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Cannabis Use Linked to Brain Thinning in Adolescents
, research in mice and humans suggested.
The multilevel study demonstrated that tetrahydrocannabinol (THC), an active substance in cannabis, causes shrinkage of dendritic arborization — the neurons’ network of antennae that play a critical role in communication between brain cells.
The connection between dendritic arborization and cortical thickness was hinted at in an earlier study by Tomáš Paus, MD, PhD, professor of psychiatry and addictology at the University of Montreal, Quebec, Canada, and colleagues, who found that cannabis use in early adolescence was associated with lower cortical thickness in boys with a high genetic risk for schizophrenia.
“We speculated at that time that the differences in cortical thickness might be related to differences in dendritic arborization, and our current study confirmed it,” Paus said.
That confirmation came in the mouse part of the study, when coauthor Graciela Piñeyro, MD, PhD, also of the University of Montreal, counted the dendritic branches of mice exposed to THC and compared the total with the number of dendritic branches in unexposed mice. “What surprised me was finding that THC in the mice was targeting the same type of cells and structures that Dr. Paus had predicted would be affected from the human studies,” she said. “Structurally, they were mostly the neurons that contribute to synapses in the cortex, and their branching was reduced.”
Paus explained that in humans, a decrease in input from the affected dendrites “makes it harder for the brain to learn new things, interact with people, cope with new situations, et cetera. In other words, it makes the brain more vulnerable to everything that can happen in a young person’s life.”
The study was published online on October 9 in the Journal of Neuroscience.
Of Mice, Men, and Cannabis
Although associations between cannabis use by teenagers and variations in brain maturation have been well studied, the cellular and molecular underpinnings of these associations were unclear, according to the authors.
To investigate further, they conducted this three-step study. First, they exposed adolescent male mice to THC or a synthetic cannabinoid (WIN 55,212-2) and assessed differentially expressed genes, spine numbers, and the extent of dendritic complexity in the frontal cortex of each mouse.
Next, using MRI, they examined differences in cortical thickness in 34 brain regions in 140 male adolescents who experimented with cannabis before age 16 years and 327 who did not.
Then, they again conducted experiments in mice and found that 13 THC-related genes correlated with variations in cortical thickness. Virtual histology revealed that these 13 genes were coexpressed with cell markers of astrocytes, microglia, and a type of pyramidal cell enriched in genes that regulate dendritic expression.
Similarly, the WIN-related genes correlated with differences in cortical thickness and showed coexpression patterns with the same three cell types.
Furthermore, the affected genes were also found in humans, particularly in the thinner cortical regions of the adolescents who experimented with cannabis.
By acting on microglia, THC seems to promote the removal of synapses and, eventually, the reduction of the dendritic tree in mice, Piñeyro explained. That’s important not only because a similar mechanism may be at work in humans but also because “we now might have a model to test different types of cannabis products to see which ones are producing the greatest effect on neurons and therefore greater removal of synapses through the microglia. This could be a way of testing drugs that are out in the street to see which would be the most or least dangerous to the synapses in the brain.”
‘Significant Implications’
Commenting on the study, Yasmin Hurd, PhD, Ward-Coleman chair of translational neuroscience at the Icahn School of Medicine at Mount Sinai and director of the Addiction Institute of Mount Sinai in New York City, said, “These findings are in line with previous results, so they are feasible. This study adds more depth by showing that cortical genes that were differentially altered by adolescent THC correlated with cannabis-related changes in cortical thickness based on human neuroimaging data.” Hurd did not participate in the research.
“The results emphasize that consumption of potent cannabis products during adolescence can impact cortical function, which has significant implications for decision-making and risky behavior as well. It also can increase vulnerability to psychiatric disorders such as schizophrenia.”
Although a mouse model is “not truly the same as the human condition, the fact that the animal model also showed evidence of the morphological changes indicative of reduced cortical thickness, [like] the humans, is strong,” she said.
Additional research could include women and assess potential sex differences, she added.
Ronald Ellis, MD, PhD, an investigator in the Center for Medicinal Cannabis Research at the University of California, San Diego School of Medicine, said, “The findings are plausible and extend prior work showing evidence of increased risk for psychotic disorders later in life in adolescents who use cannabis.” Ellis did not participate in the research.
“Future studies should explore how these findings might vary across different demographic groups, which could provide a more inclusive understanding of how cannabis impacts the brain,” he said. “Additionally, longitudinal studies to track changes in the brain over time could help to establish causal relationships more robustly.
“The take-home message to clinicians at this point is to discuss cannabis use history carefully and confidentially with adolescent patients to better provide advice on its potential risks,” he concluded.
Paus added that he would tell patients, “If you’re going to use cannabis, don’t start early. If you have to, then do so in moderation. And if you have family history of mental illness, be very careful.”
No funding for the study was reported. Paus, Piñeyro, Hurd, and Ellis declared having no relevant financial relationships.
A version of this article appeared on Medscape.com.
, research in mice and humans suggested.
The multilevel study demonstrated that tetrahydrocannabinol (THC), an active substance in cannabis, causes shrinkage of dendritic arborization — the neurons’ network of antennae that play a critical role in communication between brain cells.
The connection between dendritic arborization and cortical thickness was hinted at in an earlier study by Tomáš Paus, MD, PhD, professor of psychiatry and addictology at the University of Montreal, Quebec, Canada, and colleagues, who found that cannabis use in early adolescence was associated with lower cortical thickness in boys with a high genetic risk for schizophrenia.
“We speculated at that time that the differences in cortical thickness might be related to differences in dendritic arborization, and our current study confirmed it,” Paus said.
That confirmation came in the mouse part of the study, when coauthor Graciela Piñeyro, MD, PhD, also of the University of Montreal, counted the dendritic branches of mice exposed to THC and compared the total with the number of dendritic branches in unexposed mice. “What surprised me was finding that THC in the mice was targeting the same type of cells and structures that Dr. Paus had predicted would be affected from the human studies,” she said. “Structurally, they were mostly the neurons that contribute to synapses in the cortex, and their branching was reduced.”
Paus explained that in humans, a decrease in input from the affected dendrites “makes it harder for the brain to learn new things, interact with people, cope with new situations, et cetera. In other words, it makes the brain more vulnerable to everything that can happen in a young person’s life.”
The study was published online on October 9 in the Journal of Neuroscience.
Of Mice, Men, and Cannabis
Although associations between cannabis use by teenagers and variations in brain maturation have been well studied, the cellular and molecular underpinnings of these associations were unclear, according to the authors.
To investigate further, they conducted this three-step study. First, they exposed adolescent male mice to THC or a synthetic cannabinoid (WIN 55,212-2) and assessed differentially expressed genes, spine numbers, and the extent of dendritic complexity in the frontal cortex of each mouse.
Next, using MRI, they examined differences in cortical thickness in 34 brain regions in 140 male adolescents who experimented with cannabis before age 16 years and 327 who did not.
Then, they again conducted experiments in mice and found that 13 THC-related genes correlated with variations in cortical thickness. Virtual histology revealed that these 13 genes were coexpressed with cell markers of astrocytes, microglia, and a type of pyramidal cell enriched in genes that regulate dendritic expression.
Similarly, the WIN-related genes correlated with differences in cortical thickness and showed coexpression patterns with the same three cell types.
Furthermore, the affected genes were also found in humans, particularly in the thinner cortical regions of the adolescents who experimented with cannabis.
By acting on microglia, THC seems to promote the removal of synapses and, eventually, the reduction of the dendritic tree in mice, Piñeyro explained. That’s important not only because a similar mechanism may be at work in humans but also because “we now might have a model to test different types of cannabis products to see which ones are producing the greatest effect on neurons and therefore greater removal of synapses through the microglia. This could be a way of testing drugs that are out in the street to see which would be the most or least dangerous to the synapses in the brain.”
‘Significant Implications’
Commenting on the study, Yasmin Hurd, PhD, Ward-Coleman chair of translational neuroscience at the Icahn School of Medicine at Mount Sinai and director of the Addiction Institute of Mount Sinai in New York City, said, “These findings are in line with previous results, so they are feasible. This study adds more depth by showing that cortical genes that were differentially altered by adolescent THC correlated with cannabis-related changes in cortical thickness based on human neuroimaging data.” Hurd did not participate in the research.
“The results emphasize that consumption of potent cannabis products during adolescence can impact cortical function, which has significant implications for decision-making and risky behavior as well. It also can increase vulnerability to psychiatric disorders such as schizophrenia.”
Although a mouse model is “not truly the same as the human condition, the fact that the animal model also showed evidence of the morphological changes indicative of reduced cortical thickness, [like] the humans, is strong,” she said.
Additional research could include women and assess potential sex differences, she added.
Ronald Ellis, MD, PhD, an investigator in the Center for Medicinal Cannabis Research at the University of California, San Diego School of Medicine, said, “The findings are plausible and extend prior work showing evidence of increased risk for psychotic disorders later in life in adolescents who use cannabis.” Ellis did not participate in the research.
“Future studies should explore how these findings might vary across different demographic groups, which could provide a more inclusive understanding of how cannabis impacts the brain,” he said. “Additionally, longitudinal studies to track changes in the brain over time could help to establish causal relationships more robustly.
“The take-home message to clinicians at this point is to discuss cannabis use history carefully and confidentially with adolescent patients to better provide advice on its potential risks,” he concluded.
Paus added that he would tell patients, “If you’re going to use cannabis, don’t start early. If you have to, then do so in moderation. And if you have family history of mental illness, be very careful.”
No funding for the study was reported. Paus, Piñeyro, Hurd, and Ellis declared having no relevant financial relationships.
A version of this article appeared on Medscape.com.
, research in mice and humans suggested.
The multilevel study demonstrated that tetrahydrocannabinol (THC), an active substance in cannabis, causes shrinkage of dendritic arborization — the neurons’ network of antennae that play a critical role in communication between brain cells.
The connection between dendritic arborization and cortical thickness was hinted at in an earlier study by Tomáš Paus, MD, PhD, professor of psychiatry and addictology at the University of Montreal, Quebec, Canada, and colleagues, who found that cannabis use in early adolescence was associated with lower cortical thickness in boys with a high genetic risk for schizophrenia.
“We speculated at that time that the differences in cortical thickness might be related to differences in dendritic arborization, and our current study confirmed it,” Paus said.
That confirmation came in the mouse part of the study, when coauthor Graciela Piñeyro, MD, PhD, also of the University of Montreal, counted the dendritic branches of mice exposed to THC and compared the total with the number of dendritic branches in unexposed mice. “What surprised me was finding that THC in the mice was targeting the same type of cells and structures that Dr. Paus had predicted would be affected from the human studies,” she said. “Structurally, they were mostly the neurons that contribute to synapses in the cortex, and their branching was reduced.”
Paus explained that in humans, a decrease in input from the affected dendrites “makes it harder for the brain to learn new things, interact with people, cope with new situations, et cetera. In other words, it makes the brain more vulnerable to everything that can happen in a young person’s life.”
The study was published online on October 9 in the Journal of Neuroscience.
Of Mice, Men, and Cannabis
Although associations between cannabis use by teenagers and variations in brain maturation have been well studied, the cellular and molecular underpinnings of these associations were unclear, according to the authors.
To investigate further, they conducted this three-step study. First, they exposed adolescent male mice to THC or a synthetic cannabinoid (WIN 55,212-2) and assessed differentially expressed genes, spine numbers, and the extent of dendritic complexity in the frontal cortex of each mouse.
Next, using MRI, they examined differences in cortical thickness in 34 brain regions in 140 male adolescents who experimented with cannabis before age 16 years and 327 who did not.
Then, they again conducted experiments in mice and found that 13 THC-related genes correlated with variations in cortical thickness. Virtual histology revealed that these 13 genes were coexpressed with cell markers of astrocytes, microglia, and a type of pyramidal cell enriched in genes that regulate dendritic expression.
Similarly, the WIN-related genes correlated with differences in cortical thickness and showed coexpression patterns with the same three cell types.
Furthermore, the affected genes were also found in humans, particularly in the thinner cortical regions of the adolescents who experimented with cannabis.
By acting on microglia, THC seems to promote the removal of synapses and, eventually, the reduction of the dendritic tree in mice, Piñeyro explained. That’s important not only because a similar mechanism may be at work in humans but also because “we now might have a model to test different types of cannabis products to see which ones are producing the greatest effect on neurons and therefore greater removal of synapses through the microglia. This could be a way of testing drugs that are out in the street to see which would be the most or least dangerous to the synapses in the brain.”
‘Significant Implications’
Commenting on the study, Yasmin Hurd, PhD, Ward-Coleman chair of translational neuroscience at the Icahn School of Medicine at Mount Sinai and director of the Addiction Institute of Mount Sinai in New York City, said, “These findings are in line with previous results, so they are feasible. This study adds more depth by showing that cortical genes that were differentially altered by adolescent THC correlated with cannabis-related changes in cortical thickness based on human neuroimaging data.” Hurd did not participate in the research.
“The results emphasize that consumption of potent cannabis products during adolescence can impact cortical function, which has significant implications for decision-making and risky behavior as well. It also can increase vulnerability to psychiatric disorders such as schizophrenia.”
Although a mouse model is “not truly the same as the human condition, the fact that the animal model also showed evidence of the morphological changes indicative of reduced cortical thickness, [like] the humans, is strong,” she said.
Additional research could include women and assess potential sex differences, she added.
Ronald Ellis, MD, PhD, an investigator in the Center for Medicinal Cannabis Research at the University of California, San Diego School of Medicine, said, “The findings are plausible and extend prior work showing evidence of increased risk for psychotic disorders later in life in adolescents who use cannabis.” Ellis did not participate in the research.
“Future studies should explore how these findings might vary across different demographic groups, which could provide a more inclusive understanding of how cannabis impacts the brain,” he said. “Additionally, longitudinal studies to track changes in the brain over time could help to establish causal relationships more robustly.
“The take-home message to clinicians at this point is to discuss cannabis use history carefully and confidentially with adolescent patients to better provide advice on its potential risks,” he concluded.
Paus added that he would tell patients, “If you’re going to use cannabis, don’t start early. If you have to, then do so in moderation. And if you have family history of mental illness, be very careful.”
No funding for the study was reported. Paus, Piñeyro, Hurd, and Ellis declared having no relevant financial relationships.
A version of this article appeared on Medscape.com.
FROM THE JOURNAL OF NEUROSCIENCE
Novel Intervention Slows Cognitive Decline in At-Risk Adults
new research suggests.
The cognitive remediation intervention included a series of progressively difficult computer-based and facilitator-monitored mental exercises designed to sharpen cognitive function.
Researchers found that using cognitive remediation with tDCS slowed decline in executive function and verbal memory more than other cognitive functions. The effect was stronger among people with rMDD versus those with MCI and in those at low genetic risk for Alzheimer’s disease.
“We have developed a novel intervention, combining two interventions that if used separately have a weak effect but together have substantial and clinically meaningful effect of slowing the progression of cognitive decline,” said study author Benoit H. Mulsant, MD, chair of the Department of Psychiatry, University of Toronto, Ontario, Canada, and senior scientist at the Center for Addiction and Mental Health, also in Toronto.
The findings were published online in JAMA Psychiatry.
High-Risk Group
Research shows that older adults with MDD or MCI are at high risk for cognitive decline and dementia. Evidence also suggests that depression in early or mid-life significantly increases the risk for dementia in late life, even if the depression has been in remission for decades.
A potential mechanism underlying this increased risk for dementia could be impaired cortical plasticity, or the ability of the brain to compensate for damage.
The PACt-MD trial included 375 older adults with rMDD, MCI, or both (mean age, 72 years; 62% women) at five academic hospitals in Toronto.
Participants received either cognitive remediation plus tDCS or sham intervention 5 days per week for 8 weeks (acute phase), followed by 5-day “boosters” every 6 months.
tDCS was administered by trained personnel and involved active stimulation for 30 minutes at the beginning of each cognitive remediation group session. The intervention targets the prefrontal cortex, a critical region for cognitive compensation in normal cognitive aging.
The sham group received a weakened version of cognitive remediation, with exercises that did not get progressively more difficult. For the sham stimulation, the current flowed at full intensity for only 54 seconds before and after 30-second ramp-up and ramp-down phases, to create a blinding effect, the authors noted.
A geriatric psychiatrist followed all participants throughout the study, conducting assessments at baseline, month 2, and yearly for 3-7 years (mean follow-up, 48.3 months).
Participants’ depressive symptoms were evaluated at baseline and at all follow-ups and underwent neuropsychological testing to assess six cognitive domains: processing speed, working memory, executive functioning, verbal memory, visual memory, and language.
To get a norm for the cognitive tests, researchers recruited a comparator group of 75 subjects similar in age, gender, and years of education, with no neuropsychiatric disorder or cognitive impairment. They completed the same assessments but not the intervention.
Study participants and assessors were blinded to treatment assignment.
