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Dance training ‘drastically’ reduces Parkinson’s progression, eases symptoms
Over 3 years, weekly participation in dance training classes “drastically” reduced the expected decline in motor function and significantly improved speech, tremors, balance, and stiffness, the researchers reported.
Dance training also appeared to have benefits regarding cognition, hallucinations, depression, and anxiety.
“These findings strongly suggest the benefits of dance for people with PD as a supplement to a normal treatment regimen,” the investigators noted.
Although the mechanism of benefit is unclear, dance training may help “train neural network nodes that helps either strengthen networks damaged or builds neural road maps that pass the damage,” study investigator Joseph DeSouza, PhD, principal investigator and associate professor, department of psychology, York University, Toronto, said in an interview.
The study was published online July 7, 2021, in Brain Sciences.
Multiple benefits
PD is a neurodegenerative disease associated with progression of motor dysfunction within the first 5 years of diagnosis. The annual rate of motor decline, as determined with the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), is between 5.2 and 8.9 points.
Prior studies that assessed various styles of dance by patients with PD showed beneficial effects regarding gait speed, balance, locomotion, and aspects of quality of life.
To investigate further, DeSouza and coauthor Karolina Bearss, a PhD candidate at York University, followed 16 patients with mild to moderate PD who participated in a weekly dance class at Canada’s National Ballet School and Trinity St. Paul’s church.
Dance for Parkinson’s Disease, which is an established dance curriculum, involves aerobic and anaerobic movements. The protocol begins with a seated warm-up, followed by barre work, and ends with moving across the floor. All participants learn choreography for an upcoming performance.
In the study, 16 patients with PD who did not participant in the dance classes served as control patients.
Over 3 years, the daily rate of motor decline, as indicated by scores on part III of the MDS-UPDRS, was zero among the dancers (slope = 0.000146), indicating no motor impairment, whereas among the nondancers, the motor decline during follow-up was as expected (P < .01), the researchers reported.
In modeling the data, the researchers determined that after completing 1,000 days of dance training, dancers will have a motor score of 19.07, compared with a score of 28.27 for nondancers.
“Our data further showed that training in dance will slow the rate of PD motor impairment progression, as measured by the UPDRS III, by close to 3 points annually in comparison to our PD subjects who did not train,” the researchers reported.
Dance training also had a beneficial effect on motor or nonmotor aspects of daily living and on motor complications, for which there was no significant decline among the PD dancers.
“For those with Parkinson’s disease, even when it’s mild, motor impairment can impact their daily functioning – how they feel about themselves. Many of these motor symptoms lead to isolation because once they get extreme, these people don’t want to go out,” Dr. DeSouza said in a news release.
“These motor symptoms lead to further psychological issues, depression, social isolation and eventually the symptoms do get worse over time. Our study shows that training with dance and music can slow this down and improve their daily living and daily function,” he added.
‘Great potential’
Reached for comment, Demian Kogutek, PhD, director of music therapy, University of Evansville (Indiana), said that these preliminary findings from a longitudinal study are “promising.”
“I believe that dance therapy has a great potential for PD. The longitudinal aspect of this study undoubtedly adds to the current literature. Although it is a standardized assessment, it is somewhat subjective,” Dr. Kogutek said in an interview.
Going forward, Dr. Kogutek said he’d like to see other objective outcomes measured, such as objective assessments of balance, gait, hand strength, and dexterity.
Also weighing in on the results, Karen Lee, PhD, president and CEO of Parkinson Canada, said her organization is “encouraged by these preliminary findings as exercise and healthy activities are important for people with Parkinson’s. This study is part of a growing body of research that explores the link between the impact of activities and both motor and nonmotor symptoms of Parkinson’s.
“This research adds to growing evidence about the importance of exercise as part of the management of Parkinson’s, and we encourage people living with Parkinson’s to incorporate exercise as part of their approach to managing their health,” Dr. Lee said in an interview.
Funding for the project is provided in part by a National Science and Engineering Research Council Discovery Grant and by donations from the Irpinia Club of Toronto and others. Dr. Dr. DeSouza, Ms. Bearss, Dr. Kogutek, and Dr. Lee disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Over 3 years, weekly participation in dance training classes “drastically” reduced the expected decline in motor function and significantly improved speech, tremors, balance, and stiffness, the researchers reported.
Dance training also appeared to have benefits regarding cognition, hallucinations, depression, and anxiety.
“These findings strongly suggest the benefits of dance for people with PD as a supplement to a normal treatment regimen,” the investigators noted.
Although the mechanism of benefit is unclear, dance training may help “train neural network nodes that helps either strengthen networks damaged or builds neural road maps that pass the damage,” study investigator Joseph DeSouza, PhD, principal investigator and associate professor, department of psychology, York University, Toronto, said in an interview.
The study was published online July 7, 2021, in Brain Sciences.
Multiple benefits
PD is a neurodegenerative disease associated with progression of motor dysfunction within the first 5 years of diagnosis. The annual rate of motor decline, as determined with the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), is between 5.2 and 8.9 points.
