Neurology

DENVER – In the ongoing absence of a reliable biomarker for multiple sclerosis (MS), misdiagnosis is a common and persistent problem that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.

“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.

For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.

The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.

A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.

The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
 

The dangers of misdiagnosis

Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.

“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.

There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.

For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.

Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.

In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
 

Best hope for an accurate diagnosis

In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.

Dr. Coyle said that a comprehensive workup should include:

• A thorough neurologic history and exam.
• MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
• Adding spinal fluid evaluation, especially in any atypical cases.
• Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.

“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.

Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.

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

DENVER – In the ongoing absence of a reliable biomarker for multiple sclerosis (MS), misdiagnosis is a common and persistent problem that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.

“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.

For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.

The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.

A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.

The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
 

The dangers of misdiagnosis

Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.

“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.

There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.

For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.

Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.

In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
 

Best hope for an accurate diagnosis

In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.

Dr. Coyle said that a comprehensive workup should include:

• A thorough neurologic history and exam.
• MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
• Adding spinal fluid evaluation, especially in any atypical cases.
• Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.

“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.

Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.

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

DENVER – In the ongoing absence of a reliable biomarker for multiple sclerosis (MS), misdiagnosis is a common and persistent problem that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.

“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.

For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.

The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.

A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.

The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
 

The dangers of misdiagnosis

Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.

“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.

There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.

For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.

Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.

In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
 

Best hope for an accurate diagnosis

In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.

Dr. Coyle said that a comprehensive workup should include:

• A thorough neurologic history and exam.
• MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
• Adding spinal fluid evaluation, especially in any atypical cases.
• Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.

“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.

Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.

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

Intranasal (IN) ketamine may be a feasible treatment alternative for people with chronic, refractory migraine who don’t respond to other medications, new research shows.

Half of the study participants who used IN ketamine for chronic, treatment-refractory migraine in a new retrospective cohort study reported it as “very effective” and over one-third said it boosted their quality of life.

“In our study, we showed that with even a few uses per day, intranasal ketamine can still improve patients’ quality of life,” lead investigator Hsiangkuo Yuan, MD, PhD, said in an interview. Dr. Yuan is associate professor of neurology at Thomas Jefferson University, Philadelphia, and director of clinical research at the Jefferson Headache Center.

He added that “multiple medications failed these patients, and the majority of patients were having daily headaches. So, if anything works, even partially and shortly, it may still give patients some relief to get through the day.”

The findings were published online in Regional Anesthesia & Pain Medicine.  
 

Daily migraine, failed medications

Use of IN ketamine has not been studied for the treatment of chronic, treatment-refractory migraine – although it has been studied in patients with cluster headache and migraine, the investigators note.

Ketamine is not yet approved by the Food and Drug Administration to treat migraine.

To further explore ketamine’s effect in those with chronic, treatment-refractory migraine, the investigators retrospectively analyzed electronic health records of patients at the Jefferson Headache Center who had received IN ketamine for the treatment of migraine between January 2019 and February 2020.

Of 242 patients who had received IN ketamine, Dr. Yuan’s team followed up with 169 who agreed to be part of the study.

The majority (67%) had daily migraine, and 85% had tried more than three classes of preventive medications for migraine. They currently used a median of two medications, the most common of which was a CGRP monoclonal antibody.

On average, patients used six sprays per day for a median 10 days per month. Median pain relief onset was 52 minutes after dosage.

Almost three-quarters of patients reported at least one side effect from the ketamine, most commonly fatigue (22%), double/blurred vision (21%), and confusion/dissociation (21%). These effects were mostly temporary, the researchers report.

The most common reasons for initiating IN ketamine included an incomplete response to prior acute medications (59%), incomplete response to prior preventive medications (31%), and prior benefit from IV ketamine (23%).

Study investigators noted that ketamine has the potential to become addictive and indicated that “clinicians should only consider the use of a potentially addictive medication such as ketamine for significantly disabled patients with migraine.”

About half of the participants who used IN ketamine found it “very effective,” and 40% found it “somewhat effective.” Within the same group, 36% and 43% found the overall impact of IN ketamine on their quality of life was much better and somewhat better, respectively.

Among those still using ketamine during study follow-up, 82% reported that ketamine was very effective.

Compared with other acute headache medications, IN ketamine was considered much better (43%) or somewhat better (30%).

Nearly 75% of participants reported using fewer pain relievers when using IN ketamine.

Dr. Yuan said that future research might focus on finding predictors for IN ketamine response or determining the optimal effective and safe dose for the drug in those with chronic, treatment-refractory migraine.  

“We still need a prospective, randomized controlled trial to assess the efficacy and tolerability of intranasal ketamine,” he added.
 

‘Impressive result’

Commenting on the findings for this article, Richard Lipton, MD, professor of neurology, psychiatry and behavioral sciences and director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, said that “in this refractory population with multiple treatment failures, this is a very impressive, open-label result.”

“This real-world data suggests that ketamine is an effective option for people with medically intractable chronic migraine,” said Dr. Lipton, who was not part of the study. “In these very difficult to treat patients, 65% of those who started on ketamine persisted. Of those who remained on ketamine, 82% found it very effective.”

“This study makes me more confident that intranasal ketamine is a helpful treatment option, and I plan to use it more often in the future,” he added.

Like Dr. Yuan, Dr. Lipton highlighted the need for “well-designed placebo-controlled trials” and “rigorous comparative effectiveness studies.”

The study was funded by Miles for Migraine. Dr. Yuan has received institutional support for serving as an investigator from Teva and AbbVie, and royalties from Cambridge University Press and MedLink. Dr. Lipton has received compensation for consultation from Alder/Lumbeck, Axsome, Supernus, Theranica, Upsher-Smith, and Satsuma. He has participated in speaker bureaus for Eli Lilly and Amgen/Novartis and has received institutional support for serving as principal investigator from Teva, GammaCore, and Allergan/AbbVie. He has received payments for authorship or royalties from Demos Medical, Cambridge University Press, and MedLink.

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

Intranasal (IN) ketamine may be a feasible treatment alternative for people with chronic, refractory migraine who don’t respond to other medications, new research shows.

Half of the study participants who used IN ketamine for chronic, treatment-refractory migraine in a new retrospective cohort study reported it as “very effective” and over one-third said it boosted their quality of life.

“In our study, we showed that with even a few uses per day, intranasal ketamine can still improve patients’ quality of life,” lead investigator Hsiangkuo Yuan, MD, PhD, said in an interview. Dr. Yuan is associate professor of neurology at Thomas Jefferson University, Philadelphia, and director of clinical research at the Jefferson Headache Center.

He added that “multiple medications failed these patients, and the majority of patients were having daily headaches. So, if anything works, even partially and shortly, it may still give patients some relief to get through the day.”

The findings were published online in Regional Anesthesia & Pain Medicine.  
 

Daily migraine, failed medications

Use of IN ketamine has not been studied for the treatment of chronic, treatment-refractory migraine – although it has been studied in patients with cluster headache and migraine, the investigators note.

Ketamine is not yet approved by the Food and Drug Administration to treat migraine.

To further explore ketamine’s effect in those with chronic, treatment-refractory migraine, the investigators retrospectively analyzed electronic health records of patients at the Jefferson Headache Center who had received IN ketamine for the treatment of migraine between January 2019 and February 2020.

Of 242 patients who had received IN ketamine, Dr. Yuan’s team followed up with 169 who agreed to be part of the study.

The majority (67%) had daily migraine, and 85% had tried more than three classes of preventive medications for migraine. They currently used a median of two medications, the most common of which was a CGRP monoclonal antibody.

On average, patients used six sprays per day for a median 10 days per month. Median pain relief onset was 52 minutes after dosage.

Almost three-quarters of patients reported at least one side effect from the ketamine, most commonly fatigue (22%), double/blurred vision (21%), and confusion/dissociation (21%). These effects were mostly temporary, the researchers report.

The most common reasons for initiating IN ketamine included an incomplete response to prior acute medications (59%), incomplete response to prior preventive medications (31%), and prior benefit from IV ketamine (23%).

Study investigators noted that ketamine has the potential to become addictive and indicated that “clinicians should only consider the use of a potentially addictive medication such as ketamine for significantly disabled patients with migraine.”

About half of the participants who used IN ketamine found it “very effective,” and 40% found it “somewhat effective.” Within the same group, 36% and 43% found the overall impact of IN ketamine on their quality of life was much better and somewhat better, respectively.

Among those still using ketamine during study follow-up, 82% reported that ketamine was very effective.

Compared with other acute headache medications, IN ketamine was considered much better (43%) or somewhat better (30%).

Nearly 75% of participants reported using fewer pain relievers when using IN ketamine.

Dr. Yuan said that future research might focus on finding predictors for IN ketamine response or determining the optimal effective and safe dose for the drug in those with chronic, treatment-refractory migraine.  

“We still need a prospective, randomized controlled trial to assess the efficacy and tolerability of intranasal ketamine,” he added.
 

‘Impressive result’

Commenting on the findings for this article, Richard Lipton, MD, professor of neurology, psychiatry and behavioral sciences and director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, said that “in this refractory population with multiple treatment failures, this is a very impressive, open-label result.”

“This real-world data suggests that ketamine is an effective option for people with medically intractable chronic migraine,” said Dr. Lipton, who was not part of the study. “In these very difficult to treat patients, 65% of those who started on ketamine persisted. Of those who remained on ketamine, 82% found it very effective.”

“This study makes me more confident that intranasal ketamine is a helpful treatment option, and I plan to use it more often in the future,” he added.

Like Dr. Yuan, Dr. Lipton highlighted the need for “well-designed placebo-controlled trials” and “rigorous comparative effectiveness studies.”

The study was funded by Miles for Migraine. Dr. Yuan has received institutional support for serving as an investigator from Teva and AbbVie, and royalties from Cambridge University Press and MedLink. Dr. Lipton has received compensation for consultation from Alder/Lumbeck, Axsome, Supernus, Theranica, Upsher-Smith, and Satsuma. He has participated in speaker bureaus for Eli Lilly and Amgen/Novartis and has received institutional support for serving as principal investigator from Teva, GammaCore, and Allergan/AbbVie. He has received payments for authorship or royalties from Demos Medical, Cambridge University Press, and MedLink.

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

Intranasal (IN) ketamine may be a feasible treatment alternative for people with chronic, refractory migraine who don’t respond to other medications, new research shows.

Half of the study participants who used IN ketamine for chronic, treatment-refractory migraine in a new retrospective cohort study reported it as “very effective” and over one-third said it boosted their quality of life.

“In our study, we showed that with even a few uses per day, intranasal ketamine can still improve patients’ quality of life,” lead investigator Hsiangkuo Yuan, MD, PhD, said in an interview. Dr. Yuan is associate professor of neurology at Thomas Jefferson University, Philadelphia, and director of clinical research at the Jefferson Headache Center.

He added that “multiple medications failed these patients, and the majority of patients were having daily headaches. So, if anything works, even partially and shortly, it may still give patients some relief to get through the day.”

The findings were published online in Regional Anesthesia & Pain Medicine.  
 

Daily migraine, failed medications

Use of IN ketamine has not been studied for the treatment of chronic, treatment-refractory migraine – although it has been studied in patients with cluster headache and migraine, the investigators note.

Ketamine is not yet approved by the Food and Drug Administration to treat migraine.

To further explore ketamine’s effect in those with chronic, treatment-refractory migraine, the investigators retrospectively analyzed electronic health records of patients at the Jefferson Headache Center who had received IN ketamine for the treatment of migraine between January 2019 and February 2020.

Of 242 patients who had received IN ketamine, Dr. Yuan’s team followed up with 169 who agreed to be part of the study.

The majority (67%) had daily migraine, and 85% had tried more than three classes of preventive medications for migraine. They currently used a median of two medications, the most common of which was a CGRP monoclonal antibody.

On average, patients used six sprays per day for a median 10 days per month. Median pain relief onset was 52 minutes after dosage.

Almost three-quarters of patients reported at least one side effect from the ketamine, most commonly fatigue (22%), double/blurred vision (21%), and confusion/dissociation (21%). These effects were mostly temporary, the researchers report.

The most common reasons for initiating IN ketamine included an incomplete response to prior acute medications (59%), incomplete response to prior preventive medications (31%), and prior benefit from IV ketamine (23%).

Study investigators noted that ketamine has the potential to become addictive and indicated that “clinicians should only consider the use of a potentially addictive medication such as ketamine for significantly disabled patients with migraine.”

About half of the participants who used IN ketamine found it “very effective,” and 40% found it “somewhat effective.” Within the same group, 36% and 43% found the overall impact of IN ketamine on their quality of life was much better and somewhat better, respectively.

Among those still using ketamine during study follow-up, 82% reported that ketamine was very effective.

Compared with other acute headache medications, IN ketamine was considered much better (43%) or somewhat better (30%).

Nearly 75% of participants reported using fewer pain relievers when using IN ketamine.

Dr. Yuan said that future research might focus on finding predictors for IN ketamine response or determining the optimal effective and safe dose for the drug in those with chronic, treatment-refractory migraine.  

“We still need a prospective, randomized controlled trial to assess the efficacy and tolerability of intranasal ketamine,” he added.
 

‘Impressive result’

Commenting on the findings for this article, Richard Lipton, MD, professor of neurology, psychiatry and behavioral sciences and director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, said that “in this refractory population with multiple treatment failures, this is a very impressive, open-label result.”

“This real-world data suggests that ketamine is an effective option for people with medically intractable chronic migraine,” said Dr. Lipton, who was not part of the study. “In these very difficult to treat patients, 65% of those who started on ketamine persisted. Of those who remained on ketamine, 82% found it very effective.”

“This study makes me more confident that intranasal ketamine is a helpful treatment option, and I plan to use it more often in the future,” he added.

Like Dr. Yuan, Dr. Lipton highlighted the need for “well-designed placebo-controlled trials” and “rigorous comparative effectiveness studies.”