Slower Cognitive Decline
Participants in the intervention group had a significantly slower decline in cognitive function, compared with those in the sham group (adjusted z score difference [active – sham] at month 60, 0.21; P = .006). This is equivalent to slowing cognitive decline by about 4 years, researchers reported. The intervention also showed a positive effect on executive function and verbal memory.
“If I can push dementia from 85 to 89 years and you die at 86, in practice, I have prevented you from ever developing dementia,” Mulsant said.
The efficacy of cognitive remediation plus tDCS in rMDD could be tied to enhanced neuroplasticity, said Mulsant.
The treatment worked well in people with a history of depression, regardless of MCI status, but was not as effective for people with just MCI, researchers noted. The intervention also did not work as well among people at genetic risk for Alzheimer’s disease.
“We don’t believe we have discovered an intervention to prevent dementia in people who are at high risk for Alzheimer disease, but we have discovered an intervention that could prevent dementia in people who have an history of depression,” said Mulsant.
These results suggest the pathways to dementia among people with MCI and rMDD are different, he added.
Because previous research showed either treatment alone demonstrated little efficacy, researchers said the new results indicate that there may be a synergistic effect of combining the two.
The ideal amount of treatment and optimal age for initiation still need to be determined, said Mulsant. The study did not include a comparator group without rMDD or MCI, so the observed cognitive benefits might be specific to people with these high-risk conditions. Another study limitation is lack of diversity in terms of ethnicity, race, and education.
Promising, Important Findings
Commenting on the research, Badr Ratnakaran, MD, assistant professor and division director of geriatric psychiatry at Carilion Clinic–Virginia Tech Carilion School of Medicine, Roanoke, said the results are promising and important because there are so few treatment options for the increasing number of older patients with depression and dementia.
The side-effect profile of the combined treatment is better than that of many pharmacologic treatments, Ratnakaran noted. As more research like this comes out, Ratnakaran predicts that cognitive remediation and tCDS will become more readily available.
“This is telling us that the field of psychiatry, and also dementia, is progressing beyond your usual pharmacotherapy treatments,” said Ratnakaran, who also is chair of the American Psychiatric Association’s Council on Geriatric Psychiatry.
The study received support from the Canada Brain Research Fund of Brain Canada, Health Canada, the Chagnon Family, and the Centre for Addiction and Mental Health Discovery Fund. Mulsant reported holding and receiving support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto; being a member of the Center for Addiction and Mental Health Board of Trustees; research support from Brain Canada, Canadian Institutes of Health Research, Center for Addiction and Mental Health Foundation, Patient-Centered Outcomes Research Institute, and National Institutes of Health; and nonfinancial support from Capital Solution Design and HappyNeuron. Ratnakaran reported no relevant conflicts.
A version of this article appeared on Medscape.com.
new research suggests.
The cognitive remediation intervention included a series of progressively difficult computer-based and facilitator-monitored mental exercises designed to sharpen cognitive function.
Researchers found that using cognitive remediation with tDCS slowed decline in executive function and verbal memory more than other cognitive functions. The effect was stronger among people with rMDD versus those with MCI and in those at low genetic risk for Alzheimer’s disease.
“We have developed a novel intervention, combining two interventions that if used separately have a weak effect but together have substantial and clinically meaningful effect of slowing the progression of cognitive decline,” said study author Benoit H. Mulsant, MD, chair of the Department of Psychiatry, University of Toronto, Ontario, Canada, and senior scientist at the Center for Addiction and Mental Health, also in Toronto.
The findings were published online in JAMA Psychiatry.
High-Risk Group
Research shows that older adults with MDD or MCI are at high risk for cognitive decline and dementia. Evidence also suggests that depression in early or mid-life significantly increases the risk for dementia in late life, even if the depression has been in remission for decades.
A potential mechanism underlying this increased risk for dementia could be impaired cortical plasticity, or the ability of the brain to compensate for damage.
The PACt-MD trial included 375 older adults with rMDD, MCI, or both (mean age, 72 years; 62% women) at five academic hospitals in Toronto.
Participants received either cognitive remediation plus tDCS or sham intervention 5 days per week for 8 weeks (acute phase), followed by 5-day “boosters” every 6 months.
tDCS was administered by trained personnel and involved active stimulation for 30 minutes at the beginning of each cognitive remediation group session. The intervention targets the prefrontal cortex, a critical region for cognitive compensation in normal cognitive aging.
The sham group received a weakened version of cognitive remediation, with exercises that did not get progressively more difficult. For the sham stimulation, the current flowed at full intensity for only 54 seconds before and after 30-second ramp-up and ramp-down phases, to create a blinding effect, the authors noted.
A geriatric psychiatrist followed all participants throughout the study, conducting assessments at baseline, month 2, and yearly for 3-7 years (mean follow-up, 48.3 months).
Participants’ depressive symptoms were evaluated at baseline and at all follow-ups and underwent neuropsychological testing to assess six cognitive domains: processing speed, working memory, executive functioning, verbal memory, visual memory, and language.
To get a norm for the cognitive tests, researchers recruited a comparator group of 75 subjects similar in age, gender, and years of education, with no neuropsychiatric disorder or cognitive impairment. They completed the same assessments but not the intervention.
Study participants and assessors were blinded to treatment assignment.
Slower Cognitive Decline
Participants in the intervention group had a significantly slower decline in cognitive function, compared with those in the sham group (adjusted z score difference [active – sham] at month 60, 0.21; P = .006). This is equivalent to slowing cognitive decline by about 4 years, researchers reported. The intervention also showed a positive effect on executive function and verbal memory.
“If I can push dementia from 85 to 89 years and you die at 86, in practice, I have prevented you from ever developing dementia,” Mulsant said.
The efficacy of cognitive remediation plus tDCS in rMDD could be tied to enhanced neuroplasticity, said Mulsant.
The treatment worked well in people with a history of depression, regardless of MCI status, but was not as effective for people with just MCI, researchers noted. The intervention also did not work as well among people at genetic risk for Alzheimer’s disease.
“We don’t believe we have discovered an intervention to prevent dementia in people who are at high risk for Alzheimer disease, but we have discovered an intervention that could prevent dementia in people who have an history of depression,” said Mulsant.
These results suggest the pathways to dementia among people with MCI and rMDD are different, he added.
Because previous research showed either treatment alone demonstrated little efficacy, researchers said the new results indicate that there may be a synergistic effect of combining the two.
The ideal amount of treatment and optimal age for initiation still need to be determined, said Mulsant. The study did not include a comparator group without rMDD or MCI, so the observed cognitive benefits might be specific to people with these high-risk conditions. Another study limitation is lack of diversity in terms of ethnicity, race, and education.
Promising, Important Findings
Commenting on the research, Badr Ratnakaran, MD, assistant professor and division director of geriatric psychiatry at Carilion Clinic–Virginia Tech Carilion School of Medicine, Roanoke, said the results are promising and important because there are so few treatment options for the increasing number of older patients with depression and dementia.
The side-effect profile of the combined treatment is better than that of many pharmacologic treatments, Ratnakaran noted. As more research like this comes out, Ratnakaran predicts that cognitive remediation and tCDS will become more readily available.
“This is telling us that the field of psychiatry, and also dementia, is progressing beyond your usual pharmacotherapy treatments,” said Ratnakaran, who also is chair of the American Psychiatric Association’s Council on Geriatric Psychiatry.
The study received support from the Canada Brain Research Fund of Brain Canada, Health Canada, the Chagnon Family, and the Centre for Addiction and Mental Health Discovery Fund. Mulsant reported holding and receiving support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto; being a member of the Center for Addiction and Mental Health Board of Trustees; research support from Brain Canada, Canadian Institutes of Health Research, Center for Addiction and Mental Health Foundation, Patient-Centered Outcomes Research Institute, and National Institutes of Health; and nonfinancial support from Capital Solution Design and HappyNeuron. Ratnakaran reported no relevant conflicts.
A version of this article appeared on Medscape.com.
new research suggests.
The cognitive remediation intervention included a series of progressively difficult computer-based and facilitator-monitored mental exercises designed to sharpen cognitive function.
Researchers found that using cognitive remediation with tDCS slowed decline in executive function and verbal memory more than other cognitive functions. The effect was stronger among people with rMDD versus those with MCI and in those at low genetic risk for Alzheimer’s disease.
“We have developed a novel intervention, combining two interventions that if used separately have a weak effect but together have substantial and clinically meaningful effect of slowing the progression of cognitive decline,” said study author Benoit H. Mulsant, MD, chair of the Department of Psychiatry, University of Toronto, Ontario, Canada, and senior scientist at the Center for Addiction and Mental Health, also in Toronto.
The findings were published online in JAMA Psychiatry.
High-Risk Group
Research shows that older adults with MDD or MCI are at high risk for cognitive decline and dementia. Evidence also suggests that depression in early or mid-life significantly increases the risk for dementia in late life, even if the depression has been in remission for decades.
A potential mechanism underlying this increased risk for dementia could be impaired cortical plasticity, or the ability of the brain to compensate for damage.
The PACt-MD trial included 375 older adults with rMDD, MCI, or both (mean age, 72 years; 62% women) at five academic hospitals in Toronto.
Participants received either cognitive remediation plus tDCS or sham intervention 5 days per week for 8 weeks (acute phase), followed by 5-day “boosters” every 6 months.
tDCS was administered by trained personnel and involved active stimulation for 30 minutes at the beginning of each cognitive remediation group session. The intervention targets the prefrontal cortex, a critical region for cognitive compensation in normal cognitive aging.
The sham group received a weakened version of cognitive remediation, with exercises that did not get progressively more difficult. For the sham stimulation, the current flowed at full intensity for only 54 seconds before and after 30-second ramp-up and ramp-down phases, to create a blinding effect, the authors noted.
A geriatric psychiatrist followed all participants throughout the study, conducting assessments at baseline, month 2, and yearly for 3-7 years (mean follow-up, 48.3 months).
Participants’ depressive symptoms were evaluated at baseline and at all follow-ups and underwent neuropsychological testing to assess six cognitive domains: processing speed, working memory, executive functioning, verbal memory, visual memory, and language.
To get a norm for the cognitive tests, researchers recruited a comparator group of 75 subjects similar in age, gender, and years of education, with no neuropsychiatric disorder or cognitive impairment. They completed the same assessments but not the intervention.
Study participants and assessors were blinded to treatment assignment.
Slower Cognitive Decline
Participants in the intervention group had a significantly slower decline in cognitive function, compared with those in the sham group (adjusted z score difference [active – sham] at month 60, 0.21; P = .006). This is equivalent to slowing cognitive decline by about 4 years, researchers reported. The intervention also showed a positive effect on executive function and verbal memory.
“If I can push dementia from 85 to 89 years and you die at 86, in practice, I have prevented you from ever developing dementia,” Mulsant said.
The efficacy of cognitive remediation plus tDCS in rMDD could be tied to enhanced neuroplasticity, said Mulsant.
The treatment worked well in people with a history of depression, regardless of MCI status, but was not as effective for people with just MCI, researchers noted. The intervention also did not work as well among people at genetic risk for Alzheimer’s disease.
“We don’t believe we have discovered an intervention to prevent dementia in people who are at high risk for Alzheimer disease, but we have discovered an intervention that could prevent dementia in people who have an history of depression,” said Mulsant.
These results suggest the pathways to dementia among people with MCI and rMDD are different, he added.
Because previous research showed either treatment alone demonstrated little efficacy, researchers said the new results indicate that there may be a synergistic effect of combining the two.
The ideal amount of treatment and optimal age for initiation still need to be determined, said Mulsant. The study did not include a comparator group without rMDD or MCI, so the observed cognitive benefits might be specific to people with these high-risk conditions. Another study limitation is lack of diversity in terms of ethnicity, race, and education.
Promising, Important Findings
Commenting on the research, Badr Ratnakaran, MD, assistant professor and division director of geriatric psychiatry at Carilion Clinic–Virginia Tech Carilion School of Medicine, Roanoke, said the results are promising and important because there are so few treatment options for the increasing number of older patients with depression and dementia.
The side-effect profile of the combined treatment is better than that of many pharmacologic treatments, Ratnakaran noted. As more research like this comes out, Ratnakaran predicts that cognitive remediation and tCDS will become more readily available.
“This is telling us that the field of psychiatry, and also dementia, is progressing beyond your usual pharmacotherapy treatments,” said Ratnakaran, who also is chair of the American Psychiatric Association’s Council on Geriatric Psychiatry.
The study received support from the Canada Brain Research Fund of Brain Canada, Health Canada, the Chagnon Family, and the Centre for Addiction and Mental Health Discovery Fund. Mulsant reported holding and receiving support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto; being a member of the Center for Addiction and Mental Health Board of Trustees; research support from Brain Canada, Canadian Institutes of Health Research, Center for Addiction and Mental Health Foundation, Patient-Centered Outcomes Research Institute, and National Institutes of Health; and nonfinancial support from Capital Solution Design and HappyNeuron. Ratnakaran reported no relevant conflicts.
A version of this article appeared on Medscape.com.
FROM JAMA PSYCHIATRY
Rising Stroke Rates in Californians With Sickle Cell Disease
TOPLINE:
METHODOLOGY:
- Researchers analyzed data from the California Department of Health Care Access and Innovation (HCAI), covering emergency department and hospitalization records from 1991 to 2019.
- A total of 7636 patients with SCD were included in the study cohort.
- Cumulative incidence and rates for primary and recurrent strokes and transient ischemic attacks (TIAs) were determined pre- and post STOP trial.
- Patients with SCD were identified using ICD-9 and ICD-10 codes, with specific criteria for inclusion based on hospitalization records.
- The study utilized Fine and Gray methodology to calculate cumulative incidence functions, accounting for the competing risk for death.
TAKEAWAY:
- The cumulative incidence of first ischemic stroke in patients with SCD was 2.1% by age 20 and 13.5% by age 60.
- Ischemic stroke rates increased significantly in children and adults in the 2010-2019 period, compared with the preceding decade.
- Risk factors for stroke and TIA included increasing age, hypertension, and hyperlipidemia.
- The study found a significant increase in rates of intracranial hemorrhage in adults aged 18-30 years and TIAs in children younger than 18 years from 2010 to 2019, compared with the prior decade.
IN PRACTICE:
“Neurovascular complications, including strokes and transient ischemic attacks (TIAs), are common and cause significant morbidity in individuals with sickle cell disease (SCD). The STOP trial (1998) established chronic transfusions as the standard of care for children with SCD at high risk for stroke,” the study’s authors wrote.
SOURCE:
This study was led by Olubusola B. Oluwole, MD, MS, University of Pittsburgh in Pennsylvania, and was published online in Blood.
LIMITATIONS:
This study’s reliance on administrative data may have introduced systematic errors, particularly with the transition from ICD-9 to ICD-10 codes. The lack of laboratory results and medication data in the HCAI database limited the ability to fully assess patient conditions and treatments. Additionally, the methodology changes in 2014 likely underreported death rates in people without PDD/EDU encounters in the calendar year preceding their death.
DISCLOSURES:
The authors reported no relevant conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Researchers analyzed data from the California Department of Health Care Access and Innovation (HCAI), covering emergency department and hospitalization records from 1991 to 2019.
- A total of 7636 patients with SCD were included in the study cohort.
- Cumulative incidence and rates for primary and recurrent strokes and transient ischemic attacks (TIAs) were determined pre- and post STOP trial.
- Patients with SCD were identified using ICD-9 and ICD-10 codes, with specific criteria for inclusion based on hospitalization records.
- The study utilized Fine and Gray methodology to calculate cumulative incidence functions, accounting for the competing risk for death.
TAKEAWAY:
- The cumulative incidence of first ischemic stroke in patients with SCD was 2.1% by age 20 and 13.5% by age 60.
- Ischemic stroke rates increased significantly in children and adults in the 2010-2019 period, compared with the preceding decade.
- Risk factors for stroke and TIA included increasing age, hypertension, and hyperlipidemia.
- The study found a significant increase in rates of intracranial hemorrhage in adults aged 18-30 years and TIAs in children younger than 18 years from 2010 to 2019, compared with the prior decade.
IN PRACTICE:
“Neurovascular complications, including strokes and transient ischemic attacks (TIAs), are common and cause significant morbidity in individuals with sickle cell disease (SCD). The STOP trial (1998) established chronic transfusions as the standard of care for children with SCD at high risk for stroke,” the study’s authors wrote.
SOURCE:
This study was led by Olubusola B. Oluwole, MD, MS, University of Pittsburgh in Pennsylvania, and was published online in Blood.
LIMITATIONS:
This study’s reliance on administrative data may have introduced systematic errors, particularly with the transition from ICD-9 to ICD-10 codes. The lack of laboratory results and medication data in the HCAI database limited the ability to fully assess patient conditions and treatments. Additionally, the methodology changes in 2014 likely underreported death rates in people without PDD/EDU encounters in the calendar year preceding their death.
DISCLOSURES:
The authors reported no relevant conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Researchers analyzed data from the California Department of Health Care Access and Innovation (HCAI), covering emergency department and hospitalization records from 1991 to 2019.