Prior studies that assessed various styles of dance by patients with PD showed beneficial effects regarding gait speed, balance, locomotion, and aspects of quality of life.
To investigate further, DeSouza and coauthor Karolina Bearss, a PhD candidate at York University, followed 16 patients with mild to moderate PD who participated in a weekly dance class at Canada’s National Ballet School and Trinity St. Paul’s church.
Dance for Parkinson’s Disease, which is an established dance curriculum, involves aerobic and anaerobic movements. The protocol begins with a seated warm-up, followed by barre work, and ends with moving across the floor. All participants learn choreography for an upcoming performance.
In the study, 16 patients with PD who did not participant in the dance classes served as control patients.
Over 3 years, the daily rate of motor decline, as indicated by scores on part III of the MDS-UPDRS, was zero among the dancers (slope = 0.000146), indicating no motor impairment, whereas among the nondancers, the motor decline during follow-up was as expected (P < .01), the researchers reported.
In modeling the data, the researchers determined that after completing 1,000 days of dance training, dancers will have a motor score of 19.07, compared with a score of 28.27 for nondancers.
“Our data further showed that training in dance will slow the rate of PD motor impairment progression, as measured by the UPDRS III, by close to 3 points annually in comparison to our PD subjects who did not train,” the researchers reported.
Dance training also had a beneficial effect on motor or nonmotor aspects of daily living and on motor complications, for which there was no significant decline among the PD dancers.
“For those with Parkinson’s disease, even when it’s mild, motor impairment can impact their daily functioning – how they feel about themselves. Many of these motor symptoms lead to isolation because once they get extreme, these people don’t want to go out,” Dr. DeSouza said in a news release.
“These motor symptoms lead to further psychological issues, depression, social isolation and eventually the symptoms do get worse over time. Our study shows that training with dance and music can slow this down and improve their daily living and daily function,” he added.
‘Great potential’
Reached for comment, Demian Kogutek, PhD, director of music therapy, University of Evansville (Indiana), said that these preliminary findings from a longitudinal study are “promising.”
“I believe that dance therapy has a great potential for PD. The longitudinal aspect of this study undoubtedly adds to the current literature. Although it is a standardized assessment, it is somewhat subjective,” Dr. Kogutek said in an interview.
Going forward, Dr. Kogutek said he’d like to see other objective outcomes measured, such as objective assessments of balance, gait, hand strength, and dexterity.
Also weighing in on the results, Karen Lee, PhD, president and CEO of Parkinson Canada, said her organization is “encouraged by these preliminary findings as exercise and healthy activities are important for people with Parkinson’s. This study is part of a growing body of research that explores the link between the impact of activities and both motor and nonmotor symptoms of Parkinson’s.
“This research adds to growing evidence about the importance of exercise as part of the management of Parkinson’s, and we encourage people living with Parkinson’s to incorporate exercise as part of their approach to managing their health,” Dr. Lee said in an interview.
Funding for the project is provided in part by a National Science and Engineering Research Council Discovery Grant and by donations from the Irpinia Club of Toronto and others. Dr. Dr. DeSouza, Ms. Bearss, Dr. Kogutek, and Dr. Lee disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Over 3 years, weekly participation in dance training classes “drastically” reduced the expected decline in motor function and significantly improved speech, tremors, balance, and stiffness, the researchers reported.
Dance training also appeared to have benefits regarding cognition, hallucinations, depression, and anxiety.
“These findings strongly suggest the benefits of dance for people with PD as a supplement to a normal treatment regimen,” the investigators noted.
Although the mechanism of benefit is unclear, dance training may help “train neural network nodes that helps either strengthen networks damaged or builds neural road maps that pass the damage,” study investigator Joseph DeSouza, PhD, principal investigator and associate professor, department of psychology, York University, Toronto, said in an interview.
The study was published online July 7, 2021, in Brain Sciences.
Multiple benefits
PD is a neurodegenerative disease associated with progression of motor dysfunction within the first 5 years of diagnosis. The annual rate of motor decline, as determined with the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), is between 5.2 and 8.9 points.
Prior studies that assessed various styles of dance by patients with PD showed beneficial effects regarding gait speed, balance, locomotion, and aspects of quality of life.
To investigate further, DeSouza and coauthor Karolina Bearss, a PhD candidate at York University, followed 16 patients with mild to moderate PD who participated in a weekly dance class at Canada’s National Ballet School and Trinity St. Paul’s church.
Dance for Parkinson’s Disease, which is an established dance curriculum, involves aerobic and anaerobic movements. The protocol begins with a seated warm-up, followed by barre work, and ends with moving across the floor. All participants learn choreography for an upcoming performance.
In the study, 16 patients with PD who did not participant in the dance classes served as control patients.
Over 3 years, the daily rate of motor decline, as indicated by scores on part III of the MDS-UPDRS, was zero among the dancers (slope = 0.000146), indicating no motor impairment, whereas among the nondancers, the motor decline during follow-up was as expected (P < .01), the researchers reported.