The study was funded by Miles for Migraine. Dr. Yuan has received institutional support for serving as an investigator from Teva and AbbVie, and royalties from Cambridge University Press and MedLink. Dr. Lipton has received compensation for consultation from Alder/Lumbeck, Axsome, Supernus, Theranica, Upsher-Smith, and Satsuma. He has participated in speaker bureaus for Eli Lilly and Amgen/Novartis and has received institutional support for serving as principal investigator from Teva, GammaCore, and Allergan/AbbVie. He has received payments for authorship or royalties from Demos Medical, Cambridge University Press, and MedLink.

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

This transcript has been edited for clarity.

This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about a recent randomized clinical trial suggesting that multivitamins may improve memory and slow cognitive aging, compared with placebo, known as COSMOS (Cocoa Supplement and Multivitamins Outcome Study). This is the second COSMOS trial to show a benefit of multivitamins on memory and cognition. This trial involved a collaboration between Brigham and Columbia University and was published in the American Journal of Clinical Nutrition. I’d like to acknowledge that I am a coauthor of this study, together with Dr. Howard Sesso, who co-leads the main COSMOS trial with me.

Preserving memory and cognitive function is of critical importance to older adults. Nutritional interventions play an important role because we know the brain requires several nutrients for optimal health, and deficiencies in one or more of these nutrients may accelerate cognitive decline. Some of the micronutrients that are known to be important for brain health include vitamin B12, thiamin, other B vitamins, lutein, magnesium, and zinc, among others.

The current trial included 3,500 participants aged 60 or older, looking at performance on a web-based memory test. The multivitamin group did significantly better than the placebo group on memory tests and word recall, a finding that was estimated as the equivalent of slowing age-related memory loss by about 3 years. The benefit was first seen at 1 year and was sustained across the 3 years of the trial.

Intriguingly, in both COSMOS and COSMOS-Web, and the earlier COSMOS-Mind study, which was done in collaboration with Wake Forest, the participants with a history of cardiovascular disease showed the greatest benefits from multivitamins, perhaps due to lower nutrient status. But the basis for this finding needs to be explored further.

A few important caveats need to be emphasized. First, multivitamins and other dietary supplements will never be a substitute for a healthy diet and healthy lifestyle and should not distract from those goals. But multivitamins may have a role as a complementary strategy. Another caveat is that the randomized trials tested recommended dietary allowances and not megadoses of these micronutrients. In fact, randomized trials of high doses of isolated micronutrients have not clearly shown cognitive benefits, and this suggests that more is not necessarily better and may be worse. High doses also may be associated with toxicity, or they may interfere with absorption or bioavailability of other nutrients.

In COSMOS, over the average 3.6 years of follow-up and in the earlier Physicians’ Health Study II,  over 1 year of supplementation, multivitamins were found to be safe without any clear risks or safety concerns. A further caveat is that although Centrum Silver was tested in this trial, we would not expect that this is a brand-specific benefit, and other high-quality multivitamin brands would be expected to confer similar benefits. Of course, it’s important to check bottles for quality-control documentation such as the seals of the U.S. Pharmacopeia, National Science Foundation, ConsumerLab.com, and other auditors.

Overall, the finding that a daily multivitamin improved memory and slowed cognitive decline in two separate COSMOS randomized trials is exciting, suggesting that multivitamin supplementation holds promise as a safe, accessible, and affordable approach to protecting cognitive health in older adults. Further research will be needed to understand who is most likely to benefit and the biological mechanisms involved. Expert committees will have to look at the research and decide whether any changes in guidelines are indicated in the future.

Dr. Manson is Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School and director of the Division of Preventive Medicine, Brigham and Women’s Hospital, both in Boston. She reported receiving funding/donations from Mars Symbioscience.

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

This transcript has been edited for clarity.

This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about a recent randomized clinical trial suggesting that multivitamins may improve memory and slow cognitive aging, compared with placebo, known as COSMOS (Cocoa Supplement and Multivitamins Outcome Study). This is the second COSMOS trial to show a benefit of multivitamins on memory and cognition. This trial involved a collaboration between Brigham and Columbia University and was published in the American Journal of Clinical Nutrition. I’d like to acknowledge that I am a coauthor of this study, together with Dr. Howard Sesso, who co-leads the main COSMOS trial with me.

Preserving memory and cognitive function is of critical importance to older adults. Nutritional interventions play an important role because we know the brain requires several nutrients for optimal health, and deficiencies in one or more of these nutrients may accelerate cognitive decline. Some of the micronutrients that are known to be important for brain health include vitamin B12, thiamin, other B vitamins, lutein, magnesium, and zinc, among others.

The current trial included 3,500 participants aged 60 or older, looking at performance on a web-based memory test. The multivitamin group did significantly better than the placebo group on memory tests and word recall, a finding that was estimated as the equivalent of slowing age-related memory loss by about 3 years. The benefit was first seen at 1 year and was sustained across the 3 years of the trial.

Intriguingly, in both COSMOS and COSMOS-Web, and the earlier COSMOS-Mind study, which was done in collaboration with Wake Forest, the participants with a history of cardiovascular disease showed the greatest benefits from multivitamins, perhaps due to lower nutrient status. But the basis for this finding needs to be explored further.

A few important caveats need to be emphasized. First, multivitamins and other dietary supplements will never be a substitute for a healthy diet and healthy lifestyle and should not distract from those goals. But multivitamins may have a role as a complementary strategy. Another caveat is that the randomized trials tested recommended dietary allowances and not megadoses of these micronutrients. In fact, randomized trials of high doses of isolated micronutrients have not clearly shown cognitive benefits, and this suggests that more is not necessarily better and may be worse. High doses also may be associated with toxicity, or they may interfere with absorption or bioavailability of other nutrients.

In COSMOS, over the average 3.6 years of follow-up and in the earlier Physicians’ Health Study II,  over 1 year of supplementation, multivitamins were found to be safe without any clear risks or safety concerns. A further caveat is that although Centrum Silver was tested in this trial, we would not expect that this is a brand-specific benefit, and other high-quality multivitamin brands would be expected to confer similar benefits. Of course, it’s important to check bottles for quality-control documentation such as the seals of the U.S. Pharmacopeia, National Science Foundation, ConsumerLab.com, and other auditors.

Overall, the finding that a daily multivitamin improved memory and slowed cognitive decline in two separate COSMOS randomized trials is exciting, suggesting that multivitamin supplementation holds promise as a safe, accessible, and affordable approach to protecting cognitive health in older adults. Further research will be needed to understand who is most likely to benefit and the biological mechanisms involved. Expert committees will have to look at the research and decide whether any changes in guidelines are indicated in the future.

Dr. Manson is Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School and director of the Division of Preventive Medicine, Brigham and Women’s Hospital, both in Boston. She reported receiving funding/donations from Mars Symbioscience.

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

This transcript has been edited for clarity.

This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about a recent randomized clinical trial suggesting that multivitamins may improve memory and slow cognitive aging, compared with placebo, known as COSMOS (Cocoa Supplement and Multivitamins Outcome Study). This is the second COSMOS trial to show a benefit of multivitamins on memory and cognition. This trial involved a collaboration between Brigham and Columbia University and was published in the American Journal of Clinical Nutrition. I’d like to acknowledge that I am a coauthor of this study, together with Dr. Howard Sesso, who co-leads the main COSMOS trial with me.

Preserving memory and cognitive function is of critical importance to older adults. Nutritional interventions play an important role because we know the brain requires several nutrients for optimal health, and deficiencies in one or more of these nutrients may accelerate cognitive decline. Some of the micronutrients that are known to be important for brain health include vitamin B12, thiamin, other B vitamins, lutein, magnesium, and zinc, among others.

The current trial included 3,500 participants aged 60 or older, looking at performance on a web-based memory test. The multivitamin group did significantly better than the placebo group on memory tests and word recall, a finding that was estimated as the equivalent of slowing age-related memory loss by about 3 years. The benefit was first seen at 1 year and was sustained across the 3 years of the trial.

Intriguingly, in both COSMOS and COSMOS-Web, and the earlier COSMOS-Mind study, which was done in collaboration with Wake Forest, the participants with a history of cardiovascular disease showed the greatest benefits from multivitamins, perhaps due to lower nutrient status. But the basis for this finding needs to be explored further.

A few important caveats need to be emphasized. First, multivitamins and other dietary supplements will never be a substitute for a healthy diet and healthy lifestyle and should not distract from those goals. But multivitamins may have a role as a complementary strategy. Another caveat is that the randomized trials tested recommended dietary allowances and not megadoses of these micronutrients. In fact, randomized trials of high doses of isolated micronutrients have not clearly shown cognitive benefits, and this suggests that more is not necessarily better and may be worse. High doses also may be associated with toxicity, or they may interfere with absorption or bioavailability of other nutrients.

In COSMOS, over the average 3.6 years of follow-up and in the earlier Physicians’ Health Study II,  over 1 year of supplementation, multivitamins were found to be safe without any clear risks or safety concerns. A further caveat is that although Centrum Silver was tested in this trial, we would not expect that this is a brand-specific benefit, and other high-quality multivitamin brands would be expected to confer similar benefits. Of course, it’s important to check bottles for quality-control documentation such as the seals of the U.S. Pharmacopeia, National Science Foundation, ConsumerLab.com, and other auditors.

Overall, the finding that a daily multivitamin improved memory and slowed cognitive decline in two separate COSMOS randomized trials is exciting, suggesting that multivitamin supplementation holds promise as a safe, accessible, and affordable approach to protecting cognitive health in older adults. Further research will be needed to understand who is most likely to benefit and the biological mechanisms involved. Expert committees will have to look at the research and decide whether any changes in guidelines are indicated in the future.

Dr. Manson is Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School and director of the Division of Preventive Medicine, Brigham and Women’s Hospital, both in Boston. She reported receiving funding/donations from Mars Symbioscience.

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

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

THE CASE

A 55-year-old woman was evaluated in a family medicine clinic for clear, right-side nasal drainage. She stated that the drainage began 5 months earlier after 2 hospitalizations for severe anxiety leading to emesis and hypokalemia. She reported 3 different COVID-19 nasal swab tests performed on the right nare. Chart review showed 2 negative COVID-19 tests, 6 days apart. Since the hospitalizations, the patient had been given antihistamines for rhinorrhea at an urgent care visit. Despite this treatment, the patient reported a constant drip from the right nare with a salty taste. She also reported experiencing occasional headaches but denied nausea/vomiting. 

The patient’s history included uncontrolled hypertension, treatment-resistant anxiety and depression, obstructive sleep apnea, chronic sinus disease (observed on computed tomography [CT] scans), and type 2 diabetes. She was on amlodipine 10 mg/d for hypertension and was not taking any medication for diabetes.

On examination, the patient’s vital signs were within normal limits except for an elevated blood pressure of 158/88 mm Hg. The patient had persistent clear rhinorrhea fluid draining from the right nostril that was exacerbated when she looked down. Right nasal erythema was present. 

THE DIAGNOSIS 

The patient’s negative COVID-19 tests, lack of improvement on antihistamines, and description of the nasal fluid as salty tasting prompted us to suspect a cerebrospinal fluid (CSF) leak. The clinical work-up included a halo (“double-ring”) sign test, a β-2 transferrin test, and a sinus x-ray.

The halo sign test was negative for CSF fluid. Sinus/skull x-ray did not show a cribriform or other fracture. However, a sample of the nasal fluid collected in a sterile container was positive for β-2 transferrin, the gold-standard laboratory test to confirm a CSF leak.

The patient was sent for a maxillofacial CT scan without contrast. Results showed a 3-mm defect over the right ethmoid roof associated with a 10 × 16–mm low-attenuation structure in the right ethmoid labyrinth, suspicious for encephalocele. This defect, in the setting of the patient’s history of chronic sinus disease, furthered our suspicion of a CSF leak secondary to COVID-19 testing. Radiology confirmed the diagnosis.

DISCUSSION

CSF rhinorrhea is CSF leakage through the nasal cavity due to abnormal communication between the arachnoid membrane and nasal mucosa.¹ The most commonly reported risk factors for this include female sex, middle age (fourth to fifth decade), obesity (body mass index > 40), intracranial hypertension, and obstructive sleep apnea.^1,2

Continue to: Clear, unilateral rhinorrhea...

Clear, unilateral rhinorrhea drainage that increases at times of relatively increased intracranial pressure and has a metallic or salty taste is suspicious for CSF rhinorrhea.³ It can occur following skull‐base trauma (eg, cribriform plate, temporal bone), endoscopic sinus surgery, or neurosurgical procedures, or have a spontaneous etiology.^3,4

Modalities to confirm CSF rhinorrhea include radionuclide cisternography and testing of fluid for the halo sign, glucose, and the CSF-specific proteins β‐2 transferrin and β-trace protein.^3,4 High‐resolution CT is the imaging method most commonly used for localizing a CSF leak.⁴

Treatment is provided in the hospital

Patients with CSF rhinorrhea typically require inpatient management with bed rest, head-of-bed elevation, and frequent neurologic evaluation, as persistent CSF rhinorrhea increases the risk for meningitis, thus necessitating surgical intervention.^3,5 Some cases resolve with bed rest alone. Endonasal endoscopic repair of CSF leaks has become the standard of care because of its high success rate and lower morbidity profile.⁴ 

The preferred treatment method for encephalocele is surgical removal after diagnosis is confirmed with CT or magnetic resonance imaging.⁶

Our patient underwent surgery to remove the encephalocele. The surgeons reported no evidence of fracture. 

Endonasal endoscopic repair of CSF leaks has become the standard of care because of its high success rate and lower morbidity profile.

The final cause of her CSF leak is still uncertain. The surgeons felt confident it was due to ethmoidal encephalocele, a form of neural tube defect in which brain tissue herniates through structural weaknesses of the skull.^6-8 While more common in infants, encephalocele can manifest in adulthood due to traumatic or iatrogenic causes.^7,8

There is a previous report of encephalocele with CSF leak after COVID-19 testing.⁹ This case report suggests the possibility of a nasal swab causing trauma to a patient’s pre‐existing encephalocele—a probability in our patient’s case. It is unlikely, however, that the nasal swab itself violated the bony skull base.