- A total of 7636 patients with SCD were included in the study cohort.
- Cumulative incidence and rates for primary and recurrent strokes and transient ischemic attacks (TIAs) were determined pre- and post STOP trial.
- Patients with SCD were identified using ICD-9 and ICD-10 codes, with specific criteria for inclusion based on hospitalization records.
- The study utilized Fine and Gray methodology to calculate cumulative incidence functions, accounting for the competing risk for death.
TAKEAWAY:
- The cumulative incidence of first ischemic stroke in patients with SCD was 2.1% by age 20 and 13.5% by age 60.
- Ischemic stroke rates increased significantly in children and adults in the 2010-2019 period, compared with the preceding decade.
- Risk factors for stroke and TIA included increasing age, hypertension, and hyperlipidemia.
- The study found a significant increase in rates of intracranial hemorrhage in adults aged 18-30 years and TIAs in children younger than 18 years from 2010 to 2019, compared with the prior decade.
IN PRACTICE:
“Neurovascular complications, including strokes and transient ischemic attacks (TIAs), are common and cause significant morbidity in individuals with sickle cell disease (SCD). The STOP trial (1998) established chronic transfusions as the standard of care for children with SCD at high risk for stroke,” the study’s authors wrote.
SOURCE:
This study was led by Olubusola B. Oluwole, MD, MS, University of Pittsburgh in Pennsylvania, and was published online in Blood.
LIMITATIONS:
This study’s reliance on administrative data may have introduced systematic errors, particularly with the transition from ICD-9 to ICD-10 codes. The lack of laboratory results and medication data in the HCAI database limited the ability to fully assess patient conditions and treatments. Additionally, the methodology changes in 2014 likely underreported death rates in people without PDD/EDU encounters in the calendar year preceding their death.
DISCLOSURES:
The authors reported no relevant conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
More Evidence Ties Semaglutide to Reduced Alzheimer’s Risk
Adults with type 2 diabetes who were prescribed the GLP-1 RA semaglutide had a significantly lower risk for Alzheimer’s disease compared with their peers who were prescribed any of seven other antidiabetic medications, including other types of GLP-1 receptor–targeting medications.
“These findings support further clinical trials to assess semaglutide’s potential in delaying or preventing Alzheimer’s disease,” wrote the investigators, led by Rong Xu, PhD, with Case Western Reserve School of Medicine, Cleveland, Ohio.
The study was published online on October 24 in Alzheimer’s & Dementia.
Real-World Data
Semaglutide has shown neuroprotective effects in animal models of neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. In animal models of Alzheimer’s disease, the drug reduced beta-amyloid deposition and improved spatial learning and memory, as well as glucose metabolism in the brain.
In a real-world analysis, Xu and colleagues used electronic health record data to identify 17,104 new users of semaglutide and 1,077,657 new users of seven other antidiabetic medications, including other GLP-1 RAs, insulin, metformin, dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, sulfonylurea, and thiazolidinedione.
Over 3 years, treatment with semaglutide was associated with significantly reduced risk of developing Alzheimer’s disease, most strongly compared with insulin (hazard ratio [HR], 0.33) and most weakly compared with other GLP-1 RAs (HR, 0.59).
Compared with the other medications, semaglutide was associated with a 40%-70% reduced risk for first-time diagnosis of Alzheimer’s disease in patients with type 2 diabetes, with similar reductions seen across obesity status and gender and age groups, the authors reported.
The findings align with recent evidence suggesting GLP-1 RAs may protect cognitive function.
For example, as previously reported, in the phase 2b ELAD clinical trial, adults with early-stage Alzheimer’s disease taking the GLP-1 RA liraglutide exhibited slower decline in memory and thinking and experienced less brain atrophy over 12 months compared with placebo.
Promising, but Preliminary
Reached for comment, Courtney Kloske, PhD, Alzheimer’s Association director of scientific engagement, noted that diabetes is a known risk factor for AD and managing diabetes with drugs such as semaglutide “could benefit brain health simply by managing diabetes.”
“However, we still need large clinical trials in representative populations to determine if semaglutide specifically lowers the risk of Alzheimer’s, so it is too early to recommend it for prevention,” Kloske said.
She noted that some research suggests that GLP-1 RAs “may help reduce inflammation and positively impact brain energy use. However, more research is needed to fully understand how these processes might contribute to preventing cognitive decline or Alzheimer’s,” Kloske cautioned.
The Alzheimer’s Association’s “Part the Cloud” initiative has invested more than $68 million to advance 65 clinical trials targeting a variety of compounds, including repurposed drugs that may address known and potential new aspects of the disease, Kloske said.
The study was supported by grants from the National Institute on Aging and the National Center for Advancing Translational Sciences. Xu and Kloske have no relevant conflicts.
A version of this article appeared on Medscape.com.
Adults with type 2 diabetes who were prescribed the GLP-1 RA semaglutide had a significantly lower risk for Alzheimer’s disease compared with their peers who were prescribed any of seven other antidiabetic medications, including other types of GLP-1 receptor–targeting medications.
“These findings support further clinical trials to assess semaglutide’s potential in delaying or preventing Alzheimer’s disease,” wrote the investigators, led by Rong Xu, PhD, with Case Western Reserve School of Medicine, Cleveland, Ohio.
The study was published online on October 24 in Alzheimer’s & Dementia.
Real-World Data
Semaglutide has shown neuroprotective effects in animal models of neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. In animal models of Alzheimer’s disease, the drug reduced beta-amyloid deposition and improved spatial learning and memory, as well as glucose metabolism in the brain.
In a real-world analysis, Xu and colleagues used electronic health record data to identify 17,104 new users of semaglutide and 1,077,657 new users of seven other antidiabetic medications, including other GLP-1 RAs, insulin, metformin, dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, sulfonylurea, and thiazolidinedione.
Over 3 years, treatment with semaglutide was associated with significantly reduced risk of developing Alzheimer’s disease, most strongly compared with insulin (hazard ratio [HR], 0.33) and most weakly compared with other GLP-1 RAs (HR, 0.59).
Compared with the other medications, semaglutide was associated with a 40%-70% reduced risk for first-time diagnosis of Alzheimer’s disease in patients with type 2 diabetes, with similar reductions seen across obesity status and gender and age groups, the authors reported.
The findings align with recent evidence suggesting GLP-1 RAs may protect cognitive function.
For example, as previously reported, in the phase 2b ELAD clinical trial, adults with early-stage Alzheimer’s disease taking the GLP-1 RA liraglutide exhibited slower decline in memory and thinking and experienced less brain atrophy over 12 months compared with placebo.
Promising, but Preliminary
Reached for comment, Courtney Kloske, PhD, Alzheimer’s Association director of scientific engagement, noted that diabetes is a known risk factor for AD and managing diabetes with drugs such as semaglutide “could benefit brain health simply by managing diabetes.”
“However, we still need large clinical trials in representative populations to determine if semaglutide specifically lowers the risk of Alzheimer’s, so it is too early to recommend it for prevention,” Kloske said.
She noted that some research suggests that GLP-1 RAs “may help reduce inflammation and positively impact brain energy use. However, more research is needed to fully understand how these processes might contribute to preventing cognitive decline or Alzheimer’s,” Kloske cautioned.
The Alzheimer’s Association’s “Part the Cloud” initiative has invested more than $68 million to advance 65 clinical trials targeting a variety of compounds, including repurposed drugs that may address known and potential new aspects of the disease, Kloske said.
The study was supported by grants from the National Institute on Aging and the National Center for Advancing Translational Sciences. Xu and Kloske have no relevant conflicts.
A version of this article appeared on Medscape.com.
Adults with type 2 diabetes who were prescribed the GLP-1 RA semaglutide had a significantly lower risk for Alzheimer’s disease compared with their peers who were prescribed any of seven other antidiabetic medications, including other types of GLP-1 receptor–targeting medications.
“These findings support further clinical trials to assess semaglutide’s potential in delaying or preventing Alzheimer’s disease,” wrote the investigators, led by Rong Xu, PhD, with Case Western Reserve School of Medicine, Cleveland, Ohio.
The study was published online on October 24 in Alzheimer’s & Dementia.
Real-World Data
Semaglutide has shown neuroprotective effects in animal models of neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. In animal models of Alzheimer’s disease, the drug reduced beta-amyloid deposition and improved spatial learning and memory, as well as glucose metabolism in the brain.
In a real-world analysis, Xu and colleagues used electronic health record data to identify 17,104 new users of semaglutide and 1,077,657 new users of seven other antidiabetic medications, including other GLP-1 RAs, insulin, metformin, dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, sulfonylurea, and thiazolidinedione.
Over 3 years, treatment with semaglutide was associated with significantly reduced risk of developing Alzheimer’s disease, most strongly compared with insulin (hazard ratio [HR], 0.33) and most weakly compared with other GLP-1 RAs (HR, 0.59).
Compared with the other medications, semaglutide was associated with a 40%-70% reduced risk for first-time diagnosis of Alzheimer’s disease in patients with type 2 diabetes, with similar reductions seen across obesity status and gender and age groups, the authors reported.
The findings align with recent evidence suggesting GLP-1 RAs may protect cognitive function.
For example, as previously reported, in the phase 2b ELAD clinical trial, adults with early-stage Alzheimer’s disease taking the GLP-1 RA liraglutide exhibited slower decline in memory and thinking and experienced less brain atrophy over 12 months compared with placebo.
Promising, but Preliminary
Reached for comment, Courtney Kloske, PhD, Alzheimer’s Association director of scientific engagement, noted that diabetes is a known risk factor for AD and managing diabetes with drugs such as semaglutide “could benefit brain health simply by managing diabetes.”
“However, we still need large clinical trials in representative populations to determine if semaglutide specifically lowers the risk of Alzheimer’s, so it is too early to recommend it for prevention,” Kloske said.
She noted that some research suggests that GLP-1 RAs “may help reduce inflammation and positively impact brain energy use. However, more research is needed to fully understand how these processes might contribute to preventing cognitive decline or Alzheimer’s,” Kloske cautioned.
The Alzheimer’s Association’s “Part the Cloud” initiative has invested more than $68 million to advance 65 clinical trials targeting a variety of compounds, including repurposed drugs that may address known and potential new aspects of the disease, Kloske said.
The study was supported by grants from the National Institute on Aging and the National Center for Advancing Translational Sciences. Xu and Kloske have no relevant conflicts.
A version of this article appeared on Medscape.com.
FROM ALZHEIMER’S & DEMENTIA
A New, Easily Identifiable Sign of Concussion?
Spontaneous Headshake After a Kinematic Event (SHAAKE) refers to the rapid, back-and-forth head movement athletes exhibit following a blow to the head. This voluntary motion typically occurs within seconds to minutes after impact and is a familiar response in athletes.
In a recent survey, 7 out of 10 adult athletes recalled making this movement after a collision, and three out of four times they attributed this back-and-forth head movement to a concussion. The association was strongest among football players, who reported that over 90% of SHAAKE episodes were associated with a concussion.
The results were published online in Diagnostics.
Call to Action
“Everyone” — including sports and medical organizations — “should be adding this to their list of potential concussion signs and their protocol immediately,” study investigator Chris Nowinski, PhD, CEO and co-founder of the Concussion Legacy Foundation, told this news organization.
Nowinski said it’s “fascinating” that this concussion sign hasn’t been formally studied or added to formal concussion screening metrics before now, given that it’s been depicted in movies, television, and cartoons for decades.
Coaches, medical professionals, and concussion spotters should be trained to recognize when a SHAAKE happens, he said.
“The interesting thing is, I don’t think coaches or parents need much training other than to officially tie this to suspicion of a concussion,” Nowinski added.
The Case of Miami Dolphins QB Tua Tagovailoa
Nowinski said he was tipped off to SHAAKE as a concussion sign after Miami Dolphins quarterback Tua Tagovailoa’s controversial undiagnosed concussion during a National Football League (NFL) game in 2022.
After Tagovailoa’s head hit the ground, he rapidly shook his head side to side, indicating displaying SHAAKE, before stumbling and collapsing. At the time, a sideline doctor attributed his collapse to a prior back injury.
If Tagovailoa had been diagnosed with a concussion, he likely would not have been playing in a game just 4 days later, where he lost consciousness after suffering a suspected second concussion and was removed from the field on a stretcher.
For the survey, Nowinski and colleagues showed 347 current and former athletes, including 109 football players, video examples of SHAAKE and them asked about their experiences with this potential indicator of concussion.
Nearly 69% of athletes reported exhibiting a SHAAKE during their career, and 93% of those reported a SHAAKE in association with concussion at least once. Athletes reported SHAAKE a median of five times in their lives.
Of the athletes who reported SHAAKE, 85% linked this head-shaking movement to concussion symptoms such as disorientation (71%) and dizziness (54%).
Across all sports, SHAAKE showed a sensitivity of 49.6% and a positive predictive value (PPV) of 72.4% for diagnosing concussions.
Among football players, sensitivity improved to 52.3%, with an estimated specificity of 99.9%, a PPV of 91.9%, and an estimated negative predictive value of 99.5%.
The main limitation of the survey was the potential for recall bias due to survey participants self-reporting prior concussions. The researchers called for future prospective studies to validate SHAAKE as a sign of concussion.
Instant Replay for Brain Injury?
Experts echoed the need for validation. SHAAKE represents a “promising advance” in objective TBI assessment, particularly for sideline evaluation, said Shaheen Lakhan, MD, PhD, neurologist, and researcher based in Miami, Florida, who wasn’t involved in the research.
The potential value of SHAAKE is “particularly notable given the well-documented tendency for athletes to minimize or conceal symptoms to maintain play eligibility, a limitation that has historically challenged our reliance on subjective reporting and observational assessments,” Lakhan said.
“Moving forward, validation through prospective studies incorporating real-time video analysis, helmet sensor data, and clinician-confirmed TBI diagnoses will be essential. With appropriate validation, SHAAKE could emerge as a valuable component of our sideline assessment arsenal, complementing rather than replacing existing diagnostic approaches,” Lakhan said.
“SHAAKE could be the ‘instant replay’ for brain injuries that sports medicine has been waiting for — but like any new technology, we need to make sure it works for every player, not just some,” Lakhan added.
Also weighing in, Richard Figler, MD, director of the Concussion Center, Cleveland Clinic Sports Medicine Center, Cleveland, cautioned that the survey participants were recruited from a concussion registry and self-reported an average of 23 concussions — more than one third of which happened 5-10 years prior — which begs the question, “How much are they actually remembering?”
“Our goal is to make sure that the athletes are safe and that we’re not missing concussions, and we don’t have great tools to start off with. This study opens up the door for some prospective studies [of SHAAKE] moving forward. I think we need more data before this should be listed as a definitive marker,” said Figler, who also wasn’t involved in the study.
In any case, he said, when it comes to suspected concussion in sports, “when in doubt, you sit them out,” Figler said.
This research received no external funding. Nowinski has received travel reimbursement from the NFL Players Association (NFLPA), NFL, World Rugby, WWE, and All Elite Wrestling; served as an expert witness in cases related to concussion and chronic traumatic encephalopathy; and is compensated for speaking appearances and serving on the NFL Concussion Settlement Player Advocacy Committee. Daniel H. Daneshvar served as an expert witness in legal cases involving brain injury and concussion and received funding from the Football Players Health Study at Harvard University, which is funded by the NFLPA and evaluates patients for the MGH Brain and Body TRUST Center, sponsored in part by the NFLPA. Lakhan and Figler had no relevant disclosures.
A version of this article appeared on Medscape.com.
Spontaneous Headshake After a Kinematic Event (SHAAKE) refers to the rapid, back-and-forth head movement athletes exhibit following a blow to the head. This voluntary motion typically occurs within seconds to minutes after impact and is a familiar response in athletes.
In a recent survey, 7 out of 10 adult athletes recalled making this movement after a collision, and three out of four times they attributed this back-and-forth head movement to a concussion. The association was strongest among football players, who reported that over 90% of SHAAKE episodes were associated with a concussion.
The results were published online in Diagnostics.
Call to Action
“Everyone” — including sports and medical organizations — “should be adding this to their list of potential concussion signs and their protocol immediately,” study investigator Chris Nowinski, PhD, CEO and co-founder of the Concussion Legacy Foundation, told this news organization.
Nowinski said it’s “fascinating” that this concussion sign hasn’t been formally studied or added to formal concussion screening metrics before now, given that it’s been depicted in movies, television, and cartoons for decades.
Coaches, medical professionals, and concussion spotters should be trained to recognize when a SHAAKE happens, he said.
“The interesting thing is, I don’t think coaches or parents need much training other than to officially tie this to suspicion of a concussion,” Nowinski added.
The Case of Miami Dolphins QB Tua Tagovailoa
Nowinski said he was tipped off to SHAAKE as a concussion sign after Miami Dolphins quarterback Tua Tagovailoa’s controversial undiagnosed concussion during a National Football League (NFL) game in 2022.