In modeling the data, the researchers determined that after completing 1,000 days of dance training, dancers will have a motor score of 19.07, compared with a score of 28.27 for nondancers.
“Our data further showed that training in dance will slow the rate of PD motor impairment progression, as measured by the UPDRS III, by close to 3 points annually in comparison to our PD subjects who did not train,” the researchers reported.
Dance training also had a beneficial effect on motor or nonmotor aspects of daily living and on motor complications, for which there was no significant decline among the PD dancers.
“For those with Parkinson’s disease, even when it’s mild, motor impairment can impact their daily functioning – how they feel about themselves. Many of these motor symptoms lead to isolation because once they get extreme, these people don’t want to go out,” Dr. DeSouza said in a news release.
“These motor symptoms lead to further psychological issues, depression, social isolation and eventually the symptoms do get worse over time. Our study shows that training with dance and music can slow this down and improve their daily living and daily function,” he added.
‘Great potential’
Reached for comment, Demian Kogutek, PhD, director of music therapy, University of Evansville (Indiana), said that these preliminary findings from a longitudinal study are “promising.”
“I believe that dance therapy has a great potential for PD. The longitudinal aspect of this study undoubtedly adds to the current literature. Although it is a standardized assessment, it is somewhat subjective,” Dr. Kogutek said in an interview.
Going forward, Dr. Kogutek said he’d like to see other objective outcomes measured, such as objective assessments of balance, gait, hand strength, and dexterity.
Also weighing in on the results, Karen Lee, PhD, president and CEO of Parkinson Canada, said her organization is “encouraged by these preliminary findings as exercise and healthy activities are important for people with Parkinson’s. This study is part of a growing body of research that explores the link between the impact of activities and both motor and nonmotor symptoms of Parkinson’s.
“This research adds to growing evidence about the importance of exercise as part of the management of Parkinson’s, and we encourage people living with Parkinson’s to incorporate exercise as part of their approach to managing their health,” Dr. Lee said in an interview.
Funding for the project is provided in part by a National Science and Engineering Research Council Discovery Grant and by donations from the Irpinia Club of Toronto and others. Dr. Dr. DeSouza, Ms. Bearss, Dr. Kogutek, and Dr. Lee disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FDA updates label for controversial Alzheimer’s drug aducanumab (Aduhelm)
– the group studied in the clinical trials.
The FDA approved aducanumab in early June amid significant controversy and disregarding the recommendation by its own advisory panel not to approve the drug. The original prescribing information implied that the drug – which is administered intravenously and costs around $56,000 a year – could be used for treatment of any patient with Alzheimer’s disease.
The updated label now states that aducanumab should be initiated only in patients with mild cognitive impairment (MCI) or mild dementia stage of disease – the population in which treatment was initiated in the clinical trials leading to approval of the anti-amyloid drug.
The FDA granted accelerated approval of the drug based on data from clinical trials showing a reduction in amyloid beta plaques observed in patients with MCI or mild dementia stage of disease.
“Continued approval for the indication may be contingent upon verification of clinical benefit in confirmatory trial(s),” the label states. It emphasizes that there are no safety or effectiveness data on starting aducanumab treatment at earlier or later stages of the disease than were studied.
“Based on our ongoing conversations with prescribing physicians, FDA, and patient advocates, we submitted this label update with the goal to further clarify the patient population that was studied across the three Aduhelm clinical trials that supported approval,” Alfred Sandrock Jr., MD, PhD, Biogen’s head of research and development, said in a statement announcing the label update.
“We are committed to continue to listen to the community’s needs as clinical practice adapts to this important, first-in-class treatment option,” said Dr. Sandrock.
A version of this article first appeared on Medscape.com.
– the group studied in the clinical trials.
The FDA approved aducanumab in early June amid significant controversy and disregarding the recommendation by its own advisory panel not to approve the drug. The original prescribing information implied that the drug – which is administered intravenously and costs around $56,000 a year – could be used for treatment of any patient with Alzheimer’s disease.
The updated label now states that aducanumab should be initiated only in patients with mild cognitive impairment (MCI) or mild dementia stage of disease – the population in which treatment was initiated in the clinical trials leading to approval of the anti-amyloid drug.
The FDA granted accelerated approval of the drug based on data from clinical trials showing a reduction in amyloid beta plaques observed in patients with MCI or mild dementia stage of disease.
“Continued approval for the indication may be contingent upon verification of clinical benefit in confirmatory trial(s),” the label states. It emphasizes that there are no safety or effectiveness data on starting aducanumab treatment at earlier or later stages of the disease than were studied.
“Based on our ongoing conversations with prescribing physicians, FDA, and patient advocates, we submitted this label update with the goal to further clarify the patient population that was studied across the three Aduhelm clinical trials that supported approval,” Alfred Sandrock Jr., MD, PhD, Biogen’s head of research and development, said in a statement announcing the label update.
“We are committed to continue to listen to the community’s needs as clinical practice adapts to this important, first-in-class treatment option,” said Dr. Sandrock.
A version of this article first appeared on Medscape.com.
– the group studied in the clinical trials.