THE TAKEAWAY

This case exemplifies how unexplained local symptoms, a high index of suspicion, and adequate work-up can lead to a rare diagnosis. Diagnostic strategies employed for cases of CSF rhinorrhea vary widely due to limited evidence-based guidance.⁴ Unilateral rhinorrhea with clear fluid that increases at times of increased intracranial pressure, such as bending over, should prompt suspicion for CSF rhinorrhea. With millions of people getting nasal swabs daily during the COVID-19 pandemic, it is even more important to keep CSF leak in our differential diagnosis.

CORRESPONDENCE
Eliana Lizeth Garcia, MD, BS, BA, University of New Mexico Health Sciences Center, 1209 University Boulevard NE, Albuquerque, NM 87131-5001; [email protected]

THE CASE

A 55-year-old woman was evaluated in a family medicine clinic for clear, right-side nasal drainage. She stated that the drainage began 5 months earlier after 2 hospitalizations for severe anxiety leading to emesis and hypokalemia. She reported 3 different COVID-19 nasal swab tests performed on the right nare. Chart review showed 2 negative COVID-19 tests, 6 days apart. Since the hospitalizations, the patient had been given antihistamines for rhinorrhea at an urgent care visit. Despite this treatment, the patient reported a constant drip from the right nare with a salty taste. She also reported experiencing occasional headaches but denied nausea/vomiting. 

The patient’s history included uncontrolled hypertension, treatment-resistant anxiety and depression, obstructive sleep apnea, chronic sinus disease (observed on computed tomography [CT] scans), and type 2 diabetes. She was on amlodipine 10 mg/d for hypertension and was not taking any medication for diabetes.

On examination, the patient’s vital signs were within normal limits except for an elevated blood pressure of 158/88 mm Hg. The patient had persistent clear rhinorrhea fluid draining from the right nostril that was exacerbated when she looked down. Right nasal erythema was present. 

THE DIAGNOSIS 

The patient’s negative COVID-19 tests, lack of improvement on antihistamines, and description of the nasal fluid as salty tasting prompted us to suspect a cerebrospinal fluid (CSF) leak. The clinical work-up included a halo (“double-ring”) sign test, a β-2 transferrin test, and a sinus x-ray.

The halo sign test was negative for CSF fluid. Sinus/skull x-ray did not show a cribriform or other fracture. However, a sample of the nasal fluid collected in a sterile container was positive for β-2 transferrin, the gold-standard laboratory test to confirm a CSF leak.

The patient was sent for a maxillofacial CT scan without contrast. Results showed a 3-mm defect over the right ethmoid roof associated with a 10 × 16–mm low-attenuation structure in the right ethmoid labyrinth, suspicious for encephalocele. This defect, in the setting of the patient’s history of chronic sinus disease, furthered our suspicion of a CSF leak secondary to COVID-19 testing. Radiology confirmed the diagnosis.

DISCUSSION

CSF rhinorrhea is CSF leakage through the nasal cavity due to abnormal communication between the arachnoid membrane and nasal mucosa.¹ The most commonly reported risk factors for this include female sex, middle age (fourth to fifth decade), obesity (body mass index > 40), intracranial hypertension, and obstructive sleep apnea.^1,2

Continue to: Clear, unilateral rhinorrhea...

Clear, unilateral rhinorrhea drainage that increases at times of relatively increased intracranial pressure and has a metallic or salty taste is suspicious for CSF rhinorrhea.³ It can occur following skull‐base trauma (eg, cribriform plate, temporal bone), endoscopic sinus surgery, or neurosurgical procedures, or have a spontaneous etiology.^3,4

Modalities to confirm CSF rhinorrhea include radionuclide cisternography and testing of fluid for the halo sign, glucose, and the CSF-specific proteins β‐2 transferrin and β-trace protein.^3,4 High‐resolution CT is the imaging method most commonly used for localizing a CSF leak.⁴

Treatment is provided in the hospital

Patients with CSF rhinorrhea typically require inpatient management with bed rest, head-of-bed elevation, and frequent neurologic evaluation, as persistent CSF rhinorrhea increases the risk for meningitis, thus necessitating surgical intervention.^3,5 Some cases resolve with bed rest alone. Endonasal endoscopic repair of CSF leaks has become the standard of care because of its high success rate and lower morbidity profile.⁴ 

The preferred treatment method for encephalocele is surgical removal after diagnosis is confirmed with CT or magnetic resonance imaging.⁶

Our patient underwent surgery to remove the encephalocele. The surgeons reported no evidence of fracture. 

Endonasal endoscopic repair of CSF leaks has become the standard of care because of its high success rate and lower morbidity profile.

The final cause of her CSF leak is still uncertain. The surgeons felt confident it was due to ethmoidal encephalocele, a form of neural tube defect in which brain tissue herniates through structural weaknesses of the skull.^6-8 While more common in infants, encephalocele can manifest in adulthood due to traumatic or iatrogenic causes.^7,8

There is a previous report of encephalocele with CSF leak after COVID-19 testing.⁹ This case report suggests the possibility of a nasal swab causing trauma to a patient’s pre‐existing encephalocele—a probability in our patient’s case. It is unlikely, however, that the nasal swab itself violated the bony skull base.

THE TAKEAWAY

This case exemplifies how unexplained local symptoms, a high index of suspicion, and adequate work-up can lead to a rare diagnosis. Diagnostic strategies employed for cases of CSF rhinorrhea vary widely due to limited evidence-based guidance.⁴ Unilateral rhinorrhea with clear fluid that increases at times of increased intracranial pressure, such as bending over, should prompt suspicion for CSF rhinorrhea. With millions of people getting nasal swabs daily during the COVID-19 pandemic, it is even more important to keep CSF leak in our differential diagnosis.

CORRESPONDENCE
Eliana Lizeth Garcia, MD, BS, BA, University of New Mexico Health Sciences Center, 1209 University Boulevard NE, Albuquerque, NM 87131-5001; [email protected]

THE CASE

A 55-year-old woman was evaluated in a family medicine clinic for clear, right-side nasal drainage. She stated that the drainage began 5 months earlier after 2 hospitalizations for severe anxiety leading to emesis and hypokalemia. She reported 3 different COVID-19 nasal swab tests performed on the right nare. Chart review showed 2 negative COVID-19 tests, 6 days apart. Since the hospitalizations, the patient had been given antihistamines for rhinorrhea at an urgent care visit. Despite this treatment, the patient reported a constant drip from the right nare with a salty taste. She also reported experiencing occasional headaches but denied nausea/vomiting. 

The patient’s history included uncontrolled hypertension, treatment-resistant anxiety and depression, obstructive sleep apnea, chronic sinus disease (observed on computed tomography [CT] scans), and type 2 diabetes. She was on amlodipine 10 mg/d for hypertension and was not taking any medication for diabetes.

On examination, the patient’s vital signs were within normal limits except for an elevated blood pressure of 158/88 mm Hg. The patient had persistent clear rhinorrhea fluid draining from the right nostril that was exacerbated when she looked down. Right nasal erythema was present. 

THE DIAGNOSIS 

The patient’s negative COVID-19 tests, lack of improvement on antihistamines, and description of the nasal fluid as salty tasting prompted us to suspect a cerebrospinal fluid (CSF) leak. The clinical work-up included a halo (“double-ring”) sign test, a β-2 transferrin test, and a sinus x-ray.

The halo sign test was negative for CSF fluid. Sinus/skull x-ray did not show a cribriform or other fracture. However, a sample of the nasal fluid collected in a sterile container was positive for β-2 transferrin, the gold-standard laboratory test to confirm a CSF leak.

The patient was sent for a maxillofacial CT scan without contrast. Results showed a 3-mm defect over the right ethmoid roof associated with a 10 × 16–mm low-attenuation structure in the right ethmoid labyrinth, suspicious for encephalocele. This defect, in the setting of the patient’s history of chronic sinus disease, furthered our suspicion of a CSF leak secondary to COVID-19 testing. Radiology confirmed the diagnosis.

DISCUSSION

CSF rhinorrhea is CSF leakage through the nasal cavity due to abnormal communication between the arachnoid membrane and nasal mucosa.¹ The most commonly reported risk factors for this include female sex, middle age (fourth to fifth decade), obesity (body mass index > 40), intracranial hypertension, and obstructive sleep apnea.^1,2

Continue to: Clear, unilateral rhinorrhea...

Clear, unilateral rhinorrhea drainage that increases at times of relatively increased intracranial pressure and has a metallic or salty taste is suspicious for CSF rhinorrhea.³ It can occur following skull‐base trauma (eg, cribriform plate, temporal bone), endoscopic sinus surgery, or neurosurgical procedures, or have a spontaneous etiology.^3,4

Modalities to confirm CSF rhinorrhea include radionuclide cisternography and testing of fluid for the halo sign, glucose, and the CSF-specific proteins β‐2 transferrin and β-trace protein.^3,4 High‐resolution CT is the imaging method most commonly used for localizing a CSF leak.⁴

Treatment is provided in the hospital

Patients with CSF rhinorrhea typically require inpatient management with bed rest, head-of-bed elevation, and frequent neurologic evaluation, as persistent CSF rhinorrhea increases the risk for meningitis, thus necessitating surgical intervention.^3,5 Some cases resolve with bed rest alone. Endonasal endoscopic repair of CSF leaks has become the standard of care because of its high success rate and lower morbidity profile.⁴ 

The preferred treatment method for encephalocele is surgical removal after diagnosis is confirmed with CT or magnetic resonance imaging.⁶

Our patient underwent surgery to remove the encephalocele. The surgeons reported no evidence of fracture. 

Endonasal endoscopic repair of CSF leaks has become the standard of care because of its high success rate and lower morbidity profile.

The final cause of her CSF leak is still uncertain. The surgeons felt confident it was due to ethmoidal encephalocele, a form of neural tube defect in which brain tissue herniates through structural weaknesses of the skull.^6-8 While more common in infants, encephalocele can manifest in adulthood due to traumatic or iatrogenic causes.^7,8

There is a previous report of encephalocele with CSF leak after COVID-19 testing.⁹ This case report suggests the possibility of a nasal swab causing trauma to a patient’s pre‐existing encephalocele—a probability in our patient’s case. It is unlikely, however, that the nasal swab itself violated the bony skull base.

THE TAKEAWAY

This case exemplifies how unexplained local symptoms, a high index of suspicion, and adequate work-up can lead to a rare diagnosis. Diagnostic strategies employed for cases of CSF rhinorrhea vary widely due to limited evidence-based guidance.⁴ Unilateral rhinorrhea with clear fluid that increases at times of increased intracranial pressure, such as bending over, should prompt suspicion for CSF rhinorrhea. With millions of people getting nasal swabs daily during the COVID-19 pandemic, it is even more important to keep CSF leak in our differential diagnosis.

CORRESPONDENCE
Eliana Lizeth Garcia, MD, BS, BA, University of New Mexico Health Sciences Center, 1209 University Boulevard NE, Albuquerque, NM 87131-5001; [email protected]

THE CASE

Sam C* is a 68-year-old man who presented to his family physician in a rural health clinic due to concerns about weight loss. Since his visit 8 months prior, Mr. C unintentionally had lost 20 pounds. Upon questioning, Mr. C also reported feeling irritable and having difficulty with sleep and concentration.

A review of systems did not indicate the presence of infection or other medical conditions. In the 6 years since becoming a patient to the practice, he had reported no chronic health concerns, was taking no medications, and had only been to the clinic for his annual check-up appointments. He completed a Patient Health Questionnaire (PHQ-9) and scored 18, indicating moderately severe depression.

Mr. C had established care with his physician when he moved to the area from out of state so that he could be closer to his parents, who were in their mid-80s at the time. Mr. C’s physician also had been the family physician for his parents for the previous 20 years. Three years prior to Mr. C’s presentation for weight loss, his mother had received a diagnosis of acute leukemia; she died a year later.

Over the past year, Mr. C had needed to take a more active role in the care of his father, who was now in his early 90s. Mr. C’s father, who was previously in excellent health, had begun to develop significant health problems, including degenerative arthritis and progressive vascular dementia. He also had ataxia, leading to poor mobility, and a neurogenic bladder requiring self-catheterization, which required Mr. C’s assistance. Mr. C lived next door to his father and provided frequent assistance with activities of daily living. However, his father, who always had been the dominant figure in the family, was determined to maintain his independence and not relinquish control to others.

The strain of caregiving activities, along with managing his father’s inflexibility, was causing increasing distress for Mr. C. As he told his family physician, “I just don’t know what to do.”

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

It is estimated that more than 11 million Americans provided more than 18 billion hours in unpaid support for individuals with dementia in 2022, averaging 30 hours of care per caregiver per week.¹ As individuals with dementia progressively decline, they require increased assistance with activities of daily living (ADLs, such as bathing and dressing) and instrumental activities of daily living (IADLs, such as paying bills and using transportation). Most of this assistance comes from informal caregiving provided by family members and friends.

Caregiver burden can be defined as “the strain or load borne by a person who cares for a chronically ill, disabled, or elderly family member.”² Caregiver stress has been found to be higher for dementia caregiving than other types of caregiving.³ In particular, caring for someone with greater behavioral and psychological symptoms of dementia (BPSDs) has been associated with higher caregiver burden.^4-7

Beyond the subjective burden of care­giving, there are other potential negative ­consequences for dementia caregivers (see ­TABLE 1^8-14 and TABLE 2^15,16). In addition, caregiver distress is related to a number of care recipient outcomes, including earlier institutionalization, more hospitalizations, more BPSDs, poorer quality of life, and greater likelihood of experiencing elder abuse.¹⁷

Assessment, reassessment are key to meeting needs

Numerous factors can foster caregiver well-­being, including feelings of accomplishment and contribution, a strengthening of the relationship with the care recipient, and feeling supported by friends, family, and formal care systems.^18,19 Family physicians can play an important role by assessing and supporting patients with dementia and their caregivers. Ideally, the individual with dementia and the caregiver will be assessed both together and separately.