After Tagovailoa’s head hit the ground, he rapidly shook his head side to side, indicating displaying SHAAKE, before stumbling and collapsing. At the time, a sideline doctor attributed his collapse to a prior back injury.
If Tagovailoa had been diagnosed with a concussion, he likely would not have been playing in a game just 4 days later, where he lost consciousness after suffering a suspected second concussion and was removed from the field on a stretcher.
For the survey, Nowinski and colleagues showed 347 current and former athletes, including 109 football players, video examples of SHAAKE and them asked about their experiences with this potential indicator of concussion.
Nearly 69% of athletes reported exhibiting a SHAAKE during their career, and 93% of those reported a SHAAKE in association with concussion at least once. Athletes reported SHAAKE a median of five times in their lives.
Of the athletes who reported SHAAKE, 85% linked this head-shaking movement to concussion symptoms such as disorientation (71%) and dizziness (54%).
Across all sports, SHAAKE showed a sensitivity of 49.6% and a positive predictive value (PPV) of 72.4% for diagnosing concussions.
Among football players, sensitivity improved to 52.3%, with an estimated specificity of 99.9%, a PPV of 91.9%, and an estimated negative predictive value of 99.5%.
The main limitation of the survey was the potential for recall bias due to survey participants self-reporting prior concussions. The researchers called for future prospective studies to validate SHAAKE as a sign of concussion.
Instant Replay for Brain Injury?
Experts echoed the need for validation. SHAAKE represents a “promising advance” in objective TBI assessment, particularly for sideline evaluation, said Shaheen Lakhan, MD, PhD, neurologist, and researcher based in Miami, Florida, who wasn’t involved in the research.
The potential value of SHAAKE is “particularly notable given the well-documented tendency for athletes to minimize or conceal symptoms to maintain play eligibility, a limitation that has historically challenged our reliance on subjective reporting and observational assessments,” Lakhan said.
“Moving forward, validation through prospective studies incorporating real-time video analysis, helmet sensor data, and clinician-confirmed TBI diagnoses will be essential. With appropriate validation, SHAAKE could emerge as a valuable component of our sideline assessment arsenal, complementing rather than replacing existing diagnostic approaches,” Lakhan said.
“SHAAKE could be the ‘instant replay’ for brain injuries that sports medicine has been waiting for — but like any new technology, we need to make sure it works for every player, not just some,” Lakhan added.
Also weighing in, Richard Figler, MD, director of the Concussion Center, Cleveland Clinic Sports Medicine Center, Cleveland, cautioned that the survey participants were recruited from a concussion registry and self-reported an average of 23 concussions — more than one third of which happened 5-10 years prior — which begs the question, “How much are they actually remembering?”
“Our goal is to make sure that the athletes are safe and that we’re not missing concussions, and we don’t have great tools to start off with. This study opens up the door for some prospective studies [of SHAAKE] moving forward. I think we need more data before this should be listed as a definitive marker,” said Figler, who also wasn’t involved in the study.
In any case, he said, when it comes to suspected concussion in sports, “when in doubt, you sit them out,” Figler said.
This research received no external funding. Nowinski has received travel reimbursement from the NFL Players Association (NFLPA), NFL, World Rugby, WWE, and All Elite Wrestling; served as an expert witness in cases related to concussion and chronic traumatic encephalopathy; and is compensated for speaking appearances and serving on the NFL Concussion Settlement Player Advocacy Committee. Daniel H. Daneshvar served as an expert witness in legal cases involving brain injury and concussion and received funding from the Football Players Health Study at Harvard University, which is funded by the NFLPA and evaluates patients for the MGH Brain and Body TRUST Center, sponsored in part by the NFLPA. Lakhan and Figler had no relevant disclosures.
A version of this article appeared on Medscape.com.
Spontaneous Headshake After a Kinematic Event (SHAAKE) refers to the rapid, back-and-forth head movement athletes exhibit following a blow to the head. This voluntary motion typically occurs within seconds to minutes after impact and is a familiar response in athletes.
In a recent survey, 7 out of 10 adult athletes recalled making this movement after a collision, and three out of four times they attributed this back-and-forth head movement to a concussion. The association was strongest among football players, who reported that over 90% of SHAAKE episodes were associated with a concussion.
The results were published online in Diagnostics.
Call to Action
“Everyone” — including sports and medical organizations — “should be adding this to their list of potential concussion signs and their protocol immediately,” study investigator Chris Nowinski, PhD, CEO and co-founder of the Concussion Legacy Foundation, told this news organization.
Nowinski said it’s “fascinating” that this concussion sign hasn’t been formally studied or added to formal concussion screening metrics before now, given that it’s been depicted in movies, television, and cartoons for decades.
Coaches, medical professionals, and concussion spotters should be trained to recognize when a SHAAKE happens, he said.
“The interesting thing is, I don’t think coaches or parents need much training other than to officially tie this to suspicion of a concussion,” Nowinski added.
The Case of Miami Dolphins QB Tua Tagovailoa
Nowinski said he was tipped off to SHAAKE as a concussion sign after Miami Dolphins quarterback Tua Tagovailoa’s controversial undiagnosed concussion during a National Football League (NFL) game in 2022.
After Tagovailoa’s head hit the ground, he rapidly shook his head side to side, indicating displaying SHAAKE, before stumbling and collapsing. At the time, a sideline doctor attributed his collapse to a prior back injury.
If Tagovailoa had been diagnosed with a concussion, he likely would not have been playing in a game just 4 days later, where he lost consciousness after suffering a suspected second concussion and was removed from the field on a stretcher.
For the survey, Nowinski and colleagues showed 347 current and former athletes, including 109 football players, video examples of SHAAKE and them asked about their experiences with this potential indicator of concussion.
Nearly 69% of athletes reported exhibiting a SHAAKE during their career, and 93% of those reported a SHAAKE in association with concussion at least once. Athletes reported SHAAKE a median of five times in their lives.
Of the athletes who reported SHAAKE, 85% linked this head-shaking movement to concussion symptoms such as disorientation (71%) and dizziness (54%).
Across all sports, SHAAKE showed a sensitivity of 49.6% and a positive predictive value (PPV) of 72.4% for diagnosing concussions.
Among football players, sensitivity improved to 52.3%, with an estimated specificity of 99.9%, a PPV of 91.9%, and an estimated negative predictive value of 99.5%.
The main limitation of the survey was the potential for recall bias due to survey participants self-reporting prior concussions. The researchers called for future prospective studies to validate SHAAKE as a sign of concussion.
Instant Replay for Brain Injury?
Experts echoed the need for validation. SHAAKE represents a “promising advance” in objective TBI assessment, particularly for sideline evaluation, said Shaheen Lakhan, MD, PhD, neurologist, and researcher based in Miami, Florida, who wasn’t involved in the research.
The potential value of SHAAKE is “particularly notable given the well-documented tendency for athletes to minimize or conceal symptoms to maintain play eligibility, a limitation that has historically challenged our reliance on subjective reporting and observational assessments,” Lakhan said.
“Moving forward, validation through prospective studies incorporating real-time video analysis, helmet sensor data, and clinician-confirmed TBI diagnoses will be essential. With appropriate validation, SHAAKE could emerge as a valuable component of our sideline assessment arsenal, complementing rather than replacing existing diagnostic approaches,” Lakhan said.
“SHAAKE could be the ‘instant replay’ for brain injuries that sports medicine has been waiting for — but like any new technology, we need to make sure it works for every player, not just some,” Lakhan added.
Also weighing in, Richard Figler, MD, director of the Concussion Center, Cleveland Clinic Sports Medicine Center, Cleveland, cautioned that the survey participants were recruited from a concussion registry and self-reported an average of 23 concussions — more than one third of which happened 5-10 years prior — which begs the question, “How much are they actually remembering?”
“Our goal is to make sure that the athletes are safe and that we’re not missing concussions, and we don’t have great tools to start off with. This study opens up the door for some prospective studies [of SHAAKE] moving forward. I think we need more data before this should be listed as a definitive marker,” said Figler, who also wasn’t involved in the study.
In any case, he said, when it comes to suspected concussion in sports, “when in doubt, you sit them out,” Figler said.
This research received no external funding. Nowinski has received travel reimbursement from the NFL Players Association (NFLPA), NFL, World Rugby, WWE, and All Elite Wrestling; served as an expert witness in cases related to concussion and chronic traumatic encephalopathy; and is compensated for speaking appearances and serving on the NFL Concussion Settlement Player Advocacy Committee. Daniel H. Daneshvar served as an expert witness in legal cases involving brain injury and concussion and received funding from the Football Players Health Study at Harvard University, which is funded by the NFLPA and evaluates patients for the MGH Brain and Body TRUST Center, sponsored in part by the NFLPA. Lakhan and Figler had no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM DIAGNOSTICS
Blood Tests for Alzheimer’s Are Here... Are Clinicians Ready?
With the approval of anti-amyloid monoclonal antibodies to treat early-stage Alzheimer’s disease, the need for accurate and early diagnosis is crucial.
Recently, an expert workgroup convened by the Global CEO Initiative on Alzheimer’s Disease published recommendations for the clinical implementation of Alzheimer’s disease blood-based biomarkers.
“Our hope was to provide some recommendations that clinicians could use to develop the best pathways for their clinical practice,” said workgroup co-chair Michelle M. Mielke, PhD, with Wake Forest University School of Medicine, Winston-Salem, North Carolina.
Triage and Confirmatory Pathways
The group recommends two implementation pathways for Alzheimer’s disease blood biomarkers — one for current use for triaging and another for future use to confirm amyloid pathology once blood biomarker tests have reached sufficient performance for this purpose.
In the triage pathway, a negative blood biomarker test would flag individuals unlikely to have detectable brain amyloid pathology. This outcome would prompt clinicians to focus on evaluating non–Alzheimer’s disease-related causes of cognitive impairment, which may streamline the diagnosis of other causes of cognitive impairment, the authors said.
A positive triage blood test would suggest a higher likelihood of amyloid pathology and prompt referral to secondary care for further assessment and consideration for a second, more accurate test, such as amyloid PET or CSF for amyloid confirmation.
In the confirmatory pathway, a positive blood biomarker test result would identify amyloid pathology without the need for a second test, providing a faster route to diagnosis, the authors noted.
Mielke emphasized that these recommendations represent a “first step” and will need to be updated as experiences with the Alzheimer’s disease blood biomarkers in clinical care increase and additional barriers and facilitators are identified.
“These updates will likely include community-informed approaches that incorporate feedback from patients as well as healthcare providers, alongside results from validation in diverse real-world settings,” said workgroup co-chair Chi Udeh-Momoh, PhD, MSc, with Wake Forest University School of Medicine and the Brain and Mind Institute, Aga Khan University, Nairobi, Kenya.
The Alzheimer’s Association published “appropriate use” recommendations for blood biomarkers in 2022.
“Currently, the Alzheimer’s Association is building an updated library of clinical guidance that distills the scientific evidence using de novo systematic reviews and translates them into clear and actionable recommendations for clinical practice,” said Rebecca M. Edelmayer, PhD, vice president of scientific engagement, Alzheimer’s Association.
“The first major effort with our new process will be the upcoming Evidence-based Clinical Practice Guideline on the Use of Blood-based Biomarkers (BBMs) in Specialty Care Settings. This guideline’s recommendations will be published in early 2025,” Edelmayer said.
Availability and Accuracy
Research has shown that amyloid beta and tau protein blood biomarkers — especially a high plasma phosphorylated (p)–tau217 levels — are highly accurate in identifying Alzheimer’s disease in patients with cognitive symptoms attending primary and secondary care clinics.
Several tests targeting plasma p-tau217 are now available for use. They include the PrecivityAD2 blood test from C2N Diagnostics and the Simoa p-Tau 217 Planar Kit and LucentAD p-Tau 217 — both from Quanterix.
In a recent head-to-head comparison of seven leading blood tests for AD pathology, measures of plasma p-tau217, either individually or in combination with other plasma biomarkers, had the strongest relationships with Alzheimer’s disease outcomes.
A recent Swedish study showed that the PrecivityAD2 test had an accuracy of 91% for correctly classifying clinical, biomarker-verified Alzheimer’s disease.
“We’ve been using these blood biomarkers in research for a long time and we’re now taking the jump to start using them in clinic to risk stratify patients,” said Fanny Elahi, MD, PhD, director of fluid biomarker research for the Barbara and Maurice Deane Center for Wellness and Cognitive Health at Icahn Mount Sinai in New York City.
New York’s Mount Sinai Health System is among the first in the northeast to offer blood tests across primary and specialty care settings for early diagnosis of AD and related dementias.
Edelmayer cautioned, “There is no single, stand-alone test to diagnose Alzheimer’s disease today. Blood testing is one piece of the diagnostic process.”
“Currently, physicians use well-established diagnostic tools combined with medical history and other information, including neurological exams, cognitive and functional assessments as well as brain imaging and spinal fluid analysis and blood to make an accurate diagnosis and to understand which patients are eligible for approved treatments,” she said.
There are also emerging biomarkers in the research pipeline, Edelmayer said.
“For example, some researchers think retinal imaging has the potential to detect biological signs of Alzheimer’s disease within certain areas of the eye,” she explained.
“Other emerging biomarkers include examining components in saliva and the skin for signals that may indicate early biological changes in the brain. These biomarkers are still very exploratory, and more research is needed before these tests or biomarkers can be used more routinely to study risk or aid in diagnosis,” Edelmayer said.
Ideal Candidates for Alzheimer’s Disease Blood Testing?
Experts agree that blood tests represent a convenient and scalable option to address the anticipated surge in demand for biomarker testing with the availability of disease-modifying treatments. For now, however, they are not for all older adults worried about their memory.
“Current practice should focus on using these blood biomarkers in individuals with cognitive impairment rather than in those with normal cognition or subjective cognitive decline until further research demonstrates effective interventions for individuals considered cognitively normal with elevated levels of amyloid,” the authors of a recent JAMA editorial noted.
At Mount Sinai, “we’re not starting with stone-cold asymptomatic individuals. But ultimately, this is what the blood tests are intended for — screening,” Elahi noted.
She also noted that Mount Sinai has a “very diverse population” — some with young onset cognitive symptoms, so the entry criteria for testing are “very wide.”
“Anyone above age 40 with symptoms can qualify to get a blood test. We do ask at this stage that either the individual report symptoms or someone in their life or their clinician be worried about their cognition or their brain function,” Elahi said.
Ethical Considerations, Counseling
Elahi emphasized the importance of counseling patients who come to the clinic seeking an Alzheimer’s disease blood test. This should include how the diagnostic process will unfold and what the next steps are with a given result.
Elahi said patients need to be informed that Alzheimer’s disease blood biomarkers are still “relatively new,” and a test can help a patient “know the likelihood of having the disease, but it won’t be 100% definitive.”
To ensure the ethical principle of “do no harm,” counseling should ensure that patients are fully prepared for the implications of the test results and ensure that the decision to test aligns with the patient’s readiness and well-being, Elahi said.
Edelmayer said the forthcoming clinical practice guidelines will provide “evidence-based recommendations for physicians to help guide them through the decision-making process around who should be tested and when. In the meantime, the Alzheimer’s Association urges providers to refer to the 2022 appropriate use recommendations for blood tests in clinical practice and trial settings.”
Mielke has served on scientific advisory boards and/or having consulted for Acadia, Biogen, Eisai, LabCorp, Lilly, Merck, PeerView Institute, Roche, Siemens Healthineers, and Sunbird Bio. Edelmayer and Elahi had no relevant disclosures.
A version of this article appeared on Medscape.com.
With the approval of anti-amyloid monoclonal antibodies to treat early-stage Alzheimer’s disease, the need for accurate and early diagnosis is crucial.
Recently, an expert workgroup convened by the Global CEO Initiative on Alzheimer’s Disease published recommendations for the clinical implementation of Alzheimer’s disease blood-based biomarkers.
“Our hope was to provide some recommendations that clinicians could use to develop the best pathways for their clinical practice,” said workgroup co-chair Michelle M. Mielke, PhD, with Wake Forest University School of Medicine, Winston-Salem, North Carolina.
Triage and Confirmatory Pathways
The group recommends two implementation pathways for Alzheimer’s disease blood biomarkers — one for current use for triaging and another for future use to confirm amyloid pathology once blood biomarker tests have reached sufficient performance for this purpose.
In the triage pathway, a negative blood biomarker test would flag individuals unlikely to have detectable brain amyloid pathology. This outcome would prompt clinicians to focus on evaluating non–Alzheimer’s disease-related causes of cognitive impairment, which may streamline the diagnosis of other causes of cognitive impairment, the authors said.
A positive triage blood test would suggest a higher likelihood of amyloid pathology and prompt referral to secondary care for further assessment and consideration for a second, more accurate test, such as amyloid PET or CSF for amyloid confirmation.
In the confirmatory pathway, a positive blood biomarker test result would identify amyloid pathology without the need for a second test, providing a faster route to diagnosis, the authors noted.