The FDA approved aducanumab in early June amid significant controversy and disregarding the recommendation by its own advisory panel not to approve the drug. The original prescribing information implied that the drug – which is administered intravenously and costs around $56,000 a year – could be used for treatment of any patient with Alzheimer’s disease.
The updated label now states that aducanumab should be initiated only in patients with mild cognitive impairment (MCI) or mild dementia stage of disease – the population in which treatment was initiated in the clinical trials leading to approval of the anti-amyloid drug.
The FDA granted accelerated approval of the drug based on data from clinical trials showing a reduction in amyloid beta plaques observed in patients with MCI or mild dementia stage of disease.
“Continued approval for the indication may be contingent upon verification of clinical benefit in confirmatory trial(s),” the label states. It emphasizes that there are no safety or effectiveness data on starting aducanumab treatment at earlier or later stages of the disease than were studied.
“Based on our ongoing conversations with prescribing physicians, FDA, and patient advocates, we submitted this label update with the goal to further clarify the patient population that was studied across the three Aduhelm clinical trials that supported approval,” Alfred Sandrock Jr., MD, PhD, Biogen’s head of research and development, said in a statement announcing the label update.
“We are committed to continue to listen to the community’s needs as clinical practice adapts to this important, first-in-class treatment option,” said Dr. Sandrock.
A version of this article first appeared on Medscape.com.
Chronic stress and genetics can raise the risk of Alzheimer’s disease
The researchers also proposed a mechanism to account for how genetic factors may affect HPA axis reactivity and lead to inflammation, which is a core component of neurodegeneration.
“Chronic stress can impact the way immune cells in the brain function and increase inflammation. Genetic variants within that stress response can further affect the function of immune cells,” lead author Ayeisha Milligan Armstrong, a PhD candidate at Curtin Health Innovation Research Institute in Perth, Australia, said in an interview.
The findings were published online June 22 in Biological Reviews).
Research has found that long-term stress during early and mid-life is increasingly associated with cognitive decline and neurodegeneration. There is already evidence to suggest that chronic stress is a risk factor for the “sporadic” or late-onset subtype of Alzheimer’s disease.
A cascade of events
Stress activates the HPA, which in turn regulates bodily levels of cortisol, a glucocorticoid stress hormone. Increased levels of cortisol are frequently observed in patients with Alzheimer’s disease and “make a major contribution to the disease process,” the authors wrote. For example, the hippocampus – a part of the brain involved in processing and forming memories – has numerous glucocorticoid receptors and is “therefore particularly sensitive to the effects of glucocorticoids.” However, the molecular mechanisms involved remain poorly understood.
“There is an intimate interplay between exposure to chronic stress and pathways influencing the body’s reaction to such stress,” senior author David Groth, PhD, said in a statement. Dr. Groth is an associate professor at Curtin University in Perth, Australia.
There is variation between individuals with regard to how sensitive they are to stress and glucocorticoid responses. Environmental factors such as stress are thought to be at least partly responsible, as are genetic factors such as genetic polymorphisms and epigenetics. “Genetic variations within these pathways can influence the way the brain’s immune system behaves, leading to a dysfunctional response. In the brain, this leads to a chronic disruption of normal brain processes, increasing the risk of subsequent neurodegeneration and ultimately dementia,” Dr. Groth said.
The researchers suggested that these variations may prime the immune cells of the brain, the microglia, to cause inflammation in the brain. Normally, microglia are involved in monitoring the brain tissue for and responding to damage and infections to keep the brain healthy. However, in an inflammatory state, the microglia instead contribute to a “more neurotoxic environment through the production of proinflammatory cytokines, altered synaptic pruning, and the reduced production of protective neurotrophic factors,” the authors wrote. Microglia may also promote the accumulation of amyloid beta and tau protein, which damage the brain tissue and can cause neurodegeneration. There are different groups of microglia in the brain, each of which may respond differently to genetic and environmental stressors.
“Genome-wide association studies have found that of the genes identified as being associated with Alzheimer’s disease, 60.5% are expressed in microglia,” the authors noted.
To connect the roles of chronic stress and brain inflammation in Alzheimer’s disease, the researchers proposed a “two-hit” hypothesis: Early or mid-life exposure to stress primes the microglia to enter an inflammatory state in response to a secondary stimulus later in life.
Pay attention to stress
For clinicians, this paper highlights the importance of managing stress in patients and their families.
“Clinicians need to be attuned to the effects of stress on patients and their caregivers, and how that [stress] can affect their morbidity and mortality,” Cynthia Munro, PhD, associate professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, said in an interview. She added that attention must be paid to modifiable risk factors such as poor sleep and diet.
Although managing stress is important, that doesn’t mean that everyone who’s experienced chronic stress will develop Alzheimer’s disease. “Chronic stress can alter the HPA axis but it doesn’t necessarily do so in everyone. A cascade of events needs to occur,” said Dr. Munro. “People should always try to reduce the effects of stress to the extent that they can. Stress can lead to a whole host of negative health outcomes, not just Alzheimer’s disease.”