Caregiver distress is related to care recipient outcomes, such as earlier institutionalization, more hospitalizations, and poorer quality of life.

A thorough assessment includes gathering information about the context and quality of the caregiving relationship; caregiver perception of the care recipient’s health and functional status; caregiver values and preferences; caregiver well-being (including mental health assessment); caregiver skills, abilities, and knowledge about caregiving; and positive and negative consequences of caregiving.²⁰ Caregiver needs—including informational, care support, emotional, physical, and social needs—also should be assessed.

Continue to: Tools are available...

Tools are available to facilitate caregiver assessment. For example, the Zarit Burden Interview is a 22-item self-report measure that can be given to the caregiver²¹; shorter versions (4 and 12 items) are also available.²² Another resource available for caregiver assessment guidance is a toolkit developed by the Family Caregiver Alliance.²⁰

Continually assess for changing needs

As the condition of the individual with dementia progresses, it will be important to reassess the caregiver, as stressors and needs will change over the course of the caregiving relationship. Support should be adapted ­accordingly.

In the early stage of dementia, caregivers may need information on disease progression and dementia care planning, ways to navigate the health care system, financial planning, and useful resources. Caregivers also may need emotional support to help them adapt to the role of caregiver, deal with denial, and manage their stress.^23,24

With dementia progression, caregivers may need support related to increased decision-making responsibility, managing challenging behaviors, assisting with ADLs and IADLs, and identifying opportunities to meet personal social and well-being needs. They also may need support to accept the changes they are seeing in the individual with dementia and the shifts they are experiencing in their relationship with him or her.^23,25

In late-stage dementia, caregiver needs tend to shift to determining the need for long-term care placement vs staying at home, end-of-life planning, loneliness, and anticipatory grief.^23,26 Support with managing changing and accumulating stress typically remains a primary need throughout the progression of dementia.²⁷

Continue to: Specific populations have distinct needs

Specific populations have distinct needs. Some caregivers, including members of the LGBTQ+ community and different racial and ethnic groups, as well as caregivers of people with younger-onset dementia, may have additional support needs.²⁸

More than 11 million Americans provided more than 18 billion hours in unpaid support for individuals with dementia in 2022, averaging 30 hours of care per caregiver per week.

For example, African American and ­Latino caregivers tend to have caregiving relationships of longer duration, requiring more time-­intensive care, but use fewer formal support services than White caregivers.²⁹ Caregivers from non-White racial and ethnic groups also are more likely to experience discrimination when interacting with health care services on behalf of care recipients.³⁰

Having an awareness of potential specialized needs may help to prevent or address potential care disparities, and cultural humility may help to improve caregiver experiences with primary care physicians.

Resources to support caregivers

Family physicians are well situated to provide informational and emotional support for both patients with dementia and their informal care providers.³¹ Given the variability of caregiver concerns, multicomponent interventions addressing informational, self-care, social support, and financial needs often are needed.³¹ Supportive counseling and psychoeducation can help dementia caregivers with stress management, self-care, coping, and skills training—supporting the development of self-efficacy.^32,33

Outside resources. Although significant caregiver support can be provided directly by the physician, caregivers should be connected with outside resources, including support groups, counselors, psychotherapists, financial and legal support, and formal care services.³⁴

Continue to: Psychosocial and complementary interventions

Psychosocial and complementary interventions. Various psychosocial interventions (eg, psychoeducation, cognitive behavioral therapy, support groups) have been found to be beneficial in alleviating caregiver symptoms of depression, anxiety, and stress and improving well-being, perceived burden, and quality of life. However, systematic reviews have found variability in the degree of helpfulness of these interventions.^35,36

Some caregivers and care recipients may benefit from complementary and integrative medicine referrals. Mind–body therapies such as mindfulness, yoga, and Tai Chi have shown some beneficial effects.³⁷

Online resources. Caregivers also can be directed to online resources from organizations such as the Alzheimer’s Association (www.alz.org), the National Institutes of Health (www.alzheimers.gov), and the Family Caregiver Alliance (www.caregiver.org).

In rural settings, such as the one in which this case took place, online resources may decrease some barriers to supporting caregivers.³⁸ Internet-based interventions also have been found to have some benefit for dementia caregivers.^31,39

However, some rural locations continue to have limited reliable Internet services.⁴⁰ In affected areas, a strong relationship with a primary care physician may be even more important to the well-being of caregivers, since other support services may be less accessible.⁴¹

Continue to: Impacts of the pandemic

Impacts of the pandemic. Although our case took place prior to the COVID-19 pandemic, it is important to acknowledge ways the pandemic has impacted informal dementia caregiving.

Caregiver stress, depression, and anxiety increased during the pandemic, and the need for greater home confinement and social ­distancing amplified the negative impact of social isolation, including loneliness, on ­caregivers.^42,43 Caregivers often needed to increase their caregiving responsibilities and had more difficulty with care coordination due to limited access to in-person resources.⁴³ The pandemic led to increased reliance on technology and telehealth in the support of dementia caregivers.⁴³

THE CASE

The physician prescribed mirtazapine for Mr. C, titrating the dose as needed to address depressive symptoms and promote weight gain. The physician connected Mr. C’s father with home health services, including physical therapy for fall risk reduction. Mr. C also hired part-time support to provide additional assistance with ADLs and IADLs, allowing Mr. C to have time to attend to his own needs. Though provided with information about a local caregiver support group, Mr. C chose not to attend. The physician also assisted the family with advanced directives.

African American and Latino caregivers tend to have caregiving relationships of longer duration, requiring more time-intensive care, but they tend to use fewer formal support services than White caregivers.

A particular challenge that occurred during care for the family was addressing Mr. C’s father’s driving capacity, considering his strong need for independence. To address this concern, a family meeting was held with Mr. C, his father, and his siblings from out of town. Although Mr. C’s father was not willing to relinquish his driver’s license during that meeting, he agreed to complete a functional driving assessment.

The physician continued to meet with Mr. C and his father together, as well as with Mr. C individually, to provide supportive counseling as needed. As the father’s dementia progressed and it became more difficult to complete office appointments, the physician transitioned to home visits to provide care until the father’s death.

After the death of Mr. C’s father, the physician continued to serve as Mr. C’s primary care provider.

Keeping the “family”in family medicine

Through longitudinal assessment, needs identification, and provision of relevant information, emotional support, and resources, family physicians can provide care that can improve the quality of life and well-being and help alleviate burden experienced by dementia caregivers. Family physicians also are positioned to provide treatments that can address the negative physical and psychological health outcomes associated with informal dementia caregiving. By building relationships with multiple family members across generations, family physicians can understand the context of caregiving dynamics and work together with individuals with dementia and their caregivers throughout disease progression, providing consistent support to the family unit.

CORRESPONDENCE
Kathleen M. Young, PhD, MPH, Novant Health Family Medicine Wilmington, 2523 Delaney Avenue, Wilmington, NC 28403; [email protected]

THE CASE

Sam C* is a 68-year-old man who presented to his family physician in a rural health clinic due to concerns about weight loss. Since his visit 8 months prior, Mr. C unintentionally had lost 20 pounds. Upon questioning, Mr. C also reported feeling irritable and having difficulty with sleep and concentration.

A review of systems did not indicate the presence of infection or other medical conditions. In the 6 years since becoming a patient to the practice, he had reported no chronic health concerns, was taking no medications, and had only been to the clinic for his annual check-up appointments. He completed a Patient Health Questionnaire (PHQ-9) and scored 18, indicating moderately severe depression.

Mr. C had established care with his physician when he moved to the area from out of state so that he could be closer to his parents, who were in their mid-80s at the time. Mr. C’s physician also had been the family physician for his parents for the previous 20 years. Three years prior to Mr. C’s presentation for weight loss, his mother had received a diagnosis of acute leukemia; she died a year later.

Over the past year, Mr. C had needed to take a more active role in the care of his father, who was now in his early 90s. Mr. C’s father, who was previously in excellent health, had begun to develop significant health problems, including degenerative arthritis and progressive vascular dementia. He also had ataxia, leading to poor mobility, and a neurogenic bladder requiring self-catheterization, which required Mr. C’s assistance. Mr. C lived next door to his father and provided frequent assistance with activities of daily living. However, his father, who always had been the dominant figure in the family, was determined to maintain his independence and not relinquish control to others.

The strain of caregiving activities, along with managing his father’s inflexibility, was causing increasing distress for Mr. C. As he told his family physician, “I just don’t know what to do.”

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

It is estimated that more than 11 million Americans provided more than 18 billion hours in unpaid support for individuals with dementia in 2022, averaging 30 hours of care per caregiver per week.¹ As individuals with dementia progressively decline, they require increased assistance with activities of daily living (ADLs, such as bathing and dressing) and instrumental activities of daily living (IADLs, such as paying bills and using transportation). Most of this assistance comes from informal caregiving provided by family members and friends.

Caregiver burden can be defined as “the strain or load borne by a person who cares for a chronically ill, disabled, or elderly family member.”² Caregiver stress has been found to be higher for dementia caregiving than other types of caregiving.³ In particular, caring for someone with greater behavioral and psychological symptoms of dementia (BPSDs) has been associated with higher caregiver burden.^4-7

Beyond the subjective burden of care­giving, there are other potential negative ­consequences for dementia caregivers (see ­TABLE 1^8-14 and TABLE 2^15,16). In addition, caregiver distress is related to a number of care recipient outcomes, including earlier institutionalization, more hospitalizations, more BPSDs, poorer quality of life, and greater likelihood of experiencing elder abuse.¹⁷

Assessment, reassessment are key to meeting needs

Numerous factors can foster caregiver well-­being, including feelings of accomplishment and contribution, a strengthening of the relationship with the care recipient, and feeling supported by friends, family, and formal care systems.^18,19 Family physicians can play an important role by assessing and supporting patients with dementia and their caregivers. Ideally, the individual with dementia and the caregiver will be assessed both together and separately.

Caregiver distress is related to care recipient outcomes, such as earlier institutionalization, more hospitalizations, and poorer quality of life.

A thorough assessment includes gathering information about the context and quality of the caregiving relationship; caregiver perception of the care recipient’s health and functional status; caregiver values and preferences; caregiver well-being (including mental health assessment); caregiver skills, abilities, and knowledge about caregiving; and positive and negative consequences of caregiving.²⁰ Caregiver needs—including informational, care support, emotional, physical, and social needs—also should be assessed.

Continue to: Tools are available...

Tools are available to facilitate caregiver assessment. For example, the Zarit Burden Interview is a 22-item self-report measure that can be given to the caregiver²¹; shorter versions (4 and 12 items) are also available.²² Another resource available for caregiver assessment guidance is a toolkit developed by the Family Caregiver Alliance.²⁰

Continually assess for changing needs

As the condition of the individual with dementia progresses, it will be important to reassess the caregiver, as stressors and needs will change over the course of the caregiving relationship. Support should be adapted ­accordingly.

In the early stage of dementia, caregivers may need information on disease progression and dementia care planning, ways to navigate the health care system, financial planning, and useful resources. Caregivers also may need emotional support to help them adapt to the role of caregiver, deal with denial, and manage their stress.^23,24

With dementia progression, caregivers may need support related to increased decision-making responsibility, managing challenging behaviors, assisting with ADLs and IADLs, and identifying opportunities to meet personal social and well-being needs. They also may need support to accept the changes they are seeing in the individual with dementia and the shifts they are experiencing in their relationship with him or her.^23,25

In late-stage dementia, caregiver needs tend to shift to determining the need for long-term care placement vs staying at home, end-of-life planning, loneliness, and anticipatory grief.^23,26 Support with managing changing and accumulating stress typically remains a primary need throughout the progression of dementia.²⁷

Continue to: Specific populations have distinct needs

Specific populations have distinct needs. Some caregivers, including members of the LGBTQ+ community and different racial and ethnic groups, as well as caregivers of people with younger-onset dementia, may have additional support needs.²⁸

More than 11 million Americans provided more than 18 billion hours in unpaid support for individuals with dementia in 2022, averaging 30 hours of care per caregiver per week.

For example, African American and ­Latino caregivers tend to have caregiving relationships of longer duration, requiring more time-­intensive care, but use fewer formal support services than White caregivers.²⁹ Caregivers from non-White racial and ethnic groups also are more likely to experience discrimination when interacting with health care services on behalf of care recipients.³⁰

Having an awareness of potential specialized needs may help to prevent or address potential care disparities, and cultural humility may help to improve caregiver experiences with primary care physicians.

Resources to support caregivers

Family physicians are well situated to provide informational and emotional support for both patients with dementia and their informal care providers.³¹ Given the variability of caregiver concerns, multicomponent interventions addressing informational, self-care, social support, and financial needs often are needed.³¹ Supportive counseling and psychoeducation can help dementia caregivers with stress management, self-care, coping, and skills training—supporting the development of self-efficacy.^32,33

Outside resources. Although significant caregiver support can be provided directly by the physician, caregivers should be connected with outside resources, including support groups, counselors, psychotherapists, financial and legal support, and formal care services.³⁴

Continue to: Psychosocial and complementary interventions

Psychosocial and complementary interventions. Various psychosocial interventions (eg, psychoeducation, cognitive behavioral therapy, support groups) have been found to be beneficial in alleviating caregiver symptoms of depression, anxiety, and stress and improving well-being, perceived burden, and quality of life. However, systematic reviews have found variability in the degree of helpfulness of these interventions.^35,36

Some caregivers and care recipients may benefit from complementary and integrative medicine referrals. Mind–body therapies such as mindfulness, yoga, and Tai Chi have shown some beneficial effects.³⁷

Online resources. Caregivers also can be directed to online resources from organizations such as the Alzheimer’s Association (www.alz.org), the National Institutes of Health (www.alzheimers.gov), and the Family Caregiver Alliance (www.caregiver.org).