Mielke emphasized that these recommendations represent a “first step” and will need to be updated as experiences with the Alzheimer’s disease blood biomarkers in clinical care increase and additional barriers and facilitators are identified.
“These updates will likely include community-informed approaches that incorporate feedback from patients as well as healthcare providers, alongside results from validation in diverse real-world settings,” said workgroup co-chair Chi Udeh-Momoh, PhD, MSc, with Wake Forest University School of Medicine and the Brain and Mind Institute, Aga Khan University, Nairobi, Kenya.
The Alzheimer’s Association published “appropriate use” recommendations for blood biomarkers in 2022.
“Currently, the Alzheimer’s Association is building an updated library of clinical guidance that distills the scientific evidence using de novo systematic reviews and translates them into clear and actionable recommendations for clinical practice,” said Rebecca M. Edelmayer, PhD, vice president of scientific engagement, Alzheimer’s Association.
“The first major effort with our new process will be the upcoming Evidence-based Clinical Practice Guideline on the Use of Blood-based Biomarkers (BBMs) in Specialty Care Settings. This guideline’s recommendations will be published in early 2025,” Edelmayer said.
Availability and Accuracy
Research has shown that amyloid beta and tau protein blood biomarkers — especially a high plasma phosphorylated (p)–tau217 levels — are highly accurate in identifying Alzheimer’s disease in patients with cognitive symptoms attending primary and secondary care clinics.
Several tests targeting plasma p-tau217 are now available for use. They include the PrecivityAD2 blood test from C2N Diagnostics and the Simoa p-Tau 217 Planar Kit and LucentAD p-Tau 217 — both from Quanterix.
In a recent head-to-head comparison of seven leading blood tests for AD pathology, measures of plasma p-tau217, either individually or in combination with other plasma biomarkers, had the strongest relationships with Alzheimer’s disease outcomes.
A recent Swedish study showed that the PrecivityAD2 test had an accuracy of 91% for correctly classifying clinical, biomarker-verified Alzheimer’s disease.
“We’ve been using these blood biomarkers in research for a long time and we’re now taking the jump to start using them in clinic to risk stratify patients,” said Fanny Elahi, MD, PhD, director of fluid biomarker research for the Barbara and Maurice Deane Center for Wellness and Cognitive Health at Icahn Mount Sinai in New York City.
New York’s Mount Sinai Health System is among the first in the northeast to offer blood tests across primary and specialty care settings for early diagnosis of AD and related dementias.
Edelmayer cautioned, “There is no single, stand-alone test to diagnose Alzheimer’s disease today. Blood testing is one piece of the diagnostic process.”
“Currently, physicians use well-established diagnostic tools combined with medical history and other information, including neurological exams, cognitive and functional assessments as well as brain imaging and spinal fluid analysis and blood to make an accurate diagnosis and to understand which patients are eligible for approved treatments,” she said.
There are also emerging biomarkers in the research pipeline, Edelmayer said.
“For example, some researchers think retinal imaging has the potential to detect biological signs of Alzheimer’s disease within certain areas of the eye,” she explained.
“Other emerging biomarkers include examining components in saliva and the skin for signals that may indicate early biological changes in the brain. These biomarkers are still very exploratory, and more research is needed before these tests or biomarkers can be used more routinely to study risk or aid in diagnosis,” Edelmayer said.
Ideal Candidates for Alzheimer’s Disease Blood Testing?
Experts agree that blood tests represent a convenient and scalable option to address the anticipated surge in demand for biomarker testing with the availability of disease-modifying treatments. For now, however, they are not for all older adults worried about their memory.
“Current practice should focus on using these blood biomarkers in individuals with cognitive impairment rather than in those with normal cognition or subjective cognitive decline until further research demonstrates effective interventions for individuals considered cognitively normal with elevated levels of amyloid,” the authors of a recent JAMA editorial noted.
At Mount Sinai, “we’re not starting with stone-cold asymptomatic individuals. But ultimately, this is what the blood tests are intended for — screening,” Elahi noted.
She also noted that Mount Sinai has a “very diverse population” — some with young onset cognitive symptoms, so the entry criteria for testing are “very wide.”
“Anyone above age 40 with symptoms can qualify to get a blood test. We do ask at this stage that either the individual report symptoms or someone in their life or their clinician be worried about their cognition or their brain function,” Elahi said.
Ethical Considerations, Counseling
Elahi emphasized the importance of counseling patients who come to the clinic seeking an Alzheimer’s disease blood test. This should include how the diagnostic process will unfold and what the next steps are with a given result.
Elahi said patients need to be informed that Alzheimer’s disease blood biomarkers are still “relatively new,” and a test can help a patient “know the likelihood of having the disease, but it won’t be 100% definitive.”
To ensure the ethical principle of “do no harm,” counseling should ensure that patients are fully prepared for the implications of the test results and ensure that the decision to test aligns with the patient’s readiness and well-being, Elahi said.
Edelmayer said the forthcoming clinical practice guidelines will provide “evidence-based recommendations for physicians to help guide them through the decision-making process around who should be tested and when. In the meantime, the Alzheimer’s Association urges providers to refer to the 2022 appropriate use recommendations for blood tests in clinical practice and trial settings.”
Mielke has served on scientific advisory boards and/or having consulted for Acadia, Biogen, Eisai, LabCorp, Lilly, Merck, PeerView Institute, Roche, Siemens Healthineers, and Sunbird Bio. Edelmayer and Elahi had no relevant disclosures.
A version of this article appeared on Medscape.com.
With the approval of anti-amyloid monoclonal antibodies to treat early-stage Alzheimer’s disease, the need for accurate and early diagnosis is crucial.
Recently, an expert workgroup convened by the Global CEO Initiative on Alzheimer’s Disease published recommendations for the clinical implementation of Alzheimer’s disease blood-based biomarkers.
“Our hope was to provide some recommendations that clinicians could use to develop the best pathways for their clinical practice,” said workgroup co-chair Michelle M. Mielke, PhD, with Wake Forest University School of Medicine, Winston-Salem, North Carolina.
Triage and Confirmatory Pathways
The group recommends two implementation pathways for Alzheimer’s disease blood biomarkers — one for current use for triaging and another for future use to confirm amyloid pathology once blood biomarker tests have reached sufficient performance for this purpose.
In the triage pathway, a negative blood biomarker test would flag individuals unlikely to have detectable brain amyloid pathology. This outcome would prompt clinicians to focus on evaluating non–Alzheimer’s disease-related causes of cognitive impairment, which may streamline the diagnosis of other causes of cognitive impairment, the authors said.
A positive triage blood test would suggest a higher likelihood of amyloid pathology and prompt referral to secondary care for further assessment and consideration for a second, more accurate test, such as amyloid PET or CSF for amyloid confirmation.
In the confirmatory pathway, a positive blood biomarker test result would identify amyloid pathology without the need for a second test, providing a faster route to diagnosis, the authors noted.
Mielke emphasized that these recommendations represent a “first step” and will need to be updated as experiences with the Alzheimer’s disease blood biomarkers in clinical care increase and additional barriers and facilitators are identified.
“These updates will likely include community-informed approaches that incorporate feedback from patients as well as healthcare providers, alongside results from validation in diverse real-world settings,” said workgroup co-chair Chi Udeh-Momoh, PhD, MSc, with Wake Forest University School of Medicine and the Brain and Mind Institute, Aga Khan University, Nairobi, Kenya.
The Alzheimer’s Association published “appropriate use” recommendations for blood biomarkers in 2022.
“Currently, the Alzheimer’s Association is building an updated library of clinical guidance that distills the scientific evidence using de novo systematic reviews and translates them into clear and actionable recommendations for clinical practice,” said Rebecca M. Edelmayer, PhD, vice president of scientific engagement, Alzheimer’s Association.
“The first major effort with our new process will be the upcoming Evidence-based Clinical Practice Guideline on the Use of Blood-based Biomarkers (BBMs) in Specialty Care Settings. This guideline’s recommendations will be published in early 2025,” Edelmayer said.
Availability and Accuracy
Research has shown that amyloid beta and tau protein blood biomarkers — especially a high plasma phosphorylated (p)–tau217 levels — are highly accurate in identifying Alzheimer’s disease in patients with cognitive symptoms attending primary and secondary care clinics.
Several tests targeting plasma p-tau217 are now available for use. They include the PrecivityAD2 blood test from C2N Diagnostics and the Simoa p-Tau 217 Planar Kit and LucentAD p-Tau 217 — both from Quanterix.
In a recent head-to-head comparison of seven leading blood tests for AD pathology, measures of plasma p-tau217, either individually or in combination with other plasma biomarkers, had the strongest relationships with Alzheimer’s disease outcomes.
A recent Swedish study showed that the PrecivityAD2 test had an accuracy of 91% for correctly classifying clinical, biomarker-verified Alzheimer’s disease.
“We’ve been using these blood biomarkers in research for a long time and we’re now taking the jump to start using them in clinic to risk stratify patients,” said Fanny Elahi, MD, PhD, director of fluid biomarker research for the Barbara and Maurice Deane Center for Wellness and Cognitive Health at Icahn Mount Sinai in New York City.
New York’s Mount Sinai Health System is among the first in the northeast to offer blood tests across primary and specialty care settings for early diagnosis of AD and related dementias.
Edelmayer cautioned, “There is no single, stand-alone test to diagnose Alzheimer’s disease today. Blood testing is one piece of the diagnostic process.”
“Currently, physicians use well-established diagnostic tools combined with medical history and other information, including neurological exams, cognitive and functional assessments as well as brain imaging and spinal fluid analysis and blood to make an accurate diagnosis and to understand which patients are eligible for approved treatments,” she said.
There are also emerging biomarkers in the research pipeline, Edelmayer said.
“For example, some researchers think retinal imaging has the potential to detect biological signs of Alzheimer’s disease within certain areas of the eye,” she explained.
“Other emerging biomarkers include examining components in saliva and the skin for signals that may indicate early biological changes in the brain. These biomarkers are still very exploratory, and more research is needed before these tests or biomarkers can be used more routinely to study risk or aid in diagnosis,” Edelmayer said.
Ideal Candidates for Alzheimer’s Disease Blood Testing?
Experts agree that blood tests represent a convenient and scalable option to address the anticipated surge in demand for biomarker testing with the availability of disease-modifying treatments. For now, however, they are not for all older adults worried about their memory.
“Current practice should focus on using these blood biomarkers in individuals with cognitive impairment rather than in those with normal cognition or subjective cognitive decline until further research demonstrates effective interventions for individuals considered cognitively normal with elevated levels of amyloid,” the authors of a recent JAMA editorial noted.
At Mount Sinai, “we’re not starting with stone-cold asymptomatic individuals. But ultimately, this is what the blood tests are intended for — screening,” Elahi noted.
She also noted that Mount Sinai has a “very diverse population” — some with young onset cognitive symptoms, so the entry criteria for testing are “very wide.”
“Anyone above age 40 with symptoms can qualify to get a blood test. We do ask at this stage that either the individual report symptoms or someone in their life or their clinician be worried about their cognition or their brain function,” Elahi said.
Ethical Considerations, Counseling
Elahi emphasized the importance of counseling patients who come to the clinic seeking an Alzheimer’s disease blood test. This should include how the diagnostic process will unfold and what the next steps are with a given result.
Elahi said patients need to be informed that Alzheimer’s disease blood biomarkers are still “relatively new,” and a test can help a patient “know the likelihood of having the disease, but it won’t be 100% definitive.”
To ensure the ethical principle of “do no harm,” counseling should ensure that patients are fully prepared for the implications of the test results and ensure that the decision to test aligns with the patient’s readiness and well-being, Elahi said.
Edelmayer said the forthcoming clinical practice guidelines will provide “evidence-based recommendations for physicians to help guide them through the decision-making process around who should be tested and when. In the meantime, the Alzheimer’s Association urges providers to refer to the 2022 appropriate use recommendations for blood tests in clinical practice and trial settings.”
Mielke has served on scientific advisory boards and/or having consulted for Acadia, Biogen, Eisai, LabCorp, Lilly, Merck, PeerView Institute, Roche, Siemens Healthineers, and Sunbird Bio. Edelmayer and Elahi had no relevant disclosures.
A version of this article appeared on Medscape.com.
ASA Releases New Primary Stroke Prevention Guideline
The first update in a decade, the 2024 Guideline for the Primary Prevention of Stroke, replaces the 2014 version and is intended to be a resource for clinicians to help them implement a variety of prevention strategies in patients with no previous history of stroke. It aligns with the American Heart Association’s Life’s Essential 8.
“This guideline is an important and timely update from 2014 for multiple reasons. First, there have been groundbreaking clinical trials that have been published with new medications to not only treat the target disease [including] diabetes/obesity and high cholesterol], but also lower the risk of stroke and heart disease,” said chair of the guideline writing group, Cheryl D. Bushnell, MD, MHS, FAHA, and vice chair of the research, Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
It was published online on October 21 in Stroke.
Up to 80% of Strokes Preventable
Estimates show that every year in the United States, more than 500,000 individuals have a first stroke. However, the guideline authors noted that up to 80% of strokes may be preventable. As a result, they called for better primary stroke prevention that includes improved screening and lifestyle changes.
This includes adoption of the Mediterranean diet, which has been shown to significantly reduce stroke risk, especially when supplemented with consumption of nuts and olive oil.
The guideline recommendations also emphasize the need for physical activity, which is “essential” for cardiovascular health and stroke reduction. The authors underscored this point and provided a new recommendation to screen for sedentary behavior and advise patients to avoid inactivity and engage in regular moderate to vigorous physical activity.
Another new recommendation is based on “robust” data that glucagon-like peptide 1 receptor agonists (GLP-1s) significantly improve the management of type 2 diabetes, weight loss, and lower the risk for cardiovascular disease. As a result, guideline authors called for the use of GLP-1s in patients with diabetes and high cardiovascular risk or established cardiovascular disease.
“The glucagon-like peptide receptor agonists have been shown to not only drastically reduce blood sugars in patients with diabetes, but they also lead to significant weight loss in these patients, which has many downstream benefits. Together, this reduces the risk of stroke and other complications of diabetes,” said Bushnell.
She also noted that another drug class introduced since the 2014 guidelines were published, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have proven to be highly effective in lowering low-density lipoprotein cholesterol. These medications have also been shown to reduce the risk for stroke.
At Least Two Meds Needed to Reduce BP
Effective blood pressure (BP) management is crucial for stroke prevention. Randomized controlled trials show that a single antihypertensive medication helps only about 30% of participants reach their BP target.
Most patients only achieve the desired BP target with two to three medications. In line with these data, the committee recommends using at least two antihypertensives for primary stroke prevention in most patients who require BP-lowering medications for hypertension.
In patients with antiphospholipid syndrome or systemic lupus erythematosus and no history of stroke or unprovoked venous thromboembolism, the authors recommended antiplatelet therapy to prevent stroke. They added that patients with antiphospholipid syndrome who have had a prior unprovoked venous thrombosis will likely benefit from vitamin K antagonist therapy (target international normalized ratio, 2-3) over direct oral anticoagulants.
Emphasis on Women’s Health
Preventing pregnancy-related stroke is achieved primarily by managing hypertension, the guideline authors noted. They recommended treating verified systolic BP over 160 mm Hg or diastolic BP over 110 mm Hg during pregnancy and up to 6 weeks postpartum to lower the risk for fatal maternal intracerebral hemorrhage.
They noted that adverse pregnancy outcomes are also common and linked to chronic hypertension, which increases stroke risk later in life. Therefore, they recommended screening for these outcomes to assess and manage vascular risk factors. The guideline includes a screening tool to help with this in clinical practice.
Endometriosis, premature ovarian failure (before age 40 years), and early-onset menopause (before age 45 years) are all associated with increased stroke risk. As a result, the guideline authors said screening for all three of these conditions is a “reasonable step in the evaluation and management of vascular risk factors in these individuals to reduce stroke risk.”
Finally, the guideline authors addressed primary stroke prevention in transgender individuals, noting that transgender women undergoing estrogen therapy for gender affirmation are at increased risk. They emphasized that evaluating and modifying risk factors could be beneficial for reducing stroke risk in this patient population.
Challenges Lie Ahead
Now that the guideline has been published, the challenge lies in determining how best to implement “its screening recommendations in primary care and other practices when these clinicians are already pushed to see as many patients as possible,” Bushnell said.
Development of screening tools that can be easily incorporated into the clinic visit or the electronic health record, as well as additional personnel to provide counseling, are probably needed to disseminate them, she added.
Bushnell also emphasized that the guideline includes a strong focus on social determinants of health and related social needs.
“We worked hard to use inclusive language and to consider populations historically excluded from research. In acknowledging that social determinants of health including access to healthcare, access to education, economic stability, neighborhood and geographic location, and social and community context have a tremendous influence on stroke risk, we describe how these factors are closely tied to the prevalence and management of many medical risks like obesity, hypertension, and diabetes.
