated ventricular enlargement (mean difference +1.3 mL; +23.8% relative to change in placebo), which was driven by the subset of monoclonal antibodies that induce amyloid-related imaging abnormalities (ARIA) (+2.1 mL; +38.7% relative to change in placebo). There was a “striking correlation between ventricular volume and ARIA frequency,” the investigators reported.
The effect of ARIA-inducing monoclonal antibodies on whole brain volume varied, with accelerated whole brain volume loss caused by donanemab (mean difference –4.6 mL; +23% relative to change in placebo) and lecanemab (–5.2 mL; +36.4% relative to change in placebo). This was not observed with aducanumab and bapineuzumab.
Monoclonal antibodies did not cause accelerated volume loss to the hippocampus regardless of whether they caused ARIA.
The researchers also modeled the effect of anti–amyloid-beta drugs on brain volume changes. In this analysis, participants with mild cognitive impairment (MCI) treated with anti–amyloid-beta drugs were projected to have a “material regression” toward brain volumes typical of AD roughly 8 months earlier than untreated peers.
The data, they note, “permit robust conclusions regarding the effect of [anti–amyloid-beta] drug classes on different brain structures, but the lack of individual patient data (which has yet to be released) limits the interpretations of our findings.”
“Questions like which brain regions are impacted by [anti–amyloid-beta] drugs and whether the volume changes are related to ARIA, plaque loss, cognitive/noncognitive outcomes, or clinical factors such as age, sex, and apoE4 genotype can and should be addressed with available data,” said Dr. Ayton.
Dr. Ayton and colleagues called on data safety monitoring boards (DSMBs) for current clinical trials of anti–amyloid-beta drugs to review volumetric data to determine if patient safety is at risk, particularly in patients who develop ARIA.
In addition, they noted ethics boards that approve trials for anti–amyloid-beta drugs “should request that volume changes be actively monitored. Long-term follow-up of brain volumes should be factored into the trial designs to determine if brain atrophy is progressive, particularly in patients who develop ARIA.”
Finally, they added that drug companies that have conducted trials of anti–amyloid-beta drugs should interrogate prior data on brain volume, report the findings, and release the data for researchers to investigate.
“I have been banging on about this for years,” said Dr. Ayton. “Unfortunately, my raising of this issue has not led to any response. The data are not available, and the basic questions haven’t been asked (publicly).”
Commendable research
In an accompanying editorial, Frederik Barkhof, MD, PhD, with Amsterdam University Medical Centers, and David Knopman, MD, with Mayo Clinic Alzheimer’s Disease Research Center, Rochester, Minn., wrote that the investigators should be “commended” for their analysis.
“The reality in 2023 is that the relevance of brain volume reductions in this therapeutic context remains uncertain,” they wrote.
“Longer periods of observation will be needed to know whether the brain volume losses continue at an accelerated rate or if they attenuate or disappear. Ultimately, it’s the clinical outcomes that matter, regardless of the MRI changes,” Barkhof and Knopman concluded.
The research was supported by funds from the Australian National Health & Medical Research Council. Dr. Ayton reported being a consultant for Eisai in the past 3 years. Dr. Barkhof reported serving on the data and safety monitoring board for Prothena and the A45-AHEAD studies; being a steering committee member for Merck, Bayer, and Biogen; and being a consultant for IXICO, Roche, Celltrion, Rewind Therapeutics, and Combinostics. Dr. Knopman reported serving on the DSMB for the Dominantly Inherited Alzheimer Network Treatment Unit study; serving on a DSMB for a tau therapeutic for Biogen; being an investigator for clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. He reported consulting with Roche, Samus Therapeutics, Magellan Health, BioVie, and Alzeca Biosciences.
A version of this article first appeared on Medscape.com.
a comprehensive meta-analysis of MRI data from clinical trials suggests.
Depending on the anti–amyloid-beta drug class, these agents can accelerate loss of whole brain and hippocampal volume and increase ventricular volume. This has been shown for some of the beta-secretase inhibitors and with several of the antiamyloid monoclonal antibodies, researchers noted.
“These data warrant concern, but we can’t make any firm conclusions yet. It is possible that the finding is not detrimental, but the usual interpretation of this finding is that volume changes are a surrogate for disease progression,” study investigator Scott Ayton, PhD, of the Florey Institute of Neuroscience and Mental Health, University of Melbourne, said in an interview.
“These data should be factored into the decisions by clinicians when they consider prescribing antiamyloid therapies. Like any side effect, clinicians should inform patients regarding the risk of brain atrophy. Patients should be actively monitored for this side effect,” Dr. Ayton said.