In rural settings, such as the one in which this case took place, online resources may decrease some barriers to supporting caregivers.³⁸ Internet-based interventions also have been found to have some benefit for dementia caregivers.^31,39

However, some rural locations continue to have limited reliable Internet services.⁴⁰ In affected areas, a strong relationship with a primary care physician may be even more important to the well-being of caregivers, since other support services may be less accessible.⁴¹

Continue to: Impacts of the pandemic

Impacts of the pandemic. Although our case took place prior to the COVID-19 pandemic, it is important to acknowledge ways the pandemic has impacted informal dementia caregiving.

Caregiver stress, depression, and anxiety increased during the pandemic, and the need for greater home confinement and social ­distancing amplified the negative impact of social isolation, including loneliness, on ­caregivers.^42,43 Caregivers often needed to increase their caregiving responsibilities and had more difficulty with care coordination due to limited access to in-person resources.⁴³ The pandemic led to increased reliance on technology and telehealth in the support of dementia caregivers.⁴³

THE CASE

The physician prescribed mirtazapine for Mr. C, titrating the dose as needed to address depressive symptoms and promote weight gain. The physician connected Mr. C’s father with home health services, including physical therapy for fall risk reduction. Mr. C also hired part-time support to provide additional assistance with ADLs and IADLs, allowing Mr. C to have time to attend to his own needs. Though provided with information about a local caregiver support group, Mr. C chose not to attend. The physician also assisted the family with advanced directives.

African American and Latino caregivers tend to have caregiving relationships of longer duration, requiring more time-intensive care, but they tend to use fewer formal support services than White caregivers.

A particular challenge that occurred during care for the family was addressing Mr. C’s father’s driving capacity, considering his strong need for independence. To address this concern, a family meeting was held with Mr. C, his father, and his siblings from out of town. Although Mr. C’s father was not willing to relinquish his driver’s license during that meeting, he agreed to complete a functional driving assessment.

The physician continued to meet with Mr. C and his father together, as well as with Mr. C individually, to provide supportive counseling as needed. As the father’s dementia progressed and it became more difficult to complete office appointments, the physician transitioned to home visits to provide care until the father’s death.

After the death of Mr. C’s father, the physician continued to serve as Mr. C’s primary care provider.

Keeping the “family”in family medicine

Through longitudinal assessment, needs identification, and provision of relevant information, emotional support, and resources, family physicians can provide care that can improve the quality of life and well-being and help alleviate burden experienced by dementia caregivers. Family physicians also are positioned to provide treatments that can address the negative physical and psychological health outcomes associated with informal dementia caregiving. By building relationships with multiple family members across generations, family physicians can understand the context of caregiving dynamics and work together with individuals with dementia and their caregivers throughout disease progression, providing consistent support to the family unit.

CORRESPONDENCE
Kathleen M. Young, PhD, MPH, Novant Health Family Medicine Wilmington, 2523 Delaney Avenue, Wilmington, NC 28403; [email protected]

THE CASE

Sam C* is a 68-year-old man who presented to his family physician in a rural health clinic due to concerns about weight loss. Since his visit 8 months prior, Mr. C unintentionally had lost 20 pounds. Upon questioning, Mr. C also reported feeling irritable and having difficulty with sleep and concentration.

A review of systems did not indicate the presence of infection or other medical conditions. In the 6 years since becoming a patient to the practice, he had reported no chronic health concerns, was taking no medications, and had only been to the clinic for his annual check-up appointments. He completed a Patient Health Questionnaire (PHQ-9) and scored 18, indicating moderately severe depression.

Mr. C had established care with his physician when he moved to the area from out of state so that he could be closer to his parents, who were in their mid-80s at the time. Mr. C’s physician also had been the family physician for his parents for the previous 20 years. Three years prior to Mr. C’s presentation for weight loss, his mother had received a diagnosis of acute leukemia; she died a year later.

Over the past year, Mr. C had needed to take a more active role in the care of his father, who was now in his early 90s. Mr. C’s father, who was previously in excellent health, had begun to develop significant health problems, including degenerative arthritis and progressive vascular dementia. He also had ataxia, leading to poor mobility, and a neurogenic bladder requiring self-catheterization, which required Mr. C’s assistance. Mr. C lived next door to his father and provided frequent assistance with activities of daily living. However, his father, who always had been the dominant figure in the family, was determined to maintain his independence and not relinquish control to others.

The strain of caregiving activities, along with managing his father’s inflexibility, was causing increasing distress for Mr. C. As he told his family physician, “I just don’t know what to do.”

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

It is estimated that more than 11 million Americans provided more than 18 billion hours in unpaid support for individuals with dementia in 2022, averaging 30 hours of care per caregiver per week.¹ As individuals with dementia progressively decline, they require increased assistance with activities of daily living (ADLs, such as bathing and dressing) and instrumental activities of daily living (IADLs, such as paying bills and using transportation). Most of this assistance comes from informal caregiving provided by family members and friends.

Caregiver burden can be defined as “the strain or load borne by a person who cares for a chronically ill, disabled, or elderly family member.”² Caregiver stress has been found to be higher for dementia caregiving than other types of caregiving.³ In particular, caring for someone with greater behavioral and psychological symptoms of dementia (BPSDs) has been associated with higher caregiver burden.^4-7

Beyond the subjective burden of care­giving, there are other potential negative ­consequences for dementia caregivers (see ­TABLE 1^8-14 and TABLE 2^15,16). In addition, caregiver distress is related to a number of care recipient outcomes, including earlier institutionalization, more hospitalizations, more BPSDs, poorer quality of life, and greater likelihood of experiencing elder abuse.¹⁷

Assessment, reassessment are key to meeting needs

Numerous factors can foster caregiver well-­being, including feelings of accomplishment and contribution, a strengthening of the relationship with the care recipient, and feeling supported by friends, family, and formal care systems.^18,19 Family physicians can play an important role by assessing and supporting patients with dementia and their caregivers. Ideally, the individual with dementia and the caregiver will be assessed both together and separately.

Caregiver distress is related to care recipient outcomes, such as earlier institutionalization, more hospitalizations, and poorer quality of life.

A thorough assessment includes gathering information about the context and quality of the caregiving relationship; caregiver perception of the care recipient’s health and functional status; caregiver values and preferences; caregiver well-being (including mental health assessment); caregiver skills, abilities, and knowledge about caregiving; and positive and negative consequences of caregiving.²⁰ Caregiver needs—including informational, care support, emotional, physical, and social needs—also should be assessed.

Continue to: Tools are available...

Tools are available to facilitate caregiver assessment. For example, the Zarit Burden Interview is a 22-item self-report measure that can be given to the caregiver²¹; shorter versions (4 and 12 items) are also available.²² Another resource available for caregiver assessment guidance is a toolkit developed by the Family Caregiver Alliance.²⁰

Continually assess for changing needs

As the condition of the individual with dementia progresses, it will be important to reassess the caregiver, as stressors and needs will change over the course of the caregiving relationship. Support should be adapted ­accordingly.

In the early stage of dementia, caregivers may need information on disease progression and dementia care planning, ways to navigate the health care system, financial planning, and useful resources. Caregivers also may need emotional support to help them adapt to the role of caregiver, deal with denial, and manage their stress.^23,24

With dementia progression, caregivers may need support related to increased decision-making responsibility, managing challenging behaviors, assisting with ADLs and IADLs, and identifying opportunities to meet personal social and well-being needs. They also may need support to accept the changes they are seeing in the individual with dementia and the shifts they are experiencing in their relationship with him or her.^23,25

In late-stage dementia, caregiver needs tend to shift to determining the need for long-term care placement vs staying at home, end-of-life planning, loneliness, and anticipatory grief.^23,26 Support with managing changing and accumulating stress typically remains a primary need throughout the progression of dementia.²⁷

Continue to: Specific populations have distinct needs

Specific populations have distinct needs. Some caregivers, including members of the LGBTQ+ community and different racial and ethnic groups, as well as caregivers of people with younger-onset dementia, may have additional support needs.²⁸

More than 11 million Americans provided more than 18 billion hours in unpaid support for individuals with dementia in 2022, averaging 30 hours of care per caregiver per week.

For example, African American and ­Latino caregivers tend to have caregiving relationships of longer duration, requiring more time-­intensive care, but use fewer formal support services than White caregivers.²⁹ Caregivers from non-White racial and ethnic groups also are more likely to experience discrimination when interacting with health care services on behalf of care recipients.³⁰

Having an awareness of potential specialized needs may help to prevent or address potential care disparities, and cultural humility may help to improve caregiver experiences with primary care physicians.

Resources to support caregivers

Family physicians are well situated to provide informational and emotional support for both patients with dementia and their informal care providers.³¹ Given the variability of caregiver concerns, multicomponent interventions addressing informational, self-care, social support, and financial needs often are needed.³¹ Supportive counseling and psychoeducation can help dementia caregivers with stress management, self-care, coping, and skills training—supporting the development of self-efficacy.^32,33

Outside resources. Although significant caregiver support can be provided directly by the physician, caregivers should be connected with outside resources, including support groups, counselors, psychotherapists, financial and legal support, and formal care services.³⁴

Continue to: Psychosocial and complementary interventions

Psychosocial and complementary interventions. Various psychosocial interventions (eg, psychoeducation, cognitive behavioral therapy, support groups) have been found to be beneficial in alleviating caregiver symptoms of depression, anxiety, and stress and improving well-being, perceived burden, and quality of life. However, systematic reviews have found variability in the degree of helpfulness of these interventions.^35,36

Some caregivers and care recipients may benefit from complementary and integrative medicine referrals. Mind–body therapies such as mindfulness, yoga, and Tai Chi have shown some beneficial effects.³⁷

Online resources. Caregivers also can be directed to online resources from organizations such as the Alzheimer’s Association (www.alz.org), the National Institutes of Health (www.alzheimers.gov), and the Family Caregiver Alliance (www.caregiver.org).

In rural settings, such as the one in which this case took place, online resources may decrease some barriers to supporting caregivers.³⁸ Internet-based interventions also have been found to have some benefit for dementia caregivers.^31,39

However, some rural locations continue to have limited reliable Internet services.⁴⁰ In affected areas, a strong relationship with a primary care physician may be even more important to the well-being of caregivers, since other support services may be less accessible.⁴¹

Continue to: Impacts of the pandemic

Impacts of the pandemic. Although our case took place prior to the COVID-19 pandemic, it is important to acknowledge ways the pandemic has impacted informal dementia caregiving.

Caregiver stress, depression, and anxiety increased during the pandemic, and the need for greater home confinement and social ­distancing amplified the negative impact of social isolation, including loneliness, on ­caregivers.^42,43 Caregivers often needed to increase their caregiving responsibilities and had more difficulty with care coordination due to limited access to in-person resources.⁴³ The pandemic led to increased reliance on technology and telehealth in the support of dementia caregivers.⁴³

THE CASE

The physician prescribed mirtazapine for Mr. C, titrating the dose as needed to address depressive symptoms and promote weight gain. The physician connected Mr. C’s father with home health services, including physical therapy for fall risk reduction. Mr. C also hired part-time support to provide additional assistance with ADLs and IADLs, allowing Mr. C to have time to attend to his own needs. Though provided with information about a local caregiver support group, Mr. C chose not to attend. The physician also assisted the family with advanced directives.

African American and Latino caregivers tend to have caregiving relationships of longer duration, requiring more time-intensive care, but they tend to use fewer formal support services than White caregivers.

A particular challenge that occurred during care for the family was addressing Mr. C’s father’s driving capacity, considering his strong need for independence. To address this concern, a family meeting was held with Mr. C, his father, and his siblings from out of town. Although Mr. C’s father was not willing to relinquish his driver’s license during that meeting, he agreed to complete a functional driving assessment.

The physician continued to meet with Mr. C and his father together, as well as with Mr. C individually, to provide supportive counseling as needed. As the father’s dementia progressed and it became more difficult to complete office appointments, the physician transitioned to home visits to provide care until the father’s death.

After the death of Mr. C’s father, the physician continued to serve as Mr. C’s primary care provider.

Keeping the “family”in family medicine

Through longitudinal assessment, needs identification, and provision of relevant information, emotional support, and resources, family physicians can provide care that can improve the quality of life and well-being and help alleviate burden experienced by dementia caregivers. Family physicians also are positioned to provide treatments that can address the negative physical and psychological health outcomes associated with informal dementia caregiving. By building relationships with multiple family members across generations, family physicians can understand the context of caregiving dynamics and work together with individuals with dementia and their caregivers throughout disease progression, providing consistent support to the family unit.

CORRESPONDENCE
Kathleen M. Young, PhD, MPH, Novant Health Family Medicine Wilmington, 2523 Delaney Avenue, Wilmington, NC 28403; [email protected]

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

Members of a Food and Drug Administration advisory committee have unanimously concluded that a postmarketing study confirms the benefit of the Alzheimer’s drug lecanemab (Leqembi, Eisai), paving the way for traditional approval.

“Overall, the study demonstrated clearly that this is an effective treatment,” said acting chair Robert C. Alexander, MD, chief scientific officer, Alzheimer’s Prevention Initiative, Banner Alzheimer’s Institute, and research professor, department of psychiatry, University of Arizona, Phoenix, during the meeting.

An intravenous infusion targeting amyloid-beta, lecanemab received accelerated FDA approved earlier in 2023 for the treatment of early Alzheimer’s disease (AD). The company was required to complete a confirmatory study to verify and describe the product’s clinical benefit.

The Peripheral and Central Nervous System Drugs Advisory Committee met to discuss this phase 3 study (CLARITY-AD). The multicenter, double-blind study included 1,795 patients (mean age, 71 years) who had mild cognitive impairment caused by AD or mild AD dementia.
 

Delayed progression

Study participants had a broad range of comorbidities, and many were concomitantly receiving other medications. Black people were underrepresented in the study at just 3% of the total cohort.

Patients were randomly assigned to receive placebo or lecanemab 10 mg/kg biweekly. In addition to a placebo-controlled period and safety follow-up, the study has an ongoing extension phase of up to 4 years.

The study met its primary endpoint, showing a highly statistically significant 27% less decline on the Clinical Dementia Rating-Sum of Boxes at 18 months (difference in adjusted mean, –0.45; 95% CI, –0.67 to –0.23; P = .00005).

This was supported by a significant 26% difference on the AD Assessment Scale–Cognitive Subscale with 14 tasks (ADAS-Cog 14).

The drug also affected function, with a 37% decrease, compared with placebo, on the AD Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment.

Committee members heard that the results signal delays in disease progression by about 5 months, giving patients more time to live independently and participate in hobbies and interests.

Patients who received the active drug also experienced quality of life benefits. Compared with patients who received placebo, those who took lecanemab had 49% less decline as measured with the European Quality of Life–5 Dimensions scale and 56% less decline as measured by the Quality of Life in AD scale, and caregivers reported less burden.

Lecanemab also affected biomarkers of amyloid, tau, and neurodegeneration, providing a biological basis for the treatment effects consistent with slowing of disease progression.
 

Unanimous support

All six committee members agreed by vote that the study provides evidence of clinical benefit. They variously descried the study and results as “robust,” “compelling,” “well conducted,” “clear and consistent,” and “clinically meaningful.”

In the active treatment group, there was a higher incidence of amyloid-related imaging abnormalities (ARIAs), which can be serious and life-threatening but are usually asymptomatic. In this study, most ARIAs had resolved by 3 months.

Deaths occurred in 0.8% of the placebo and 0.7% of the treatment group. Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., noted that the numbers of deaths and serious adverse events were “quite similar” in the two groups.

“And for serious ARIA, there was an imbalance favoring placebo, but overall, these were pretty rare,” he said.
 

Subgroup concerns

Committee members discussed the risk/benefit profile for three subgroups of patients – those with apolipoprotein E4 (apo E4) allele, patients taking an anticoagulant, and those with cerebral amyloid angiopathy (CAA).

In the apo E4 group, the study’s primary endpoint did not favor the drug, but secondary endpoints did.

“I think the general feeling [for apo E4 status] is that the risk/benefit still remains favorable, especially when looking across multiple endpoints,” said Dr. Alexander.

However, some members supported recommending genetic testing before initiating the drug.

The views were more diverse for the use of lecanemab in the presence of an anticoagulant, which may increase the risk for cerebral hemorrhage. Some committee members strongly recommended that these patients not receive lecanemab, while others highlighted the need for more information, owing to uncertainties about the risks.

With respect to CAA, most members supported the idea of considering use of the drug in the presence of this condition, but only after discussing the risks with patients and their families and in the presence of a robust reporting system.

An Alzheimer’s Association representative was in attendance during the public hearing portion of the meeting to express support for traditional approval of lecanemab for people with early AD.

The association strongly favors full Medicare coverage for FDA-approved AD treatments. The Centers for Medicare & Medicaid Services has determined that AD treatments receiving traditional FDA approval will be covered if clinicians register and enter data in a registry.

“While this is an important signal that CMS wants to improve access to FDA-approved treatments, registry as a condition of coverage is an unnecessary and potentially harmful barrier,” said the Alzheimer’s Association in a press release following the meeting.

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

Members of a Food and Drug Administration advisory committee have unanimously concluded that a postmarketing study confirms the benefit of the Alzheimer’s drug lecanemab (Leqembi, Eisai), paving the way for traditional approval.

“Overall, the study demonstrated clearly that this is an effective treatment,” said acting chair Robert C. Alexander, MD, chief scientific officer, Alzheimer’s Prevention Initiative, Banner Alzheimer’s Institute, and research professor, department of psychiatry, University of Arizona, Phoenix, during the meeting.

An intravenous infusion targeting amyloid-beta, lecanemab received accelerated FDA approved earlier in 2023 for the treatment of early Alzheimer’s disease (AD). The company was required to complete a confirmatory study to verify and describe the product’s clinical benefit.

The Peripheral and Central Nervous System Drugs Advisory Committee met to discuss this phase 3 study (CLARITY-AD). The multicenter, double-blind study included 1,795 patients (mean age, 71 years) who had mild cognitive impairment caused by AD or mild AD dementia.
 

Delayed progression

Study participants had a broad range of comorbidities, and many were concomitantly receiving other medications. Black people were underrepresented in the study at just 3% of the total cohort.

Patients were randomly assigned to receive placebo or lecanemab 10 mg/kg biweekly. In addition to a placebo-controlled period and safety follow-up, the study has an ongoing extension phase of up to 4 years.

The study met its primary endpoint, showing a highly statistically significant 27% less decline on the Clinical Dementia Rating-Sum of Boxes at 18 months (difference in adjusted mean, –0.45; 95% CI, –0.67 to –0.23; P = .00005).

This was supported by a significant 26% difference on the AD Assessment Scale–Cognitive Subscale with 14 tasks (ADAS-Cog 14).

The drug also affected function, with a 37% decrease, compared with placebo, on the AD Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment.

Committee members heard that the results signal delays in disease progression by about 5 months, giving patients more time to live independently and participate in hobbies and interests.

Patients who received the active drug also experienced quality of life benefits. Compared with patients who received placebo, those who took lecanemab had 49% less decline as measured with the European Quality of Life–5 Dimensions scale and 56% less decline as measured by the Quality of Life in AD scale, and caregivers reported less burden.

Lecanemab also affected biomarkers of amyloid, tau, and neurodegeneration, providing a biological basis for the treatment effects consistent with slowing of disease progression.
 

Unanimous support

All six committee members agreed by vote that the study provides evidence of clinical benefit. They variously descried the study and results as “robust,” “compelling,” “well conducted,” “clear and consistent,” and “clinically meaningful.”

In the active treatment group, there was a higher incidence of amyloid-related imaging abnormalities (ARIAs), which can be serious and life-threatening but are usually asymptomatic. In this study, most ARIAs had resolved by 3 months.

Deaths occurred in 0.8% of the placebo and 0.7% of the treatment group. Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., noted that the numbers of deaths and serious adverse events were “quite similar” in the two groups.

“And for serious ARIA, there was an imbalance favoring placebo, but overall, these were pretty rare,” he said.
 

Subgroup concerns

Committee members discussed the risk/benefit profile for three subgroups of patients – those with apolipoprotein E4 (apo E4) allele, patients taking an anticoagulant, and those with cerebral amyloid angiopathy (CAA).

In the apo E4 group, the study’s primary endpoint did not favor the drug, but secondary endpoints did.

“I think the general feeling [for apo E4 status] is that the risk/benefit still remains favorable, especially when looking across multiple endpoints,” said Dr. Alexander.

However, some members supported recommending genetic testing before initiating the drug.

The views were more diverse for the use of lecanemab in the presence of an anticoagulant, which may increase the risk for cerebral hemorrhage. Some committee members strongly recommended that these patients not receive lecanemab, while others highlighted the need for more information, owing to uncertainties about the risks.

With respect to CAA, most members supported the idea of considering use of the drug in the presence of this condition, but only after discussing the risks with patients and their families and in the presence of a robust reporting system.

An Alzheimer’s Association representative was in attendance during the public hearing portion of the meeting to express support for traditional approval of lecanemab for people with early AD.

The association strongly favors full Medicare coverage for FDA-approved AD treatments. The Centers for Medicare & Medicaid Services has determined that AD treatments receiving traditional FDA approval will be covered if clinicians register and enter data in a registry.

“While this is an important signal that CMS wants to improve access to FDA-approved treatments, registry as a condition of coverage is an unnecessary and potentially harmful barrier,” said the Alzheimer’s Association in a press release following the meeting.

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

Members of a Food and Drug Administration advisory committee have unanimously concluded that a postmarketing study confirms the benefit of the Alzheimer’s drug lecanemab (Leqembi, Eisai), paving the way for traditional approval.

“Overall, the study demonstrated clearly that this is an effective treatment,” said acting chair Robert C. Alexander, MD, chief scientific officer, Alzheimer’s Prevention Initiative, Banner Alzheimer’s Institute, and research professor, department of psychiatry, University of Arizona, Phoenix, during the meeting.

An intravenous infusion targeting amyloid-beta, lecanemab received accelerated FDA approved earlier in 2023 for the treatment of early Alzheimer’s disease (AD). The company was required to complete a confirmatory study to verify and describe the product’s clinical benefit.

The Peripheral and Central Nervous System Drugs Advisory Committee met to discuss this phase 3 study (CLARITY-AD). The multicenter, double-blind study included 1,795 patients (mean age, 71 years) who had mild cognitive impairment caused by AD or mild AD dementia.
 

Delayed progression

Study participants had a broad range of comorbidities, and many were concomitantly receiving other medications. Black people were underrepresented in the study at just 3% of the total cohort.

Patients were randomly assigned to receive placebo or lecanemab 10 mg/kg biweekly. In addition to a placebo-controlled period and safety follow-up, the study has an ongoing extension phase of up to 4 years.

The study met its primary endpoint, showing a highly statistically significant 27% less decline on the Clinical Dementia Rating-Sum of Boxes at 18 months (difference in adjusted mean, –0.45; 95% CI, –0.67 to –0.23; P = .00005).

This was supported by a significant 26% difference on the AD Assessment Scale–Cognitive Subscale with 14 tasks (ADAS-Cog 14).

The drug also affected function, with a 37% decrease, compared with placebo, on the AD Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment.

Committee members heard that the results signal delays in disease progression by about 5 months, giving patients more time to live independently and participate in hobbies and interests.

Patients who received the active drug also experienced quality of life benefits. Compared with patients who received placebo, those who took lecanemab had 49% less decline as measured with the European Quality of Life–5 Dimensions scale and 56% less decline as measured by the Quality of Life in AD scale, and caregivers reported less burden.

Lecanemab also affected biomarkers of amyloid, tau, and neurodegeneration, providing a biological basis for the treatment effects consistent with slowing of disease progression.
 

Unanimous support

All six committee members agreed by vote that the study provides evidence of clinical benefit. They variously descried the study and results as “robust,” “compelling,” “well conducted,” “clear and consistent,” and “clinically meaningful.”

In the active treatment group, there was a higher incidence of amyloid-related imaging abnormalities (ARIAs), which can be serious and life-threatening but are usually asymptomatic. In this study, most ARIAs had resolved by 3 months.

Deaths occurred in 0.8% of the placebo and 0.7% of the treatment group. Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., noted that the numbers of deaths and serious adverse events were “quite similar” in the two groups.

“And for serious ARIA, there was an imbalance favoring placebo, but overall, these were pretty rare,” he said.
 

Subgroup concerns

Committee members discussed the risk/benefit profile for three subgroups of patients – those with apolipoprotein E4 (apo E4) allele, patients taking an anticoagulant, and those with cerebral amyloid angiopathy (CAA).

In the apo E4 group, the study’s primary endpoint did not favor the drug, but secondary endpoints did.

“I think the general feeling [for apo E4 status] is that the risk/benefit still remains favorable, especially when looking across multiple endpoints,” said Dr. Alexander.

However, some members supported recommending genetic testing before initiating the drug.

The views were more diverse for the use of lecanemab in the presence of an anticoagulant, which may increase the risk for cerebral hemorrhage. Some committee members strongly recommended that these patients not receive lecanemab, while others highlighted the need for more information, owing to uncertainties about the risks.

With respect to CAA, most members supported the idea of considering use of the drug in the presence of this condition, but only after discussing the risks with patients and their families and in the presence of a robust reporting system.

An Alzheimer’s Association representative was in attendance during the public hearing portion of the meeting to express support for traditional approval of lecanemab for people with early AD.

The association strongly favors full Medicare coverage for FDA-approved AD treatments. The Centers for Medicare & Medicaid Services has determined that AD treatments receiving traditional FDA approval will be covered if clinicians register and enter data in a registry.

“While this is an important signal that CMS wants to improve access to FDA-approved treatments, registry as a condition of coverage is an unnecessary and potentially harmful barrier,” said the Alzheimer’s Association in a press release following the meeting.

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

Muscle adiposity may be a novel risk factor for cognitive decline in older adults, new research suggests.

Investigators assessed muscle fat in more than 1,600 adults in their 70s and evaluated their cognitive function over a 10-year period. They found that increases in muscle adiposity from year 1 to year 6 were associated with greater cognitive decline over time, independent of total weight, other fat deposits, muscle characteristics, and traditional dementia risk factors.

The findings were similar between Black and White people and between men and women.

“Increasing adiposity – or fat deposition – in skeletal muscles predicted faster cognitive decline, irrespective of demographics or other disease, and this effect was distinct from that of other types of fat or other muscle characteristics, such as strength or mass,” study investigator Caterina Rosano MD, MPH, professor of epidemiology at the University of Pittsburgh, said in an interview.

The study was published in the Journal of the American Geriatrics Society.
 

Biologically plausible

“There has been a growing recognition that overall adiposity and muscle measures, such as strength and mass, are individual indicators of future dementia risk and both strengthen the algorithms to predict cognitive decline,” said Dr. Rosano, associate director for clinical translation at the University of Pittsburgh’s Aging Institute. “However, adiposity in the muscle has not been examined.”

Some evidence supports a “biologically plausible link” between muscle adiposity and dementia risk. For example, muscle adiposity increases the risk for type 2 diabetes and hypertension, both of which are dementia risk factors.

Skeletal muscle adiposity increases with older age, even in older adults who lose weight, and is “highly prevalent” among older adults of African ancestry.

The researchers examined a large, biracial sample of older adults participating in the Health, Aging and Body Composition study, which enrolled men and women aged between 70 and 79 years. Participants were followed for an average of 9.0 ± 1.8 years.

During years 1 and 6, participants’ body composition was analyzed, including intermuscular adipose tissue (IMAT), visceral and subcutaneous adiposity, total fat mass, and muscle area.

In years 1, 3, 5, 8, and 10, participants’ cognition was measured using the modified Mini-Mental State (3MS) exam.

The main independent variable was 5-year change in thigh IMAT (year 6 minus year 1), and the main dependent variable was 3MS decline (from year 5 to year 10).

The researchers adjusted all the models for traditional dementia risk factors at baseline including 3MS, education, apo E4 allele, diabetes, hypertension, and physical activity and also calculated interactions between IMAT change by race or sex.

These models also accounted for change in muscle strength, muscle area, body weight, abdominal subcutaneous and visceral adiposity, and total body fat mass as well as cytokines related to adiposity.
 

‘Rich and engaging crosstalk’

The final sample included 1634 participants (mean age, 73.38 years at baseline; 48% female; 35% Black; mean baseline 3MS score, 91.6).

Thigh IMAT increased by 39.0% in all participants from year 1 to year 6, which corresponded to an increase of 4.85 cm² or 0.97 cm²/year. During the same time period, muscle strength decreased by 14.0% (P < .05), although thigh muscle area remained stable, decreasing less than 0.5%.

There were decreases in both abdominal subcutaneous and visceral adiposity of 3.92% and 6.43%, respectively (P < .05). There was a decrease of 3.3% in 3MS from year 5 to year 10.

Several variables were associated with 3MS decline, independent of any change in thigh IMAT: older age, less education, and having at least one copy of the APOe4 allele. These variables were included in the model of IMAT change predicting 3MS change.

A statistically significant association of IMAT increase with 3MS decline was found. The IMAT increase of 4.85 cm² corresponded to a 3MS decline of an additional 3.6 points (P < .0001) from year 5 to year 10, “indicating a clinically important change.”

The association between increasing thigh IMAT with declining 3MS “remained statistically significant” after adjusting for race, age, education, and apo E4 (P < .0001) and was independent of changes in thigh muscle area, muscle strength, and other adiposity measures.

In participants with increased IMAT in years 1-6, the mean 3MS score fell to approximately 87 points at year 10, compared with those without increased IMAT, with a 3MS score that dropped to approximately 89 points.

Interactions by race and sex were not statistically significant (P > .08).

“Our results suggest that adiposity in muscles can predict cognitive decline, in addition to (not instead of) other traditional dementia risk factors,” said Dr. Rosano.

There is “a rich and engaging crosstalk between muscle, adipose tissue, and the brain all throughout our lives, happening through factors released in the bloodstream that can reach the brain, however, the specific identity of the factors responsible for the crosstalk of muscle adiposity and brain in older adults has not yet been discovered,” she noted.

Although muscle adiposity is “not yet routinely measured in clinical settings, it is being measured opportunistically on clinical CT scans obtained as part of routine patient care,” she added. “These CT measurements have already been validated in many studies of older adults; thus, clinicians could have access to this novel information without additional cost, time, or radiation exposure.”
 

Causality not proven

In a comment, Bruce Albala, PhD, professor, department of environmental and occupational health, University of California, Irvine, noted that the 3MS assessment is scored on a 100-point scale, with a score less than 78 “generally regarded as indicating cognitive impairment or approaching a dementia condition.” In the current study, the mean 3MS score of participants with increased IMAT was still “well above the dementia cut-off.”

Moreover, “even if there is a relationship or correlation between IMAT and cognition, this does not prove or even suggest causality, especially from a biological mechanistic approach,” said Dr. Albaba, an adjunct professor of neurology, who was not involved in the study. “Clearly, more research is needed even to understand the relationship between these two factors.”

The study was supported by the National Institute on Aging. Dr. Rosano and coauthors and Dr. Albala declared no relevant financial relationships.

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

Muscle adiposity may be a novel risk factor for cognitive decline in older adults, new research suggests.

Investigators assessed muscle fat in more than 1,600 adults in their 70s and evaluated their cognitive function over a 10-year period. They found that increases in muscle adiposity from year 1 to year 6 were associated with greater cognitive decline over time, independent of total weight, other fat deposits, muscle characteristics, and traditional dementia risk factors.

The findings were similar between Black and White people and between men and women.

“Increasing adiposity – or fat deposition – in skeletal muscles predicted faster cognitive decline, irrespective of demographics or other disease, and this effect was distinct from that of other types of fat or other muscle characteristics, such as strength or mass,” study investigator Caterina Rosano MD, MPH, professor of epidemiology at the University of Pittsburgh, said in an interview.

The study was published in the Journal of the American Geriatrics Society.
 

Biologically plausible

“There has been a growing recognition that overall adiposity and muscle measures, such as strength and mass, are individual indicators of future dementia risk and both strengthen the algorithms to predict cognitive decline,” said Dr. Rosano, associate director for clinical translation at the University of Pittsburgh’s Aging Institute. “However, adiposity in the muscle has not been examined.”

Some evidence supports a “biologically plausible link” between muscle adiposity and dementia risk. For example, muscle adiposity increases the risk for type 2 diabetes and hypertension, both of which are dementia risk factors.

Skeletal muscle adiposity increases with older age, even in older adults who lose weight, and is “highly prevalent” among older adults of African ancestry.

The researchers examined a large, biracial sample of older adults participating in the Health, Aging and Body Composition study, which enrolled men and women aged between 70 and 79 years. Participants were followed for an average of 9.0 ± 1.8 years.

During years 1 and 6, participants’ body composition was analyzed, including intermuscular adipose tissue (IMAT), visceral and subcutaneous adiposity, total fat mass, and muscle area.

In years 1, 3, 5, 8, and 10, participants’ cognition was measured using the modified Mini-Mental State (3MS) exam.

The main independent variable was 5-year change in thigh IMAT (year 6 minus year 1), and the main dependent variable was 3MS decline (from year 5 to year 10).

The researchers adjusted all the models for traditional dementia risk factors at baseline including 3MS, education, apo E4 allele, diabetes, hypertension, and physical activity and also calculated interactions between IMAT change by race or sex.

These models also accounted for change in muscle strength, muscle area, body weight, abdominal subcutaneous and visceral adiposity, and total body fat mass as well as cytokines related to adiposity.
 

‘Rich and engaging crosstalk’

The final sample included 1634 participants (mean age, 73.38 years at baseline; 48% female; 35% Black; mean baseline 3MS score, 91.6).

Thigh IMAT increased by 39.0% in all participants from year 1 to year 6, which corresponded to an increase of 4.85 cm² or 0.97 cm²/year. During the same time period, muscle strength decreased by 14.0% (P < .05), although thigh muscle area remained stable, decreasing less than 0.5%.

There were decreases in both abdominal subcutaneous and visceral adiposity of 3.92% and 6.43%, respectively (P < .05). There was a decrease of 3.3% in 3MS from year 5 to year 10.

Several variables were associated with 3MS decline, independent of any change in thigh IMAT: older age, less education, and having at least one copy of the APOe4 allele. These variables were included in the model of IMAT change predicting 3MS change.

A statistically significant association of IMAT increase with 3MS decline was found. The IMAT increase of 4.85 cm² corresponded to a 3MS decline of an additional 3.6 points (P < .0001) from year 5 to year 10, “indicating a clinically important change.”

The association between increasing thigh IMAT with declining 3MS “remained statistically significant” after adjusting for race, age, education, and apo E4 (P < .0001) and was independent of changes in thigh muscle area, muscle strength, and other adiposity measures.

In participants with increased IMAT in years 1-6, the mean 3MS score fell to approximately 87 points at year 10, compared with those without increased IMAT, with a 3MS score that dropped to approximately 89 points.

Interactions by race and sex were not statistically significant (P > .08).

“Our results suggest that adiposity in muscles can predict cognitive decline, in addition to (not instead of) other traditional dementia risk factors,” said Dr. Rosano.

There is “a rich and engaging crosstalk between muscle, adipose tissue, and the brain all throughout our lives, happening through factors released in the bloodstream that can reach the brain, however, the specific identity of the factors responsible for the crosstalk of muscle adiposity and brain in older adults has not yet been discovered,” she noted.

Although muscle adiposity is “not yet routinely measured in clinical settings, it is being measured opportunistically on clinical CT scans obtained as part of routine patient care,” she added. “These CT measurements have already been validated in many studies of older adults; thus, clinicians could have access to this novel information without additional cost, time, or radiation exposure.”
 

Causality not proven

In a comment, Bruce Albala, PhD, professor, department of environmental and occupational health, University of California, Irvine, noted that the 3MS assessment is scored on a 100-point scale, with a score less than 78 “generally regarded as indicating cognitive impairment or approaching a dementia condition.” In the current study, the mean 3MS score of participants with increased IMAT was still “well above the dementia cut-off.”

Moreover, “even if there is a relationship or correlation between IMAT and cognition, this does not prove or even suggest causality, especially from a biological mechanistic approach,” said Dr. Albaba, an adjunct professor of neurology, who was not involved in the study. “Clearly, more research is needed even to understand the relationship between these two factors.”

The study was supported by the National Institute on Aging. Dr. Rosano and coauthors and Dr. Albala declared no relevant financial relationships.

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

Muscle adiposity may be a novel risk factor for cognitive decline in older adults, new research suggests.

Investigators assessed muscle fat in more than 1,600 adults in their 70s and evaluated their cognitive function over a 10-year period. They found that increases in muscle adiposity from year 1 to year 6 were associated with greater cognitive decline over time, independent of total weight, other fat deposits, muscle characteristics, and traditional dementia risk factors.

The findings were similar between Black and White people and between men and women.

“Increasing adiposity – or fat deposition – in skeletal muscles predicted faster cognitive decline, irrespective of demographics or other disease, and this effect was distinct from that of other types of fat or other muscle characteristics, such as strength or mass,” study investigator Caterina Rosano MD, MPH, professor of epidemiology at the University of Pittsburgh, said in an interview.

The study was published in the Journal of the American Geriatrics Society.
 

Biologically plausible

“There has been a growing recognition that overall adiposity and muscle measures, such as strength and mass, are individual indicators of future dementia risk and both strengthen the algorithms to predict cognitive decline,” said Dr. Rosano, associate director for clinical translation at the University of Pittsburgh’s Aging Institute. “However, adiposity in the muscle has not been examined.”

Some evidence supports a “biologically plausible link” between muscle adiposity and dementia risk. For example, muscle adiposity increases the risk for type 2 diabetes and hypertension, both of which are dementia risk factors.

Skeletal muscle adiposity increases with older age, even in older adults who lose weight, and is “highly prevalent” among older adults of African ancestry.

The researchers examined a large, biracial sample of older adults participating in the Health, Aging and Body Composition study, which enrolled men and women aged between 70 and 79 years. Participants were followed for an average of 9.0 ± 1.8 years.

During years 1 and 6, participants’ body composition was analyzed, including intermuscular adipose tissue (IMAT), visceral and subcutaneous adiposity, total fat mass, and muscle area.

In years 1, 3, 5, 8, and 10, participants’ cognition was measured using the modified Mini-Mental State (3MS) exam.

The main independent variable was 5-year change in thigh IMAT (year 6 minus year 1), and the main dependent variable was 3MS decline (from year 5 to year 10).

The researchers adjusted all the models for traditional dementia risk factors at baseline including 3MS, education, apo E4 allele, diabetes, hypertension, and physical activity and also calculated interactions between IMAT change by race or sex.

These models also accounted for change in muscle strength, muscle area, body weight, abdominal subcutaneous and visceral adiposity, and total body fat mass as well as cytokines related to adiposity.
 

‘Rich and engaging crosstalk’

The final sample included 1634 participants (mean age, 73.38 years at baseline; 48% female; 35% Black; mean baseline 3MS score, 91.6).

Thigh IMAT increased by 39.0% in all participants from year 1 to year 6, which corresponded to an increase of 4.85 cm² or 0.97 cm²/year. During the same time period, muscle strength decreased by 14.0% (P < .05), although thigh muscle area remained stable, decreasing less than 0.5%.

There were decreases in both abdominal subcutaneous and visceral adiposity of 3.92% and 6.43%, respectively (P < .05). There was a decrease of 3.3% in 3MS from year 5 to year 10.

Several variables were associated with 3MS decline, independent of any change in thigh IMAT: older age, less education, and having at least one copy of the APOe4 allele. These variables were included in the model of IMAT change predicting 3MS change.

A statistically significant association of IMAT increase with 3MS decline was found. The IMAT increase of 4.85 cm² corresponded to a 3MS decline of an additional 3.6 points (P < .0001) from year 5 to year 10, “indicating a clinically important change.”

The association between increasing thigh IMAT with declining 3MS “remained statistically significant” after adjusting for race, age, education, and apo E4 (P < .0001) and was independent of changes in thigh muscle area, muscle strength, and other adiposity measures.

In participants with increased IMAT in years 1-6, the mean 3MS score fell to approximately 87 points at year 10, compared with those without increased IMAT, with a 3MS score that dropped to approximately 89 points.

Interactions by race and sex were not statistically significant (P > .08).

“Our results suggest that adiposity in muscles can predict cognitive decline, in addition to (not instead of) other traditional dementia risk factors,” said Dr. Rosano.

There is “a rich and engaging crosstalk between muscle, adipose tissue, and the brain all throughout our lives, happening through factors released in the bloodstream that can reach the brain, however, the specific identity of the factors responsible for the crosstalk of muscle adiposity and brain in older adults has not yet been discovered,” she noted.

Although muscle adiposity is “not yet routinely measured in clinical settings, it is being measured opportunistically on clinical CT scans obtained as part of routine patient care,” she added. “These CT measurements have already been validated in many studies of older adults; thus, clinicians could have access to this novel information without additional cost, time, or radiation exposure.”
 

Causality not proven

In a comment, Bruce Albala, PhD, professor, department of environmental and occupational health, University of California, Irvine, noted that the 3MS assessment is scored on a 100-point scale, with a score less than 78 “generally regarded as indicating cognitive impairment or approaching a dementia condition.” In the current study, the mean 3MS score of participants with increased IMAT was still “well above the dementia cut-off.”

Moreover, “even if there is a relationship or correlation between IMAT and cognition, this does not prove or even suggest causality, especially from a biological mechanistic approach,” said Dr. Albaba, an adjunct professor of neurology, who was not involved in the study. “Clearly, more research is needed even to understand the relationship between these two factors.”

The study was supported by the National Institute on Aging. Dr. Rosano and coauthors and Dr. Albala declared no relevant financial relationships.

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

A blood biomarker that measures astrocyte reactivity may help determine who, among cognitively unimpaired older adults with amyloid-beta, will go on to develop Alzheimer’s disease (AD), new research suggests.

Investigators tested the blood of 1,000 cognitively healthy individuals with and without amyloid-beta pathology and found that only those with a combination of amyloid-beta burden and abnormal astrocyte activation subsequently progressed to AD.

“Our study argues that testing for the presence of brain amyloid along with blood biomarkers of astrocyte reactivity is the optimal screening to identify patients who are most at risk for progressing to Alzheimer’s disease,” senior investigator Tharick A. Pascoal, MD, PhD, associate professor of psychiatry and neurology, University of Pittsburgh, said in a release.

At this point, the biomarker is a research tool, but its application in clinical practice “is not very far away,” Dr. Pascoal told this news organization.

The study was published online  in Nature Medicine.  
 

Multicenter study

In AD, accumulation of amyloid-beta in the brain precedes tau pathology, but not everyone with amyloid-beta develops tau, and, consequently, clinical symptoms. Approximately 30% of older adults have brain amyloid but many never progress to AD, said Dr. Pascoal.

This suggests other biological processes may trigger the deleterious effects of amyloid-beta in the early stages of AD.

Finding predictive markers of early amyloid-beta–related tau pathology would help identify cognitively normal individuals who are more likely to develop AD.

Post-mortem studies show astrocyte reactivity – changes in glial cells in the brain and spinal cord because of an insult in the brain – is an early AD abnormality. Other research suggests a close link between amyloid-beta, astrocyte reactivity, and tau.

In addition, evidence suggests plasma measures of glial fibrillary acidic protein (GFAP) could be a strong proxy of astrocyte reactivity in the brain. Dr. Pascoal explained that when astrocytes are changed or become bigger, more GFAP is released.

The study included 1,016 cognitively normal individuals from three centers; some had amyloid pathology, some did not. Participants’ mean age was 69.6 years, and all were deemed negative or positive for astrocyte reactivity based on plasma GFAP levels.

Results showed amyloid-beta is associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity. In addition, analyses using PET scans showed an AD-like pattern of tau tangle accumulation as a function of amyloid-beta exclusively in those same individuals.
 

Early upstream event

The findings suggest abnormalities in astrocyte reactivity is an early upstream event that likely occurs prior to tau pathology, which is closely related to the development of neurodegeneration and cognitive decline.

It’s likely many types of insults or processes can lead to astrocyte reactivity, possibly including COVID, but more research in this area is needed, said Dr. Pascoal.

“Our study only looked at the consequence of having both amyloid and astrocyte reactivity; it did not elucidate what is causing either of them,” he said.

Although “we were able to have very good results” in the current study, additional studies are needed to better establish the cut-off for GFAP levels that signal progression, said Dr. Pascoal.

The effect of astrocyte reactivity on the association between amyloid-beta and tau phosphorylation was greater in men than women. Dr. Pascoal noted anti-amyloid therapies, which might be modifying the amyloid-beta-astrocyte-tau pathway, tend to have a much larger effect in men than women.

Further studies that measure amyloid-beta, tau, and GFAP biomarkers at multiple timepoints, and with long follow-up, are needed, the investigators note.

The results may have implications for clinical trials, which have increasingly focused on individuals in the earliest preclinical phases of AD. Future studies should include cognitively normal patients who are positive for both amyloid pathology and astrocyte reactivity but have no overt p-tau abnormality, said Dr. Pascoal.

This may provide a time window for interventions very early in the disease process in those at increased risk for AD-related progression.

The study did not determine whether participants with both amyloid and astrocyte reactivity will inevitably develop AD, and to do so would require a longer follow up. “Our outcome was correlation to tau in the brain, which is something we know will lead to AD.”

Although the cohort represents significant socioeconomic diversity, a main limitation of the study was that subjects were mainly White, which limits the generalizability of the findings to a more diverse population.

The study received support from the National Institute of Aging; National Heart Lung and Blood Institute; Alzheimer’s Association; Fonds de Recherche du Québec-Santé; Canadian Consortium of Neurodegeneration in Aging; Weston Brain Institute; Colin Adair Charitable Foundation; Swedish Research Council; Wallenberg Scholar; BrightFocus Foundation; Swedish Alzheimer Foundation; Swedish Brain Foundation; Agneta Prytz-Folkes & Gösta Folkes Foundation; European Union; Swedish State Support for Clinical Research; Alzheimer Drug Discovery Foundation; Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden; the UK Dementia Research Institute at UCL; National Academy of Neuropsychology; Fundação de Amparo a pesquisa do Rio Grande do Sul; Instituto Serrapilheira; and Hjärnfonden.

Dr. Pascoal reports no relevant financial relationships.

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

A blood biomarker that measures astrocyte reactivity may help determine who, among cognitively unimpaired older adults with amyloid-beta, will go on to develop Alzheimer’s disease (AD), new research suggests.

Investigators tested the blood of 1,000 cognitively healthy individuals with and without amyloid-beta pathology and found that only those with a combination of amyloid-beta burden and abnormal astrocyte activation subsequently progressed to AD.

“Our study argues that testing for the presence of brain amyloid along with blood biomarkers of astrocyte reactivity is the optimal screening to identify patients who are most at risk for progressing to Alzheimer’s disease,” senior investigator Tharick A. Pascoal, MD, PhD, associate professor of psychiatry and neurology, University of Pittsburgh, said in a release.

At this point, the biomarker is a research tool, but its application in clinical practice “is not very far away,” Dr. Pascoal told this news organization.

The study was published online  in Nature Medicine.  
 

Multicenter study

In AD, accumulation of amyloid-beta in the brain precedes tau pathology, but not everyone with amyloid-beta develops tau, and, consequently, clinical symptoms. Approximately 30% of older adults have brain amyloid but many never progress to AD, said Dr. Pascoal.

This suggests other biological processes may trigger the deleterious effects of amyloid-beta in the early stages of AD.

Finding predictive markers of early amyloid-beta–related tau pathology would help identify cognitively normal individuals who are more likely to develop AD.

Post-mortem studies show astrocyte reactivity – changes in glial cells in the brain and spinal cord because of an insult in the brain – is an early AD abnormality. Other research suggests a close link between amyloid-beta, astrocyte reactivity, and tau.

In addition, evidence suggests plasma measures of glial fibrillary acidic protein (GFAP) could be a strong proxy of astrocyte reactivity in the brain. Dr. Pascoal explained that when astrocytes are changed or become bigger, more GFAP is released.

The study included 1,016 cognitively normal individuals from three centers; some had amyloid pathology, some did not. Participants’ mean age was 69.6 years, and all were deemed negative or positive for astrocyte reactivity based on plasma GFAP levels.

Results showed amyloid-beta is associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity. In addition, analyses using PET scans showed an AD-like pattern of tau tangle accumulation as a function of amyloid-beta exclusively in those same individuals.
 

Early upstream event

The findings suggest abnormalities in astrocyte reactivity is an early upstream event that likely occurs prior to tau pathology, which is closely related to the development of neurodegeneration and cognitive decline.

It’s likely many types of insults or processes can lead to astrocyte reactivity, possibly including COVID, but more research in this area is needed, said Dr. Pascoal.

“Our study only looked at the consequence of having both amyloid and astrocyte reactivity; it did not elucidate what is causing either of them,” he said.

Although “we were able to have very good results” in the current study, additional studies are needed to better establish the cut-off for GFAP levels that signal progression, said Dr. Pascoal.

The effect of astrocyte reactivity on the association between amyloid-beta and tau phosphorylation was greater in men than women. Dr. Pascoal noted anti-amyloid therapies, which might be modifying the amyloid-beta-astrocyte-tau pathway, tend to have a much larger effect in men than women.

Further studies that measure amyloid-beta, tau, and GFAP biomarkers at multiple timepoints, and with long follow-up, are needed, the investigators note.

The results may have implications for clinical trials, which have increasingly focused on individuals in the earliest preclinical phases of AD. Future studies should include cognitively normal patients who are positive for both amyloid pathology and astrocyte reactivity but have no overt p-tau abnormality, said Dr. Pascoal.

This may provide a time window for interventions very early in the disease process in those at increased risk for AD-related progression.

The study did not determine whether participants with both amyloid and astrocyte reactivity will inevitably develop AD, and to do so would require a longer follow up. “Our outcome was correlation to tau in the brain, which is something we know will lead to AD.”

Although the cohort represents significant socioeconomic diversity, a main limitation of the study was that subjects were mainly White, which limits the generalizability of the findings to a more diverse population.

The study received support from the National Institute of Aging; National Heart Lung and Blood Institute; Alzheimer’s Association; Fonds de Recherche du Québec-Santé; Canadian Consortium of Neurodegeneration in Aging; Weston Brain Institute; Colin Adair Charitable Foundation; Swedish Research Council; Wallenberg Scholar; BrightFocus Foundation; Swedish Alzheimer Foundation; Swedish Brain Foundation; Agneta Prytz-Folkes & Gösta Folkes Foundation; European Union; Swedish State Support for Clinical Research; Alzheimer Drug Discovery Foundation; Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden; the UK Dementia Research Institute at UCL; National Academy of Neuropsychology; Fundação de Amparo a pesquisa do Rio Grande do Sul; Instituto Serrapilheira; and Hjärnfonden.

Dr. Pascoal reports no relevant financial relationships.

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

A blood biomarker that measures astrocyte reactivity may help determine who, among cognitively unimpaired older adults with amyloid-beta, will go on to develop Alzheimer’s disease (AD), new research suggests.

Investigators tested the blood of 1,000 cognitively healthy individuals with and without amyloid-beta pathology and found that only those with a combination of amyloid-beta burden and abnormal astrocyte activation subsequently progressed to AD.

“Our study argues that testing for the presence of brain amyloid along with blood biomarkers of astrocyte reactivity is the optimal screening to identify patients who are most at risk for progressing to Alzheimer’s disease,” senior investigator Tharick A. Pascoal, MD, PhD, associate professor of psychiatry and neurology, University of Pittsburgh, said in a release.

At this point, the biomarker is a research tool, but its application in clinical practice “is not very far away,” Dr. Pascoal told this news organization.

The study was published online  in Nature Medicine.  
 

Multicenter study

In AD, accumulation of amyloid-beta in the brain precedes tau pathology, but not everyone with amyloid-beta develops tau, and, consequently, clinical symptoms. Approximately 30% of older adults have brain amyloid but many never progress to AD, said Dr. Pascoal.

This suggests other biological processes may trigger the deleterious effects of amyloid-beta in the early stages of AD.

Finding predictive markers of early amyloid-beta–related tau pathology would help identify cognitively normal individuals who are more likely to develop AD.

Post-mortem studies show astrocyte reactivity – changes in glial cells in the brain and spinal cord because of an insult in the brain – is an early AD abnormality. Other research suggests a close link between amyloid-beta, astrocyte reactivity, and tau.

In addition, evidence suggests plasma measures of glial fibrillary acidic protein (GFAP) could be a strong proxy of astrocyte reactivity in the brain. Dr. Pascoal explained that when astrocytes are changed or become bigger, more GFAP is released.

The study included 1,016 cognitively normal individuals from three centers; some had amyloid pathology, some did not. Participants’ mean age was 69.6 years, and all were deemed negative or positive for astrocyte reactivity based on plasma GFAP levels.

Results showed amyloid-beta is associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity. In addition, analyses using PET scans showed an AD-like pattern of tau tangle accumulation as a function of amyloid-beta exclusively in those same individuals.
 

Early upstream event

The findings suggest abnormalities in astrocyte reactivity is an early upstream event that likely occurs prior to tau pathology, which is closely related to the development of neurodegeneration and cognitive decline.

It’s likely many types of insults or processes can lead to astrocyte reactivity, possibly including COVID, but more research in this area is needed, said Dr. Pascoal.

“Our study only looked at the consequence of having both amyloid and astrocyte reactivity; it did not elucidate what is causing either of them,” he said.

Although “we were able to have very good results” in the current study, additional studies are needed to better establish the cut-off for GFAP levels that signal progression, said Dr. Pascoal.

The effect of astrocyte reactivity on the association between amyloid-beta and tau phosphorylation was greater in men than women. Dr. Pascoal noted anti-amyloid therapies, which might be modifying the amyloid-beta-astrocyte-tau pathway, tend to have a much larger effect in men than women.

Further studies that measure amyloid-beta, tau, and GFAP biomarkers at multiple timepoints, and with long follow-up, are needed, the investigators note.

The results may have implications for clinical trials, which have increasingly focused on individuals in the earliest preclinical phases of AD. Future studies should include cognitively normal patients who are positive for both amyloid pathology and astrocyte reactivity but have no overt p-tau abnormality, said Dr. Pascoal.

This may provide a time window for interventions very early in the disease process in those at increased risk for AD-related progression.

The study did not determine whether participants with both amyloid and astrocyte reactivity will inevitably develop AD, and to do so would require a longer follow up. “Our outcome was correlation to tau in the brain, which is something we know will lead to AD.”

Although the cohort represents significant socioeconomic diversity, a main limitation of the study was that subjects were mainly White, which limits the generalizability of the findings to a more diverse population.

The study received support from the National Institute of Aging; National Heart Lung and Blood Institute; Alzheimer’s Association; Fonds de Recherche du Québec-Santé; Canadian Consortium of Neurodegeneration in Aging; Weston Brain Institute; Colin Adair Charitable Foundation; Swedish Research Council; Wallenberg Scholar; BrightFocus Foundation; Swedish Alzheimer Foundation; Swedish Brain Foundation; Agneta Prytz-Folkes & Gösta Folkes Foundation; European Union; Swedish State Support for Clinical Research; Alzheimer Drug Discovery Foundation; Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden; the UK Dementia Research Institute at UCL; National Academy of Neuropsychology; Fundação de Amparo a pesquisa do Rio Grande do Sul; Instituto Serrapilheira; and Hjärnfonden.

Dr. Pascoal reports no relevant financial relationships.

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