“Our recommendations offer practical steps for screening and addressing essential health-related social needs, including access to nutritious food, stable housing, and reliable transportation, within clinical practice. By considering these factors more comprehensively, we believe we can make meaningful strides toward reducing the disparities in stroke risk,” said Bushnell.
A version of this article appeared on Medscape.com.
The first update in a decade, the 2024 Guideline for the Primary Prevention of Stroke, replaces the 2014 version and is intended to be a resource for clinicians to help them implement a variety of prevention strategies in patients with no previous history of stroke. It aligns with the American Heart Association’s Life’s Essential 8.
“This guideline is an important and timely update from 2014 for multiple reasons. First, there have been groundbreaking clinical trials that have been published with new medications to not only treat the target disease [including] diabetes/obesity and high cholesterol], but also lower the risk of stroke and heart disease,” said chair of the guideline writing group, Cheryl D. Bushnell, MD, MHS, FAHA, and vice chair of the research, Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
It was published online on October 21 in Stroke.
Up to 80% of Strokes Preventable
Estimates show that every year in the United States, more than 500,000 individuals have a first stroke. However, the guideline authors noted that up to 80% of strokes may be preventable. As a result, they called for better primary stroke prevention that includes improved screening and lifestyle changes.
This includes adoption of the Mediterranean diet, which has been shown to significantly reduce stroke risk, especially when supplemented with consumption of nuts and olive oil.
The guideline recommendations also emphasize the need for physical activity, which is “essential” for cardiovascular health and stroke reduction. The authors underscored this point and provided a new recommendation to screen for sedentary behavior and advise patients to avoid inactivity and engage in regular moderate to vigorous physical activity.
Another new recommendation is based on “robust” data that glucagon-like peptide 1 receptor agonists (GLP-1s) significantly improve the management of type 2 diabetes, weight loss, and lower the risk for cardiovascular disease. As a result, guideline authors called for the use of GLP-1s in patients with diabetes and high cardiovascular risk or established cardiovascular disease.
“The glucagon-like peptide receptor agonists have been shown to not only drastically reduce blood sugars in patients with diabetes, but they also lead to significant weight loss in these patients, which has many downstream benefits. Together, this reduces the risk of stroke and other complications of diabetes,” said Bushnell.
She also noted that another drug class introduced since the 2014 guidelines were published, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have proven to be highly effective in lowering low-density lipoprotein cholesterol. These medications have also been shown to reduce the risk for stroke.
At Least Two Meds Needed to Reduce BP
Effective blood pressure (BP) management is crucial for stroke prevention. Randomized controlled trials show that a single antihypertensive medication helps only about 30% of participants reach their BP target.
Most patients only achieve the desired BP target with two to three medications. In line with these data, the committee recommends using at least two antihypertensives for primary stroke prevention in most patients who require BP-lowering medications for hypertension.
In patients with antiphospholipid syndrome or systemic lupus erythematosus and no history of stroke or unprovoked venous thromboembolism, the authors recommended antiplatelet therapy to prevent stroke. They added that patients with antiphospholipid syndrome who have had a prior unprovoked venous thrombosis will likely benefit from vitamin K antagonist therapy (target international normalized ratio, 2-3) over direct oral anticoagulants.
Emphasis on Women’s Health
Preventing pregnancy-related stroke is achieved primarily by managing hypertension, the guideline authors noted. They recommended treating verified systolic BP over 160 mm Hg or diastolic BP over 110 mm Hg during pregnancy and up to 6 weeks postpartum to lower the risk for fatal maternal intracerebral hemorrhage.
They noted that adverse pregnancy outcomes are also common and linked to chronic hypertension, which increases stroke risk later in life. Therefore, they recommended screening for these outcomes to assess and manage vascular risk factors. The guideline includes a screening tool to help with this in clinical practice.
Endometriosis, premature ovarian failure (before age 40 years), and early-onset menopause (before age 45 years) are all associated with increased stroke risk. As a result, the guideline authors said screening for all three of these conditions is a “reasonable step in the evaluation and management of vascular risk factors in these individuals to reduce stroke risk.”
Finally, the guideline authors addressed primary stroke prevention in transgender individuals, noting that transgender women undergoing estrogen therapy for gender affirmation are at increased risk. They emphasized that evaluating and modifying risk factors could be beneficial for reducing stroke risk in this patient population.
Challenges Lie Ahead
Now that the guideline has been published, the challenge lies in determining how best to implement “its screening recommendations in primary care and other practices when these clinicians are already pushed to see as many patients as possible,” Bushnell said.
Development of screening tools that can be easily incorporated into the clinic visit or the electronic health record, as well as additional personnel to provide counseling, are probably needed to disseminate them, she added.
Bushnell also emphasized that the guideline includes a strong focus on social determinants of health and related social needs.
“We worked hard to use inclusive language and to consider populations historically excluded from research. In acknowledging that social determinants of health including access to healthcare, access to education, economic stability, neighborhood and geographic location, and social and community context have a tremendous influence on stroke risk, we describe how these factors are closely tied to the prevalence and management of many medical risks like obesity, hypertension, and diabetes.
“Our recommendations offer practical steps for screening and addressing essential health-related social needs, including access to nutritious food, stable housing, and reliable transportation, within clinical practice. By considering these factors more comprehensively, we believe we can make meaningful strides toward reducing the disparities in stroke risk,” said Bushnell.
A version of this article appeared on Medscape.com.
The first update in a decade, the 2024 Guideline for the Primary Prevention of Stroke, replaces the 2014 version and is intended to be a resource for clinicians to help them implement a variety of prevention strategies in patients with no previous history of stroke. It aligns with the American Heart Association’s Life’s Essential 8.
“This guideline is an important and timely update from 2014 for multiple reasons. First, there have been groundbreaking clinical trials that have been published with new medications to not only treat the target disease [including] diabetes/obesity and high cholesterol], but also lower the risk of stroke and heart disease,” said chair of the guideline writing group, Cheryl D. Bushnell, MD, MHS, FAHA, and vice chair of the research, Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
It was published online on October 21 in Stroke.
Up to 80% of Strokes Preventable
Estimates show that every year in the United States, more than 500,000 individuals have a first stroke. However, the guideline authors noted that up to 80% of strokes may be preventable. As a result, they called for better primary stroke prevention that includes improved screening and lifestyle changes.
This includes adoption of the Mediterranean diet, which has been shown to significantly reduce stroke risk, especially when supplemented with consumption of nuts and olive oil.
The guideline recommendations also emphasize the need for physical activity, which is “essential” for cardiovascular health and stroke reduction. The authors underscored this point and provided a new recommendation to screen for sedentary behavior and advise patients to avoid inactivity and engage in regular moderate to vigorous physical activity.
Another new recommendation is based on “robust” data that glucagon-like peptide 1 receptor agonists (GLP-1s) significantly improve the management of type 2 diabetes, weight loss, and lower the risk for cardiovascular disease. As a result, guideline authors called for the use of GLP-1s in patients with diabetes and high cardiovascular risk or established cardiovascular disease.
“The glucagon-like peptide receptor agonists have been shown to not only drastically reduce blood sugars in patients with diabetes, but they also lead to significant weight loss in these patients, which has many downstream benefits. Together, this reduces the risk of stroke and other complications of diabetes,” said Bushnell.
She also noted that another drug class introduced since the 2014 guidelines were published, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have proven to be highly effective in lowering low-density lipoprotein cholesterol. These medications have also been shown to reduce the risk for stroke.
At Least Two Meds Needed to Reduce BP
Effective blood pressure (BP) management is crucial for stroke prevention. Randomized controlled trials show that a single antihypertensive medication helps only about 30% of participants reach their BP target.
Most patients only achieve the desired BP target with two to three medications. In line with these data, the committee recommends using at least two antihypertensives for primary stroke prevention in most patients who require BP-lowering medications for hypertension.
In patients with antiphospholipid syndrome or systemic lupus erythematosus and no history of stroke or unprovoked venous thromboembolism, the authors recommended antiplatelet therapy to prevent stroke. They added that patients with antiphospholipid syndrome who have had a prior unprovoked venous thrombosis will likely benefit from vitamin K antagonist therapy (target international normalized ratio, 2-3) over direct oral anticoagulants.
Emphasis on Women’s Health
Preventing pregnancy-related stroke is achieved primarily by managing hypertension, the guideline authors noted. They recommended treating verified systolic BP over 160 mm Hg or diastolic BP over 110 mm Hg during pregnancy and up to 6 weeks postpartum to lower the risk for fatal maternal intracerebral hemorrhage.
They noted that adverse pregnancy outcomes are also common and linked to chronic hypertension, which increases stroke risk later in life. Therefore, they recommended screening for these outcomes to assess and manage vascular risk factors. The guideline includes a screening tool to help with this in clinical practice.
Endometriosis, premature ovarian failure (before age 40 years), and early-onset menopause (before age 45 years) are all associated with increased stroke risk. As a result, the guideline authors said screening for all three of these conditions is a “reasonable step in the evaluation and management of vascular risk factors in these individuals to reduce stroke risk.”
Finally, the guideline authors addressed primary stroke prevention in transgender individuals, noting that transgender women undergoing estrogen therapy for gender affirmation are at increased risk. They emphasized that evaluating and modifying risk factors could be beneficial for reducing stroke risk in this patient population.
Challenges Lie Ahead
Now that the guideline has been published, the challenge lies in determining how best to implement “its screening recommendations in primary care and other practices when these clinicians are already pushed to see as many patients as possible,” Bushnell said.
Development of screening tools that can be easily incorporated into the clinic visit or the electronic health record, as well as additional personnel to provide counseling, are probably needed to disseminate them, she added.
Bushnell also emphasized that the guideline includes a strong focus on social determinants of health and related social needs.
“We worked hard to use inclusive language and to consider populations historically excluded from research. In acknowledging that social determinants of health including access to healthcare, access to education, economic stability, neighborhood and geographic location, and social and community context have a tremendous influence on stroke risk, we describe how these factors are closely tied to the prevalence and management of many medical risks like obesity, hypertension, and diabetes.
“Our recommendations offer practical steps for screening and addressing essential health-related social needs, including access to nutritious food, stable housing, and reliable transportation, within clinical practice. By considering these factors more comprehensively, we believe we can make meaningful strides toward reducing the disparities in stroke risk,” said Bushnell.
A version of this article appeared on Medscape.com.
AHA Scientific Statement Links Three Common Cardiovascular Diseases to Cognitive Decline, Dementia
The statement includes an extensive research review and offers compelling evidence of the inextricable link between heart health and brain health, which investigators said underscores the benefit of early intervention.
The cumulative evidence “confirms that the trajectories of cardiac health and brain health are inextricably intertwined through modifiable and nonmodifiable factors,” the authors wrote.
Investigators say the findings reinforce the message that addressing cardiovascular health early in life may deter the onset or progression of cognitive impairment later on.
And the earlier this is done, the better, said lead author Fernando D. Testai, MD, PhD, a professor of neurology and the vascular neurology section head, Department of Neurology and Rehabilitation, University of Illinois, Chicago.
The statement was published online in Stroke.
Bridging the Research Gap
It’s well known that there’s a bidirectional relationship between heart and brain function. For example, heart failure can lead to decreased blood flow that can damage the brain, and stroke in some areas of the brain can affect the heart.
However, that’s only part of the puzzle and doesn’t address all the gaps in the understanding of how cardiovascular disease contributes to cognition, said Testai.
“What we’re trying to do here is to go one step further and describe other connections between the heart and the brain,” he said.
Investigators carried out an extensive PubMed search for heart failure, atrial fibrillation, and coronary heart disease. Researchers detailed the frequency of each condition, mechanisms by which they might cause cognitive impairment, and prospects for prevention and treatment to maintain brain health.
A recurring theme in the paper is the role of inflammation. Evidence shows there are “remarkable similarities in the inflammatory response that takes place,” with both cardiac disease and cognitive decline, said Testai.
Another potential shared mechanism relates to biomarkers, particularly amyloid, which is strongly linked to Alzheimer’s disease.
“But some studies show amyloid can also be present in the heart, especially in patients who have decreased ejection fraction,” said Testai.
Robust Heart-Brain Connection
The statement’s authors collected a substantial amount of evidence showing vascular risk factors such as hypertension and diabetes “can change how the brain processes and clears up amyloid,” Testai added.
The paper also provides a compilation of evidence of shared genetic predispositions when it comes to heart and brain disorders.
“We noticed that some genetic signatures that have historically been associated with heart disease seem to also correlate with structural changes in the brain. That means that at the end of the day, some patients may be born with a genetic predisposition to developing both conditions,” said Testai.
This indicates that the link between the two organs “begins as early as conception” and underscores the importance of adopting healthy lifestyle habits as early as possible, he added.
“That means you can avoid bad habits that eventually lead to hypertension, diabetes, and cholesterol, that eventually will lead to cardiac disease, which eventually will lead to stroke, which eventually will lead to cognitive decline,” Testai noted.
However, cardiovascular health is more complicated than having good genes and adhering to a healthy lifestyle. It’s not clear, for example, why some people who should be predisposed to developing heart disease do not develop it, something Testai refers to as enhanced “resilience.”
For example, Hispanic or Latino patients, who have relatively poor cardiovascular risk factor profiles, seem to be less susceptible to developing cardiac disease.
More Research Needed
While genetics may partly explain the paradox, Testai believes other protective factors are at play, including strong social support networks.
Testai referred to the AHA’s “Life’s Essential 8” — the eight components of cardiovascular health. These include a healthy diet, participation in physical activity, nicotine avoidance, healthy sleep, healthy weight, and healthy levels of blood lipids, blood glucose, and blood pressure.
More evidence is needed to show that effective management of cardiac disease positively affects cognition. Currently, cognitive measures are rarely included in studies examining various heart disease treatments, said Testai.
“There should probably be an effort to include brain health outcomes in some of the cardiac literature to make sure we can also measure whether the intervention in the heart leads to an advantage for the brain,” he said.
More research is also needed to determine whether immunomodulation has a beneficial effect on the cognitive trajectory, the statement’s authors noted.
They point out that the interpretation and generalizability of the studies described in the statement are confounded by disparate methodologies, including small sample sizes, cross-sectional designs, and underrepresentation of Black and Hispanic individuals.
‘An Important Step’
Reached for a comment, Natalia S. Rost, MD, Chief of the Stroke Division at Massachusetts General Hospital and professor of neurology at Harvard Medical School, both in Boston, said this paper “is an important step” in terms of pulling together pertinent information on the topic of heart-brain health.
She praised the authors for gathering evidence on risk factors related to atrial fibrillation, heart failure, and coronary heart disease, which is “the part of the puzzle that is controllable.”
This helps reinforce the message that controlling vascular risk factors helps with brain health, said Rost.
But brain health is “much more complex than just vascular health,” she said. It includes other elements such as freedom from epilepsy, migraine, traumatic brain injury, and adult learning disabilities.
No relevant conflicts of interest were disclosed.
A version of this article first appeared on Medscape.com.
The statement includes an extensive research review and offers compelling evidence of the inextricable link between heart health and brain health, which investigators said underscores the benefit of early intervention.
The cumulative evidence “confirms that the trajectories of cardiac health and brain health are inextricably intertwined through modifiable and nonmodifiable factors,” the authors wrote.
Investigators say the findings reinforce the message that addressing cardiovascular health early in life may deter the onset or progression of cognitive impairment later on.
And the earlier this is done, the better, said lead author Fernando D. Testai, MD, PhD, a professor of neurology and the vascular neurology section head, Department of Neurology and Rehabilitation, University of Illinois, Chicago.
The statement was published online in Stroke.
Bridging the Research Gap
It’s well known that there’s a bidirectional relationship between heart and brain function. For example, heart failure can lead to decreased blood flow that can damage the brain, and stroke in some areas of the brain can affect the heart.
However, that’s only part of the puzzle and doesn’t address all the gaps in the understanding of how cardiovascular disease contributes to cognition, said Testai.
“What we’re trying to do here is to go one step further and describe other connections between the heart and the brain,” he said.
Investigators carried out an extensive PubMed search for heart failure, atrial fibrillation, and coronary heart disease. Researchers detailed the frequency of each condition, mechanisms by which they might cause cognitive impairment, and prospects for prevention and treatment to maintain brain health.
A recurring theme in the paper is the role of inflammation. Evidence shows there are “remarkable similarities in the inflammatory response that takes place,” with both cardiac disease and cognitive decline, said Testai.
Another potential shared mechanism relates to biomarkers, particularly amyloid, which is strongly linked to Alzheimer’s disease.
“But some studies show amyloid can also be present in the heart, especially in patients who have decreased ejection fraction,” said Testai.
Robust Heart-Brain Connection
The statement’s authors collected a substantial amount of evidence showing vascular risk factors such as hypertension and diabetes “can change how the brain processes and clears up amyloid,” Testai added.
The paper also provides a compilation of evidence of shared genetic predispositions when it comes to heart and brain disorders.
“We noticed that some genetic signatures that have historically been associated with heart disease seem to also correlate with structural changes in the brain. That means that at the end of the day, some patients may be born with a genetic predisposition to developing both conditions,” said Testai.
This indicates that the link between the two organs “begins as early as conception” and underscores the importance of adopting healthy lifestyle habits as early as possible, he added.
“That means you can avoid bad habits that eventually lead to hypertension, diabetes, and cholesterol, that eventually will lead to cardiac disease, which eventually will lead to stroke, which eventually will lead to cognitive decline,” Testai noted.
However, cardiovascular health is more complicated than having good genes and adhering to a healthy lifestyle. It’s not clear, for example, why some people who should be predisposed to developing heart disease do not develop it, something Testai refers to as enhanced “resilience.”
For example, Hispanic or Latino patients, who have relatively poor cardiovascular risk factor profiles, seem to be less susceptible to developing cardiac disease.
More Research Needed
While genetics may partly explain the paradox, Testai believes other protective factors are at play, including strong social support networks.
Testai referred to the AHA’s “Life’s Essential 8” — the eight components of cardiovascular health. These include a healthy diet, participation in physical activity, nicotine avoidance, healthy sleep, healthy weight, and healthy levels of blood lipids, blood glucose, and blood pressure.
More evidence is needed to show that effective management of cardiac disease positively affects cognition. Currently, cognitive measures are rarely included in studies examining various heart disease treatments, said Testai.
“There should probably be an effort to include brain health outcomes in some of the cardiac literature to make sure we can also measure whether the intervention in the heart leads to an advantage for the brain,” he said.
More research is also needed to determine whether immunomodulation has a beneficial effect on the cognitive trajectory, the statement’s authors noted.
They point out that the interpretation and generalizability of the studies described in the statement are confounded by disparate methodologies, including small sample sizes, cross-sectional designs, and underrepresentation of Black and Hispanic individuals.
‘An Important Step’
Reached for a comment, Natalia S. Rost, MD, Chief of the Stroke Division at Massachusetts General Hospital and professor of neurology at Harvard Medical School, both in Boston, said this paper “is an important step” in terms of pulling together pertinent information on the topic of heart-brain health.
She praised the authors for gathering evidence on risk factors related to atrial fibrillation, heart failure, and coronary heart disease, which is “the part of the puzzle that is controllable.”
This helps reinforce the message that controlling vascular risk factors helps with brain health, said Rost.
But brain health is “much more complex than just vascular health,” she said. It includes other elements such as freedom from epilepsy, migraine, traumatic brain injury, and adult learning disabilities.
No relevant conflicts of interest were disclosed.
A version of this article first appeared on Medscape.com.
The statement includes an extensive research review and offers compelling evidence of the inextricable link between heart health and brain health, which investigators said underscores the benefit of early intervention.
The cumulative evidence “confirms that the trajectories of cardiac health and brain health are inextricably intertwined through modifiable and nonmodifiable factors,” the authors wrote.
Investigators say the findings reinforce the message that addressing cardiovascular health early in life may deter the onset or progression of cognitive impairment later on.
And the earlier this is done, the better, said lead author Fernando D. Testai, MD, PhD, a professor of neurology and the vascular neurology section head, Department of Neurology and Rehabilitation, University of Illinois, Chicago.
The statement was published online in Stroke.
Bridging the Research Gap
It’s well known that there’s a bidirectional relationship between heart and brain function. For example, heart failure can lead to decreased blood flow that can damage the brain, and stroke in some areas of the brain can affect the heart.
However, that’s only part of the puzzle and doesn’t address all the gaps in the understanding of how cardiovascular disease contributes to cognition, said Testai.
“What we’re trying to do here is to go one step further and describe other connections between the heart and the brain,” he said.
Investigators carried out an extensive PubMed search for heart failure, atrial fibrillation, and coronary heart disease. Researchers detailed the frequency of each condition, mechanisms by which they might cause cognitive impairment, and prospects for prevention and treatment to maintain brain health.
A recurring theme in the paper is the role of inflammation. Evidence shows there are “remarkable similarities in the inflammatory response that takes place,” with both cardiac disease and cognitive decline, said Testai.
Another potential shared mechanism relates to biomarkers, particularly amyloid, which is strongly linked to Alzheimer’s disease.
“But some studies show amyloid can also be present in the heart, especially in patients who have decreased ejection fraction,” said Testai.
Robust Heart-Brain Connection
The statement’s authors collected a substantial amount of evidence showing vascular risk factors such as hypertension and diabetes “can change how the brain processes and clears up amyloid,” Testai added.
The paper also provides a compilation of evidence of shared genetic predispositions when it comes to heart and brain disorders.
“We noticed that some genetic signatures that have historically been associated with heart disease seem to also correlate with structural changes in the brain. That means that at the end of the day, some patients may be born with a genetic predisposition to developing both conditions,” said Testai.
This indicates that the link between the two organs “begins as early as conception” and underscores the importance of adopting healthy lifestyle habits as early as possible, he added.
“That means you can avoid bad habits that eventually lead to hypertension, diabetes, and cholesterol, that eventually will lead to cardiac disease, which eventually will lead to stroke, which eventually will lead to cognitive decline,” Testai noted.
However, cardiovascular health is more complicated than having good genes and adhering to a healthy lifestyle. It’s not clear, for example, why some people who should be predisposed to developing heart disease do not develop it, something Testai refers to as enhanced “resilience.”
For example, Hispanic or Latino patients, who have relatively poor cardiovascular risk factor profiles, seem to be less susceptible to developing cardiac disease.
More Research Needed
While genetics may partly explain the paradox, Testai believes other protective factors are at play, including strong social support networks.
Testai referred to the AHA’s “Life’s Essential 8” — the eight components of cardiovascular health. These include a healthy diet, participation in physical activity, nicotine avoidance, healthy sleep, healthy weight, and healthy levels of blood lipids, blood glucose, and blood pressure.
More evidence is needed to show that effective management of cardiac disease positively affects cognition. Currently, cognitive measures are rarely included in studies examining various heart disease treatments, said Testai.
“There should probably be an effort to include brain health outcomes in some of the cardiac literature to make sure we can also measure whether the intervention in the heart leads to an advantage for the brain,” he said.
More research is also needed to determine whether immunomodulation has a beneficial effect on the cognitive trajectory, the statement’s authors noted.
They point out that the interpretation and generalizability of the studies described in the statement are confounded by disparate methodologies, including small sample sizes, cross-sectional designs, and underrepresentation of Black and Hispanic individuals.
‘An Important Step’
Reached for a comment, Natalia S. Rost, MD, Chief of the Stroke Division at Massachusetts General Hospital and professor of neurology at Harvard Medical School, both in Boston, said this paper “is an important step” in terms of pulling together pertinent information on the topic of heart-brain health.
She praised the authors for gathering evidence on risk factors related to atrial fibrillation, heart failure, and coronary heart disease, which is “the part of the puzzle that is controllable.”
This helps reinforce the message that controlling vascular risk factors helps with brain health, said Rost.
But brain health is “much more complex than just vascular health,” she said. It includes other elements such as freedom from epilepsy, migraine, traumatic brain injury, and adult learning disabilities.
No relevant conflicts of interest were disclosed.
A version of this article first appeared on Medscape.com.
FROM STROKE
Crisugabalin Alleviates Postherpetic Neuralgia Symptoms in Phase 3 Study
TOPLINE:
METHODOLOGY:
- Researchers conducted a phase 3 multicenter, double-blind study involving 366 patients in China (median age, 63 years; 52.7% men) with PHN with an average daily pain score (ADPS) of 4 or greater on the numeric pain rating scale who were randomly assigned to receive either crisugabalin 40 mg/d (n = 121), 80 mg/d (n = 121), or placebo (n = 124) for 12 weeks.
- Patients who did not experience any serious toxic effects in these 12 weeks entered a 14-week open-label extension phase and received crisugabalin 40 mg twice daily.
- The primary efficacy endpoint was the change in ADPS from baseline at week 12.
- Secondary efficacy endpoints included the proportion of patients achieving at least 30% and 50% reduction in ADPS at week 12; changes in the Short-Form McGill Pain Questionnaire (SF-MPQ), Visual Analog Scale, and Average Daily Sleep Interference Scale scores at week 12; and change in the SF-MPQ Present Pain Intensity scores at weeks 12 and 26.
TAKEAWAY:
- At week 12, among those on crisugabalin 40 mg/d and 80 mg/d, there were significant reductions in ADPS compared with placebo (least squares mean [LSM] change from baseline, −2.2 and −2.6 vs −1.1, respectively; P < .001).
- A greater proportion of patients on crisugabalin 40 mg/d (61.2%) and 80 mg/d (54.5%) achieved 30% or greater reduction in ADPS (P < .001) than patients who received placebo (35.5%). Similarly, a 50% or greater reduction in ADPS was achieved by 37.2% of patients on crisugabalin 40 mg/d (P = .002) and 38% on 80 mg/d (P < .001), compared with 20.2% for placebo.
- Crisugabalin 40 mg/d and crisugabalin 80 mg/d were associated with greater reductions in the pain intensity at week 12 than placebo (LSM, −1.0 and −1.2 vs −0.5, respectively; P < .001). Similar patterns were noted for other pain-related measures at weeks 12 and 26.
- Serious treatment-emergent adverse events occurred in four patients in each group; only 2.4% of those on 40 mg/d and 1.6% on 80 mg/d discontinued treatment because of side effects.
IN PRACTICE:
“Crisugabalin 40 mg/d or crisugabalin 80 mg/d was well-tolerated and significantly improved ADPS compared to placebo,” the authors wrote, adding that “crisugabalin can be flexibly selected depending on individual patient response and tolerability at 40 mg/d or 80 mg/d.”
SOURCE:
The study was led by Daying Zhang, PhD, of the Department of Pain Medicine at The First Affiliated Hospital of Nanchang University, Nanchang, China. It was published online in JAMA Dermatology.
LIMITATIONS:
The findings may not be generalizable to the global population as the study population was limited to Chinese patients. The study only provided short-term efficacy and safety data on crisugabalin, lacked an active comparator, and did not reflect the standard of care observed in the United States or Europe, where oral tricyclic antidepressants, pregabalin, and the lidocaine patch are recommended as first-line therapies.
DISCLOSURES:
The study was sponsored and funded by Haisco Pharmaceutical. Dr. Zhang and another author reported receiving support from Haisco. Two authors are company employees.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Researchers conducted a phase 3 multicenter, double-blind study involving 366 patients in China (median age, 63 years; 52.7% men) with PHN with an average daily pain score (ADPS) of 4 or greater on the numeric pain rating scale who were randomly assigned to receive either crisugabalin 40 mg/d (n = 121), 80 mg/d (n = 121), or placebo (n = 124) for 12 weeks.
- Patients who did not experience any serious toxic effects in these 12 weeks entered a 14-week open-label extension phase and received crisugabalin 40 mg twice daily.
- The primary efficacy endpoint was the change in ADPS from baseline at week 12.
- Secondary efficacy endpoints included the proportion of patients achieving at least 30% and 50% reduction in ADPS at week 12; changes in the Short-Form McGill Pain Questionnaire (SF-MPQ), Visual Analog Scale, and Average Daily Sleep Interference Scale scores at week 12; and change in the SF-MPQ Present Pain Intensity scores at weeks 12 and 26.
TAKEAWAY:
- At week 12, among those on crisugabalin 40 mg/d and 80 mg/d, there were significant reductions in ADPS compared with placebo (least squares mean [LSM] change from baseline, −2.2 and −2.6 vs −1.1, respectively; P < .001).
- A greater proportion of patients on crisugabalin 40 mg/d (61.2%) and 80 mg/d (54.5%) achieved 30% or greater reduction in ADPS (P < .001) than patients who received placebo (35.5%). Similarly, a 50% or greater reduction in ADPS was achieved by 37.2% of patients on crisugabalin 40 mg/d (P = .002) and 38% on 80 mg/d (P < .001), compared with 20.2% for placebo.
- Crisugabalin 40 mg/d and crisugabalin 80 mg/d were associated with greater reductions in the pain intensity at week 12 than placebo (LSM, −1.0 and −1.2 vs −0.5, respectively; P < .001). Similar patterns were noted for other pain-related measures at weeks 12 and 26.
- Serious treatment-emergent adverse events occurred in four patients in each group; only 2.4% of those on 40 mg/d and 1.6% on 80 mg/d discontinued treatment because of side effects.
IN PRACTICE:
“Crisugabalin 40 mg/d or crisugabalin 80 mg/d was well-tolerated and significantly improved ADPS compared to placebo,” the authors wrote, adding that “crisugabalin can be flexibly selected depending on individual patient response and tolerability at 40 mg/d or 80 mg/d.”
SOURCE:
The study was led by Daying Zhang, PhD, of the Department of Pain Medicine at The First Affiliated Hospital of Nanchang University, Nanchang, China. It was published online in JAMA Dermatology.
LIMITATIONS:
The findings may not be generalizable to the global population as the study population was limited to Chinese patients. The study only provided short-term efficacy and safety data on crisugabalin, lacked an active comparator, and did not reflect the standard of care observed in the United States or Europe, where oral tricyclic antidepressants, pregabalin, and the lidocaine patch are recommended as first-line therapies.
DISCLOSURES:
The study was sponsored and funded by Haisco Pharmaceutical. Dr. Zhang and another author reported receiving support from Haisco. Two authors are company employees.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Researchers conducted a phase 3 multicenter, double-blind study involving 366 patients in China (median age, 63 years; 52.7% men) with PHN with an average daily pain score (ADPS) of 4 or greater on the numeric pain rating scale who were randomly assigned to receive either crisugabalin 40 mg/d (n = 121), 80 mg/d (n = 121), or placebo (n = 124) for 12 weeks.
- Patients who did not experience any serious toxic effects in these 12 weeks entered a 14-week open-label extension phase and received crisugabalin 40 mg twice daily.
- The primary efficacy endpoint was the change in ADPS from baseline at week 12.
- Secondary efficacy endpoints included the proportion of patients achieving at least 30% and 50% reduction in ADPS at week 12; changes in the Short-Form McGill Pain Questionnaire (SF-MPQ), Visual Analog Scale, and Average Daily Sleep Interference Scale scores at week 12; and change in the SF-MPQ Present Pain Intensity scores at weeks 12 and 26.
TAKEAWAY:
- At week 12, among those on crisugabalin 40 mg/d and 80 mg/d, there were significant reductions in ADPS compared with placebo (least squares mean [LSM] change from baseline, −2.2 and −2.6 vs −1.1, respectively; P < .001).
- A greater proportion of patients on crisugabalin 40 mg/d (61.2%) and 80 mg/d (54.5%) achieved 30% or greater reduction in ADPS (P < .001) than patients who received placebo (35.5%). Similarly, a 50% or greater reduction in ADPS was achieved by 37.2% of patients on crisugabalin 40 mg/d (P = .002) and 38% on 80 mg/d (P < .001), compared with 20.2% for placebo.
- Crisugabalin 40 mg/d and crisugabalin 80 mg/d were associated with greater reductions in the pain intensity at week 12 than placebo (LSM, −1.0 and −1.2 vs −0.5, respectively; P < .001). Similar patterns were noted for other pain-related measures at weeks 12 and 26.
- Serious treatment-emergent adverse events occurred in four patients in each group; only 2.4% of those on 40 mg/d and 1.6% on 80 mg/d discontinued treatment because of side effects.
IN PRACTICE:
“Crisugabalin 40 mg/d or crisugabalin 80 mg/d was well-tolerated and significantly improved ADPS compared to placebo,” the authors wrote, adding that “crisugabalin can be flexibly selected depending on individual patient response and tolerability at 40 mg/d or 80 mg/d.”
SOURCE:
The study was led by Daying Zhang, PhD, of the Department of Pain Medicine at The First Affiliated Hospital of Nanchang University, Nanchang, China. It was published online in JAMA Dermatology.
LIMITATIONS:
The findings may not be generalizable to the global population as the study population was limited to Chinese patients. The study only provided short-term efficacy and safety data on crisugabalin, lacked an active comparator, and did not reflect the standard of care observed in the United States or Europe, where oral tricyclic antidepressants, pregabalin, and the lidocaine patch are recommended as first-line therapies.
DISCLOSURES:
The study was sponsored and funded by Haisco Pharmaceutical. Dr. Zhang and another author reported receiving support from Haisco. Two authors are company employees.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Erenumab Reduces Nonopioid Medication Overuse Headache in Chronic Migraine
In a recent study of 6 monthly injections of 140 mg erenumab (Aimovig, Amgen), most patients with chronic migraine and nonopioid medication overuse headache (MOH) achieved remission. Published online in JAMA Neurology, the study is the first prospective, double-blind, randomized, placebo-controlled attempt to investigate patients with chronic migraine and MOH related to nonopioid medications, according to lead author Stewart J. Tepper, MD, and his coauthors.
Prior Studies Did Not Focus on MOH
Several prior phase 2 and 3 trials of calcitonin gene-related peptide (CGRP) ligand or receptor inhibitors that have been FDA-approved for migraine prevention have been performed. These drugs include erenumab, fremanezumab (Ajovy, Teva), galcanezumab (Emgality, Lilly), and eptinezumab (Vyepti, Lundbeck), for patients with and without medication overuse, said Alan M. Rapoport, MD, who was not involved with the new study. Dr. Rapoport is a clinical professor of neurology at the David Geffen School of Medicine of the University of California, in Los Angeles; past president of the International Headache Society; and founder and director emeritus of The New England Center for Headache in Stamford, Connecticut.
“But we could not call them patients with MOH because they weren’t studied prospectively, so that they had medication overuse according to International Classification of Headache Disorders (ICHD-3) criteria,” said Dr. Rapoport.
Phase 4, Randomized, Placebo-Controlled Trial
In the present clinical trial, investigators enrolled 584 patients with nonopioid MOH and history of failing at least one preventive treatment. After a 4-week baseline phase, researchers randomized patients 1:1:1 to 6 months’ treatment with erenumab 70 mg, erenumab 140 mg, or placebo.
Investigators defined remission as either of the following through months 4-6:
- < 10 mean monthly acute headache medication days per month (AHMD)
- < 14 mean monthly headache days (MHD)
In the primary analysis, 69.1% of patients in the 140 mg cohort achieved remission (P < .001) versus placebo. Remission rates in the 70 mg and the placebo cohorts were 60.3% (P < .13) and 52.6%, respectively. AHMD for the 140-mg, 70-mg, and placebo groups fell by 9.4, 7.8, and 6.6 days per month, respectively. Migraine Physical Function Impact Diary (non-EU sites) and Headache Impact Test-6 (EU sites) scores also showed greater improvement for patients treated with erenumab.
No new safety signals emerged, although erenumab-treated participants experienced 2-2.5 times as much COVID-19 disease.
Regarding the primary endpoint, said Dr. Rapoport, the 70-mg dose might also have yielded statistically significant improvement over placebo with a larger sample size. “I have seen that the higher dose of erenumab can be superior for efficacy than the lower in some of the double-blind trials,” he said. The 52.6% placebo response rate was rather high, he added, but not necessarily higher than in other migraine prevention trials.
“Placebo is a type of treatment,” Dr. Rapoport said. “It’s not as strong as the actual medication, which is specific for prevention, but it does work on the brain to some extent.”
He was more concerned, however, that authors did not counsel study patients about reducing or discontinuing their overused medications in a unified manner. Rather, it was left to individual investigators’ discretion, in different countries, as to whether to educate patients about the harms of medication overuse. “The fascinating aspect of this paper was that no patient was asked to detoxify from the overused medication,” said Dr. Rapoport, “and yet so many patients no longer had MOH at 6 months.”
Detox Versus No Detox
In a pioneering study of migraine medication overuse headache (then called rebound headache) published by Lee Kudrow, MD, in Advances in Neurology in 1982, patients who discontinued the overused medication fared much better than those who did not. Adding amitriptyline for migraine prevention further improved results, mostly in those who discontinued their overused medication.
Anticipating possible concerns, the authors wrote that their approach “may also be seen as a strength, as it represents a scenario closer to real life and avoids undue interference with the physician-patient relationship.” Indeed, said Dr. Rapoport, study results are perhaps more impressive because they were achieved through treatment with erenumab alone, without detoxification.
Managing Chronic Migraine and MOH
Until erenumab’s 2018 approval, migraine prevention options were limited to tricyclic antidepressants, beta blockers, and antiseizure medicines – though these medicines never seemed to work very well without detoxification, said Dr. Rapoport. Neurologists still use these categories for migraine prevention, he added, “because insurance companies insist that before we give the more expensive, newer medications like those that block CGRP, patients must fail 2 of those 3 categories of older medications which are not approved for chronic migraine.” Only onabotulinumtoxinA (Botox) is FDA-approved for chronic migraine. “There has been no head-to-head comparison of it and any of the monoclonal antibodies against CGRP,” he said.
In a March 2024 publication in Headache, the American Headache Society stated that requiring patients to fail older drugs is inappropriate, and that CGRP inhibitors, though costly, should be first-line for headache prevention. The key advantage of any drug that blocks CGRP in treating MOH is that unlike older drugs, CGRP inhibitors appear to work well even without detoxification, said Dr. Rapoport.
Additional study limitations included the possibility that the 24-week treatment period might not have allowed complete evaluation of long-term efficacy, the authors wrote. “These are usually pretty sick patients,” said Dr. Rapoport, who acknowledged the difficulty of keeping placebo patients off preventive medication altogether for 6 months. The study was extended to 12 months, and the results of an opiate overusers cohort also will be published.
Authors noted that according to a study published in Headache in 2022, most Americans with chronic migraine commonly go without preventive medications. Moreover, such medications do not always work. Accordingly, Dr. Rapoport said, the study duration was reasonable provided patients understood that they had a 33% chance of receiving no effective preventive medication over 6 months.
Extending the study’s month-long baseline period to 3 months before starting erenumab might have been helpful, he added, as that is the timeframe required to confirm MOH diagnosis according to ICHD-3. “However,” said Dr. Rapoport, “3 months with only usual medications, and then 1/3 of patients going 6-12 months with only placebo, would be tough for some patients.”
Dr. Rapoport reports no relevant financial conflicts.
In a recent study of 6 monthly injections of 140 mg erenumab (Aimovig, Amgen), most patients with chronic migraine and nonopioid medication overuse headache (MOH) achieved remission. Published online in JAMA Neurology, the study is the first prospective, double-blind, randomized, placebo-controlled attempt to investigate patients with chronic migraine and MOH related to nonopioid medications, according to lead author Stewart J. Tepper, MD, and his coauthors.
Prior Studies Did Not Focus on MOH
Several prior phase 2 and 3 trials of calcitonin gene-related peptide (CGRP) ligand or receptor inhibitors that have been FDA-approved for migraine prevention have been performed. These drugs include erenumab, fremanezumab (Ajovy, Teva), galcanezumab (Emgality, Lilly), and eptinezumab (Vyepti, Lundbeck), for patients with and without medication overuse, said Alan M. Rapoport, MD, who was not involved with the new study. Dr. Rapoport is a clinical professor of neurology at the David Geffen School of Medicine of the University of California, in Los Angeles; past president of the International Headache Society; and founder and director emeritus of The New England Center for Headache in Stamford, Connecticut.
“But we could not call them patients with MOH because they weren’t studied prospectively, so that they had medication overuse according to International Classification of Headache Disorders (ICHD-3) criteria,” said Dr. Rapoport.
Phase 4, Randomized, Placebo-Controlled Trial
In the present clinical trial, investigators enrolled 584 patients with nonopioid MOH and history of failing at least one preventive treatment. After a 4-week baseline phase, researchers randomized patients 1:1:1 to 6 months’ treatment with erenumab 70 mg, erenumab 140 mg, or placebo.
Investigators defined remission as either of the following through months 4-6:
- < 10 mean monthly acute headache medication days per month (AHMD)
- < 14 mean monthly headache days (MHD)
In the primary analysis, 69.1% of patients in the 140 mg cohort achieved remission (P < .001) versus placebo. Remission rates in the 70 mg and the placebo cohorts were 60.3% (P < .13) and 52.6%, respectively. AHMD for the 140-mg, 70-mg, and placebo groups fell by 9.4, 7.8, and 6.6 days per month, respectively. Migraine Physical Function Impact Diary (non-EU sites) and Headache Impact Test-6 (EU sites) scores also showed greater improvement for patients treated with erenumab.
No new safety signals emerged, although erenumab-treated participants experienced 2-2.5 times as much COVID-19 disease.
Regarding the primary endpoint, said Dr. Rapoport, the 70-mg dose might also have yielded statistically significant improvement over placebo with a larger sample size. “I have seen that the higher dose of erenumab can be superior for efficacy than the lower in some of the double-blind trials,” he said. The 52.6% placebo response rate was rather high, he added, but not necessarily higher than in other migraine prevention trials.
“Placebo is a type of treatment,” Dr. Rapoport said. “It’s not as strong as the actual medication, which is specific for prevention, but it does work on the brain to some extent.”
He was more concerned, however, that authors did not counsel study patients about reducing or discontinuing their overused medications in a unified manner. Rather, it was left to individual investigators’ discretion, in different countries, as to whether to educate patients about the harms of medication overuse. “The fascinating aspect of this paper was that no patient was asked to detoxify from the overused medication,” said Dr. Rapoport, “and yet so many patients no longer had MOH at 6 months.”
Detox Versus No Detox
In a pioneering study of migraine medication overuse headache (then called rebound headache) published by Lee Kudrow, MD, in Advances in Neurology in 1982, patients who discontinued the overused medication fared much better than those who did not. Adding amitriptyline for migraine prevention further improved results, mostly in those who discontinued their overused medication.
Anticipating possible concerns, the authors wrote that their approach “may also be seen as a strength, as it represents a scenario closer to real life and avoids undue interference with the physician-patient relationship.” Indeed, said Dr. Rapoport, study results are perhaps more impressive because they were achieved through treatment with erenumab alone, without detoxification.
Managing Chronic Migraine and MOH
Until erenumab’s 2018 approval, migraine prevention options were limited to tricyclic antidepressants, beta blockers, and antiseizure medicines – though these medicines never seemed to work very well without detoxification, said Dr. Rapoport. Neurologists still use these categories for migraine prevention, he added, “because insurance companies insist that before we give the more expensive, newer medications like those that block CGRP, patients must fail 2 of those 3 categories of older medications which are not approved for chronic migraine.” Only onabotulinumtoxinA (Botox) is FDA-approved for chronic migraine. “There has been no head-to-head comparison of it and any of the monoclonal antibodies against CGRP,” he said.
In a March 2024 publication in Headache, the American Headache Society stated that requiring patients to fail older drugs is inappropriate, and that CGRP inhibitors, though costly, should be first-line for headache prevention. The key advantage of any drug that blocks CGRP in treating MOH is that unlike older drugs, CGRP inhibitors appear to work well even without detoxification, said Dr. Rapoport.
Additional study limitations included the possibility that the 24-week treatment period might not have allowed complete evaluation of long-term efficacy, the authors wrote. “These are usually pretty sick patients,” said Dr. Rapoport, who acknowledged the difficulty of keeping placebo patients off preventive medication altogether for 6 months. The study was extended to 12 months, and the results of an opiate overusers cohort also will be published.
Authors noted that according to a study published in Headache in 2022, most Americans with chronic migraine commonly go without preventive medications. Moreover, such medications do not always work. Accordingly, Dr. Rapoport said, the study duration was reasonable provided patients understood that they had a 33% chance of receiving no effective preventive medication over 6 months.
Extending the study’s month-long baseline period to 3 months before starting erenumab might have been helpful, he added, as that is the timeframe required to confirm MOH diagnosis according to ICHD-3. “However,” said Dr. Rapoport, “3 months with only usual medications, and then 1/3 of patients going 6-12 months with only placebo, would be tough for some patients.”
Dr. Rapoport reports no relevant financial conflicts.
In a recent study of 6 monthly injections of 140 mg erenumab (Aimovig, Amgen), most patients with chronic migraine and nonopioid medication overuse headache (MOH) achieved remission. Published online in JAMA Neurology, the study is the first prospective, double-blind, randomized, placebo-controlled attempt to investigate patients with chronic migraine and MOH related to nonopioid medications, according to lead author Stewart J. Tepper, MD, and his coauthors.
Prior Studies Did Not Focus on MOH
Several prior phase 2 and 3 trials of calcitonin gene-related peptide (CGRP) ligand or receptor inhibitors that have been FDA-approved for migraine prevention have been performed. These drugs include erenumab, fremanezumab (Ajovy, Teva), galcanezumab (Emgality, Lilly), and eptinezumab (Vyepti, Lundbeck), for patients with and without medication overuse, said Alan M. Rapoport, MD, who was not involved with the new study. Dr. Rapoport is a clinical professor of neurology at the David Geffen School of Medicine of the University of California, in Los Angeles; past president of the International Headache Society; and founder and director emeritus of The New England Center for Headache in Stamford, Connecticut.
“But we could not call them patients with MOH because they weren’t studied prospectively, so that they had medication overuse according to International Classification of Headache Disorders (ICHD-3) criteria,” said Dr. Rapoport.
Phase 4, Randomized, Placebo-Controlled Trial
In the present clinical trial, investigators enrolled 584 patients with nonopioid MOH and history of failing at least one preventive treatment. After a 4-week baseline phase, researchers randomized patients 1:1:1 to 6 months’ treatment with erenumab 70 mg, erenumab 140 mg, or placebo.
Investigators defined remission as either of the following through months 4-6:
- < 10 mean monthly acute headache medication days per month (AHMD)
- < 14 mean monthly headache days (MHD)
In the primary analysis, 69.1% of patients in the 140 mg cohort achieved remission (P < .001) versus placebo. Remission rates in the 70 mg and the placebo cohorts were 60.3% (P < .13) and 52.6%, respectively. AHMD for the 140-mg, 70-mg, and placebo groups fell by 9.4, 7.8, and 6.6 days per month, respectively. Migraine Physical Function Impact Diary (non-EU sites) and Headache Impact Test-6 (EU sites) scores also showed greater improvement for patients treated with erenumab.
No new safety signals emerged, although erenumab-treated participants experienced 2-2.5 times as much COVID-19 disease.
Regarding the primary endpoint, said Dr. Rapoport, the 70-mg dose might also have yielded statistically significant improvement over placebo with a larger sample size. “I have seen that the higher dose of erenumab can be superior for efficacy than the lower in some of the double-blind trials,” he said. The 52.6% placebo response rate was rather high, he added, but not necessarily higher than in other migraine prevention trials.
“Placebo is a type of treatment,” Dr. Rapoport said. “It’s not as strong as the actual medication, which is specific for prevention, but it does work on the brain to some extent.”
He was more concerned, however, that authors did not counsel study patients about reducing or discontinuing their overused medications in a unified manner. Rather, it was left to individual investigators’ discretion, in different countries, as to whether to educate patients about the harms of medication overuse. “The fascinating aspect of this paper was that no patient was asked to detoxify from the overused medication,” said Dr. Rapoport, “and yet so many patients no longer had MOH at 6 months.”
Detox Versus No Detox
In a pioneering study of migraine medication overuse headache (then called rebound headache) published by Lee Kudrow, MD, in Advances in Neurology in 1982, patients who discontinued the overused medication fared much better than those who did not. Adding amitriptyline for migraine prevention further improved results, mostly in those who discontinued their overused medication.
Anticipating possible concerns, the authors wrote that their approach “may also be seen as a strength, as it represents a scenario closer to real life and avoids undue interference with the physician-patient relationship.” Indeed, said Dr. Rapoport, study results are perhaps more impressive because they were achieved through treatment with erenumab alone, without detoxification.
Managing Chronic Migraine and MOH
Until erenumab’s 2018 approval, migraine prevention options were limited to tricyclic antidepressants, beta blockers, and antiseizure medicines – though these medicines never seemed to work very well without detoxification, said Dr. Rapoport. Neurologists still use these categories for migraine prevention, he added, “because insurance companies insist that before we give the more expensive, newer medications like those that block CGRP, patients must fail 2 of those 3 categories of older medications which are not approved for chronic migraine.” Only onabotulinumtoxinA (Botox) is FDA-approved for chronic migraine. “There has been no head-to-head comparison of it and any of the monoclonal antibodies against CGRP,” he said.
In a March 2024 publication in Headache, the American Headache Society stated that requiring patients to fail older drugs is inappropriate, and that CGRP inhibitors, though costly, should be first-line for headache prevention. The key advantage of any drug that blocks CGRP in treating MOH is that unlike older drugs, CGRP inhibitors appear to work well even without detoxification, said Dr. Rapoport.
Additional study limitations included the possibility that the 24-week treatment period might not have allowed complete evaluation of long-term efficacy, the authors wrote. “These are usually pretty sick patients,” said Dr. Rapoport, who acknowledged the difficulty of keeping placebo patients off preventive medication altogether for 6 months. The study was extended to 12 months, and the results of an opiate overusers cohort also will be published.
Authors noted that according to a study published in Headache in 2022, most Americans with chronic migraine commonly go without preventive medications. Moreover, such medications do not always work. Accordingly, Dr. Rapoport said, the study duration was reasonable provided patients understood that they had a 33% chance of receiving no effective preventive medication over 6 months.
Extending the study’s month-long baseline period to 3 months before starting erenumab might have been helpful, he added, as that is the timeframe required to confirm MOH diagnosis according to ICHD-3. “However,” said Dr. Rapoport, “3 months with only usual medications, and then 1/3 of patients going 6-12 months with only placebo, would be tough for some patients.”
Dr. Rapoport reports no relevant financial conflicts.
FROM JAMA NEUROLOGY