The study was published online in Neurology.
Earlier progression from MCI to AD?
Dr. Ayton and colleagues evaluated brain volume changes in 31 clinical trials of anti–amyloid-beta drugs that demonstrated a favorable change in at least one biomarker of pathological amyloid-beta and included detailed MRI data sufficient to assess the volumetric changes in at least one brain region.
A meta-analysis on the highest dose in each trial on the hippocampus, ventricles, and whole brain showed drug-induced acceleration of volume changes that varied by anti–amyloid-beta drug class.
Secretase inhibitors accelerated atrophy in the hippocampus (mean difference –37.1 mcL; –19.6% relative to change in placebo) and whole brain (mean difference –3.3 mL; –21.8% relative to change in placebo), but not ventricles.
Conversely, monoclonal antibodies caused accelerated ventricular enlargement (mean difference +1.3 mL; +23.8% relative to change in placebo), which was driven by the subset of monoclonal antibodies that induce amyloid-related imaging abnormalities (ARIA) (+2.1 mL; +38.7% relative to change in placebo). There was a “striking correlation between ventricular volume and ARIA frequency,” the investigators reported.
The effect of ARIA-inducing monoclonal antibodies on whole brain volume varied, with accelerated whole brain volume loss caused by donanemab (mean difference –4.6 mL; +23% relative to change in placebo) and lecanemab (–5.2 mL; +36.4% relative to change in placebo). This was not observed with aducanumab and bapineuzumab.
Monoclonal antibodies did not cause accelerated volume loss to the hippocampus regardless of whether they caused ARIA.
The researchers also modeled the effect of anti–amyloid-beta drugs on brain volume changes. In this analysis, participants with mild cognitive impairment (MCI) treated with anti–amyloid-beta drugs were projected to have a “material regression” toward brain volumes typical of AD roughly 8 months earlier than untreated peers.
The data, they note, “permit robust conclusions regarding the effect of [anti–amyloid-beta] drug classes on different brain structures, but the lack of individual patient data (which has yet to be released) limits the interpretations of our findings.”
“Questions like which brain regions are impacted by [anti–amyloid-beta] drugs and whether the volume changes are related to ARIA, plaque loss, cognitive/noncognitive outcomes, or clinical factors such as age, sex, and apoE4 genotype can and should be addressed with available data,” said Dr. Ayton.
Dr. Ayton and colleagues called on data safety monitoring boards (DSMBs) for current clinical trials of anti–amyloid-beta drugs to review volumetric data to determine if patient safety is at risk, particularly in patients who develop ARIA.
In addition, they noted ethics boards that approve trials for anti–amyloid-beta drugs “should request that volume changes be actively monitored. Long-term follow-up of brain volumes should be factored into the trial designs to determine if brain atrophy is progressive, particularly in patients who develop ARIA.”
Finally, they added that drug companies that have conducted trials of anti–amyloid-beta drugs should interrogate prior data on brain volume, report the findings, and release the data for researchers to investigate.
“I have been banging on about this for years,” said Dr. Ayton. “Unfortunately, my raising of this issue has not led to any response. The data are not available, and the basic questions haven’t been asked (publicly).”
Commendable research
In an accompanying editorial, Frederik Barkhof, MD, PhD, with Amsterdam University Medical Centers, and David Knopman, MD, with Mayo Clinic Alzheimer’s Disease Research Center, Rochester, Minn., wrote that the investigators should be “commended” for their analysis.
“The reality in 2023 is that the relevance of brain volume reductions in this therapeutic context remains uncertain,” they wrote.
“Longer periods of observation will be needed to know whether the brain volume losses continue at an accelerated rate or if they attenuate or disappear. Ultimately, it’s the clinical outcomes that matter, regardless of the MRI changes,” Barkhof and Knopman concluded.
The research was supported by funds from the Australian National Health & Medical Research Council. Dr. Ayton reported being a consultant for Eisai in the past 3 years. Dr. Barkhof reported serving on the data and safety monitoring board for Prothena and the A45-AHEAD studies; being a steering committee member for Merck, Bayer, and Biogen; and being a consultant for IXICO, Roche, Celltrion, Rewind Therapeutics, and Combinostics. Dr. Knopman reported serving on the DSMB for the Dominantly Inherited Alzheimer Network Treatment Unit study; serving on a DSMB for a tau therapeutic for Biogen; being an investigator for clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. He reported consulting with Roche, Samus Therapeutics, Magellan Health, BioVie, and Alzeca Biosciences.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY