Neurology

DUBLIN – As healthcare systems across Europe deal with an increasing prevalence of cognitive impairment, family doctors are emerging as key players in assessing and supporting patients’ decision-making capacities. 

This was a central theme at the 29th WONCA Europe Conference, where the European Young Family Doctors Movement (EYFDM) presented insights from a project conducted across Europe, involving young general practitioners who participated in workshops held in multiple countries.

“Family doctors are the linchpin in these decisions,” said Alina Zidaru, MD, from the Irish College of Physicians, Dublin. “They understand the patient’s history, build long-term relationships, and are best positioned to ensure that decisions reflect the patient’s values, not just what the law or the family might say.”

Dr. Zidaru and her colleague, Nick Mamo, MD, member of EYFDM in Glasgow, Scotland, emphasized the central role family doctors play in ensuring that patient rights and preferences are respected, regardless of their cognitive state. They are often the first to identify cognitive impairments and must carefully navigate the legal and ethical landscape of decision-making support.

“Often, we focus too much on avoiding harm and overlook the principle of autonomy,” said Dr. Mamo. “But it’s essential to give patients the right to make their own decisions, even when those decisions might seem unwise to us.”
 

The Case of Jay

Dr. Zidaru said: “We’ve conducted workshops in Brussels, Vienna, and Sydney, focusing on how to build habits that support patients. We presented real-life cases, like Jay, a 43-year-old man with trisomy and a moderate intellectual disability who must decide whether to undergo surgery for a hernia. The most significant challenge was ensuring continuity of care and respecting his autonomy, despite cognitive limitations.”

Jay’s case illustrates the complex ethical dilemmas faced by family doctors when balancing autonomy with patient safety. In many cases, cognitive impairments raise concerns about whether a patient can make decisions independently. 

During the session, the audience was asked to share their thoughts on the case and to indicate whether they would allow Jay to make his own decision, and if they felt confident in assessing his cognitive capacity. The responses revealed a range of mixed feelings. 
 

Legal and Cultural Variations Across Europe

The session also explored how different European countries approach decision-making for cognitively impaired individuals. A clear divide exists between nations that give family members automatic decision-making rights and those that require legal appointments. 

In the United Kingdom, the Mental Capacity Act 2005 presumes capacity unless proven otherwise. Family doctors can assess patients’ decision-making abilities using any validated tool they find suitable. They should also aim to ensure that decisions are made in the patient’s best interests if they lack capacity. Family members only have legal authority if appointed through formal means, such as a lasting power of attorney.

In Spain and Italy, functional assessments are performed when patients retain decision-making authority in areas where they demonstrate competence. Legal guardianship can be appointed by the courts, sometimes limited to specific areas, but it is intended to support rather than replace the patient’s autonomy. 

In France and Portugal, guardianship may be implemented in specific domains, but the patient’s ability to participate in decisions is always prioritized. 

In Turkey, according to Turkish general practitioners in the audience, the courts and close family members often share the decision-making responsibility.

Dr. Zidaru added that Ireland’s Assisted Decision-Making (Capacity) Act 2015 introduced significant changes to how cognitive impairment is managed there. “Ireland adopted a standardized functional test of capacity, used by any doctor. A person can still make decisions as long as they understand, retain, and weigh the information needed to make that choice. If their capacity diminishes, a decision-making assistant, co–decision-maker, or representative can be appointed, but the patient’s will and preferences always come first.”
 

Family Doctors, a Growing Responsibility

“It’s not just about the legal framework: it’s about cultural awareness and early communication,” added Dr. Mamo. “We have to ask ourselves: Do patients have the right to make bad decisions? And how do we, as family doctors, respect that while still ensuring their safety?”

The session concluded with a discussion on how the role of family doctors in decision-making for cognitively impaired patients will evolve as populations age and the incidence of conditions like dementia increases. The workload is rising, and the need for clear, consistent guidelines is critical.

“Family doctors will continue to play a central role in managing these challenges,” Dr. Zidaru emphasized. “But we need more resources, more education, and more support to ensure we can respect patient autonomy without compromising their well-being.”

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

DUBLIN – As healthcare systems across Europe deal with an increasing prevalence of cognitive impairment, family doctors are emerging as key players in assessing and supporting patients’ decision-making capacities. 

This was a central theme at the 29th WONCA Europe Conference, where the European Young Family Doctors Movement (EYFDM) presented insights from a project conducted across Europe, involving young general practitioners who participated in workshops held in multiple countries.

“Family doctors are the linchpin in these decisions,” said Alina Zidaru, MD, from the Irish College of Physicians, Dublin. “They understand the patient’s history, build long-term relationships, and are best positioned to ensure that decisions reflect the patient’s values, not just what the law or the family might say.”

Dr. Zidaru and her colleague, Nick Mamo, MD, member of EYFDM in Glasgow, Scotland, emphasized the central role family doctors play in ensuring that patient rights and preferences are respected, regardless of their cognitive state. They are often the first to identify cognitive impairments and must carefully navigate the legal and ethical landscape of decision-making support.

“Often, we focus too much on avoiding harm and overlook the principle of autonomy,” said Dr. Mamo. “But it’s essential to give patients the right to make their own decisions, even when those decisions might seem unwise to us.”
 

The Case of Jay

Dr. Zidaru said: “We’ve conducted workshops in Brussels, Vienna, and Sydney, focusing on how to build habits that support patients. We presented real-life cases, like Jay, a 43-year-old man with trisomy and a moderate intellectual disability who must decide whether to undergo surgery for a hernia. The most significant challenge was ensuring continuity of care and respecting his autonomy, despite cognitive limitations.”

Jay’s case illustrates the complex ethical dilemmas faced by family doctors when balancing autonomy with patient safety. In many cases, cognitive impairments raise concerns about whether a patient can make decisions independently. 

During the session, the audience was asked to share their thoughts on the case and to indicate whether they would allow Jay to make his own decision, and if they felt confident in assessing his cognitive capacity. The responses revealed a range of mixed feelings. 
 

Legal and Cultural Variations Across Europe

The session also explored how different European countries approach decision-making for cognitively impaired individuals. A clear divide exists between nations that give family members automatic decision-making rights and those that require legal appointments. 

In the United Kingdom, the Mental Capacity Act 2005 presumes capacity unless proven otherwise. Family doctors can assess patients’ decision-making abilities using any validated tool they find suitable. They should also aim to ensure that decisions are made in the patient’s best interests if they lack capacity. Family members only have legal authority if appointed through formal means, such as a lasting power of attorney.

In Spain and Italy, functional assessments are performed when patients retain decision-making authority in areas where they demonstrate competence. Legal guardianship can be appointed by the courts, sometimes limited to specific areas, but it is intended to support rather than replace the patient’s autonomy. 

In France and Portugal, guardianship may be implemented in specific domains, but the patient’s ability to participate in decisions is always prioritized. 

In Turkey, according to Turkish general practitioners in the audience, the courts and close family members often share the decision-making responsibility.

Dr. Zidaru added that Ireland’s Assisted Decision-Making (Capacity) Act 2015 introduced significant changes to how cognitive impairment is managed there. “Ireland adopted a standardized functional test of capacity, used by any doctor. A person can still make decisions as long as they understand, retain, and weigh the information needed to make that choice. If their capacity diminishes, a decision-making assistant, co–decision-maker, or representative can be appointed, but the patient’s will and preferences always come first.”
 

Family Doctors, a Growing Responsibility

“It’s not just about the legal framework: it’s about cultural awareness and early communication,” added Dr. Mamo. “We have to ask ourselves: Do patients have the right to make bad decisions? And how do we, as family doctors, respect that while still ensuring their safety?”

The session concluded with a discussion on how the role of family doctors in decision-making for cognitively impaired patients will evolve as populations age and the incidence of conditions like dementia increases. The workload is rising, and the need for clear, consistent guidelines is critical.

“Family doctors will continue to play a central role in managing these challenges,” Dr. Zidaru emphasized. “But we need more resources, more education, and more support to ensure we can respect patient autonomy without compromising their well-being.”

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

DUBLIN – As healthcare systems across Europe deal with an increasing prevalence of cognitive impairment, family doctors are emerging as key players in assessing and supporting patients’ decision-making capacities. 

This was a central theme at the 29th WONCA Europe Conference, where the European Young Family Doctors Movement (EYFDM) presented insights from a project conducted across Europe, involving young general practitioners who participated in workshops held in multiple countries.

“Family doctors are the linchpin in these decisions,” said Alina Zidaru, MD, from the Irish College of Physicians, Dublin. “They understand the patient’s history, build long-term relationships, and are best positioned to ensure that decisions reflect the patient’s values, not just what the law or the family might say.”

Dr. Zidaru and her colleague, Nick Mamo, MD, member of EYFDM in Glasgow, Scotland, emphasized the central role family doctors play in ensuring that patient rights and preferences are respected, regardless of their cognitive state. They are often the first to identify cognitive impairments and must carefully navigate the legal and ethical landscape of decision-making support.

“Often, we focus too much on avoiding harm and overlook the principle of autonomy,” said Dr. Mamo. “But it’s essential to give patients the right to make their own decisions, even when those decisions might seem unwise to us.”
 

The Case of Jay

Dr. Zidaru said: “We’ve conducted workshops in Brussels, Vienna, and Sydney, focusing on how to build habits that support patients. We presented real-life cases, like Jay, a 43-year-old man with trisomy and a moderate intellectual disability who must decide whether to undergo surgery for a hernia. The most significant challenge was ensuring continuity of care and respecting his autonomy, despite cognitive limitations.”

Jay’s case illustrates the complex ethical dilemmas faced by family doctors when balancing autonomy with patient safety. In many cases, cognitive impairments raise concerns about whether a patient can make decisions independently. 

During the session, the audience was asked to share their thoughts on the case and to indicate whether they would allow Jay to make his own decision, and if they felt confident in assessing his cognitive capacity. The responses revealed a range of mixed feelings. 
 

Legal and Cultural Variations Across Europe

The session also explored how different European countries approach decision-making for cognitively impaired individuals. A clear divide exists between nations that give family members automatic decision-making rights and those that require legal appointments. 

In the United Kingdom, the Mental Capacity Act 2005 presumes capacity unless proven otherwise. Family doctors can assess patients’ decision-making abilities using any validated tool they find suitable. They should also aim to ensure that decisions are made in the patient’s best interests if they lack capacity. Family members only have legal authority if appointed through formal means, such as a lasting power of attorney.

In Spain and Italy, functional assessments are performed when patients retain decision-making authority in areas where they demonstrate competence. Legal guardianship can be appointed by the courts, sometimes limited to specific areas, but it is intended to support rather than replace the patient’s autonomy. 

In France and Portugal, guardianship may be implemented in specific domains, but the patient’s ability to participate in decisions is always prioritized. 

In Turkey, according to Turkish general practitioners in the audience, the courts and close family members often share the decision-making responsibility.

Dr. Zidaru added that Ireland’s Assisted Decision-Making (Capacity) Act 2015 introduced significant changes to how cognitive impairment is managed there. “Ireland adopted a standardized functional test of capacity, used by any doctor. A person can still make decisions as long as they understand, retain, and weigh the information needed to make that choice. If their capacity diminishes, a decision-making assistant, co–decision-maker, or representative can be appointed, but the patient’s will and preferences always come first.”
 

Family Doctors, a Growing Responsibility

“It’s not just about the legal framework: it’s about cultural awareness and early communication,” added Dr. Mamo. “We have to ask ourselves: Do patients have the right to make bad decisions? And how do we, as family doctors, respect that while still ensuring their safety?”

The session concluded with a discussion on how the role of family doctors in decision-making for cognitively impaired patients will evolve as populations age and the incidence of conditions like dementia increases. The workload is rising, and the need for clear, consistent guidelines is critical.

“Family doctors will continue to play a central role in managing these challenges,” Dr. Zidaru emphasized. “But we need more resources, more education, and more support to ensure we can respect patient autonomy without compromising their well-being.”

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

COPENHAGEN — Growing evidence supports the use of highly effective disease-modifying therapies for children with multiple sclerosis (MS). However, only few of these medications are licensed for pediatric use, indicating it may be time to reconsider the standard treatment approach for this patient population.

Treatments for pediatric-onset MS have mostly been used off-label until the recent approvals of fingolimod, dimethyl fumarate, and teriflunomide. Typically, children with MS start with moderately effective therapies, while more potent options are reserved for those who don’t respond.

However, recent research suggests this may not be the most effective treatment strategy for this patient population. Several studies suggesting impressive treatment responses to highly effective therapies (HETs) in children were presented at the 2024 ECTRIMS annual meeting.

In one study, initiating monoclonal antibody treatment during childhood was associated with reduced disability into early adulthood and beyond.

“Our findings are a strong argument for rethinking current treatment guidelines,” said study investigator Sifat Sharmin, PhD, The University of Melbourne, Australia.

“By allowing earlier access to highly effective treatments, we can significantly enhance the quality of life for children with MS and reduce the burden of long-term disability,” she added.

In another presentation, Yael Hacohen, MD, Great Ormond Street Hospital, London, England, noted that the use of these more effective monoclonal antibody therapies in children with MS has been associated with some improvements in Expanded Disability Status Scale (EDSS) scores after 2 or 3 years of treatment.

Maybe this is a sign that “this is a population that can repair, in contrast to adult patients,” she wondered.

MS is primarily a disease of adults, but pediatric MS accounts for up to 5% of all cases. Children with MS tend to have much more active disease than adults, Dr. Hacohen explained. However, they also tend to recover from attacks more quickly with little disability, which sometimes causes diagnostic delays.

A pediatrician or family doctor will often dismiss pins and needles or blurred vision that only lasts a couple of days and won’t send the patient for an MRI, she said. But on MRI, pediatric patients with MS often have multiple lesions, even though they may have had very few symptoms. The EDSS may not change very much, but there can still be significant brain atrophy.

Over the past 20 years, there’s been an explosion of new disease-modifying treatments for MS, but these high-efficacy treatments, such as antibody therapies, are often not prescribed until the patient reaches the age of 18 years, both Dr. Sharmin and Dr. Hacohen pointed out.

“We need to get some of these medications approved for use in children,” Dr. Hacohen said.
 

Slowed Disability

In her presentation, Dr. Sharmin reported an observational study that included 282 patients younger than 18 years at MS onset identified from the French MS Registry, the Italian MS Register, and the Global MSBase Registry.

Of these, 110 (39%) had initiated therapy with ocrelizumab, rituximab, or natalizumab early in the disease course between ages 12 and 17 years and 172 (61%) had initiated treatment with one of these agents at ages 20-22 years.

The primary outcome was the difference in EDSS scores from baseline (at age 18 years) to ages 23-27 years between those who had started treatment with one of these agents early and those who had started late.

At the baseline of age 18 years, the median EDSS score was 1.5 in the early group and 1.3 in the late group. Median follow-up time was 10.8 years.

The data were adjusted for baseline differences in factors such as sex, age at symptom onset, time from onset to clinically definite MS, and the number of relapses (using inverse probability treatment weighting based on propensity scores).

Results showed that between ages 23 and 27 years, disability was a 0.57 step lower in the early group than in the late group. The mean absolute differences in EDSS from baseline were 0.40 in the early group and 0.95 in the late group. This benefit of early treatment persisted throughout the rest of the follow-up period.

The substantially lower risk of progressing to higher disability levels in the early treatment group was particularly evident in the moderate disability range, where further progression was reduced by up to 97%, Dr. Sharmin noted.

“Starting these highly effective therapies, before the onset of significant neurological impairments, appears crucial for preserving neurological function in children with relapsing-remitting MS over the long term,” she said.

These findings highlight the critical importance of early intervention in pediatric-onset MS, she concluded.

The researchers are planning further work to generate more evidence to support the proactive treatment of pediatric-onset MS, with a particular focus on assessing the long-term risks for immunosuppressive therapies in this population.
 

Ocrelizumab Experience in Children

Dr. Hacohen reported on a UK cohort of children with MS treated with ocrelizumab, with 66 patients having more than 12 months of follow-up. Of these, only four patients had relapses, and there was no evidence of disease activity in 94% patients.

“We’ve stopped doing relapse clinic because they really don’t relapse,” Dr. Hacohen reported.

“This has completely changed our practice in pediatric MS,” she said. Twice a year, patients come in to have pre-infusion bloods and clinical assessments and then return a month later for treatment.

“They only have to come to the hospital for 4 days a year, and the rest of the time, they can forget they have MS,” said Dr. Hacohen.

In terms of complications, one patient in the UK cohort developed enterovirus meningitis but recovered completely, and two patients had hypogammaglobulinemia and were changed to an extended interval or to a different agent.

Dr. Hacohen cautioned that hypogammaglobulinemia — a condition in which immunoglobulin levels are below normal — is “something that hypothetically we should maybe be more worried about in the pediatric population, particularly as these patients are more likely to be on anti-CD20 therapies for a much longer time.”

She said this complication tends to happen after about 4 or 5 years of treatment. “If we start seeing IgG levels dropping, we need to come up with a plan about extending the dosing interval. We need clinical trials to look at this.”

Dr. Hacohen also drew attention to the issue of vaccinations not being effective in patients on anti-CD20 antibody therapy, which could be a particular problem in children.

However, given that vaccinations do seem to be effective in patients taking natalizumab, pediatric patients with highly active disease could receive the drug for 3-6 months while receiving vaccines and then switched over to ocrelizumab, she said.

Giving natalizumab for such a short period is not believed to have a high risk of developing JCV antibodies, she added.

In another presentation, Brenda Banwell, MD, Johns Hopkins Children’s Center, Baltimore, reported new data from an early study (OPERETTA 1) with ocrelizumab in pediatric relapsing-remitting MS showing a safety profile similar to that observed in adults. The suggested dose is 300 mg for children under 35 kg and 600 mg for adults over 35 kg, administered every 24 weeks. These doses will be further investigated in the ongoing phase III OPERETTA 2 trial.

Dr. Sharmin received a postdoctoral fellowship from MS Australia. The OPERETTA studies were sponsored by F. Hoffmann-La Roche. Dr. Banwell served as a consultant to Roche. Dr. Hacohen reported no relevant disclosures.
 

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

COPENHAGEN — Growing evidence supports the use of highly effective disease-modifying therapies for children with multiple sclerosis (MS). However, only few of these medications are licensed for pediatric use, indicating it may be time to reconsider the standard treatment approach for this patient population.

Treatments for pediatric-onset MS have mostly been used off-label until the recent approvals of fingolimod, dimethyl fumarate, and teriflunomide. Typically, children with MS start with moderately effective therapies, while more potent options are reserved for those who don’t respond.

However, recent research suggests this may not be the most effective treatment strategy for this patient population. Several studies suggesting impressive treatment responses to highly effective therapies (HETs) in children were presented at the 2024 ECTRIMS annual meeting.

In one study, initiating monoclonal antibody treatment during childhood was associated with reduced disability into early adulthood and beyond.

“Our findings are a strong argument for rethinking current treatment guidelines,” said study investigator Sifat Sharmin, PhD, The University of Melbourne, Australia.

“By allowing earlier access to highly effective treatments, we can significantly enhance the quality of life for children with MS and reduce the burden of long-term disability,” she added.

In another presentation, Yael Hacohen, MD, Great Ormond Street Hospital, London, England, noted that the use of these more effective monoclonal antibody therapies in children with MS has been associated with some improvements in Expanded Disability Status Scale (EDSS) scores after 2 or 3 years of treatment.

Maybe this is a sign that “this is a population that can repair, in contrast to adult patients,” she wondered.

MS is primarily a disease of adults, but pediatric MS accounts for up to 5% of all cases. Children with MS tend to have much more active disease than adults, Dr. Hacohen explained. However, they also tend to recover from attacks more quickly with little disability, which sometimes causes diagnostic delays.

A pediatrician or family doctor will often dismiss pins and needles or blurred vision that only lasts a couple of days and won’t send the patient for an MRI, she said. But on MRI, pediatric patients with MS often have multiple lesions, even though they may have had very few symptoms. The EDSS may not change very much, but there can still be significant brain atrophy.

Over the past 20 years, there’s been an explosion of new disease-modifying treatments for MS, but these high-efficacy treatments, such as antibody therapies, are often not prescribed until the patient reaches the age of 18 years, both Dr. Sharmin and Dr. Hacohen pointed out.

“We need to get some of these medications approved for use in children,” Dr. Hacohen said.
 

Slowed Disability

In her presentation, Dr. Sharmin reported an observational study that included 282 patients younger than 18 years at MS onset identified from the French MS Registry, the Italian MS Register, and the Global MSBase Registry.

Of these, 110 (39%) had initiated therapy with ocrelizumab, rituximab, or natalizumab early in the disease course between ages 12 and 17 years and 172 (61%) had initiated treatment with one of these agents at ages 20-22 years.

The primary outcome was the difference in EDSS scores from baseline (at age 18 years) to ages 23-27 years between those who had started treatment with one of these agents early and those who had started late.

At the baseline of age 18 years, the median EDSS score was 1.5 in the early group and 1.3 in the late group. Median follow-up time was 10.8 years.

The data were adjusted for baseline differences in factors such as sex, age at symptom onset, time from onset to clinically definite MS, and the number of relapses (using inverse probability treatment weighting based on propensity scores).

Results showed that between ages 23 and 27 years, disability was a 0.57 step lower in the early group than in the late group. The mean absolute differences in EDSS from baseline were 0.40 in the early group and 0.95 in the late group. This benefit of early treatment persisted throughout the rest of the follow-up period.

The substantially lower risk of progressing to higher disability levels in the early treatment group was particularly evident in the moderate disability range, where further progression was reduced by up to 97%, Dr. Sharmin noted.

“Starting these highly effective therapies, before the onset of significant neurological impairments, appears crucial for preserving neurological function in children with relapsing-remitting MS over the long term,” she said.

These findings highlight the critical importance of early intervention in pediatric-onset MS, she concluded.

The researchers are planning further work to generate more evidence to support the proactive treatment of pediatric-onset MS, with a particular focus on assessing the long-term risks for immunosuppressive therapies in this population.
 

Ocrelizumab Experience in Children

Dr. Hacohen reported on a UK cohort of children with MS treated with ocrelizumab, with 66 patients having more than 12 months of follow-up. Of these, only four patients had relapses, and there was no evidence of disease activity in 94% patients.

“We’ve stopped doing relapse clinic because they really don’t relapse,” Dr. Hacohen reported.

“This has completely changed our practice in pediatric MS,” she said. Twice a year, patients come in to have pre-infusion bloods and clinical assessments and then return a month later for treatment.

“They only have to come to the hospital for 4 days a year, and the rest of the time, they can forget they have MS,” said Dr. Hacohen.

In terms of complications, one patient in the UK cohort developed enterovirus meningitis but recovered completely, and two patients had hypogammaglobulinemia and were changed to an extended interval or to a different agent.

Dr. Hacohen cautioned that hypogammaglobulinemia — a condition in which immunoglobulin levels are below normal — is “something that hypothetically we should maybe be more worried about in the pediatric population, particularly as these patients are more likely to be on anti-CD20 therapies for a much longer time.”

She said this complication tends to happen after about 4 or 5 years of treatment. “If we start seeing IgG levels dropping, we need to come up with a plan about extending the dosing interval. We need clinical trials to look at this.”

Dr. Hacohen also drew attention to the issue of vaccinations not being effective in patients on anti-CD20 antibody therapy, which could be a particular problem in children.

However, given that vaccinations do seem to be effective in patients taking natalizumab, pediatric patients with highly active disease could receive the drug for 3-6 months while receiving vaccines and then switched over to ocrelizumab, she said.

Giving natalizumab for such a short period is not believed to have a high risk of developing JCV antibodies, she added.

In another presentation, Brenda Banwell, MD, Johns Hopkins Children’s Center, Baltimore, reported new data from an early study (OPERETTA 1) with ocrelizumab in pediatric relapsing-remitting MS showing a safety profile similar to that observed in adults. The suggested dose is 300 mg for children under 35 kg and 600 mg for adults over 35 kg, administered every 24 weeks. These doses will be further investigated in the ongoing phase III OPERETTA 2 trial.

Dr. Sharmin received a postdoctoral fellowship from MS Australia. The OPERETTA studies were sponsored by F. Hoffmann-La Roche. Dr. Banwell served as a consultant to Roche. Dr. Hacohen reported no relevant disclosures.
 

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

COPENHAGEN — Growing evidence supports the use of highly effective disease-modifying therapies for children with multiple sclerosis (MS). However, only few of these medications are licensed for pediatric use, indicating it may be time to reconsider the standard treatment approach for this patient population.

Treatments for pediatric-onset MS have mostly been used off-label until the recent approvals of fingolimod, dimethyl fumarate, and teriflunomide. Typically, children with MS start with moderately effective therapies, while more potent options are reserved for those who don’t respond.

However, recent research suggests this may not be the most effective treatment strategy for this patient population. Several studies suggesting impressive treatment responses to highly effective therapies (HETs) in children were presented at the 2024 ECTRIMS annual meeting.

In one study, initiating monoclonal antibody treatment during childhood was associated with reduced disability into early adulthood and beyond.

“Our findings are a strong argument for rethinking current treatment guidelines,” said study investigator Sifat Sharmin, PhD, The University of Melbourne, Australia.

“By allowing earlier access to highly effective treatments, we can significantly enhance the quality of life for children with MS and reduce the burden of long-term disability,” she added.

In another presentation, Yael Hacohen, MD, Great Ormond Street Hospital, London, England, noted that the use of these more effective monoclonal antibody therapies in children with MS has been associated with some improvements in Expanded Disability Status Scale (EDSS) scores after 2 or 3 years of treatment.

Maybe this is a sign that “this is a population that can repair, in contrast to adult patients,” she wondered.

MS is primarily a disease of adults, but pediatric MS accounts for up to 5% of all cases. Children with MS tend to have much more active disease than adults, Dr. Hacohen explained. However, they also tend to recover from attacks more quickly with little disability, which sometimes causes diagnostic delays.

A pediatrician or family doctor will often dismiss pins and needles or blurred vision that only lasts a couple of days and won’t send the patient for an MRI, she said. But on MRI, pediatric patients with MS often have multiple lesions, even though they may have had very few symptoms. The EDSS may not change very much, but there can still be significant brain atrophy.

Over the past 20 years, there’s been an explosion of new disease-modifying treatments for MS, but these high-efficacy treatments, such as antibody therapies, are often not prescribed until the patient reaches the age of 18 years, both Dr. Sharmin and Dr. Hacohen pointed out.

“We need to get some of these medications approved for use in children,” Dr. Hacohen said.
 

Slowed Disability

In her presentation, Dr. Sharmin reported an observational study that included 282 patients younger than 18 years at MS onset identified from the French MS Registry, the Italian MS Register, and the Global MSBase Registry.

Of these, 110 (39%) had initiated therapy with ocrelizumab, rituximab, or natalizumab early in the disease course between ages 12 and 17 years and 172 (61%) had initiated treatment with one of these agents at ages 20-22 years.

The primary outcome was the difference in EDSS scores from baseline (at age 18 years) to ages 23-27 years between those who had started treatment with one of these agents early and those who had started late.

At the baseline of age 18 years, the median EDSS score was 1.5 in the early group and 1.3 in the late group. Median follow-up time was 10.8 years.

The data were adjusted for baseline differences in factors such as sex, age at symptom onset, time from onset to clinically definite MS, and the number of relapses (using inverse probability treatment weighting based on propensity scores).

Results showed that between ages 23 and 27 years, disability was a 0.57 step lower in the early group than in the late group. The mean absolute differences in EDSS from baseline were 0.40 in the early group and 0.95 in the late group. This benefit of early treatment persisted throughout the rest of the follow-up period.

The substantially lower risk of progressing to higher disability levels in the early treatment group was particularly evident in the moderate disability range, where further progression was reduced by up to 97%, Dr. Sharmin noted.

“Starting these highly effective therapies, before the onset of significant neurological impairments, appears crucial for preserving neurological function in children with relapsing-remitting MS over the long term,” she said.

These findings highlight the critical importance of early intervention in pediatric-onset MS, she concluded.

The researchers are planning further work to generate more evidence to support the proactive treatment of pediatric-onset MS, with a particular focus on assessing the long-term risks for immunosuppressive therapies in this population.
 

Ocrelizumab Experience in Children

Dr. Hacohen reported on a UK cohort of children with MS treated with ocrelizumab, with 66 patients having more than 12 months of follow-up. Of these, only four patients had relapses, and there was no evidence of disease activity in 94% patients.

“We’ve stopped doing relapse clinic because they really don’t relapse,” Dr. Hacohen reported.

“This has completely changed our practice in pediatric MS,” she said. Twice a year, patients come in to have pre-infusion bloods and clinical assessments and then return a month later for treatment.

“They only have to come to the hospital for 4 days a year, and the rest of the time, they can forget they have MS,” said Dr. Hacohen.

In terms of complications, one patient in the UK cohort developed enterovirus meningitis but recovered completely, and two patients had hypogammaglobulinemia and were changed to an extended interval or to a different agent.

Dr. Hacohen cautioned that hypogammaglobulinemia — a condition in which immunoglobulin levels are below normal — is “something that hypothetically we should maybe be more worried about in the pediatric population, particularly as these patients are more likely to be on anti-CD20 therapies for a much longer time.”

She said this complication tends to happen after about 4 or 5 years of treatment. “If we start seeing IgG levels dropping, we need to come up with a plan about extending the dosing interval. We need clinical trials to look at this.”

Dr. Hacohen also drew attention to the issue of vaccinations not being effective in patients on anti-CD20 antibody therapy, which could be a particular problem in children.

However, given that vaccinations do seem to be effective in patients taking natalizumab, pediatric patients with highly active disease could receive the drug for 3-6 months while receiving vaccines and then switched over to ocrelizumab, she said.

Giving natalizumab for such a short period is not believed to have a high risk of developing JCV antibodies, she added.

In another presentation, Brenda Banwell, MD, Johns Hopkins Children’s Center, Baltimore, reported new data from an early study (OPERETTA 1) with ocrelizumab in pediatric relapsing-remitting MS showing a safety profile similar to that observed in adults. The suggested dose is 300 mg for children under 35 kg and 600 mg for adults over 35 kg, administered every 24 weeks. These doses will be further investigated in the ongoing phase III OPERETTA 2 trial.

Dr. Sharmin received a postdoctoral fellowship from MS Australia. The OPERETTA studies were sponsored by F. Hoffmann-La Roche. Dr. Banwell served as a consultant to Roche. Dr. Hacohen reported no relevant disclosures.
 

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

PHILADELPHIA — The investigational agent ecopipam reduces tic severity in children and adolescents with Tourette syndrome without exacerbating common psychiatric comorbidities, results of a new analysis suggest.

As previously reported, the first-in-class dopamine-1 (D1) receptor antagonist reduced the primary endpoint of tic severity scores by 30% compared with placebo among 149 patients in the 12-week, phase 2b D1AMOND trial. 

What was unknown, however, is whether ecopipam would affect the comorbidities of attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder (OCD), and depression that were present in two thirds of participants.

The two key findings in this post hoc analysis were “first, that patients with a nonmotor diagnosis like depression or ADHD did not do any worse in terms of tic efficacy; and second, we didn’t find any evidence that any of the nonmotor symptoms of Tourette’s got worse with ecopipam,” said study investigator Donald Gilbert, MD, professor of pediatrics and neurology at University of Cincinnati Children’s Hospital Medical Center.

Dr. Gilbert presented the results at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024. 
 

No Worsening of ADHD Symptoms

Tourette syndrome affects approximately 1 in 160 children between 5 and 17 years of age in the United States, data from the Tourette Association of America show. Research has shown that 85% of patients with Tourette syndrome will have a co-occurring psychiatric condition. 

Guidelines recommend Comprehensive Behavioral Intervention for Tics (CBIT) as first-line treatment for Tourette syndrome, but cost and access are barriers. The only currently approved medications to treat Tourette syndrome are antipsychotics that act on the D2 receptor, but their use is limited by the potential for weight gain, metabolic changes, drug-induced movement disorders, and risk for suicidality, said Dr. Gilbert. 

The D1AMOND study randomly assigned patients aged 6-17 years with Tourette syndrome and a Yale Global Tic Severity Total Tic Scale score of at least 20 to receive a target steady-state dose of 2 mg/kg/d of oral ecopipam or placebo for a 4-week titration period, followed by an 8-week treatment phase before being tapered off the study drug. 

Patients were allowed to remain on medications without D2-receptor blocking activity for anxiety, OCD, and ADHD if the dosage was stable for 4 weeks before screening and not specifically prescribed for tics. 

A mixed model for repeated measures was used to assess changes in several scales administered at baseline and at weeks 4, 6, 8, and 12: the Swanson, Nolan, and Pelham Teacher and Parent Rating Scale (SNAP-IV); Pediatric Anxiety Rating Scale; Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), and Children’s Depression Rating Scale–Revised (CDRS-R). 

In patients with a co-occurring psychiatric condition, no significant differences were found over time between ecopipam and placebo in terms of SNAP-IV (-4.4; P = .45), Pediatric Anxiety Rating Scale (1.0; P = .62), CDRS-R (-3.2; P = .65), or CY-BOCS (-0.7; P = .76) scores.

For ADHD, the most frequent comorbidity, scores trended lower in the ecopipam group but were not significantly different from those in the placebo group. “We found no evidence that ecopipam worsened ADHD symptoms,” Dr. Gilbert said.
 

No Weight Gain

Suicidal ideation was reported during the dosing period in eight patients in the placebo group and none in the ecopipam group. One patient treated with ecopipam had multiple depressive episodes and dropped out of the study on day 79. Ecopipam was discontinued in another patient because of anxiety. 

Notably, there was more weight gain in the placebo group than in the ecopipam group (2.4 kg vs 1.8 kg) by 12 weeks. No shifts from baseline were seen in blood glucose, A1c, total cholesterol, or triglycerides in either group. 

The lack of weight gain with ecopipam is important, Dr. Gilbert stressed. “Medicines that block D2 so often cause weight gain, and a lot of our patients, unfortunately, can be heavier already,” he explained. “We don’t want to make that worse or put them at a long-term risk of type 2 diabetes.”  

For patients with more severe disease, we really “do need something else besides D2-blockers in our tool kit,” he added. 

Commenting on the study, Tanya Simuni, MD, co-moderator of the session and director of the Parkinson’s Disease and Movement Disorders Center, Northwestern Feinberg School of Medicine, Chicago, said the aim of assessing D1-directed medications is to reduce the negative impact of traditional antipsychotics with a theoretical benefit on hyperkinetic movement.

But the most important thing that they’ve shown is that “there was no negative effect, no liability for the nonmotor manifestations of Tourette’s. That is important because Tourette’s is not a pure motor syndrome, and psychiatric manifestations in a lot of cases are associated with more disease-related quality of life impairment compared to the motor manifestations,” said Dr. Simuni.

That said, she noted, the “ideal drug would be the one that would have benefit for both motor and nonmotor domains.” 
 

Multiple Agents in the Pipeline 

“The neuropharmacology of Tourette syndrome has long remained stagnant, and most existing treatments often fail to balance efficacy with tolerability, underscoring the urgent need for newer therapeutics,” Christos Ganos, MD, professor of neurology, University of Toronto, said in a press release.

He noted that three studies have been published on ecopipam since 2014: an 8-week, open-label trial in adults with Tourette syndrome, a 4-week, placebo-controlled crossover trial in 38 children with Tourette syndrome, and the 12-week D1AMOND trial.

“These studies demonstrated clinically meaningful reductions in tics, without relevant safety concerns or changes in Tourette syndrome-typical neuropsychiatric measures, as also shown by the abstract highlighted here,” Dr. Ganos said. 

“This emerging body of research provides a solid foundation for introducing ecopipam as a novel pharmacological agent to treat tics and may motivate further work, both on the pathophysiology and pharmacotherapy of tic disorders and their associations.”

A single-arm, phase 3 trial is currently underway at 58 centers in North America and Europe investigating the long-term safety and tolerability of ecopipam over 24 months in 150 children, adolescents, and adults with Tourette syndrome. The study is expected to be completed in 2027.

Several other new medications are also under investigation including the vesicular monoamine transporter (VMAT2) inhibitors tetrabenazine, deutetrabenazine, and valbenazine; the PEDE10A inhibitor gemlapodect; the allopregnanolone antagonist sepranolone; and SCI-110, which combines dronabinol (the synthetic form of tetrahydrocannabinol) and the endocannabinoid palmitoylethanolamide.

The study was funded by Emalex Biosciences. Dr. Gilbert’s institution received research support from Emalex Biosciences and PTC Therapeutics. Dr. Gilbert has received publishing royalties from a healthcare-related publication; compensation for serving as a medical expert with Teladoc; Advanced Medical; and the National Vaccine Injury Compensation Program, US Department of Health and Human Services. Simuni reports no relevant conflicts of interest. Dr. Ganos has received honoraria for educational activities from the Movement Disorder Society and academic research support from VolkswagenStiftung. 
 

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

PHILADELPHIA — The investigational agent ecopipam reduces tic severity in children and adolescents with Tourette syndrome without exacerbating common psychiatric comorbidities, results of a new analysis suggest.

As previously reported, the first-in-class dopamine-1 (D1) receptor antagonist reduced the primary endpoint of tic severity scores by 30% compared with placebo among 149 patients in the 12-week, phase 2b D1AMOND trial. 

What was unknown, however, is whether ecopipam would affect the comorbidities of attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder (OCD), and depression that were present in two thirds of participants.

The two key findings in this post hoc analysis were “first, that patients with a nonmotor diagnosis like depression or ADHD did not do any worse in terms of tic efficacy; and second, we didn’t find any evidence that any of the nonmotor symptoms of Tourette’s got worse with ecopipam,” said study investigator Donald Gilbert, MD, professor of pediatrics and neurology at University of Cincinnati Children’s Hospital Medical Center.

Dr. Gilbert presented the results at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024. 
 

No Worsening of ADHD Symptoms

Tourette syndrome affects approximately 1 in 160 children between 5 and 17 years of age in the United States, data from the Tourette Association of America show. Research has shown that 85% of patients with Tourette syndrome will have a co-occurring psychiatric condition. 

Guidelines recommend Comprehensive Behavioral Intervention for Tics (CBIT) as first-line treatment for Tourette syndrome, but cost and access are barriers. The only currently approved medications to treat Tourette syndrome are antipsychotics that act on the D2 receptor, but their use is limited by the potential for weight gain, metabolic changes, drug-induced movement disorders, and risk for suicidality, said Dr. Gilbert. 

The D1AMOND study randomly assigned patients aged 6-17 years with Tourette syndrome and a Yale Global Tic Severity Total Tic Scale score of at least 20 to receive a target steady-state dose of 2 mg/kg/d of oral ecopipam or placebo for a 4-week titration period, followed by an 8-week treatment phase before being tapered off the study drug. 

Patients were allowed to remain on medications without D2-receptor blocking activity for anxiety, OCD, and ADHD if the dosage was stable for 4 weeks before screening and not specifically prescribed for tics. 

A mixed model for repeated measures was used to assess changes in several scales administered at baseline and at weeks 4, 6, 8, and 12: the Swanson, Nolan, and Pelham Teacher and Parent Rating Scale (SNAP-IV); Pediatric Anxiety Rating Scale; Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), and Children’s Depression Rating Scale–Revised (CDRS-R). 

In patients with a co-occurring psychiatric condition, no significant differences were found over time between ecopipam and placebo in terms of SNAP-IV (-4.4; P = .45), Pediatric Anxiety Rating Scale (1.0; P = .62), CDRS-R (-3.2; P = .65), or CY-BOCS (-0.7; P = .76) scores.

For ADHD, the most frequent comorbidity, scores trended lower in the ecopipam group but were not significantly different from those in the placebo group. “We found no evidence that ecopipam worsened ADHD symptoms,” Dr. Gilbert said.
 

No Weight Gain

Suicidal ideation was reported during the dosing period in eight patients in the placebo group and none in the ecopipam group. One patient treated with ecopipam had multiple depressive episodes and dropped out of the study on day 79. Ecopipam was discontinued in another patient because of anxiety. 

Notably, there was more weight gain in the placebo group than in the ecopipam group (2.4 kg vs 1.8 kg) by 12 weeks. No shifts from baseline were seen in blood glucose, A1c, total cholesterol, or triglycerides in either group. 

The lack of weight gain with ecopipam is important, Dr. Gilbert stressed. “Medicines that block D2 so often cause weight gain, and a lot of our patients, unfortunately, can be heavier already,” he explained. “We don’t want to make that worse or put them at a long-term risk of type 2 diabetes.”  

For patients with more severe disease, we really “do need something else besides D2-blockers in our tool kit,” he added. 

Commenting on the study, Tanya Simuni, MD, co-moderator of the session and director of the Parkinson’s Disease and Movement Disorders Center, Northwestern Feinberg School of Medicine, Chicago, said the aim of assessing D1-directed medications is to reduce the negative impact of traditional antipsychotics with a theoretical benefit on hyperkinetic movement.

But the most important thing that they’ve shown is that “there was no negative effect, no liability for the nonmotor manifestations of Tourette’s. That is important because Tourette’s is not a pure motor syndrome, and psychiatric manifestations in a lot of cases are associated with more disease-related quality of life impairment compared to the motor manifestations,” said Dr. Simuni.

That said, she noted, the “ideal drug would be the one that would have benefit for both motor and nonmotor domains.” 
 

Multiple Agents in the Pipeline 

“The neuropharmacology of Tourette syndrome has long remained stagnant, and most existing treatments often fail to balance efficacy with tolerability, underscoring the urgent need for newer therapeutics,” Christos Ganos, MD, professor of neurology, University of Toronto, said in a press release.

He noted that three studies have been published on ecopipam since 2014: an 8-week, open-label trial in adults with Tourette syndrome, a 4-week, placebo-controlled crossover trial in 38 children with Tourette syndrome, and the 12-week D1AMOND trial.

“These studies demonstrated clinically meaningful reductions in tics, without relevant safety concerns or changes in Tourette syndrome-typical neuropsychiatric measures, as also shown by the abstract highlighted here,” Dr. Ganos said. 

“This emerging body of research provides a solid foundation for introducing ecopipam as a novel pharmacological agent to treat tics and may motivate further work, both on the pathophysiology and pharmacotherapy of tic disorders and their associations.”

A single-arm, phase 3 trial is currently underway at 58 centers in North America and Europe investigating the long-term safety and tolerability of ecopipam over 24 months in 150 children, adolescents, and adults with Tourette syndrome. The study is expected to be completed in 2027.

Several other new medications are also under investigation including the vesicular monoamine transporter (VMAT2) inhibitors tetrabenazine, deutetrabenazine, and valbenazine; the PEDE10A inhibitor gemlapodect; the allopregnanolone antagonist sepranolone; and SCI-110, which combines dronabinol (the synthetic form of tetrahydrocannabinol) and the endocannabinoid palmitoylethanolamide.

The study was funded by Emalex Biosciences. Dr. Gilbert’s institution received research support from Emalex Biosciences and PTC Therapeutics. Dr. Gilbert has received publishing royalties from a healthcare-related publication; compensation for serving as a medical expert with Teladoc; Advanced Medical; and the National Vaccine Injury Compensation Program, US Department of Health and Human Services. Simuni reports no relevant conflicts of interest. Dr. Ganos has received honoraria for educational activities from the Movement Disorder Society and academic research support from VolkswagenStiftung. 
 

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

PHILADELPHIA — The investigational agent ecopipam reduces tic severity in children and adolescents with Tourette syndrome without exacerbating common psychiatric comorbidities, results of a new analysis suggest.

As previously reported, the first-in-class dopamine-1 (D1) receptor antagonist reduced the primary endpoint of tic severity scores by 30% compared with placebo among 149 patients in the 12-week, phase 2b D1AMOND trial. 

What was unknown, however, is whether ecopipam would affect the comorbidities of attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder (OCD), and depression that were present in two thirds of participants.

The two key findings in this post hoc analysis were “first, that patients with a nonmotor diagnosis like depression or ADHD did not do any worse in terms of tic efficacy; and second, we didn’t find any evidence that any of the nonmotor symptoms of Tourette’s got worse with ecopipam,” said study investigator Donald Gilbert, MD, professor of pediatrics and neurology at University of Cincinnati Children’s Hospital Medical Center.

Dr. Gilbert presented the results at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024. 
 

No Worsening of ADHD Symptoms

Tourette syndrome affects approximately 1 in 160 children between 5 and 17 years of age in the United States, data from the Tourette Association of America show. Research has shown that 85% of patients with Tourette syndrome will have a co-occurring psychiatric condition. 

Guidelines recommend Comprehensive Behavioral Intervention for Tics (CBIT) as first-line treatment for Tourette syndrome, but cost and access are barriers. The only currently approved medications to treat Tourette syndrome are antipsychotics that act on the D2 receptor, but their use is limited by the potential for weight gain, metabolic changes, drug-induced movement disorders, and risk for suicidality, said Dr. Gilbert. 

The D1AMOND study randomly assigned patients aged 6-17 years with Tourette syndrome and a Yale Global Tic Severity Total Tic Scale score of at least 20 to receive a target steady-state dose of 2 mg/kg/d of oral ecopipam or placebo for a 4-week titration period, followed by an 8-week treatment phase before being tapered off the study drug. 

Patients were allowed to remain on medications without D2-receptor blocking activity for anxiety, OCD, and ADHD if the dosage was stable for 4 weeks before screening and not specifically prescribed for tics. 

A mixed model for repeated measures was used to assess changes in several scales administered at baseline and at weeks 4, 6, 8, and 12: the Swanson, Nolan, and Pelham Teacher and Parent Rating Scale (SNAP-IV); Pediatric Anxiety Rating Scale; Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), and Children’s Depression Rating Scale–Revised (CDRS-R). 

In patients with a co-occurring psychiatric condition, no significant differences were found over time between ecopipam and placebo in terms of SNAP-IV (-4.4; P = .45), Pediatric Anxiety Rating Scale (1.0; P = .62), CDRS-R (-3.2; P = .65), or CY-BOCS (-0.7; P = .76) scores.

For ADHD, the most frequent comorbidity, scores trended lower in the ecopipam group but were not significantly different from those in the placebo group. “We found no evidence that ecopipam worsened ADHD symptoms,” Dr. Gilbert said.
 

No Weight Gain

Suicidal ideation was reported during the dosing period in eight patients in the placebo group and none in the ecopipam group. One patient treated with ecopipam had multiple depressive episodes and dropped out of the study on day 79. Ecopipam was discontinued in another patient because of anxiety. 

Notably, there was more weight gain in the placebo group than in the ecopipam group (2.4 kg vs 1.8 kg) by 12 weeks. No shifts from baseline were seen in blood glucose, A1c, total cholesterol, or triglycerides in either group. 

The lack of weight gain with ecopipam is important, Dr. Gilbert stressed. “Medicines that block D2 so often cause weight gain, and a lot of our patients, unfortunately, can be heavier already,” he explained. “We don’t want to make that worse or put them at a long-term risk of type 2 diabetes.”  

For patients with more severe disease, we really “do need something else besides D2-blockers in our tool kit,” he added. 

Commenting on the study, Tanya Simuni, MD, co-moderator of the session and director of the Parkinson’s Disease and Movement Disorders Center, Northwestern Feinberg School of Medicine, Chicago, said the aim of assessing D1-directed medications is to reduce the negative impact of traditional antipsychotics with a theoretical benefit on hyperkinetic movement.

But the most important thing that they’ve shown is that “there was no negative effect, no liability for the nonmotor manifestations of Tourette’s. That is important because Tourette’s is not a pure motor syndrome, and psychiatric manifestations in a lot of cases are associated with more disease-related quality of life impairment compared to the motor manifestations,” said Dr. Simuni.

That said, she noted, the “ideal drug would be the one that would have benefit for both motor and nonmotor domains.” 
 

Multiple Agents in the Pipeline 

“The neuropharmacology of Tourette syndrome has long remained stagnant, and most existing treatments often fail to balance efficacy with tolerability, underscoring the urgent need for newer therapeutics,” Christos Ganos, MD, professor of neurology, University of Toronto, said in a press release.

He noted that three studies have been published on ecopipam since 2014: an 8-week, open-label trial in adults with Tourette syndrome, a 4-week, placebo-controlled crossover trial in 38 children with Tourette syndrome, and the 12-week D1AMOND trial.

“These studies demonstrated clinically meaningful reductions in tics, without relevant safety concerns or changes in Tourette syndrome-typical neuropsychiatric measures, as also shown by the abstract highlighted here,” Dr. Ganos said. 

“This emerging body of research provides a solid foundation for introducing ecopipam as a novel pharmacological agent to treat tics and may motivate further work, both on the pathophysiology and pharmacotherapy of tic disorders and their associations.”

A single-arm, phase 3 trial is currently underway at 58 centers in North America and Europe investigating the long-term safety and tolerability of ecopipam over 24 months in 150 children, adolescents, and adults with Tourette syndrome. The study is expected to be completed in 2027.

Several other new medications are also under investigation including the vesicular monoamine transporter (VMAT2) inhibitors tetrabenazine, deutetrabenazine, and valbenazine; the PEDE10A inhibitor gemlapodect; the allopregnanolone antagonist sepranolone; and SCI-110, which combines dronabinol (the synthetic form of tetrahydrocannabinol) and the endocannabinoid palmitoylethanolamide.

The study was funded by Emalex Biosciences. Dr. Gilbert’s institution received research support from Emalex Biosciences and PTC Therapeutics. Dr. Gilbert has received publishing royalties from a healthcare-related publication; compensation for serving as a medical expert with Teladoc; Advanced Medical; and the National Vaccine Injury Compensation Program, US Department of Health and Human Services. Simuni reports no relevant conflicts of interest. Dr. Ganos has received honoraria for educational activities from the Movement Disorder Society and academic research support from VolkswagenStiftung. 
 

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

Alzheimer’s disease (AD), the most common cause of dementia, is the fifth leading cause of death in the United States. An estimated 6.9 million Americans aged 65 years or older have AD. Comorbid conditions in AD may exacerbate the progression of dementia and negatively affect overall health.

Although the exact mechanisms remain unclear, systemic inflammation is thought to play a significant role in the development of many common comorbidities associated with AD. Among the most frequently observed comorbid conditions are hypertension, diabetes, and depression. The presence of these comorbidities affects the treatment and management of AD, underscoring the need to understand the mechanisms of their interrelationship and develop effective management strategies. 
 

Hypertension 

Hypertension is a well-established risk factor for numerous health conditions, including AD. A comprehensive review of five meta-analyses and 52 primary studies revealed that elevated systolic blood pressure (SBP) correlates with an 11 % increased risk of developing AD, raising the question of whether early intervention and control of blood pressure would mitigate the risk for AD later in life. 

Findings from the Northern Manhattan Study suggest that although elevated SBP contributes to cognitive decline in older patients, the use of antihypertensive medications can neutralize the effects of high SBP on certain cognitive functions. Furthermore, a systematic review and meta-analysis comprising 12 trials (92,135 participants) demonstrated a significant reduction in the risk for dementia and cognitive impairment with antihypertensive treatment.

Notably, a retrospective cohort study involving 69,081 participants treated with beta-blockers for hypertension found that beta-blockers with high blood-brain barrier permeability were associated with a reduced risk for AD compared with those with low blood-brain barrier permeability. Additionally, a secondary analysis of the SPRINT trial found antihypertensive medications that stimulate vs inhibit type 2 and 4 angiotensin II receptors were associated with a lower incidence of cognitive impairment. Although further clinical trials are necessary to directly assess specific medications, these findings emphasize the potential of antihypertensive treatment as a strategic approach to reduce the risk for AD.
 

Type 2 Diabetes 

The connection between AD and type 2 diabetes is such that AD is sometimes referred to as “type 3 diabetes.” Both diseases share some of the same underlying pathophysiologic mechanisms, particularly the development of insulin resistance and oxidative stress. A prospective cohort study of 10,095 participants showed that diabetes was significantly associated with a higher risk of developing dementia; this risk is even greater in patients who develop diabetes at an earlier age.

In an interview with this news organization, Alvaro Pascual-Leone, MD, PhD, a professor of neurology at Harvard Medical School, Boston, said, “In addition to being a comorbidity factor, diabetes appears to be a predisposing risk factor for AD.” This is supported by a comprehensive literature review showing an increased progression from mild cognitive impairment (MCI) to dementia in patients with diabetes, prediabetes, or metabolic syndrome, with a pooled odds ratio for dementia progression in individuals with diabetes of 1.53.

Owing to the overlapping pathophysiologic mechanisms in AD and diabetes, treating one condition may have beneficial effects on the other. A systematic umbrella review and meta-analysis that included 10 meta-analyses across nine classes of diabetes drugs found a protective effect against dementia with the use of metformin, thiazolidinediones (including pioglitazone), glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors. Moreover, a cohort study of 12,220 patients who discontinued metformin early (ie, stopped using metformin without a prior history of abnormal kidney function) and 29,126 patients considered routine users found an increased risk for dementia in the early terminator group. Although further research is warranted, the concurrent treatment of AD and diabetes with antidiabetic agents holds considerable promise.
 

Depression and Anxiety

Anxiety and depression are significant risk factors for AD, and conversely, AD increases the likelihood of developing these psychiatric conditions. A systematic review of 14,760 studies showed dysthymia often emerges during the early stages of AD as an emotional response to cognitive decline. 

Data from the Australian Imaging Biomarkers and Lifestyle study showed a markedly elevated risk for AD and MCI among individuals with preexisting anxiety or depression. This study also found that age, sex, and marital status are important determinants, with men and single individuals with depression being particularly susceptible to developing AD. Conversely, a cohort study of 129,410 AD patients with AD, 390,088 patients with all-cause dementia, and 3,900,880 age-matched controls without a history of depression showed a cumulative incidence of depression of 13% in the AD group vs 3% in the control group, suggesting a heightened risk for depression following an AD diagnosis. 

These findings underscore the importance of targeted screening and assessment for patients with anxiety and depression who may be at risk for AD or those diagnosed with AD who are at risk for subsequent depression and anxiety. Although antidepressants are effective in treating depression in general, their efficacy in AD-related depression is of variable quality, probably owing to differing pathophysiologic mechanisms of the disease. Further research is necessary to explore both pharmacologic and nonpharmacologic interventions for treating depression in AD patients. Some studies have found that cognitive behavioral-therapy can be effective in improving depression in patients with AD.
 

Sleep Disorders

Research has shown a strong correlation between AD and sleep disorders, particularly obstructive sleep apnea, insomnia, and circadian rhythm disruptions. Additionally, studies suggest that insomnia and sleep deprivation contribute to increased amyloid beta production and tau pathology, hallmark features of AD. A scoping review of 70 studies proposed that this relationship is mediated by the glymphatic system (glial-dependent waste clearance pathway in the central nervous system), and that sleep deprivation disrupts its function, leading to protein accumulation and subsequent neurologic symptoms of AD. Another study showed that sleep deprivation triggers glial cell activation, initiating an inflammatory cascade that accelerates AD progression.

Given that the gold standard treatment for obstructive sleep apnea is continuous positive airway pressure (CPAP), it has been hypothesized that CPAP could also alleviate AD symptoms owing to shared pathophysiologic mechanisms of these conditions. A large systemic review found that CPAP use improved AD symptoms in patients with mild AD or MCI, though other sleep interventions, such as cognitive-behavioral therapy and melatonin supplementation, have yielded mixed outcomes. However, most studies in this area are small in scale, and there remains a paucity of research on treating sleep disorders in AD patients, indicating a need for further investigation.
 

Musculoskeletal Disorders

Although no direct causative link has been established, research indicates an association between osteoarthritis (OA) and dementia, likely because of similar pathophysiologic mechanisms, including systemic inflammation. Longitudinal analyses of data from the Alzheimer’s Disease Neuroimaging Initiative study found cognitively normal older individuals with OA experience more rapid declines in hippocampal volumes compared to those without OA, suggesting that OA may elevate the risk of cognitive impairment. Current treatments for OA, such as nonsteroidal anti-inflammatory drugs, glucocorticoids, and disease-modifying OA drugs, might also help alleviate AD symptoms related to inflammation, though the research in this area is limited.

AD has also been linked to osteoporosis. In a longitudinal follow-up study involving 78,994 patients with osteoporosis and 78,994 controls, AD developed in 5856 patients with osteoporosis compared with 3761 patients in the control group. These findings represent a 1.27-fold higher incidence of AD in patients with osteoporosis than in the control group, suggesting that osteoporosis might be a risk factor for AD.

Additionally, research has identified a relationship between AD and increased fracture risk and decreased bone mineral density, with AD patients exhibiting a significantly higher likelihood of bone fractures compared with those without AD. “Falls and fractures, aside from the risk they pose in all geriatric patients, in individuals with cognitive impairment — whether due to AD or another cause — have higher risk to cause delirium and that can result in greater morbidity and mortality and a lasting increase in cognitive disability,” stated Dr. Pascual-Leone. Current recommendations emphasize exercise and fall prevention strategies to reduce fracture risk in patients with AD, but there is a lack of comprehensive research on the safety and efficacy of osteoporosis medications in this population.
 

Implications for Clinical Practice

The intricate interplay between AD and its comorbidities highlights the need for a comprehensive and integrated approach to patient care. The overlapping pathophysiologic mechanisms suggest that these comorbidities can contribute to the evolution and progression of AD. Likewise, AD can exacerbate comorbid conditions. As such, a holistic assessment strategy that prioritizes early detection and management of comorbid conditions to mitigate their impact on AD progression would be beneficial. Dr. Pascual-Leone added, “The presence of any of these comorbidities suggests a need to screen for MCI earlier than might otherwise be indicated or as part of the treatment for the comorbid condition. In many cases, patients can make lifestyle modifications that improve not only the comorbid condition but also reduce its effect on dementia.” In doing so, healthcare providers can help improve patient outcomes and enhance the overall quality of life for individuals living with AD.

Alissa Hershberger, Professor of Nursing, University of Central Missouri, Lee’s Summit, Missouri, has disclosed no relevant financial relationships.

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

Alzheimer’s disease (AD), the most common cause of dementia, is the fifth leading cause of death in the United States. An estimated 6.9 million Americans aged 65 years or older have AD. Comorbid conditions in AD may exacerbate the progression of dementia and negatively affect overall health.

Although the exact mechanisms remain unclear, systemic inflammation is thought to play a significant role in the development of many common comorbidities associated with AD. Among the most frequently observed comorbid conditions are hypertension, diabetes, and depression. The presence of these comorbidities affects the treatment and management of AD, underscoring the need to understand the mechanisms of their interrelationship and develop effective management strategies. 
 

Hypertension 

Hypertension is a well-established risk factor for numerous health conditions, including AD. A comprehensive review of five meta-analyses and 52 primary studies revealed that elevated systolic blood pressure (SBP) correlates with an 11 % increased risk of developing AD, raising the question of whether early intervention and control of blood pressure would mitigate the risk for AD later in life. 

Findings from the Northern Manhattan Study suggest that although elevated SBP contributes to cognitive decline in older patients, the use of antihypertensive medications can neutralize the effects of high SBP on certain cognitive functions. Furthermore, a systematic review and meta-analysis comprising 12 trials (92,135 participants) demonstrated a significant reduction in the risk for dementia and cognitive impairment with antihypertensive treatment.

Notably, a retrospective cohort study involving 69,081 participants treated with beta-blockers for hypertension found that beta-blockers with high blood-brain barrier permeability were associated with a reduced risk for AD compared with those with low blood-brain barrier permeability. Additionally, a secondary analysis of the SPRINT trial found antihypertensive medications that stimulate vs inhibit type 2 and 4 angiotensin II receptors were associated with a lower incidence of cognitive impairment. Although further clinical trials are necessary to directly assess specific medications, these findings emphasize the potential of antihypertensive treatment as a strategic approach to reduce the risk for AD.
 

Type 2 Diabetes 

The connection between AD and type 2 diabetes is such that AD is sometimes referred to as “type 3 diabetes.” Both diseases share some of the same underlying pathophysiologic mechanisms, particularly the development of insulin resistance and oxidative stress. A prospective cohort study of 10,095 participants showed that diabetes was significantly associated with a higher risk of developing dementia; this risk is even greater in patients who develop diabetes at an earlier age.

In an interview with this news organization, Alvaro Pascual-Leone, MD, PhD, a professor of neurology at Harvard Medical School, Boston, said, “In addition to being a comorbidity factor, diabetes appears to be a predisposing risk factor for AD.” This is supported by a comprehensive literature review showing an increased progression from mild cognitive impairment (MCI) to dementia in patients with diabetes, prediabetes, or metabolic syndrome, with a pooled odds ratio for dementia progression in individuals with diabetes of 1.53.

Owing to the overlapping pathophysiologic mechanisms in AD and diabetes, treating one condition may have beneficial effects on the other. A systematic umbrella review and meta-analysis that included 10 meta-analyses across nine classes of diabetes drugs found a protective effect against dementia with the use of metformin, thiazolidinediones (including pioglitazone), glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors. Moreover, a cohort study of 12,220 patients who discontinued metformin early (ie, stopped using metformin without a prior history of abnormal kidney function) and 29,126 patients considered routine users found an increased risk for dementia in the early terminator group. Although further research is warranted, the concurrent treatment of AD and diabetes with antidiabetic agents holds considerable promise.
 

Depression and Anxiety

Anxiety and depression are significant risk factors for AD, and conversely, AD increases the likelihood of developing these psychiatric conditions. A systematic review of 14,760 studies showed dysthymia often emerges during the early stages of AD as an emotional response to cognitive decline. 

Data from the Australian Imaging Biomarkers and Lifestyle study showed a markedly elevated risk for AD and MCI among individuals with preexisting anxiety or depression. This study also found that age, sex, and marital status are important determinants, with men and single individuals with depression being particularly susceptible to developing AD. Conversely, a cohort study of 129,410 AD patients with AD, 390,088 patients with all-cause dementia, and 3,900,880 age-matched controls without a history of depression showed a cumulative incidence of depression of 13% in the AD group vs 3% in the control group, suggesting a heightened risk for depression following an AD diagnosis. 

These findings underscore the importance of targeted screening and assessment for patients with anxiety and depression who may be at risk for AD or those diagnosed with AD who are at risk for subsequent depression and anxiety. Although antidepressants are effective in treating depression in general, their efficacy in AD-related depression is of variable quality, probably owing to differing pathophysiologic mechanisms of the disease. Further research is necessary to explore both pharmacologic and nonpharmacologic interventions for treating depression in AD patients. Some studies have found that cognitive behavioral-therapy can be effective in improving depression in patients with AD.
 

Sleep Disorders

Research has shown a strong correlation between AD and sleep disorders, particularly obstructive sleep apnea, insomnia, and circadian rhythm disruptions. Additionally, studies suggest that insomnia and sleep deprivation contribute to increased amyloid beta production and tau pathology, hallmark features of AD. A scoping review of 70 studies proposed that this relationship is mediated by the glymphatic system (glial-dependent waste clearance pathway in the central nervous system), and that sleep deprivation disrupts its function, leading to protein accumulation and subsequent neurologic symptoms of AD. Another study showed that sleep deprivation triggers glial cell activation, initiating an inflammatory cascade that accelerates AD progression.

Given that the gold standard treatment for obstructive sleep apnea is continuous positive airway pressure (CPAP), it has been hypothesized that CPAP could also alleviate AD symptoms owing to shared pathophysiologic mechanisms of these conditions. A large systemic review found that CPAP use improved AD symptoms in patients with mild AD or MCI, though other sleep interventions, such as cognitive-behavioral therapy and melatonin supplementation, have yielded mixed outcomes. However, most studies in this area are small in scale, and there remains a paucity of research on treating sleep disorders in AD patients, indicating a need for further investigation.
 

Musculoskeletal Disorders

Although no direct causative link has been established, research indicates an association between osteoarthritis (OA) and dementia, likely because of similar pathophysiologic mechanisms, including systemic inflammation. Longitudinal analyses of data from the Alzheimer’s Disease Neuroimaging Initiative study found cognitively normal older individuals with OA experience more rapid declines in hippocampal volumes compared to those without OA, suggesting that OA may elevate the risk of cognitive impairment. Current treatments for OA, such as nonsteroidal anti-inflammatory drugs, glucocorticoids, and disease-modifying OA drugs, might also help alleviate AD symptoms related to inflammation, though the research in this area is limited.

AD has also been linked to osteoporosis. In a longitudinal follow-up study involving 78,994 patients with osteoporosis and 78,994 controls, AD developed in 5856 patients with osteoporosis compared with 3761 patients in the control group. These findings represent a 1.27-fold higher incidence of AD in patients with osteoporosis than in the control group, suggesting that osteoporosis might be a risk factor for AD.

Additionally, research has identified a relationship between AD and increased fracture risk and decreased bone mineral density, with AD patients exhibiting a significantly higher likelihood of bone fractures compared with those without AD. “Falls and fractures, aside from the risk they pose in all geriatric patients, in individuals with cognitive impairment — whether due to AD or another cause — have higher risk to cause delirium and that can result in greater morbidity and mortality and a lasting increase in cognitive disability,” stated Dr. Pascual-Leone. Current recommendations emphasize exercise and fall prevention strategies to reduce fracture risk in patients with AD, but there is a lack of comprehensive research on the safety and efficacy of osteoporosis medications in this population.
 

Implications for Clinical Practice

The intricate interplay between AD and its comorbidities highlights the need for a comprehensive and integrated approach to patient care. The overlapping pathophysiologic mechanisms suggest that these comorbidities can contribute to the evolution and progression of AD. Likewise, AD can exacerbate comorbid conditions. As such, a holistic assessment strategy that prioritizes early detection and management of comorbid conditions to mitigate their impact on AD progression would be beneficial. Dr. Pascual-Leone added, “The presence of any of these comorbidities suggests a need to screen for MCI earlier than might otherwise be indicated or as part of the treatment for the comorbid condition. In many cases, patients can make lifestyle modifications that improve not only the comorbid condition but also reduce its effect on dementia.” In doing so, healthcare providers can help improve patient outcomes and enhance the overall quality of life for individuals living with AD.

Alissa Hershberger, Professor of Nursing, University of Central Missouri, Lee’s Summit, Missouri, has disclosed no relevant financial relationships.

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

Alzheimer’s disease (AD), the most common cause of dementia, is the fifth leading cause of death in the United States. An estimated 6.9 million Americans aged 65 years or older have AD. Comorbid conditions in AD may exacerbate the progression of dementia and negatively affect overall health.

Although the exact mechanisms remain unclear, systemic inflammation is thought to play a significant role in the development of many common comorbidities associated with AD. Among the most frequently observed comorbid conditions are hypertension, diabetes, and depression. The presence of these comorbidities affects the treatment and management of AD, underscoring the need to understand the mechanisms of their interrelationship and develop effective management strategies. 
 

Hypertension 

Hypertension is a well-established risk factor for numerous health conditions, including AD. A comprehensive review of five meta-analyses and 52 primary studies revealed that elevated systolic blood pressure (SBP) correlates with an 11 % increased risk of developing AD, raising the question of whether early intervention and control of blood pressure would mitigate the risk for AD later in life. 

Findings from the Northern Manhattan Study suggest that although elevated SBP contributes to cognitive decline in older patients, the use of antihypertensive medications can neutralize the effects of high SBP on certain cognitive functions. Furthermore, a systematic review and meta-analysis comprising 12 trials (92,135 participants) demonstrated a significant reduction in the risk for dementia and cognitive impairment with antihypertensive treatment.

Notably, a retrospective cohort study involving 69,081 participants treated with beta-blockers for hypertension found that beta-blockers with high blood-brain barrier permeability were associated with a reduced risk for AD compared with those with low blood-brain barrier permeability. Additionally, a secondary analysis of the SPRINT trial found antihypertensive medications that stimulate vs inhibit type 2 and 4 angiotensin II receptors were associated with a lower incidence of cognitive impairment. Although further clinical trials are necessary to directly assess specific medications, these findings emphasize the potential of antihypertensive treatment as a strategic approach to reduce the risk for AD.
 

Type 2 Diabetes 

The connection between AD and type 2 diabetes is such that AD is sometimes referred to as “type 3 diabetes.” Both diseases share some of the same underlying pathophysiologic mechanisms, particularly the development of insulin resistance and oxidative stress. A prospective cohort study of 10,095 participants showed that diabetes was significantly associated with a higher risk of developing dementia; this risk is even greater in patients who develop diabetes at an earlier age.

In an interview with this news organization, Alvaro Pascual-Leone, MD, PhD, a professor of neurology at Harvard Medical School, Boston, said, “In addition to being a comorbidity factor, diabetes appears to be a predisposing risk factor for AD.” This is supported by a comprehensive literature review showing an increased progression from mild cognitive impairment (MCI) to dementia in patients with diabetes, prediabetes, or metabolic syndrome, with a pooled odds ratio for dementia progression in individuals with diabetes of 1.53.

Owing to the overlapping pathophysiologic mechanisms in AD and diabetes, treating one condition may have beneficial effects on the other. A systematic umbrella review and meta-analysis that included 10 meta-analyses across nine classes of diabetes drugs found a protective effect against dementia with the use of metformin, thiazolidinediones (including pioglitazone), glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors. Moreover, a cohort study of 12,220 patients who discontinued metformin early (ie, stopped using metformin without a prior history of abnormal kidney function) and 29,126 patients considered routine users found an increased risk for dementia in the early terminator group. Although further research is warranted, the concurrent treatment of AD and diabetes with antidiabetic agents holds considerable promise.
 

Depression and Anxiety

Anxiety and depression are significant risk factors for AD, and conversely, AD increases the likelihood of developing these psychiatric conditions. A systematic review of 14,760 studies showed dysthymia often emerges during the early stages of AD as an emotional response to cognitive decline. 

Data from the Australian Imaging Biomarkers and Lifestyle study showed a markedly elevated risk for AD and MCI among individuals with preexisting anxiety or depression. This study also found that age, sex, and marital status are important determinants, with men and single individuals with depression being particularly susceptible to developing AD. Conversely, a cohort study of 129,410 AD patients with AD, 390,088 patients with all-cause dementia, and 3,900,880 age-matched controls without a history of depression showed a cumulative incidence of depression of 13% in the AD group vs 3% in the control group, suggesting a heightened risk for depression following an AD diagnosis. 

These findings underscore the importance of targeted screening and assessment for patients with anxiety and depression who may be at risk for AD or those diagnosed with AD who are at risk for subsequent depression and anxiety. Although antidepressants are effective in treating depression in general, their efficacy in AD-related depression is of variable quality, probably owing to differing pathophysiologic mechanisms of the disease. Further research is necessary to explore both pharmacologic and nonpharmacologic interventions for treating depression in AD patients. Some studies have found that cognitive behavioral-therapy can be effective in improving depression in patients with AD.
 

Sleep Disorders

Research has shown a strong correlation between AD and sleep disorders, particularly obstructive sleep apnea, insomnia, and circadian rhythm disruptions. Additionally, studies suggest that insomnia and sleep deprivation contribute to increased amyloid beta production and tau pathology, hallmark features of AD. A scoping review of 70 studies proposed that this relationship is mediated by the glymphatic system (glial-dependent waste clearance pathway in the central nervous system), and that sleep deprivation disrupts its function, leading to protein accumulation and subsequent neurologic symptoms of AD. Another study showed that sleep deprivation triggers glial cell activation, initiating an inflammatory cascade that accelerates AD progression.

Given that the gold standard treatment for obstructive sleep apnea is continuous positive airway pressure (CPAP), it has been hypothesized that CPAP could also alleviate AD symptoms owing to shared pathophysiologic mechanisms of these conditions. A large systemic review found that CPAP use improved AD symptoms in patients with mild AD or MCI, though other sleep interventions, such as cognitive-behavioral therapy and melatonin supplementation, have yielded mixed outcomes. However, most studies in this area are small in scale, and there remains a paucity of research on treating sleep disorders in AD patients, indicating a need for further investigation.
 

Musculoskeletal Disorders

Although no direct causative link has been established, research indicates an association between osteoarthritis (OA) and dementia, likely because of similar pathophysiologic mechanisms, including systemic inflammation. Longitudinal analyses of data from the Alzheimer’s Disease Neuroimaging Initiative study found cognitively normal older individuals with OA experience more rapid declines in hippocampal volumes compared to those without OA, suggesting that OA may elevate the risk of cognitive impairment. Current treatments for OA, such as nonsteroidal anti-inflammatory drugs, glucocorticoids, and disease-modifying OA drugs, might also help alleviate AD symptoms related to inflammation, though the research in this area is limited.

AD has also been linked to osteoporosis. In a longitudinal follow-up study involving 78,994 patients with osteoporosis and 78,994 controls, AD developed in 5856 patients with osteoporosis compared with 3761 patients in the control group. These findings represent a 1.27-fold higher incidence of AD in patients with osteoporosis than in the control group, suggesting that osteoporosis might be a risk factor for AD.

Additionally, research has identified a relationship between AD and increased fracture risk and decreased bone mineral density, with AD patients exhibiting a significantly higher likelihood of bone fractures compared with those without AD. “Falls and fractures, aside from the risk they pose in all geriatric patients, in individuals with cognitive impairment — whether due to AD or another cause — have higher risk to cause delirium and that can result in greater morbidity and mortality and a lasting increase in cognitive disability,” stated Dr. Pascual-Leone. Current recommendations emphasize exercise and fall prevention strategies to reduce fracture risk in patients with AD, but there is a lack of comprehensive research on the safety and efficacy of osteoporosis medications in this population.
 

Implications for Clinical Practice

The intricate interplay between AD and its comorbidities highlights the need for a comprehensive and integrated approach to patient care. The overlapping pathophysiologic mechanisms suggest that these comorbidities can contribute to the evolution and progression of AD. Likewise, AD can exacerbate comorbid conditions. As such, a holistic assessment strategy that prioritizes early detection and management of comorbid conditions to mitigate their impact on AD progression would be beneficial. Dr. Pascual-Leone added, “The presence of any of these comorbidities suggests a need to screen for MCI earlier than might otherwise be indicated or as part of the treatment for the comorbid condition. In many cases, patients can make lifestyle modifications that improve not only the comorbid condition but also reduce its effect on dementia.” In doing so, healthcare providers can help improve patient outcomes and enhance the overall quality of life for individuals living with AD.

Alissa Hershberger, Professor of Nursing, University of Central Missouri, Lee’s Summit, Missouri, has disclosed no relevant financial relationships.

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

COPENHAGEN — Women of childbearing age with multiple sclerosis (MS) receive fewer highly effective medications than do men with similar levels of disability, even after accounting for treatment discontinuations during pregnancy and the postpartum period, new research suggested.

“We believe that pregnancy-related considerations probably still explain the major part of this gap,” said Antoine Gavoille, MD, University of Lyon, France, who presented the study at the 2024 ECTRIMS annual meeting.

This is likely due to “factors such as anticipation of pregnancy long before it occurs and fear of exposing women of childbearing age to certain treatments even in the absence of planned pregnancy,” he added.

Caution is warranted when medications are first marketed because there are no data on safety in pregnancy. However, in 2024, “this lesser treatment in women is unacceptable,” said Dr. Gavoille. “We now have several highly effective treatment options which are compatible with pregnancy,” he noted.

The researchers analyzed the French MS registry of 22,657 patients with relapsing MS (74.2% women) between 1997 and 2022 for treatment differences between women and their male counterparts. The results were adjusted for multiple factors including educational level, disease activity, disability levels, and discontinuation of drugs during pregnancy.

They found that over a median follow-up of 11.6 years, women had a significantly lower probability of receiving any disease-modifying treatment (odds ratio [OR], 0.92; 95% CI, 0.87-0.97).

In addition, women were even less likely to receive high-efficacy treatments such as natalizumab, anti-CD20 antibodies, or S1P modulators such as fingolimod (OR, 0.80; 95% CI, 0.74-0.86).

The difference in disease-modifying treatment usage varied across different treatments and over time. Teriflunomide, fingolimod, and anti-CD20 therapies were significantly underused throughout their entire availability (OR, 0.87, 0.78, and 0.80, respectively).

Interferon and natalizumab were initially used less frequently in women, but the use of these medications equalized over time.

In contrast, glatiramer acetate and dimethyl fumarate were initially used equally between genders but eventually became more commonly prescribed to women (OR, 1.27 and 1.17, respectively).

The disparity in treatment emerged after 2 years of disease duration for disease-modifying treatments in general and as early as 1 year for highly effective treatments.

The gender-based treatment gap did not significantly vary with patient age, indicating that therapeutic inertia may persist regardless of a woman’s age.

“Women may not be receiving the most effective therapies at the optimal time, often due to concerns about pregnancy risks that may never materialize,” said the study’s lead investigator Sandra Vukusic, MD, Lyon University Hospital, France.

“The main impact of this therapeutic inertia in women is the less effective control of disease activity, leading to the accumulation of lesions and an increased risk of long-term disability. This represents a real loss of opportunity for women, especially in an era where disease-modifying treatments so effective when used early,” she added.

Dr. Gavoille said that recommendations in France allow the use of moderately active drugs, including interferon and glatiramer acetate, during pregnancy or in women planning a pregnancy. More recently there has been enough data to allow the use of natalizumab up until the second trimester.

In addition, although not in the guidelines, it is thought that the anti-CD20 monoclonal antibodies, such as rituximab or ocrelizumab, may be safe as they are very long acting. Women can be dosed before pregnancy and be covered for the whole pregnancy period without exposing the fetus to the drug, he explained.

“The message is that now we have both moderately and highly effective treatments that are compatible with a pregnancy plan,” Dr. Gavoille said.

First, clinicians have to select a level of treatment based on disease activity and then choose the best option, depending on the woman’s plans with respect to pregnancy.

Drugs that are contraindicated in pregnancy include teriflunomide and S1P modulators such as fingolimod, which have been shown to be harmful to the fetus.

“But they could still be used in women of childbearing years as long as they are not planning a pregnancy and understand the need for contraception,” Dr. Gavoille noted.

He believes both neurologists and patients are afraid of using drugs in pregnancy. “It is, of course, important to be cautious on this issue, but we should not let fear stop these women receiving the best treatments available.”

However, he added, clinical practice is changing, and confidence is gradually building around using highly effective treatments in women of childbearing age.

Dr. Gavoille also called for more research to collate data in pregnant women with MS who are exposed to various treatments, starting with case reports and then academic registries, which he described as “difficult but important work.”

Commenting on the study, Robert Hoepner, MD, University Hospital of Bern, Switzerland, agreed that this treatment disparity between men and women is “unacceptable.”

Dr. Hoepner noted that a recent study showed that women have different relapse symptoms than men, which may also affect treatment choice.

Dr. Gavoille responded that other research has shown that women are less likely to have treatment escalation post-relapse. “This could be because of a difference in symptoms. But this is something we haven’t looked at yet.” 

Also commenting on the research, Frauke Zipp, MD, University Medical Center Mainz in Germany, said it would be interesting to follow this cohort over the long term to see if the women do less well several years down the line.

The study authors and commentators reported no relevant disclosures.
 

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

COPENHAGEN — Women of childbearing age with multiple sclerosis (MS) receive fewer highly effective medications than do men with similar levels of disability, even after accounting for treatment discontinuations during pregnancy and the postpartum period, new research suggested.

“We believe that pregnancy-related considerations probably still explain the major part of this gap,” said Antoine Gavoille, MD, University of Lyon, France, who presented the study at the 2024 ECTRIMS annual meeting.

This is likely due to “factors such as anticipation of pregnancy long before it occurs and fear of exposing women of childbearing age to certain treatments even in the absence of planned pregnancy,” he added.

Caution is warranted when medications are first marketed because there are no data on safety in pregnancy. However, in 2024, “this lesser treatment in women is unacceptable,” said Dr. Gavoille. “We now have several highly effective treatment options which are compatible with pregnancy,” he noted.

The researchers analyzed the French MS registry of 22,657 patients with relapsing MS (74.2% women) between 1997 and 2022 for treatment differences between women and their male counterparts. The results were adjusted for multiple factors including educational level, disease activity, disability levels, and discontinuation of drugs during pregnancy.

They found that over a median follow-up of 11.6 years, women had a significantly lower probability of receiving any disease-modifying treatment (odds ratio [OR], 0.92; 95% CI, 0.87-0.97).

In addition, women were even less likely to receive high-efficacy treatments such as natalizumab, anti-CD20 antibodies, or S1P modulators such as fingolimod (OR, 0.80; 95% CI, 0.74-0.86).

The difference in disease-modifying treatment usage varied across different treatments and over time. Teriflunomide, fingolimod, and anti-CD20 therapies were significantly underused throughout their entire availability (OR, 0.87, 0.78, and 0.80, respectively).

Interferon and natalizumab were initially used less frequently in women, but the use of these medications equalized over time.

In contrast, glatiramer acetate and dimethyl fumarate were initially used equally between genders but eventually became more commonly prescribed to women (OR, 1.27 and 1.17, respectively).

The disparity in treatment emerged after 2 years of disease duration for disease-modifying treatments in general and as early as 1 year for highly effective treatments.

The gender-based treatment gap did not significantly vary with patient age, indicating that therapeutic inertia may persist regardless of a woman’s age.

“Women may not be receiving the most effective therapies at the optimal time, often due to concerns about pregnancy risks that may never materialize,” said the study’s lead investigator Sandra Vukusic, MD, Lyon University Hospital, France.

“The main impact of this therapeutic inertia in women is the less effective control of disease activity, leading to the accumulation of lesions and an increased risk of long-term disability. This represents a real loss of opportunity for women, especially in an era where disease-modifying treatments so effective when used early,” she added.

Dr. Gavoille said that recommendations in France allow the use of moderately active drugs, including interferon and glatiramer acetate, during pregnancy or in women planning a pregnancy. More recently there has been enough data to allow the use of natalizumab up until the second trimester.

In addition, although not in the guidelines, it is thought that the anti-CD20 monoclonal antibodies, such as rituximab or ocrelizumab, may be safe as they are very long acting. Women can be dosed before pregnancy and be covered for the whole pregnancy period without exposing the fetus to the drug, he explained.

“The message is that now we have both moderately and highly effective treatments that are compatible with a pregnancy plan,” Dr. Gavoille said.

First, clinicians have to select a level of treatment based on disease activity and then choose the best option, depending on the woman’s plans with respect to pregnancy.

Drugs that are contraindicated in pregnancy include teriflunomide and S1P modulators such as fingolimod, which have been shown to be harmful to the fetus.

“But they could still be used in women of childbearing years as long as they are not planning a pregnancy and understand the need for contraception,” Dr. Gavoille noted.

He believes both neurologists and patients are afraid of using drugs in pregnancy. “It is, of course, important to be cautious on this issue, but we should not let fear stop these women receiving the best treatments available.”

However, he added, clinical practice is changing, and confidence is gradually building around using highly effective treatments in women of childbearing age.

Dr. Gavoille also called for more research to collate data in pregnant women with MS who are exposed to various treatments, starting with case reports and then academic registries, which he described as “difficult but important work.”

Commenting on the study, Robert Hoepner, MD, University Hospital of Bern, Switzerland, agreed that this treatment disparity between men and women is “unacceptable.”

Dr. Hoepner noted that a recent study showed that women have different relapse symptoms than men, which may also affect treatment choice.

Dr. Gavoille responded that other research has shown that women are less likely to have treatment escalation post-relapse. “This could be because of a difference in symptoms. But this is something we haven’t looked at yet.” 

Also commenting on the research, Frauke Zipp, MD, University Medical Center Mainz in Germany, said it would be interesting to follow this cohort over the long term to see if the women do less well several years down the line.

The study authors and commentators reported no relevant disclosures.
 

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

COPENHAGEN — Women of childbearing age with multiple sclerosis (MS) receive fewer highly effective medications than do men with similar levels of disability, even after accounting for treatment discontinuations during pregnancy and the postpartum period, new research suggested.

“We believe that pregnancy-related considerations probably still explain the major part of this gap,” said Antoine Gavoille, MD, University of Lyon, France, who presented the study at the 2024 ECTRIMS annual meeting.

This is likely due to “factors such as anticipation of pregnancy long before it occurs and fear of exposing women of childbearing age to certain treatments even in the absence of planned pregnancy,” he added.

Caution is warranted when medications are first marketed because there are no data on safety in pregnancy. However, in 2024, “this lesser treatment in women is unacceptable,” said Dr. Gavoille. “We now have several highly effective treatment options which are compatible with pregnancy,” he noted.

The researchers analyzed the French MS registry of 22,657 patients with relapsing MS (74.2% women) between 1997 and 2022 for treatment differences between women and their male counterparts. The results were adjusted for multiple factors including educational level, disease activity, disability levels, and discontinuation of drugs during pregnancy.

They found that over a median follow-up of 11.6 years, women had a significantly lower probability of receiving any disease-modifying treatment (odds ratio [OR], 0.92; 95% CI, 0.87-0.97).

In addition, women were even less likely to receive high-efficacy treatments such as natalizumab, anti-CD20 antibodies, or S1P modulators such as fingolimod (OR, 0.80; 95% CI, 0.74-0.86).

The difference in disease-modifying treatment usage varied across different treatments and over time. Teriflunomide, fingolimod, and anti-CD20 therapies were significantly underused throughout their entire availability (OR, 0.87, 0.78, and 0.80, respectively).

Interferon and natalizumab were initially used less frequently in women, but the use of these medications equalized over time.

In contrast, glatiramer acetate and dimethyl fumarate were initially used equally between genders but eventually became more commonly prescribed to women (OR, 1.27 and 1.17, respectively).

The disparity in treatment emerged after 2 years of disease duration for disease-modifying treatments in general and as early as 1 year for highly effective treatments.

The gender-based treatment gap did not significantly vary with patient age, indicating that therapeutic inertia may persist regardless of a woman’s age.

“Women may not be receiving the most effective therapies at the optimal time, often due to concerns about pregnancy risks that may never materialize,” said the study’s lead investigator Sandra Vukusic, MD, Lyon University Hospital, France.

“The main impact of this therapeutic inertia in women is the less effective control of disease activity, leading to the accumulation of lesions and an increased risk of long-term disability. This represents a real loss of opportunity for women, especially in an era where disease-modifying treatments so effective when used early,” she added.

Dr. Gavoille said that recommendations in France allow the use of moderately active drugs, including interferon and glatiramer acetate, during pregnancy or in women planning a pregnancy. More recently there has been enough data to allow the use of natalizumab up until the second trimester.

In addition, although not in the guidelines, it is thought that the anti-CD20 monoclonal antibodies, such as rituximab or ocrelizumab, may be safe as they are very long acting. Women can be dosed before pregnancy and be covered for the whole pregnancy period without exposing the fetus to the drug, he explained.

“The message is that now we have both moderately and highly effective treatments that are compatible with a pregnancy plan,” Dr. Gavoille said.

First, clinicians have to select a level of treatment based on disease activity and then choose the best option, depending on the woman’s plans with respect to pregnancy.

Drugs that are contraindicated in pregnancy include teriflunomide and S1P modulators such as fingolimod, which have been shown to be harmful to the fetus.

“But they could still be used in women of childbearing years as long as they are not planning a pregnancy and understand the need for contraception,” Dr. Gavoille noted.

He believes both neurologists and patients are afraid of using drugs in pregnancy. “It is, of course, important to be cautious on this issue, but we should not let fear stop these women receiving the best treatments available.”

However, he added, clinical practice is changing, and confidence is gradually building around using highly effective treatments in women of childbearing age.

Dr. Gavoille also called for more research to collate data in pregnant women with MS who are exposed to various treatments, starting with case reports and then academic registries, which he described as “difficult but important work.”

Commenting on the study, Robert Hoepner, MD, University Hospital of Bern, Switzerland, agreed that this treatment disparity between men and women is “unacceptable.”

Dr. Hoepner noted that a recent study showed that women have different relapse symptoms than men, which may also affect treatment choice.

Dr. Gavoille responded that other research has shown that women are less likely to have treatment escalation post-relapse. “This could be because of a difference in symptoms. But this is something we haven’t looked at yet.” 

Also commenting on the research, Frauke Zipp, MD, University Medical Center Mainz in Germany, said it would be interesting to follow this cohort over the long term to see if the women do less well several years down the line.

The study authors and commentators reported no relevant disclosures.
 

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

MILAN — Antidepressants escitalopram and duloxetine have been shown to improve verbal memory in moderate to severe depression, a clinical effect linked to changes in serotonin 4 (5-HT4) receptor levels in the brain, as shown on PET.

These findings suggested there is a role for specifically targeting the 5-HT4 receptor to improve verbal memory in depression, said investigator Vibeke H. Dam, PhD, from Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

“Verbal memory is often impaired in depression, and this has a lot of impact on patients’ ability to work and have a normal life. That’s why we’re so excited about this receptor in particular,” Dr. Dam said.

“If we can find a way to activate it more directly, we’re thinking this could be a way to treat this memory symptom that a lot of patients have and that currently we don’t really have a treatment for,” she added.

The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress and recently published in Biological Psychiatry .
 

Largest Trial of Its Kind

The study is the largest single-site PET trial investigating serotonergic neurotransmission in major depressive disorder over the course of antidepressant treatment to date. It included 90 patients with moderate to severe depression who underwent baseline cognitive tests and brain scans to measure 5-HT4 receptor levels before starting their treatment with the selective serotonin reuptake inhibitor escitalopram.

Patients who showed no improvement in depressive symptoms after 4 weeks (n = 14), as assessed by the Hamilton Depression Rating Scale 6 (HAMD6), were switched to the serotonin-norepinephrine reuptake inhibitor duloxetine.

Both escitalopram and duloxetine inhibit the reuptake of 5-HT4, enhancing neurotransmitter activity; escitalopram primarily increases serotonin levels, while duloxetine increases both serotonin and norepinephrine levels.

The primary cognitive outcome measure was change in the Verbal Affective Memory Task 26. Secondary cognitive outcomes were change in working memory, reaction time, emotion recognition bias, and negative social emotion.

After 8 weeks of treatment, a subset of 40 patients repeated PET scans, and at 12 weeks, all patients repeated cognitive testing.

Matching neuroimaging and cognitive data were available for 88 patients at baseline and for 39 patients with rescan.

As expected, the study showed that antidepressant treatment resulted in the downregulation of 5-HT4 receptor levels. “One hypothesis is that if we increase the availability of serotonin [with treatment], downregulation of the receptors might be a response,” said Dr. Dam.

“What was interesting was that this was the effect across all patients, whether they [clinically] responded or not. So we see the medication does what it’s supposed to do in the brain.” But, she said, there was no association between 5-HT4 receptor levels and HAMD6 scores.
 

Gains in Verbal Memory

Although the downregulation of 5-HT4 did not correlate with somatic or mood symptoms, it did correlate with cognitive symptoms.

Interestingly, while most patients showed improvement in depressive symptoms — many reaching remission or recovery — they also experienced gains in verbal memory. However, these improvements were not correlated. It was possible for one to improve more than the other, with no apparent link between the two, said Dr. Dam.

“What was linked was how the brain responded to the medication for this particular receptor. So even though there is this downregulation of the receptor, there’s still a lot of activation of it, and our thinking is that it’s activation of the receptor that is the important bit.”

Work by other groups has shown that another medication, prucalopride, which is used to treat gastroparesis, can more directly activate the 5-HT4 receptor, and that the treatment of healthy volunteers with this medication can boost memory and learning, said Dr. Dam.

“We could repurpose this drug, and we’re currently looking for funding to test this in a wide variety of different groups such as concussion, diabetes, and depression.”

The study’s coinvestigator, Vibe G. Frokjaer, MD, said more research is required to understand the potential implications of the findings.

“Poor cognitive function is very hard to treat efficiently and may require extra treatment. This work points to the possibility of stimulating this specific receptor so that we can treat cognitive problems, even aside from whether or not the patient has overcome the core symptoms of depression,” she said in a release.

Commenting on the research, Philip Cowen, MD, professor of psychopharmacology at the University of Oxford, England, said in a release that in light of “recent controversies about the role of brain serotonin in clinical depression, it is noteworthy that the PET studies of the Copenhagen Group provide unequivocal evidence that brain 5-HT4 receptors are decreased in unmedicated depressed patients.

“Their work also demonstrates the intimate role of brain 5-HT4 receptors in cognitive function,” he added. “This confirms recent work from Oxford, showing that the 5-HT4 receptor stimulant, prucalopride — a drug licensed for the treatment of constipation — improves memory in both healthy participants and people at risk of depression,” he added.

The study was funded by the Innovation Fund Denmark, Research Fund of the Mental Health Services – Capital Region of Denmark, Independent Research Fund Denmark, Global Justice Foundation, Research Council of Rigshospitalet, Augustinus Foundation, Savværksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Lundbeck Foundation, and H. Lundbeck A/S.

Dr. Dam reported serving as a speaker for H. Lundbeck. Frokjaer reported serving as a consultant for Sage Therapeutics and lecturer for H. Lundbeck, Janssen-Cilag, and Gedeon Richter. Study investigator Martin B. Jørgensen has given talks sponsored by Boehringer Ingelheim and Lundbeck Pharma. All other investigators reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

MILAN — Antidepressants escitalopram and duloxetine have been shown to improve verbal memory in moderate to severe depression, a clinical effect linked to changes in serotonin 4 (5-HT4) receptor levels in the brain, as shown on PET.

These findings suggested there is a role for specifically targeting the 5-HT4 receptor to improve verbal memory in depression, said investigator Vibeke H. Dam, PhD, from Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

“Verbal memory is often impaired in depression, and this has a lot of impact on patients’ ability to work and have a normal life. That’s why we’re so excited about this receptor in particular,” Dr. Dam said.

“If we can find a way to activate it more directly, we’re thinking this could be a way to treat this memory symptom that a lot of patients have and that currently we don’t really have a treatment for,” she added.

The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress and recently published in Biological Psychiatry .
 

Largest Trial of Its Kind

The study is the largest single-site PET trial investigating serotonergic neurotransmission in major depressive disorder over the course of antidepressant treatment to date. It included 90 patients with moderate to severe depression who underwent baseline cognitive tests and brain scans to measure 5-HT4 receptor levels before starting their treatment with the selective serotonin reuptake inhibitor escitalopram.

Patients who showed no improvement in depressive symptoms after 4 weeks (n = 14), as assessed by the Hamilton Depression Rating Scale 6 (HAMD6), were switched to the serotonin-norepinephrine reuptake inhibitor duloxetine.

Both escitalopram and duloxetine inhibit the reuptake of 5-HT4, enhancing neurotransmitter activity; escitalopram primarily increases serotonin levels, while duloxetine increases both serotonin and norepinephrine levels.

The primary cognitive outcome measure was change in the Verbal Affective Memory Task 26. Secondary cognitive outcomes were change in working memory, reaction time, emotion recognition bias, and negative social emotion.

After 8 weeks of treatment, a subset of 40 patients repeated PET scans, and at 12 weeks, all patients repeated cognitive testing.

Matching neuroimaging and cognitive data were available for 88 patients at baseline and for 39 patients with rescan.

As expected, the study showed that antidepressant treatment resulted in the downregulation of 5-HT4 receptor levels. “One hypothesis is that if we increase the availability of serotonin [with treatment], downregulation of the receptors might be a response,” said Dr. Dam.

“What was interesting was that this was the effect across all patients, whether they [clinically] responded or not. So we see the medication does what it’s supposed to do in the brain.” But, she said, there was no association between 5-HT4 receptor levels and HAMD6 scores.
 

Gains in Verbal Memory

Although the downregulation of 5-HT4 did not correlate with somatic or mood symptoms, it did correlate with cognitive symptoms.

Interestingly, while most patients showed improvement in depressive symptoms — many reaching remission or recovery — they also experienced gains in verbal memory. However, these improvements were not correlated. It was possible for one to improve more than the other, with no apparent link between the two, said Dr. Dam.

“What was linked was how the brain responded to the medication for this particular receptor. So even though there is this downregulation of the receptor, there’s still a lot of activation of it, and our thinking is that it’s activation of the receptor that is the important bit.”

Work by other groups has shown that another medication, prucalopride, which is used to treat gastroparesis, can more directly activate the 5-HT4 receptor, and that the treatment of healthy volunteers with this medication can boost memory and learning, said Dr. Dam.

“We could repurpose this drug, and we’re currently looking for funding to test this in a wide variety of different groups such as concussion, diabetes, and depression.”

The study’s coinvestigator, Vibe G. Frokjaer, MD, said more research is required to understand the potential implications of the findings.

“Poor cognitive function is very hard to treat efficiently and may require extra treatment. This work points to the possibility of stimulating this specific receptor so that we can treat cognitive problems, even aside from whether or not the patient has overcome the core symptoms of depression,” she said in a release.

Commenting on the research, Philip Cowen, MD, professor of psychopharmacology at the University of Oxford, England, said in a release that in light of “recent controversies about the role of brain serotonin in clinical depression, it is noteworthy that the PET studies of the Copenhagen Group provide unequivocal evidence that brain 5-HT4 receptors are decreased in unmedicated depressed patients.

“Their work also demonstrates the intimate role of brain 5-HT4 receptors in cognitive function,” he added. “This confirms recent work from Oxford, showing that the 5-HT4 receptor stimulant, prucalopride — a drug licensed for the treatment of constipation — improves memory in both healthy participants and people at risk of depression,” he added.

The study was funded by the Innovation Fund Denmark, Research Fund of the Mental Health Services – Capital Region of Denmark, Independent Research Fund Denmark, Global Justice Foundation, Research Council of Rigshospitalet, Augustinus Foundation, Savværksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Lundbeck Foundation, and H. Lundbeck A/S.

Dr. Dam reported serving as a speaker for H. Lundbeck. Frokjaer reported serving as a consultant for Sage Therapeutics and lecturer for H. Lundbeck, Janssen-Cilag, and Gedeon Richter. Study investigator Martin B. Jørgensen has given talks sponsored by Boehringer Ingelheim and Lundbeck Pharma. All other investigators reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

MILAN — Antidepressants escitalopram and duloxetine have been shown to improve verbal memory in moderate to severe depression, a clinical effect linked to changes in serotonin 4 (5-HT4) receptor levels in the brain, as shown on PET.

These findings suggested there is a role for specifically targeting the 5-HT4 receptor to improve verbal memory in depression, said investigator Vibeke H. Dam, PhD, from Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

“Verbal memory is often impaired in depression, and this has a lot of impact on patients’ ability to work and have a normal life. That’s why we’re so excited about this receptor in particular,” Dr. Dam said.

“If we can find a way to activate it more directly, we’re thinking this could be a way to treat this memory symptom that a lot of patients have and that currently we don’t really have a treatment for,” she added.

The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress and recently published in Biological Psychiatry .
 

Largest Trial of Its Kind

The study is the largest single-site PET trial investigating serotonergic neurotransmission in major depressive disorder over the course of antidepressant treatment to date. It included 90 patients with moderate to severe depression who underwent baseline cognitive tests and brain scans to measure 5-HT4 receptor levels before starting their treatment with the selective serotonin reuptake inhibitor escitalopram.

Patients who showed no improvement in depressive symptoms after 4 weeks (n = 14), as assessed by the Hamilton Depression Rating Scale 6 (HAMD6), were switched to the serotonin-norepinephrine reuptake inhibitor duloxetine.

Both escitalopram and duloxetine inhibit the reuptake of 5-HT4, enhancing neurotransmitter activity; escitalopram primarily increases serotonin levels, while duloxetine increases both serotonin and norepinephrine levels.

The primary cognitive outcome measure was change in the Verbal Affective Memory Task 26. Secondary cognitive outcomes were change in working memory, reaction time, emotion recognition bias, and negative social emotion.

After 8 weeks of treatment, a subset of 40 patients repeated PET scans, and at 12 weeks, all patients repeated cognitive testing.

Matching neuroimaging and cognitive data were available for 88 patients at baseline and for 39 patients with rescan.

As expected, the study showed that antidepressant treatment resulted in the downregulation of 5-HT4 receptor levels. “One hypothesis is that if we increase the availability of serotonin [with treatment], downregulation of the receptors might be a response,” said Dr. Dam.

“What was interesting was that this was the effect across all patients, whether they [clinically] responded or not. So we see the medication does what it’s supposed to do in the brain.” But, she said, there was no association between 5-HT4 receptor levels and HAMD6 scores.
 

Gains in Verbal Memory

Although the downregulation of 5-HT4 did not correlate with somatic or mood symptoms, it did correlate with cognitive symptoms.

Interestingly, while most patients showed improvement in depressive symptoms — many reaching remission or recovery — they also experienced gains in verbal memory. However, these improvements were not correlated. It was possible for one to improve more than the other, with no apparent link between the two, said Dr. Dam.

“What was linked was how the brain responded to the medication for this particular receptor. So even though there is this downregulation of the receptor, there’s still a lot of activation of it, and our thinking is that it’s activation of the receptor that is the important bit.”

Work by other groups has shown that another medication, prucalopride, which is used to treat gastroparesis, can more directly activate the 5-HT4 receptor, and that the treatment of healthy volunteers with this medication can boost memory and learning, said Dr. Dam.

“We could repurpose this drug, and we’re currently looking for funding to test this in a wide variety of different groups such as concussion, diabetes, and depression.”

The study’s coinvestigator, Vibe G. Frokjaer, MD, said more research is required to understand the potential implications of the findings.

“Poor cognitive function is very hard to treat efficiently and may require extra treatment. This work points to the possibility of stimulating this specific receptor so that we can treat cognitive problems, even aside from whether or not the patient has overcome the core symptoms of depression,” she said in a release.

Commenting on the research, Philip Cowen, MD, professor of psychopharmacology at the University of Oxford, England, said in a release that in light of “recent controversies about the role of brain serotonin in clinical depression, it is noteworthy that the PET studies of the Copenhagen Group provide unequivocal evidence that brain 5-HT4 receptors are decreased in unmedicated depressed patients.

“Their work also demonstrates the intimate role of brain 5-HT4 receptors in cognitive function,” he added. “This confirms recent work from Oxford, showing that the 5-HT4 receptor stimulant, prucalopride — a drug licensed for the treatment of constipation — improves memory in both healthy participants and people at risk of depression,” he added.

The study was funded by the Innovation Fund Denmark, Research Fund of the Mental Health Services – Capital Region of Denmark, Independent Research Fund Denmark, Global Justice Foundation, Research Council of Rigshospitalet, Augustinus Foundation, Savværksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Lundbeck Foundation, and H. Lundbeck A/S.

Dr. Dam reported serving as a speaker for H. Lundbeck. Frokjaer reported serving as a consultant for Sage Therapeutics and lecturer for H. Lundbeck, Janssen-Cilag, and Gedeon Richter. Study investigator Martin B. Jørgensen has given talks sponsored by Boehringer Ingelheim and Lundbeck Pharma. All other investigators reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

MILAN — Recent research allaying concerns about suicidality linked to glucagon-like peptide 1 (GLP-1) receptor agonists, along with evidence of these agents’ potential psychiatric and cognitive benefits, has prompted the lead investigator of a major analysis to urge researchers to explore the potential of these drugs for mental illness.

“So far, we’ve been talking about the safety from a neuropsychiatric perspective in diabetes, but there is also the safety and benefit in people with mental disorders,” Riccardo De Giorgi, MD, PhD, from the Department of Psychiatry, University of Oxford in England, said in an interview.

The results of the meta-analysis were previously reported by this news organization and reviewed by Dr. De Giorgi at the 37th European College of Neuropsychopharmacology (ECNP) Congress. Dr. De Giorgi broached whether GLP-1 inhibitors such as semaglutide might also offer the same benefits in patients without diabetes as they do in those with diabetes, in terms of cognitive deficits and substance use or mood disorders.

Noting that GLP-1s are not approved for psychiatric disorders, Dr. De Giorgi said it can’t be assumed that the “metabolic or maybe even more general mechanisms that are being modified with these medications in diabetes or even in obesity are the same for people with psychiatric disorders. We’re talking about very different things. From a clinical perspective, you could do real harm,” he told this news organization.

Yet Dr. De Giorgi emphasized the importance of exploring the potential benefits of these medications in psychiatry.

“From a research perspective ... I am very worried about missing an opportunity here. This happened with rimonabant, a cannabis medication that was used for weight loss back in 2012 and was withdrawn quite dramatically in Europe immediately after licensing because it increased suicide risk. Since then, nobody has been touching the cannabinoid system, and that’s a shame because in psychiatry, we don’t have that much we can work on. So we don’t want to miss an opportunity with the GLP-1 system — that’s why we need to be cautious and look at safety first,” he said.
 

Signal of Efficacy?

Dr. De Giorgi’s research suggested several potential neurobiological effects of GLP-1 inhibition in diabetes research.

“There was a bit of a signal specifically for the big three dementias — vascular, Lewy Body, and frontotemporal — although there was not enough power,” he reported. “We also saw a reduced risk in nicotine misuse, especially amongst other substance use disorders ... and finally a more tentative association for reduced depression.”

He noted that GLP-1s for psychiatric illness likely have limitations and may not cure mental disorders but could help specific subsets of patients. Rather than aiming for large-scale studies, the focus should be on small, incremental studies to advance the research.

Asked by the session chair, John Cryan, PhD, from University College Cork in Ireland, and chair of the ECNP Scientific Committee whether improvement in patients’ mood could be attributed to weight loss, Dr. De Giorgi replied no.

“We now have quite a lot of studies that show that if there is an effect or association it is seen quite a bit earlier than any weight loss. Remember, weight loss takes quite a lot of time, and at quite high doses, but more provocatively, even if that’s the case, does it matter? We as psychiatrists do worry that we need to disentangle these things, but they don’t do that in cardiology, for example. If they see a benefit in mortality they don’t really care if it’s specifically an effect on heart failure or ischemic disease,” said Dr. De Giorgi.

Regardless of their neuropsychiatric potential, the cardiometabolic benefits of GLP-1 inhibitors are sorely needed in the psychiatric population, noted two experts in a recent JAMA Psychiatry viewpoint article.

Sri Mahavir Agarwal, MD, PhD, and Margaret Hahn, MD, PhD, from the University of Toronto and the Schizophrenia Division at the Centre for Addiction and Mental Health, in Toronto, Ontario, Canada, pointed out that “individuals with severe mental illness (SMI) have exceedingly high rates of metabolic comorbidity; three of four are overweight or obese, whereas the prevalence of type 2 diabetes (T2D) is several-fold higher than in the general population. Consequently, individuals with SMI die 15-20 years earlier from cardiovascular disease (CVD) than do those in the general population with CVD,” they noted.

“The arrival of semaglutide has infused significant enthusiasm in the field of mental health research. The proximal effects of weight and related CV comorbidities are significant in themselves. It is plausible that semaglutide could act through neurogenesis or secondary benefits of improving metabolic health on other important outcomes, such as cognitive health and quality of life, thereby filling an unmet need in the treatment of SMI,” Dr. Agarwal and Dr. Hahn added.
 

An Exciting Opportunity

Current research investigating GLP-1s in psychiatry and neurology is increasingly focused on neuroinflammation, said Dr. De Giorgi.

Research shows significant evidence that certain medications may help reduce dysfunctional inflammatory processes linked to various cognitive and psychiatric disorders, he added.

Many patients with established psychiatric conditions also have physical health issues, which contribute to increased mortality risk, said Dr. De Giorgi. It’s crucial to understand that, if these treatments improve mortality outcomes for psychiatric patients, the specific mechanisms involved are secondary to the results. Psychiatrists must be equipped to prescribe, manage, and initiate these therapies.

“While trials involving psychosis patients are ongoing, we are making progress and should seize this opportunity” said Dr. De Giorgi.

Dr. Cryan agreed: “I think we’ll get there. What these drugs have shown is that you can, through a single mechanism, have multitude effects related to brain-body interactions, and why not focus that on mood and anxiety and cognitive performance? It’s exciting no matter what. We now need to do longitudinal, cross-sectional, placebo-controlled trials in specific patient populations.”

This study received funding from the National Institute for Health and Care Research Oxford Health Biomedical Research Centre and Medical Research Council. Dr. De Giorgi’s coauthors reported receiving funding for other work from Novo Nordisk, Five Lives, Cognetivity Ltd., Cognex, P1vital, Lundbeck, Servier, UCB, Zogenix, Johnson & Johnson, and Syndesi. Dr. Cryan reported no relevant disclosures.

A version of this article appeared on Medscape.com.

MILAN — Recent research allaying concerns about suicidality linked to glucagon-like peptide 1 (GLP-1) receptor agonists, along with evidence of these agents’ potential psychiatric and cognitive benefits, has prompted the lead investigator of a major analysis to urge researchers to explore the potential of these drugs for mental illness.

“So far, we’ve been talking about the safety from a neuropsychiatric perspective in diabetes, but there is also the safety and benefit in people with mental disorders,” Riccardo De Giorgi, MD, PhD, from the Department of Psychiatry, University of Oxford in England, said in an interview.

The results of the meta-analysis were previously reported by this news organization and reviewed by Dr. De Giorgi at the 37th European College of Neuropsychopharmacology (ECNP) Congress. Dr. De Giorgi broached whether GLP-1 inhibitors such as semaglutide might also offer the same benefits in patients without diabetes as they do in those with diabetes, in terms of cognitive deficits and substance use or mood disorders.

Noting that GLP-1s are not approved for psychiatric disorders, Dr. De Giorgi said it can’t be assumed that the “metabolic or maybe even more general mechanisms that are being modified with these medications in diabetes or even in obesity are the same for people with psychiatric disorders. We’re talking about very different things. From a clinical perspective, you could do real harm,” he told this news organization.

Yet Dr. De Giorgi emphasized the importance of exploring the potential benefits of these medications in psychiatry.

“From a research perspective ... I am very worried about missing an opportunity here. This happened with rimonabant, a cannabis medication that was used for weight loss back in 2012 and was withdrawn quite dramatically in Europe immediately after licensing because it increased suicide risk. Since then, nobody has been touching the cannabinoid system, and that’s a shame because in psychiatry, we don’t have that much we can work on. So we don’t want to miss an opportunity with the GLP-1 system — that’s why we need to be cautious and look at safety first,” he said.
 

Signal of Efficacy?

Dr. De Giorgi’s research suggested several potential neurobiological effects of GLP-1 inhibition in diabetes research.

“There was a bit of a signal specifically for the big three dementias — vascular, Lewy Body, and frontotemporal — although there was not enough power,” he reported. “We also saw a reduced risk in nicotine misuse, especially amongst other substance use disorders ... and finally a more tentative association for reduced depression.”

He noted that GLP-1s for psychiatric illness likely have limitations and may not cure mental disorders but could help specific subsets of patients. Rather than aiming for large-scale studies, the focus should be on small, incremental studies to advance the research.

Asked by the session chair, John Cryan, PhD, from University College Cork in Ireland, and chair of the ECNP Scientific Committee whether improvement in patients’ mood could be attributed to weight loss, Dr. De Giorgi replied no.

“We now have quite a lot of studies that show that if there is an effect or association it is seen quite a bit earlier than any weight loss. Remember, weight loss takes quite a lot of time, and at quite high doses, but more provocatively, even if that’s the case, does it matter? We as psychiatrists do worry that we need to disentangle these things, but they don’t do that in cardiology, for example. If they see a benefit in mortality they don’t really care if it’s specifically an effect on heart failure or ischemic disease,” said Dr. De Giorgi.

Regardless of their neuropsychiatric potential, the cardiometabolic benefits of GLP-1 inhibitors are sorely needed in the psychiatric population, noted two experts in a recent JAMA Psychiatry viewpoint article.

Sri Mahavir Agarwal, MD, PhD, and Margaret Hahn, MD, PhD, from the University of Toronto and the Schizophrenia Division at the Centre for Addiction and Mental Health, in Toronto, Ontario, Canada, pointed out that “individuals with severe mental illness (SMI) have exceedingly high rates of metabolic comorbidity; three of four are overweight or obese, whereas the prevalence of type 2 diabetes (T2D) is several-fold higher than in the general population. Consequently, individuals with SMI die 15-20 years earlier from cardiovascular disease (CVD) than do those in the general population with CVD,” they noted.

“The arrival of semaglutide has infused significant enthusiasm in the field of mental health research. The proximal effects of weight and related CV comorbidities are significant in themselves. It is plausible that semaglutide could act through neurogenesis or secondary benefits of improving metabolic health on other important outcomes, such as cognitive health and quality of life, thereby filling an unmet need in the treatment of SMI,” Dr. Agarwal and Dr. Hahn added.
 

An Exciting Opportunity

Current research investigating GLP-1s in psychiatry and neurology is increasingly focused on neuroinflammation, said Dr. De Giorgi.

Research shows significant evidence that certain medications may help reduce dysfunctional inflammatory processes linked to various cognitive and psychiatric disorders, he added.

Many patients with established psychiatric conditions also have physical health issues, which contribute to increased mortality risk, said Dr. De Giorgi. It’s crucial to understand that, if these treatments improve mortality outcomes for psychiatric patients, the specific mechanisms involved are secondary to the results. Psychiatrists must be equipped to prescribe, manage, and initiate these therapies.

“While trials involving psychosis patients are ongoing, we are making progress and should seize this opportunity” said Dr. De Giorgi.

Dr. Cryan agreed: “I think we’ll get there. What these drugs have shown is that you can, through a single mechanism, have multitude effects related to brain-body interactions, and why not focus that on mood and anxiety and cognitive performance? It’s exciting no matter what. We now need to do longitudinal, cross-sectional, placebo-controlled trials in specific patient populations.”

This study received funding from the National Institute for Health and Care Research Oxford Health Biomedical Research Centre and Medical Research Council. Dr. De Giorgi’s coauthors reported receiving funding for other work from Novo Nordisk, Five Lives, Cognetivity Ltd., Cognex, P1vital, Lundbeck, Servier, UCB, Zogenix, Johnson & Johnson, and Syndesi. Dr. Cryan reported no relevant disclosures.

A version of this article appeared on Medscape.com.

MILAN — Recent research allaying concerns about suicidality linked to glucagon-like peptide 1 (GLP-1) receptor agonists, along with evidence of these agents’ potential psychiatric and cognitive benefits, has prompted the lead investigator of a major analysis to urge researchers to explore the potential of these drugs for mental illness.

“So far, we’ve been talking about the safety from a neuropsychiatric perspective in diabetes, but there is also the safety and benefit in people with mental disorders,” Riccardo De Giorgi, MD, PhD, from the Department of Psychiatry, University of Oxford in England, said in an interview.

The results of the meta-analysis were previously reported by this news organization and reviewed by Dr. De Giorgi at the 37th European College of Neuropsychopharmacology (ECNP) Congress. Dr. De Giorgi broached whether GLP-1 inhibitors such as semaglutide might also offer the same benefits in patients without diabetes as they do in those with diabetes, in terms of cognitive deficits and substance use or mood disorders.

Noting that GLP-1s are not approved for psychiatric disorders, Dr. De Giorgi said it can’t be assumed that the “metabolic or maybe even more general mechanisms that are being modified with these medications in diabetes or even in obesity are the same for people with psychiatric disorders. We’re talking about very different things. From a clinical perspective, you could do real harm,” he told this news organization.

Yet Dr. De Giorgi emphasized the importance of exploring the potential benefits of these medications in psychiatry.

“From a research perspective ... I am very worried about missing an opportunity here. This happened with rimonabant, a cannabis medication that was used for weight loss back in 2012 and was withdrawn quite dramatically in Europe immediately after licensing because it increased suicide risk. Since then, nobody has been touching the cannabinoid system, and that’s a shame because in psychiatry, we don’t have that much we can work on. So we don’t want to miss an opportunity with the GLP-1 system — that’s why we need to be cautious and look at safety first,” he said.
 

Signal of Efficacy?

Dr. De Giorgi’s research suggested several potential neurobiological effects of GLP-1 inhibition in diabetes research.

“There was a bit of a signal specifically for the big three dementias — vascular, Lewy Body, and frontotemporal — although there was not enough power,” he reported. “We also saw a reduced risk in nicotine misuse, especially amongst other substance use disorders ... and finally a more tentative association for reduced depression.”

He noted that GLP-1s for psychiatric illness likely have limitations and may not cure mental disorders but could help specific subsets of patients. Rather than aiming for large-scale studies, the focus should be on small, incremental studies to advance the research.

Asked by the session chair, John Cryan, PhD, from University College Cork in Ireland, and chair of the ECNP Scientific Committee whether improvement in patients’ mood could be attributed to weight loss, Dr. De Giorgi replied no.

“We now have quite a lot of studies that show that if there is an effect or association it is seen quite a bit earlier than any weight loss. Remember, weight loss takes quite a lot of time, and at quite high doses, but more provocatively, even if that’s the case, does it matter? We as psychiatrists do worry that we need to disentangle these things, but they don’t do that in cardiology, for example. If they see a benefit in mortality they don’t really care if it’s specifically an effect on heart failure or ischemic disease,” said Dr. De Giorgi.

Regardless of their neuropsychiatric potential, the cardiometabolic benefits of GLP-1 inhibitors are sorely needed in the psychiatric population, noted two experts in a recent JAMA Psychiatry viewpoint article.

Sri Mahavir Agarwal, MD, PhD, and Margaret Hahn, MD, PhD, from the University of Toronto and the Schizophrenia Division at the Centre for Addiction and Mental Health, in Toronto, Ontario, Canada, pointed out that “individuals with severe mental illness (SMI) have exceedingly high rates of metabolic comorbidity; three of four are overweight or obese, whereas the prevalence of type 2 diabetes (T2D) is several-fold higher than in the general population. Consequently, individuals with SMI die 15-20 years earlier from cardiovascular disease (CVD) than do those in the general population with CVD,” they noted.

“The arrival of semaglutide has infused significant enthusiasm in the field of mental health research. The proximal effects of weight and related CV comorbidities are significant in themselves. It is plausible that semaglutide could act through neurogenesis or secondary benefits of improving metabolic health on other important outcomes, such as cognitive health and quality of life, thereby filling an unmet need in the treatment of SMI,” Dr. Agarwal and Dr. Hahn added.
 

An Exciting Opportunity

Current research investigating GLP-1s in psychiatry and neurology is increasingly focused on neuroinflammation, said Dr. De Giorgi.

Research shows significant evidence that certain medications may help reduce dysfunctional inflammatory processes linked to various cognitive and psychiatric disorders, he added.

Many patients with established psychiatric conditions also have physical health issues, which contribute to increased mortality risk, said Dr. De Giorgi. It’s crucial to understand that, if these treatments improve mortality outcomes for psychiatric patients, the specific mechanisms involved are secondary to the results. Psychiatrists must be equipped to prescribe, manage, and initiate these therapies.

“While trials involving psychosis patients are ongoing, we are making progress and should seize this opportunity” said Dr. De Giorgi.

Dr. Cryan agreed: “I think we’ll get there. What these drugs have shown is that you can, through a single mechanism, have multitude effects related to brain-body interactions, and why not focus that on mood and anxiety and cognitive performance? It’s exciting no matter what. We now need to do longitudinal, cross-sectional, placebo-controlled trials in specific patient populations.”

This study received funding from the National Institute for Health and Care Research Oxford Health Biomedical Research Centre and Medical Research Council. Dr. De Giorgi’s coauthors reported receiving funding for other work from Novo Nordisk, Five Lives, Cognetivity Ltd., Cognex, P1vital, Lundbeck, Servier, UCB, Zogenix, Johnson & Johnson, and Syndesi. Dr. Cryan reported no relevant disclosures.

A version of this article appeared on Medscape.com.

COPENHAGEN — A higher cumulative genetic burden for depression is associated with an increased risk for relapse and worsening disability in people with multiple sclerosis (MS), early results of a new study showed.

Unlike the previous research, the current analysis used polygenic risk scores for depression, which summarize the estimated effect of genetic variants to determine the potential association with MS disease activity, so results are less likely to be explained by reverse causality.

This study increases awareness of the link between depression and MS, said study investigator Kaarina Kowalec, PhD, assistant professor, College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. “We’re starting to understand how depression affects relapses and disability progression in MS,” she said.

The findings were presented at the 2024 ECTRIMS annual meeting.
 

Common Comorbidity

Depression is a common comorbidity in patients with MS and is associated with increased relapse and disability progression. Depression risk is partly polygenic in nature, involving numerous common genetic variants, said Dr. Kowalec.

The case-control study included 3420 relapsing-onset MS cases of European ancestry from four existing cohorts in three countries.

The Canadian cohort included those enrolled in a prospective longitudinal study of psychiatric comorbidity in chronic immune-mediated inflammatory disease (IMID), including MS; the Swedish cohort was an MS registry (SSReg) that encompasses 64 MS clinics (the cohort was split into two groups); and the US cohort was enrolled in a clinical trial of combined therapy with interferon and glatiramer acetate (CombiRx) in patients with MS.

The median follow-up in these cohorts ranged from 3 to 5 years.

Not surprisingly, most participants were women (from 71% in one of the Swedish cohorts to 83% in the Canadian cohort), and the age at MS onset ranged from 29 years in the Canadian cohort to 35 years in one of the Swedish cohorts.

The median baseline Expanded Disability Status Scale (EDSS) score was higher in the Canadian cohort (3.5) than in the Swedish (1.5) and US (2.0) cohorts, “reflective of the Canadian cohort being slightly more progressed,” said Dr. Kowalec.
 

Inherited Variants

To measure depression heritability, researchers generated a polygenic risk score in whole-genome imputed genotypes. The score reflects the number of inherited common genetic variants, weighted by effect sizes.

Researchers investigated the association between depression polygenic risk scores (top 20% vs. bottom 80%) with annualized relapse rate and worsening disability in MS measured by the rate of change in EDSS score. In the US cohort, they also explored the association between depression polygenic risk scores and time to relapse and confirmed EDSS worsening.

Covariates included use of disease-modifying therapy, age, sex, and the first five genetic ancestry principal components. The latter was done to capture residual stratification by genetic ancestry, although Dr. Kowalec stressed analyses were done only in those of European ancestry.

Investigators found a higher depression polygenic risk score was associated with relapse risk (incident rate ratio, 1.23; 95% CI, 1.01-1.49).

“Essentially, for every one standard deviation increase in the depression polygenic score, we found a significant increased hazard of 23% for experiencing a relapse over the follow-up period,” said Dr. Kowalec, who is also affiliated with the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

She noted the Canadian cohort did not have many relapses, while the US and Swedish cohorts “had an increased rate.”

Other analyses examined the risk of having a relapse or worsening disability. Every one SD increase in the depression polygenic risk score was significantly associated with a 2.2 greater risk of experiencing relapse (hazard ratio [HR], 2.20; 95% CI, 1.35-3.60) and a 51% increased risk for confirmed EDSS progression (HR, 1.51; 95% CI, 1.03-2.22).
 

‘An Ideal Marker’

Use of polygenetic risk scores reduces the possibility of reverse causation, noted Dr. Kowalec. “These markers are fixed at birth and don’t change over your lifespan, so they’re really an ideal marker.”

The results suggest polygenetic risk scores represent a potential biomarker for risk stratification in people with MS, said Dr. Kowalec. Although depression polygenic risk scores are not currently available in clinical practice, “I would hope this would change in the next 3-4 years,” she said.

Asked by a delegate if confounding by a third variable is possible, Dr. Kowalec said because genetic markers don’t change over time, there is a hint that the direction is causal and that depression is driving the outcome. However, she added, further confirmation is needed.

Dr. Kowalec noted that there were no data on antidepressant use but noted that about half of the Canadian and US cohorts — and likely the same number in the Swedish cohorts — self-reported depression.

A limitation of the study was that it included only participants of European ancestry.
 

Clinical Implications Unclear

Commenting on the research, Lauren Gluck, MD, program director, Montefiore Multiple Sclerosis Center, Bronx, New York, described the study as “fascinating” but noted that it’s unclear how to use this new information in clinical practice.

“Clinicians frequently ask people with MS about mood symptoms and offer interventions like antidepressants and referrals to therapists. However, genetic testing is not routine, so we don’t yet know who to target based on these data.”

Preexisting depression or more severe depression could be viewed as a “red flag” for risk for more disease activity in the future, she said.

“This could encourage clinicians to use more highly effective therapy in these patients, similar to our strategies for people with MS with frequent attacks and more disease burden on MRIs.”

The study received support from the Consortium of Multiple Sclerosis Centers and the Congressionally Directed Medical Research Programs, Department of Defense.

Dr. Kowalec reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

COPENHAGEN — A higher cumulative genetic burden for depression is associated with an increased risk for relapse and worsening disability in people with multiple sclerosis (MS), early results of a new study showed.

Unlike the previous research, the current analysis used polygenic risk scores for depression, which summarize the estimated effect of genetic variants to determine the potential association with MS disease activity, so results are less likely to be explained by reverse causality.

This study increases awareness of the link between depression and MS, said study investigator Kaarina Kowalec, PhD, assistant professor, College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. “We’re starting to understand how depression affects relapses and disability progression in MS,” she said.

The findings were presented at the 2024 ECTRIMS annual meeting.
 

Common Comorbidity

Depression is a common comorbidity in patients with MS and is associated with increased relapse and disability progression. Depression risk is partly polygenic in nature, involving numerous common genetic variants, said Dr. Kowalec.

The case-control study included 3420 relapsing-onset MS cases of European ancestry from four existing cohorts in three countries.

The Canadian cohort included those enrolled in a prospective longitudinal study of psychiatric comorbidity in chronic immune-mediated inflammatory disease (IMID), including MS; the Swedish cohort was an MS registry (SSReg) that encompasses 64 MS clinics (the cohort was split into two groups); and the US cohort was enrolled in a clinical trial of combined therapy with interferon and glatiramer acetate (CombiRx) in patients with MS.

The median follow-up in these cohorts ranged from 3 to 5 years.

Not surprisingly, most participants were women (from 71% in one of the Swedish cohorts to 83% in the Canadian cohort), and the age at MS onset ranged from 29 years in the Canadian cohort to 35 years in one of the Swedish cohorts.

The median baseline Expanded Disability Status Scale (EDSS) score was higher in the Canadian cohort (3.5) than in the Swedish (1.5) and US (2.0) cohorts, “reflective of the Canadian cohort being slightly more progressed,” said Dr. Kowalec.
 

Inherited Variants

To measure depression heritability, researchers generated a polygenic risk score in whole-genome imputed genotypes. The score reflects the number of inherited common genetic variants, weighted by effect sizes.

Researchers investigated the association between depression polygenic risk scores (top 20% vs. bottom 80%) with annualized relapse rate and worsening disability in MS measured by the rate of change in EDSS score. In the US cohort, they also explored the association between depression polygenic risk scores and time to relapse and confirmed EDSS worsening.

Covariates included use of disease-modifying therapy, age, sex, and the first five genetic ancestry principal components. The latter was done to capture residual stratification by genetic ancestry, although Dr. Kowalec stressed analyses were done only in those of European ancestry.

Investigators found a higher depression polygenic risk score was associated with relapse risk (incident rate ratio, 1.23; 95% CI, 1.01-1.49).

“Essentially, for every one standard deviation increase in the depression polygenic score, we found a significant increased hazard of 23% for experiencing a relapse over the follow-up period,” said Dr. Kowalec, who is also affiliated with the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

She noted the Canadian cohort did not have many relapses, while the US and Swedish cohorts “had an increased rate.”

Other analyses examined the risk of having a relapse or worsening disability. Every one SD increase in the depression polygenic risk score was significantly associated with a 2.2 greater risk of experiencing relapse (hazard ratio [HR], 2.20; 95% CI, 1.35-3.60) and a 51% increased risk for confirmed EDSS progression (HR, 1.51; 95% CI, 1.03-2.22).
 

‘An Ideal Marker’

Use of polygenetic risk scores reduces the possibility of reverse causation, noted Dr. Kowalec. “These markers are fixed at birth and don’t change over your lifespan, so they’re really an ideal marker.”

The results suggest polygenetic risk scores represent a potential biomarker for risk stratification in people with MS, said Dr. Kowalec. Although depression polygenic risk scores are not currently available in clinical practice, “I would hope this would change in the next 3-4 years,” she said.

Asked by a delegate if confounding by a third variable is possible, Dr. Kowalec said because genetic markers don’t change over time, there is a hint that the direction is causal and that depression is driving the outcome. However, she added, further confirmation is needed.

Dr. Kowalec noted that there were no data on antidepressant use but noted that about half of the Canadian and US cohorts — and likely the same number in the Swedish cohorts — self-reported depression.

A limitation of the study was that it included only participants of European ancestry.
 

Clinical Implications Unclear

Commenting on the research, Lauren Gluck, MD, program director, Montefiore Multiple Sclerosis Center, Bronx, New York, described the study as “fascinating” but noted that it’s unclear how to use this new information in clinical practice.

“Clinicians frequently ask people with MS about mood symptoms and offer interventions like antidepressants and referrals to therapists. However, genetic testing is not routine, so we don’t yet know who to target based on these data.”

Preexisting depression or more severe depression could be viewed as a “red flag” for risk for more disease activity in the future, she said.

“This could encourage clinicians to use more highly effective therapy in these patients, similar to our strategies for people with MS with frequent attacks and more disease burden on MRIs.”

The study received support from the Consortium of Multiple Sclerosis Centers and the Congressionally Directed Medical Research Programs, Department of Defense.

Dr. Kowalec reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

COPENHAGEN — A higher cumulative genetic burden for depression is associated with an increased risk for relapse and worsening disability in people with multiple sclerosis (MS), early results of a new study showed.

Unlike the previous research, the current analysis used polygenic risk scores for depression, which summarize the estimated effect of genetic variants to determine the potential association with MS disease activity, so results are less likely to be explained by reverse causality.

This study increases awareness of the link between depression and MS, said study investigator Kaarina Kowalec, PhD, assistant professor, College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. “We’re starting to understand how depression affects relapses and disability progression in MS,” she said.

The findings were presented at the 2024 ECTRIMS annual meeting.
 

Common Comorbidity

Depression is a common comorbidity in patients with MS and is associated with increased relapse and disability progression. Depression risk is partly polygenic in nature, involving numerous common genetic variants, said Dr. Kowalec.

The case-control study included 3420 relapsing-onset MS cases of European ancestry from four existing cohorts in three countries.

The Canadian cohort included those enrolled in a prospective longitudinal study of psychiatric comorbidity in chronic immune-mediated inflammatory disease (IMID), including MS; the Swedish cohort was an MS registry (SSReg) that encompasses 64 MS clinics (the cohort was split into two groups); and the US cohort was enrolled in a clinical trial of combined therapy with interferon and glatiramer acetate (CombiRx) in patients with MS.

The median follow-up in these cohorts ranged from 3 to 5 years.

Not surprisingly, most participants were women (from 71% in one of the Swedish cohorts to 83% in the Canadian cohort), and the age at MS onset ranged from 29 years in the Canadian cohort to 35 years in one of the Swedish cohorts.

The median baseline Expanded Disability Status Scale (EDSS) score was higher in the Canadian cohort (3.5) than in the Swedish (1.5) and US (2.0) cohorts, “reflective of the Canadian cohort being slightly more progressed,” said Dr. Kowalec.
 

Inherited Variants

To measure depression heritability, researchers generated a polygenic risk score in whole-genome imputed genotypes. The score reflects the number of inherited common genetic variants, weighted by effect sizes.

Researchers investigated the association between depression polygenic risk scores (top 20% vs. bottom 80%) with annualized relapse rate and worsening disability in MS measured by the rate of change in EDSS score. In the US cohort, they also explored the association between depression polygenic risk scores and time to relapse and confirmed EDSS worsening.

Covariates included use of disease-modifying therapy, age, sex, and the first five genetic ancestry principal components. The latter was done to capture residual stratification by genetic ancestry, although Dr. Kowalec stressed analyses were done only in those of European ancestry.

Investigators found a higher depression polygenic risk score was associated with relapse risk (incident rate ratio, 1.23; 95% CI, 1.01-1.49).

“Essentially, for every one standard deviation increase in the depression polygenic score, we found a significant increased hazard of 23% for experiencing a relapse over the follow-up period,” said Dr. Kowalec, who is also affiliated with the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

She noted the Canadian cohort did not have many relapses, while the US and Swedish cohorts “had an increased rate.”

Other analyses examined the risk of having a relapse or worsening disability. Every one SD increase in the depression polygenic risk score was significantly associated with a 2.2 greater risk of experiencing relapse (hazard ratio [HR], 2.20; 95% CI, 1.35-3.60) and a 51% increased risk for confirmed EDSS progression (HR, 1.51; 95% CI, 1.03-2.22).
 

‘An Ideal Marker’

Use of polygenetic risk scores reduces the possibility of reverse causation, noted Dr. Kowalec. “These markers are fixed at birth and don’t change over your lifespan, so they’re really an ideal marker.”

The results suggest polygenetic risk scores represent a potential biomarker for risk stratification in people with MS, said Dr. Kowalec. Although depression polygenic risk scores are not currently available in clinical practice, “I would hope this would change in the next 3-4 years,” she said.

Asked by a delegate if confounding by a third variable is possible, Dr. Kowalec said because genetic markers don’t change over time, there is a hint that the direction is causal and that depression is driving the outcome. However, she added, further confirmation is needed.

Dr. Kowalec noted that there were no data on antidepressant use but noted that about half of the Canadian and US cohorts — and likely the same number in the Swedish cohorts — self-reported depression.

A limitation of the study was that it included only participants of European ancestry.
 

Clinical Implications Unclear

Commenting on the research, Lauren Gluck, MD, program director, Montefiore Multiple Sclerosis Center, Bronx, New York, described the study as “fascinating” but noted that it’s unclear how to use this new information in clinical practice.

“Clinicians frequently ask people with MS about mood symptoms and offer interventions like antidepressants and referrals to therapists. However, genetic testing is not routine, so we don’t yet know who to target based on these data.”

Preexisting depression or more severe depression could be viewed as a “red flag” for risk for more disease activity in the future, she said.

“This could encourage clinicians to use more highly effective therapy in these patients, similar to our strategies for people with MS with frequent attacks and more disease burden on MRIs.”

The study received support from the Consortium of Multiple Sclerosis Centers and the Congressionally Directed Medical Research Programs, Department of Defense.

Dr. Kowalec reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Diabetes and prediabetes are associated with accelerated brain aging with brain age gaps of 2.29 and 0.50 years, respectively. This association is more pronounced in men and those with poor cardiometabolic health but may be mitigated by a healthy lifestyle.

METHODOLOGY:

• Diabetes is a known risk factor for cognitive impairment, dementia, and global brain atrophy but conflicting results have been reported for prediabetes, and it’s unknown whether a healthy lifestyle can counteract the negative impact of prediabetes.
• Researchers examined the cross-sectional and longitudinal relationship between hyperglycemia and brain aging, as well as the potential mitigating effect of a healthy lifestyle in 31,229 dementia-free adults (mean age, 54.8 years; 53% women) from the UK Biobank, including 13,518 participants with prediabetes and 1149 with diabetes.
• The glycemic status of the participants was determined by their medical history, medication use, and A1c levels.
• The brain age gap was calculated as a difference between chronologic age and brain age estimated from MRI data from six modalities vs several hundred brain MRI phenotypes that were modeled from a subset of healthy individuals.
• The role of sex, cardiometabolic risk factors, and a healthy lifestyle and their association with brain age was also explored, with a healthy lifestyle defined as never smoking, no or light or moderate alcohol consumption, and high physical activity.

TAKEAWAY:

• Prediabetes and diabetes were associated with a higher brain age gap than normoglycemia (beta-coefficient, 0.22 and 2.01; 95% CI, 0.10-0.34 and 1.70-2.32, respectively), and diabetes was more pronounced in men vs women and those with a higher vs lower burden of cardiometabolic risk factors.
• The brain ages of those with prediabetes and diabetes were 0.50 years and 2.29 years older on average than their respective chronologic ages.
• In an exploratory longitudinal analysis of the 2414 participants with two brain MRI scans, diabetes was linked to a 0.27-year annual increase in the brain age gap, and higher A1c, but not prediabetes, was associated with a significant increase in brain age gap.
• A healthy lifestyle attenuated the association between diabetes and a higher brain age gap (P = .003), reducing it by 1.68 years, also with a significant interaction between glycemic status and lifestyle.

IN PRACTICE:

“Our findings highlight diabetes and prediabetes as ideal targets for lifestyle-based interventions to promote brain health,” the authors wrote.

SOURCE:

This study, led by Abigail Dove, Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden, was published online in Diabetes Care.

LIMITATIONS:

The generalizability of the findings was limited due to a healthy volunteer bias in the UK Biobank. A high proportion of missing data prevented the inclusion of diet in the healthy lifestyle construct. Reverse causality may be possible as an older brain may contribute to the development of prediabetes by making it more difficult to manage medical conditions and adhere to a healthy lifestyle. A1c levels were measured only at baseline, preventing the assessment of changes in glycemic control over time.

DISCLOSURES:

The authors reported receiving funding from the Swedish Research Council; Swedish Research Council for Health, Working Life and Welfare; Karolinska Institutet Board of Research; Riksbankens Jubileumsfond; Marianne and Marcus Wallenberg Foundation; Alzheimerfonden; and Demensfonden. They declared no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Diabetes and prediabetes are associated with accelerated brain aging with brain age gaps of 2.29 and 0.50 years, respectively. This association is more pronounced in men and those with poor cardiometabolic health but may be mitigated by a healthy lifestyle.

METHODOLOGY:

• Diabetes is a known risk factor for cognitive impairment, dementia, and global brain atrophy but conflicting results have been reported for prediabetes, and it’s unknown whether a healthy lifestyle can counteract the negative impact of prediabetes.
• Researchers examined the cross-sectional and longitudinal relationship between hyperglycemia and brain aging, as well as the potential mitigating effect of a healthy lifestyle in 31,229 dementia-free adults (mean age, 54.8 years; 53% women) from the UK Biobank, including 13,518 participants with prediabetes and 1149 with diabetes.
• The glycemic status of the participants was determined by their medical history, medication use, and A1c levels.
• The brain age gap was calculated as a difference between chronologic age and brain age estimated from MRI data from six modalities vs several hundred brain MRI phenotypes that were modeled from a subset of healthy individuals.
• The role of sex, cardiometabolic risk factors, and a healthy lifestyle and their association with brain age was also explored, with a healthy lifestyle defined as never smoking, no or light or moderate alcohol consumption, and high physical activity.

TAKEAWAY:

• Prediabetes and diabetes were associated with a higher brain age gap than normoglycemia (beta-coefficient, 0.22 and 2.01; 95% CI, 0.10-0.34 and 1.70-2.32, respectively), and diabetes was more pronounced in men vs women and those with a higher vs lower burden of cardiometabolic risk factors.
• The brain ages of those with prediabetes and diabetes were 0.50 years and 2.29 years older on average than their respective chronologic ages.
• In an exploratory longitudinal analysis of the 2414 participants with two brain MRI scans, diabetes was linked to a 0.27-year annual increase in the brain age gap, and higher A1c, but not prediabetes, was associated with a significant increase in brain age gap.
• A healthy lifestyle attenuated the association between diabetes and a higher brain age gap (P = .003), reducing it by 1.68 years, also with a significant interaction between glycemic status and lifestyle.

IN PRACTICE:

“Our findings highlight diabetes and prediabetes as ideal targets for lifestyle-based interventions to promote brain health,” the authors wrote.

SOURCE:

This study, led by Abigail Dove, Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden, was published online in Diabetes Care.

LIMITATIONS:

The generalizability of the findings was limited due to a healthy volunteer bias in the UK Biobank. A high proportion of missing data prevented the inclusion of diet in the healthy lifestyle construct. Reverse causality may be possible as an older brain may contribute to the development of prediabetes by making it more difficult to manage medical conditions and adhere to a healthy lifestyle. A1c levels were measured only at baseline, preventing the assessment of changes in glycemic control over time.

DISCLOSURES:

The authors reported receiving funding from the Swedish Research Council; Swedish Research Council for Health, Working Life and Welfare; Karolinska Institutet Board of Research; Riksbankens Jubileumsfond; Marianne and Marcus Wallenberg Foundation; Alzheimerfonden; and Demensfonden. They declared no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Diabetes and prediabetes are associated with accelerated brain aging with brain age gaps of 2.29 and 0.50 years, respectively. This association is more pronounced in men and those with poor cardiometabolic health but may be mitigated by a healthy lifestyle.

METHODOLOGY:

• Diabetes is a known risk factor for cognitive impairment, dementia, and global brain atrophy but conflicting results have been reported for prediabetes, and it’s unknown whether a healthy lifestyle can counteract the negative impact of prediabetes.
• Researchers examined the cross-sectional and longitudinal relationship between hyperglycemia and brain aging, as well as the potential mitigating effect of a healthy lifestyle in 31,229 dementia-free adults (mean age, 54.8 years; 53% women) from the UK Biobank, including 13,518 participants with prediabetes and 1149 with diabetes.
• The glycemic status of the participants was determined by their medical history, medication use, and A1c levels.
• The brain age gap was calculated as a difference between chronologic age and brain age estimated from MRI data from six modalities vs several hundred brain MRI phenotypes that were modeled from a subset of healthy individuals.
• The role of sex, cardiometabolic risk factors, and a healthy lifestyle and their association with brain age was also explored, with a healthy lifestyle defined as never smoking, no or light or moderate alcohol consumption, and high physical activity.

TAKEAWAY:

• Prediabetes and diabetes were associated with a higher brain age gap than normoglycemia (beta-coefficient, 0.22 and 2.01; 95% CI, 0.10-0.34 and 1.70-2.32, respectively), and diabetes was more pronounced in men vs women and those with a higher vs lower burden of cardiometabolic risk factors.
• The brain ages of those with prediabetes and diabetes were 0.50 years and 2.29 years older on average than their respective chronologic ages.
• In an exploratory longitudinal analysis of the 2414 participants with two brain MRI scans, diabetes was linked to a 0.27-year annual increase in the brain age gap, and higher A1c, but not prediabetes, was associated with a significant increase in brain age gap.
• A healthy lifestyle attenuated the association between diabetes and a higher brain age gap (P = .003), reducing it by 1.68 years, also with a significant interaction between glycemic status and lifestyle.

IN PRACTICE:

“Our findings highlight diabetes and prediabetes as ideal targets for lifestyle-based interventions to promote brain health,” the authors wrote.

SOURCE:

This study, led by Abigail Dove, Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden, was published online in Diabetes Care.

LIMITATIONS:

The generalizability of the findings was limited due to a healthy volunteer bias in the UK Biobank. A high proportion of missing data prevented the inclusion of diet in the healthy lifestyle construct. Reverse causality may be possible as an older brain may contribute to the development of prediabetes by making it more difficult to manage medical conditions and adhere to a healthy lifestyle. A1c levels were measured only at baseline, preventing the assessment of changes in glycemic control over time.

DISCLOSURES:

The authors reported receiving funding from the Swedish Research Council; Swedish Research Council for Health, Working Life and Welfare; Karolinska Institutet Board of Research; Riksbankens Jubileumsfond; Marianne and Marcus Wallenberg Foundation; Alzheimerfonden; and Demensfonden. They declared no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Air pollution, high temperatures, and metabolic risk factors are driving global increases in stroke, contributing to 12 million cases and more than 7 million deaths from stroke each year, new data from the Global Burden of Disease (GBD) study showed.

Between 1990 and 2021, the number of people who experienced a stroke increased to 11.9 million (up by 70% since 1990), while the number of stroke survivors rose to 93.8 million (up by 86%), and stroke-related deaths rose to 7.3 million (up by 44%), making stroke the third leading cause of death worldwide after ischemic heart disease and COVID-19, investigators found.

Stroke is highly preventable, the investigators noted, with 84% of the stroke burden in 2021 attributable to 23 modifiable risk factors, including air pollution, excess body weight, high blood pressure, smoking, and physical inactivity.

This means there are “tremendous opportunities to alter the trajectory of stroke risk for the next generation,” Catherine O. Johnson, MPH, PhD, co-author and lead research scientist at the Institute for Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.

The study was published online in The Lancet Neurology.
 

Top Risk Factor for Subarachnoid Hemorrhage

Since 1990, the contribution of high temperatures to poor health and early death due to stroke has risen 72%, a trend likely to increase in the future — underscoring the impact of environmental factors on the growing stroke burden, the authors said.

“Given that ambient air pollution is reciprocally linked with ambient temperature and climate change, the importance of urgent climate actions and measures to reduce air pollution cannot be overestimated,” Dr. Johnson said.

Mitchell S.V. Elkind, MD, MS, chief clinical science officer for the American Heart Association, who wasn’t involved in the study, told this news organization that environmental factors such as air pollution, particulate matter from wildfires and other sources, and excessive heat are now recognized as major contributors to the risk for stroke. “This should not be surprising as we have long recognized the risks of stroke associated with toxins in cigarette smoke, which likely share mechanisms for vascular damage with pollutants,” Dr. Elkind said.

The data also reveal for the first time that ambient particulate matter air pollution is a top risk factor for subarachnoid hemorrhage, contributing to 14% of the death and disability caused by this serious stroke subtype, on a par with smoking.

Dr. Elkind noted that smoking is “a major risk factor for subarachnoid hemorrhage. It makes sense that particulate air pollution would therefore similarly be a risk factor for subarachnoid hemorrhage, which similarly damages blood vessels. Prior studies were likely too small or did not assess the role of air pollution in subarachnoid hemorrhage.”

The analysis also showed substantial increases between 1990 and 2021 in the global stroke burden linked to high body mass index (up by 88%), high blood sugar (up 32%), a diet high in sugar-sweetened drinks (up 23%), low physical activity (up 11%), high systolic blood pressure (up 7%), and a diet low in omega-6 polyunsaturated fatty acids (up 5%).

“And with increasing exposure to risk factors such as high blood sugar and diet high in sugar-sweetened drinks, there is a critical need for interventions focused on obesity and metabolic syndromes,” Dr. Johnson said.

“Identifying sustainable ways to work with communities to take action to prevent and control modifiable risk factors for stroke is essential to address this growing crisis,” she added.
 

Prevention Strategies Fall Short

The data also showed that stroke-related disability-adjusted life-years rose from around 121.4 million years of healthy life lost in 1990 to 160.5 million years in 2021, making stroke the fourth leading cause of health loss worldwide after COVID-19, ischemic heart disease, and neonatal disorders.

“The global growth of the number of people who develop stroke and died from or remain disabled by stroke is growing fast, strongly suggesting that currently used stroke prevention strategies are not sufficiently effective,” lead author Valery L. Feigin, MD, PhD, from Auckland University of Technology, Auckland, New Zealand, and affiliate professor at IHME, said in the release.

“New, proven effective population-wide and motivational individual prevention strategies that could be applied to all people at risk of having a stroke, regardless of the level of risk, as recommended in the recent Lancet Neurology Commission on Stroke should be implemented across the globe urgently,” said Dr. Feigin.

Dr. Elkind said the AHA supports research on the effects of air quality on risk for vascular injury and stroke and has “long advocated for policies to mitigate the adverse health impacts of air pollutants, including reduction of vehicle emissions and renewable portfolio standards, taking into account racial, ethnic, and economic disparities.”

“AHA, and the healthcare sector more broadly, must take a leadership role in recommending policies to improve environmental air quality and in working with the private sector and industry to improve air quality,” Dr. Elkind said.

In an accompanying commentary, Ming Liu, MD, and Simiao Wu, MD, PhD, West China Hospital, Sichuan University, Chengdu, China, wrote that “pragmatic solutions to the enormous and increasing stroke burden include surveillance, prevention, acute care, and rehabilitation.”

“Surveillance strategies include establishing a national-level framework for regular monitoring of stroke burden, risk factors, and healthcare services via community-based surveys and health records,” they noted.

“Artificial intelligence and mobile technologies might not only facilitate the dissemination of evidence-based health services but also increase the number of data sources and encourage participation of multidisciplinary collaborators, potentially improving the validity and accuracy of future GBD estimates,” they added.

This study was funded by the Bill & Melinda Gates Foundation. Author disclosures are listed with the original article.

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

Air pollution, high temperatures, and metabolic risk factors are driving global increases in stroke, contributing to 12 million cases and more than 7 million deaths from stroke each year, new data from the Global Burden of Disease (GBD) study showed.

Between 1990 and 2021, the number of people who experienced a stroke increased to 11.9 million (up by 70% since 1990), while the number of stroke survivors rose to 93.8 million (up by 86%), and stroke-related deaths rose to 7.3 million (up by 44%), making stroke the third leading cause of death worldwide after ischemic heart disease and COVID-19, investigators found.

Stroke is highly preventable, the investigators noted, with 84% of the stroke burden in 2021 attributable to 23 modifiable risk factors, including air pollution, excess body weight, high blood pressure, smoking, and physical inactivity.

This means there are “tremendous opportunities to alter the trajectory of stroke risk for the next generation,” Catherine O. Johnson, MPH, PhD, co-author and lead research scientist at the Institute for Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.

The study was published online in The Lancet Neurology.
 

Top Risk Factor for Subarachnoid Hemorrhage

Since 1990, the contribution of high temperatures to poor health and early death due to stroke has risen 72%, a trend likely to increase in the future — underscoring the impact of environmental factors on the growing stroke burden, the authors said.

“Given that ambient air pollution is reciprocally linked with ambient temperature and climate change, the importance of urgent climate actions and measures to reduce air pollution cannot be overestimated,” Dr. Johnson said.

Mitchell S.V. Elkind, MD, MS, chief clinical science officer for the American Heart Association, who wasn’t involved in the study, told this news organization that environmental factors such as air pollution, particulate matter from wildfires and other sources, and excessive heat are now recognized as major contributors to the risk for stroke. “This should not be surprising as we have long recognized the risks of stroke associated with toxins in cigarette smoke, which likely share mechanisms for vascular damage with pollutants,” Dr. Elkind said.

The data also reveal for the first time that ambient particulate matter air pollution is a top risk factor for subarachnoid hemorrhage, contributing to 14% of the death and disability caused by this serious stroke subtype, on a par with smoking.

Dr. Elkind noted that smoking is “a major risk factor for subarachnoid hemorrhage. It makes sense that particulate air pollution would therefore similarly be a risk factor for subarachnoid hemorrhage, which similarly damages blood vessels. Prior studies were likely too small or did not assess the role of air pollution in subarachnoid hemorrhage.”

The analysis also showed substantial increases between 1990 and 2021 in the global stroke burden linked to high body mass index (up by 88%), high blood sugar (up 32%), a diet high in sugar-sweetened drinks (up 23%), low physical activity (up 11%), high systolic blood pressure (up 7%), and a diet low in omega-6 polyunsaturated fatty acids (up 5%).

“And with increasing exposure to risk factors such as high blood sugar and diet high in sugar-sweetened drinks, there is a critical need for interventions focused on obesity and metabolic syndromes,” Dr. Johnson said.

“Identifying sustainable ways to work with communities to take action to prevent and control modifiable risk factors for stroke is essential to address this growing crisis,” she added.
 

Prevention Strategies Fall Short

The data also showed that stroke-related disability-adjusted life-years rose from around 121.4 million years of healthy life lost in 1990 to 160.5 million years in 2021, making stroke the fourth leading cause of health loss worldwide after COVID-19, ischemic heart disease, and neonatal disorders.

“The global growth of the number of people who develop stroke and died from or remain disabled by stroke is growing fast, strongly suggesting that currently used stroke prevention strategies are not sufficiently effective,” lead author Valery L. Feigin, MD, PhD, from Auckland University of Technology, Auckland, New Zealand, and affiliate professor at IHME, said in the release.

“New, proven effective population-wide and motivational individual prevention strategies that could be applied to all people at risk of having a stroke, regardless of the level of risk, as recommended in the recent Lancet Neurology Commission on Stroke should be implemented across the globe urgently,” said Dr. Feigin.

Dr. Elkind said the AHA supports research on the effects of air quality on risk for vascular injury and stroke and has “long advocated for policies to mitigate the adverse health impacts of air pollutants, including reduction of vehicle emissions and renewable portfolio standards, taking into account racial, ethnic, and economic disparities.”

“AHA, and the healthcare sector more broadly, must take a leadership role in recommending policies to improve environmental air quality and in working with the private sector and industry to improve air quality,” Dr. Elkind said.

In an accompanying commentary, Ming Liu, MD, and Simiao Wu, MD, PhD, West China Hospital, Sichuan University, Chengdu, China, wrote that “pragmatic solutions to the enormous and increasing stroke burden include surveillance, prevention, acute care, and rehabilitation.”

“Surveillance strategies include establishing a national-level framework for regular monitoring of stroke burden, risk factors, and healthcare services via community-based surveys and health records,” they noted.

“Artificial intelligence and mobile technologies might not only facilitate the dissemination of evidence-based health services but also increase the number of data sources and encourage participation of multidisciplinary collaborators, potentially improving the validity and accuracy of future GBD estimates,” they added.

This study was funded by the Bill & Melinda Gates Foundation. Author disclosures are listed with the original article.

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

Air pollution, high temperatures, and metabolic risk factors are driving global increases in stroke, contributing to 12 million cases and more than 7 million deaths from stroke each year, new data from the Global Burden of Disease (GBD) study showed.

Between 1990 and 2021, the number of people who experienced a stroke increased to 11.9 million (up by 70% since 1990), while the number of stroke survivors rose to 93.8 million (up by 86%), and stroke-related deaths rose to 7.3 million (up by 44%), making stroke the third leading cause of death worldwide after ischemic heart disease and COVID-19, investigators found.

Stroke is highly preventable, the investigators noted, with 84% of the stroke burden in 2021 attributable to 23 modifiable risk factors, including air pollution, excess body weight, high blood pressure, smoking, and physical inactivity.

This means there are “tremendous opportunities to alter the trajectory of stroke risk for the next generation,” Catherine O. Johnson, MPH, PhD, co-author and lead research scientist at the Institute for Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.

The study was published online in The Lancet Neurology.
 

Top Risk Factor for Subarachnoid Hemorrhage

Since 1990, the contribution of high temperatures to poor health and early death due to stroke has risen 72%, a trend likely to increase in the future — underscoring the impact of environmental factors on the growing stroke burden, the authors said.

“Given that ambient air pollution is reciprocally linked with ambient temperature and climate change, the importance of urgent climate actions and measures to reduce air pollution cannot be overestimated,” Dr. Johnson said.

Mitchell S.V. Elkind, MD, MS, chief clinical science officer for the American Heart Association, who wasn’t involved in the study, told this news organization that environmental factors such as air pollution, particulate matter from wildfires and other sources, and excessive heat are now recognized as major contributors to the risk for stroke. “This should not be surprising as we have long recognized the risks of stroke associated with toxins in cigarette smoke, which likely share mechanisms for vascular damage with pollutants,” Dr. Elkind said.

The data also reveal for the first time that ambient particulate matter air pollution is a top risk factor for subarachnoid hemorrhage, contributing to 14% of the death and disability caused by this serious stroke subtype, on a par with smoking.

Dr. Elkind noted that smoking is “a major risk factor for subarachnoid hemorrhage. It makes sense that particulate air pollution would therefore similarly be a risk factor for subarachnoid hemorrhage, which similarly damages blood vessels. Prior studies were likely too small or did not assess the role of air pollution in subarachnoid hemorrhage.”

The analysis also showed substantial increases between 1990 and 2021 in the global stroke burden linked to high body mass index (up by 88%), high blood sugar (up 32%), a diet high in sugar-sweetened drinks (up 23%), low physical activity (up 11%), high systolic blood pressure (up 7%), and a diet low in omega-6 polyunsaturated fatty acids (up 5%).

“And with increasing exposure to risk factors such as high blood sugar and diet high in sugar-sweetened drinks, there is a critical need for interventions focused on obesity and metabolic syndromes,” Dr. Johnson said.

“Identifying sustainable ways to work with communities to take action to prevent and control modifiable risk factors for stroke is essential to address this growing crisis,” she added.
 

Prevention Strategies Fall Short

The data also showed that stroke-related disability-adjusted life-years rose from around 121.4 million years of healthy life lost in 1990 to 160.5 million years in 2021, making stroke the fourth leading cause of health loss worldwide after COVID-19, ischemic heart disease, and neonatal disorders.

“The global growth of the number of people who develop stroke and died from or remain disabled by stroke is growing fast, strongly suggesting that currently used stroke prevention strategies are not sufficiently effective,” lead author Valery L. Feigin, MD, PhD, from Auckland University of Technology, Auckland, New Zealand, and affiliate professor at IHME, said in the release.

“New, proven effective population-wide and motivational individual prevention strategies that could be applied to all people at risk of having a stroke, regardless of the level of risk, as recommended in the recent Lancet Neurology Commission on Stroke should be implemented across the globe urgently,” said Dr. Feigin.

Dr. Elkind said the AHA supports research on the effects of air quality on risk for vascular injury and stroke and has “long advocated for policies to mitigate the adverse health impacts of air pollutants, including reduction of vehicle emissions and renewable portfolio standards, taking into account racial, ethnic, and economic disparities.”

“AHA, and the healthcare sector more broadly, must take a leadership role in recommending policies to improve environmental air quality and in working with the private sector and industry to improve air quality,” Dr. Elkind said.

In an accompanying commentary, Ming Liu, MD, and Simiao Wu, MD, PhD, West China Hospital, Sichuan University, Chengdu, China, wrote that “pragmatic solutions to the enormous and increasing stroke burden include surveillance, prevention, acute care, and rehabilitation.”

“Surveillance strategies include establishing a national-level framework for regular monitoring of stroke burden, risk factors, and healthcare services via community-based surveys and health records,” they noted.

“Artificial intelligence and mobile technologies might not only facilitate the dissemination of evidence-based health services but also increase the number of data sources and encourage participation of multidisciplinary collaborators, potentially improving the validity and accuracy of future GBD estimates,” they added.

This study was funded by the Bill & Melinda Gates Foundation. Author disclosures are listed with the original article.

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