Next steps
Moving forward, the researchers plan to further investigate the molecular mechanisms responsible for the role of stress in Alzheimer’s disease and how genetic variants affect neurodegeneration, Ms. Armstrong said. Ultimately, understanding how stress and genetics contribute to Alzheimer’s disease may lead to the identification of possible therapeutic targets.
Ms. Armstrong and Dr. Munro declared no relevant financial relationships. The study was independently funded.
The researchers also proposed a mechanism to account for how genetic factors may affect HPA axis reactivity and lead to inflammation, which is a core component of neurodegeneration.
“Chronic stress can impact the way immune cells in the brain function and increase inflammation. Genetic variants within that stress response can further affect the function of immune cells,” lead author Ayeisha Milligan Armstrong, a PhD candidate at Curtin Health Innovation Research Institute in Perth, Australia, said in an interview.
The findings were published online June 22 in Biological Reviews).
Research has found that long-term stress during early and mid-life is increasingly associated with cognitive decline and neurodegeneration. There is already evidence to suggest that chronic stress is a risk factor for the “sporadic” or late-onset subtype of Alzheimer’s disease.
A cascade of events
Stress activates the HPA, which in turn regulates bodily levels of cortisol, a glucocorticoid stress hormone. Increased levels of cortisol are frequently observed in patients with Alzheimer’s disease and “make a major contribution to the disease process,” the authors wrote. For example, the hippocampus – a part of the brain involved in processing and forming memories – has numerous glucocorticoid receptors and is “therefore particularly sensitive to the effects of glucocorticoids.” However, the molecular mechanisms involved remain poorly understood.
“There is an intimate interplay between exposure to chronic stress and pathways influencing the body’s reaction to such stress,” senior author David Groth, PhD, said in a statement. Dr. Groth is an associate professor at Curtin University in Perth, Australia.
There is variation between individuals with regard to how sensitive they are to stress and glucocorticoid responses. Environmental factors such as stress are thought to be at least partly responsible, as are genetic factors such as genetic polymorphisms and epigenetics. “Genetic variations within these pathways can influence the way the brain’s immune system behaves, leading to a dysfunctional response. In the brain, this leads to a chronic disruption of normal brain processes, increasing the risk of subsequent neurodegeneration and ultimately dementia,” Dr. Groth said.
The researchers suggested that these variations may prime the immune cells of the brain, the microglia, to cause inflammation in the brain. Normally, microglia are involved in monitoring the brain tissue for and responding to damage and infections to keep the brain healthy. However, in an inflammatory state, the microglia instead contribute to a “more neurotoxic environment through the production of proinflammatory cytokines, altered synaptic pruning, and the reduced production of protective neurotrophic factors,” the authors wrote. Microglia may also promote the accumulation of amyloid beta and tau protein, which damage the brain tissue and can cause neurodegeneration. There are different groups of microglia in the brain, each of which may respond differently to genetic and environmental stressors.
“Genome-wide association studies have found that of the genes identified as being associated with Alzheimer’s disease, 60.5% are expressed in microglia,” the authors noted.
To connect the roles of chronic stress and brain inflammation in Alzheimer’s disease, the researchers proposed a “two-hit” hypothesis: Early or mid-life exposure to stress primes the microglia to enter an inflammatory state in response to a secondary stimulus later in life.
Pay attention to stress
For clinicians, this paper highlights the importance of managing stress in patients and their families.
“Clinicians need to be attuned to the effects of stress on patients and their caregivers, and how that [stress] can affect their morbidity and mortality,” Cynthia Munro, PhD, associate professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, said in an interview. She added that attention must be paid to modifiable risk factors such as poor sleep and diet.
Although managing stress is important, that doesn’t mean that everyone who’s experienced chronic stress will develop Alzheimer’s disease. “Chronic stress can alter the HPA axis but it doesn’t necessarily do so in everyone. A cascade of events needs to occur,” said Dr. Munro. “People should always try to reduce the effects of stress to the extent that they can. Stress can lead to a whole host of negative health outcomes, not just Alzheimer’s disease.”
Next steps
Moving forward, the researchers plan to further investigate the molecular mechanisms responsible for the role of stress in Alzheimer’s disease and how genetic variants affect neurodegeneration, Ms. Armstrong said. Ultimately, understanding how stress and genetics contribute to Alzheimer’s disease may lead to the identification of possible therapeutic targets.
Ms. Armstrong and Dr. Munro declared no relevant financial relationships. The study was independently funded.
The researchers also proposed a mechanism to account for how genetic factors may affect HPA axis reactivity and lead to inflammation, which is a core component of neurodegeneration.
“Chronic stress can impact the way immune cells in the brain function and increase inflammation. Genetic variants within that stress response can further affect the function of immune cells,” lead author Ayeisha Milligan Armstrong, a PhD candidate at Curtin Health Innovation Research Institute in Perth, Australia, said in an interview.
The findings were published online June 22 in Biological Reviews).
Research has found that long-term stress during early and mid-life is increasingly associated with cognitive decline and neurodegeneration. There is already evidence to suggest that chronic stress is a risk factor for the “sporadic” or late-onset subtype of Alzheimer’s disease.
A cascade of events
Stress activates the HPA, which in turn regulates bodily levels of cortisol, a glucocorticoid stress hormone. Increased levels of cortisol are frequently observed in patients with Alzheimer’s disease and “make a major contribution to the disease process,” the authors wrote. For example, the hippocampus – a part of the brain involved in processing and forming memories – has numerous glucocorticoid receptors and is “therefore particularly sensitive to the effects of glucocorticoids.” However, the molecular mechanisms involved remain poorly understood.
“There is an intimate interplay between exposure to chronic stress and pathways influencing the body’s reaction to such stress,” senior author David Groth, PhD, said in a statement. Dr. Groth is an associate professor at Curtin University in Perth, Australia.
There is variation between individuals with regard to how sensitive they are to stress and glucocorticoid responses. Environmental factors such as stress are thought to be at least partly responsible, as are genetic factors such as genetic polymorphisms and epigenetics. “Genetic variations within these pathways can influence the way the brain’s immune system behaves, leading to a dysfunctional response. In the brain, this leads to a chronic disruption of normal brain processes, increasing the risk of subsequent neurodegeneration and ultimately dementia,” Dr. Groth said.
The researchers suggested that these variations may prime the immune cells of the brain, the microglia, to cause inflammation in the brain. Normally, microglia are involved in monitoring the brain tissue for and responding to damage and infections to keep the brain healthy. However, in an inflammatory state, the microglia instead contribute to a “more neurotoxic environment through the production of proinflammatory cytokines, altered synaptic pruning, and the reduced production of protective neurotrophic factors,” the authors wrote. Microglia may also promote the accumulation of amyloid beta and tau protein, which damage the brain tissue and can cause neurodegeneration. There are different groups of microglia in the brain, each of which may respond differently to genetic and environmental stressors.
“Genome-wide association studies have found that of the genes identified as being associated with Alzheimer’s disease, 60.5% are expressed in microglia,” the authors noted.
To connect the roles of chronic stress and brain inflammation in Alzheimer’s disease, the researchers proposed a “two-hit” hypothesis: Early or mid-life exposure to stress primes the microglia to enter an inflammatory state in response to a secondary stimulus later in life.
Pay attention to stress
For clinicians, this paper highlights the importance of managing stress in patients and their families.
“Clinicians need to be attuned to the effects of stress on patients and their caregivers, and how that [stress] can affect their morbidity and mortality,” Cynthia Munro, PhD, associate professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, said in an interview. She added that attention must be paid to modifiable risk factors such as poor sleep and diet.
Although managing stress is important, that doesn’t mean that everyone who’s experienced chronic stress will develop Alzheimer’s disease. “Chronic stress can alter the HPA axis but it doesn’t necessarily do so in everyone. A cascade of events needs to occur,” said Dr. Munro. “People should always try to reduce the effects of stress to the extent that they can. Stress can lead to a whole host of negative health outcomes, not just Alzheimer’s disease.”
Next steps
Moving forward, the researchers plan to further investigate the molecular mechanisms responsible for the role of stress in Alzheimer’s disease and how genetic variants affect neurodegeneration, Ms. Armstrong said. Ultimately, understanding how stress and genetics contribute to Alzheimer’s disease may lead to the identification of possible therapeutic targets.
Ms. Armstrong and Dr. Munro declared no relevant financial relationships. The study was independently funded.
FROM BIOLOGICAL REVIEWS
Is walking speed following stroke a good predictor of recovery?
, suggests new research backed by imaging data.
In secondary analysis of a previous study, training enabled both “good” and “limited” walkers to increase travel distance during a 2-minute walk. However, for “dual-task” walking, good walkers improved their distance by approximately 10 m after training, whereas limited walkers improved by only 1 m. Brain imaging showed increased brain activity in the limited walkers, which could reduce cognitive resources available for performing a second task while walking.
These findings, which were published online May 30 in Clinical Rehabilitation, may explain the apparent lack of superiority, shown previously, of dual-task training compared with single-task training for patients with stroke and impaired walking ability, researchers noted.
“Imaging data were consistent with our hypothesis that walking automaticity might explain these results,” said lead author Johnny Collett, PhD, senior clinical research fellow at Oxford Brookes University, United Kingdom.
At baseline, participants who walked slowly had increased resting state connectivity between contralesional M1 and cortical areas associated with conscious gait control.
“In response to the intervention, we found increased connectivity with the precuneus in those who walked slowly at baseline, an adaptation that might support walking in more complex situations,” Dr. Collett said.
Benefits questioned
After stroke, many patients have difficulty walking while performing a second task, such as holding a conversation. Training in dual-task walking has provided uncertain benefits, according to clinical research.
In healthy individuals, walking is believed to be a largely automatic process that requires minimal executive resources. Previous studies have suggested that a certain minimum walking speed is required to enable automatic control of walking in the brain.
“We know that those with better walking ability after stroke are better able to cope with additional cognitive loads while walking,” said Dr. Collett. “Here, we proposed that increased automatic gait control may provide a mechanism whereby executive resources are freed up to attend to additional tasks,” he added.
The investigators further hypothesized that greater walking speed is required for automatic gait control. To test these hypotheses, they analyzed data from a previously conducted randomized trial of single- and dual-task walking interventions.
Trial participants were aged 18 years or older, had survived a stroke that had occurred at least 6 months before enrollment, had reduced 2-minute walk distance relative to their peers, and had no comorbid neurologic or psychologic disorders.
Over 10 weeks, participants underwent 20 sessions that included 30 minutes of walking on a treadmill. They were randomly assigned to undergo single-task walking or dual-task walking. The latter incorporated cognitive tasks as distractions.
Good versus limited walkers
In the current study, investigators analyzed various assessments that had been conducted at baseline and after completion of the training sessions, including distance on 2-minute walks with and without a distracting task. In addition, participants underwent imaging with functional near-infrared spectroscopy (fNIRS) and fMRI.
Using previous research as a basis, the researchers defined good walking speed as 0.8 m/sec. They categorized all participants, regardless of their intervention assignments, as having good walking capacity (0.8 m/sec or more) or limited walking capacity (less than 0.79 m/sec).
A total of 50 participants enrolled in the study (mean age, 62 years), and 45 completed the interventions. Of those who completed the interventions, 22 were randomly assigned to undergo single-task training, and 23 were assigned to dual-task training.
The researchers categorized 21 participants as having good walking capacity and 24 as having limited walking capacity. Participants in each category were divided approximately evenly between treatment assignments.
Barthel index score, which assesses functional independence, was higher in the group of good walkers.
Increased travel distance
Results showed that after the interventions, distance traveled during the single-task 2-minute walk increased by 8.9 m for good walkers and by 5.3 m for limited walkers. For the dual-task 2-minute walk, the distance traveled increased by 10.4 m among good walkers and by 1.3 m for limited walkers. Change from baseline on the dual-task walk was not significant for limited walkers.
There was no significant difference between good walkers and limited walkers in their perceptions of participation in community walking. Neither group increased its walking activity significantly following the interventions.
At baseline, limited walkers, in comparison with good walkers, had significantly greater activation in the contralesional hemisphere during dual-task walking, which consisted of incorporating a planning task.
In contrast, for many good walkers, there was a decrease in activation during dual-task walking. Activation in the contralesional hemisphere correlated negatively with dual-task 2-minute walk distance.
The researchers also found a negative correlation between activation and dual-task 2-minute walk distance when the second task was the Stroop task.
Initial step
“The original trial was never designed or powered to compare groups formed by walking speed or test our automaticity hypothesis, and the results need to be viewed within this context,” said Dr. Collett. The small sample size did not allow the researchers to detect small effects of the intervention, especially in the imaging data, he added.
It also prevented the investigators from comparing limited walking and good walking groups according to whether they underwent the single-task or dual-task intervention, “which would be a superior way to investigate our hypotheses,” Dr. Collett said.
“The result of this study should be seen as exploratory, with further investigation needed,” he noted.
Helping stroke survivors to walk in the community is challenging, and new interventions that enable them to navigate complex surroundings need to be designed, said Dr. Collett. “Research is required to better understand the conscious and automatic contribution to gait control, especially with neurological impairment,” he added.
Overall, “our results suggest that improving automatic walking may be an initial step to improve capacity to respond to more complex walking interventions. However, [future] trials are required to test this,” he concluded.
The next frontier?
Commenting on the findings, Louis R. Caplan, MD, professor of neurology at Harvard University and senior neurologist at Beth Israel Deaconess Medical Center, Boston, said that “recovery and rehab are going to be the next frontier in stroke neurology, because there has to be a limitation in the present emphasis on acute care.”
Some patients do not receive acute care on time, and current treatment is not curative, added Dr. Caplan, who was not involved with the research.
Little scientific attention has been paid to how doctors can enhance recovery after stroke, what interventions delay recovery, and what the natural history of recovery is, he said. “This is a very nice study about that.”
Although the study’s methodology was sound, there were some limitations, including that strokes and underlying brain lesions were heterogeneous and that the study population was relatively small, Dr. Caplan said.
He added that “it’s a difficult study to do” and that it is difficult to organize participants into homogeneous groups.
Another limitation cited was lack of long-term follow-up that could indicate whether training provided sustained improvements in walking.
“It would be nice to revisit the same people later and see if their walking has improved, if they’re doing it differently, and if their subjective responses are different,” said Dr. Caplan.
In addition, the study did not examine whether the interventions made it easier for participants to walk with other people or to socialize more. “It may be that it really requires some time for them to gain confidence and for them to integrate that into their social network,” Dr. Caplan said.
“I would call it a proof-of-principle study, not a final study,” he noted. “It’s a study that shows that you can scientifically study rehab” and indicates the possible methodology that could be used.
The study was funded by the Stroke Association. Dr. Collett and Dr. Caplan have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, suggests new research backed by imaging data.
In secondary analysis of a previous study, training enabled both “good” and “limited” walkers to increase travel distance during a 2-minute walk. However, for “dual-task” walking, good walkers improved their distance by approximately 10 m after training, whereas limited walkers improved by only 1 m. Brain imaging showed increased brain activity in the limited walkers, which could reduce cognitive resources available for performing a second task while walking.
These findings, which were published online May 30 in Clinical Rehabilitation, may explain the apparent lack of superiority, shown previously, of dual-task training compared with single-task training for patients with stroke and impaired walking ability, researchers noted.
“Imaging data were consistent with our hypothesis that walking automaticity might explain these results,” said lead author Johnny Collett, PhD, senior clinical research fellow at Oxford Brookes University, United Kingdom.
At baseline, participants who walked slowly had increased resting state connectivity between contralesional M1 and cortical areas associated with conscious gait control.
“In response to the intervention, we found increased connectivity with the precuneus in those who walked slowly at baseline, an adaptation that might support walking in more complex situations,” Dr. Collett said.
Benefits questioned
After stroke, many patients have difficulty walking while performing a second task, such as holding a conversation. Training in dual-task walking has provided uncertain benefits, according to clinical research.
In healthy individuals, walking is believed to be a largely automatic process that requires minimal executive resources. Previous studies have suggested that a certain minimum walking speed is required to enable automatic control of walking in the brain.
“We know that those with better walking ability after stroke are better able to cope with additional cognitive loads while walking,” said Dr. Collett. “Here, we proposed that increased automatic gait control may provide a mechanism whereby executive resources are freed up to attend to additional tasks,” he added.
The investigators further hypothesized that greater walking speed is required for automatic gait control. To test these hypotheses, they analyzed data from a previously conducted randomized trial of single- and dual-task walking interventions.
Trial participants were aged 18 years or older, had survived a stroke that had occurred at least 6 months before enrollment, had reduced 2-minute walk distance relative to their peers, and had no comorbid neurologic or psychologic disorders.
Over 10 weeks, participants underwent 20 sessions that included 30 minutes of walking on a treadmill. They were randomly assigned to undergo single-task walking or dual-task walking. The latter incorporated cognitive tasks as distractions.
Good versus limited walkers
In the current study, investigators analyzed various assessments that had been conducted at baseline and after completion of the training sessions, including distance on 2-minute walks with and without a distracting task. In addition, participants underwent imaging with functional near-infrared spectroscopy (fNIRS) and fMRI.
Using previous research as a basis, the researchers defined good walking speed as 0.8 m/sec. They categorized all participants, regardless of their intervention assignments, as having good walking capacity (0.8 m/sec or more) or limited walking capacity (less than 0.79 m/sec).
A total of 50 participants enrolled in the study (mean age, 62 years), and 45 completed the interventions. Of those who completed the interventions, 22 were randomly assigned to undergo single-task training, and 23 were assigned to dual-task training.
The researchers categorized 21 participants as having good walking capacity and 24 as having limited walking capacity. Participants in each category were divided approximately evenly between treatment assignments.
Barthel index score, which assesses functional independence, was higher in the group of good walkers.
Increased travel distance
Results showed that after the interventions, distance traveled during the single-task 2-minute walk increased by 8.9 m for good walkers and by 5.3 m for limited walkers. For the dual-task 2-minute walk, the distance traveled increased by 10.4 m among good walkers and by 1.3 m for limited walkers. Change from baseline on the dual-task walk was not significant for limited walkers.
There was no significant difference between good walkers and limited walkers in their perceptions of participation in community walking. Neither group increased its walking activity significantly following the interventions.
At baseline, limited walkers, in comparison with good walkers, had significantly greater activation in the contralesional hemisphere during dual-task walking, which consisted of incorporating a planning task.
In contrast, for many good walkers, there was a decrease in activation during dual-task walking. Activation in the contralesional hemisphere correlated negatively with dual-task 2-minute walk distance.
The researchers also found a negative correlation between activation and dual-task 2-minute walk distance when the second task was the Stroop task.
Initial step
“The original trial was never designed or powered to compare groups formed by walking speed or test our automaticity hypothesis, and the results need to be viewed within this context,” said Dr. Collett. The small sample size did not allow the researchers to detect small effects of the intervention, especially in the imaging data, he added.
It also prevented the investigators from comparing limited walking and good walking groups according to whether they underwent the single-task or dual-task intervention, “which would be a superior way to investigate our hypotheses,” Dr. Collett said.
“The result of this study should be seen as exploratory, with further investigation needed,” he noted.
Helping stroke survivors to walk in the community is challenging, and new interventions that enable them to navigate complex surroundings need to be designed, said Dr. Collett. “Research is required to better understand the conscious and automatic contribution to gait control, especially with neurological impairment,” he added.
Overall, “our results suggest that improving automatic walking may be an initial step to improve capacity to respond to more complex walking interventions. However, [future] trials are required to test this,” he concluded.
The next frontier?
Commenting on the findings, Louis R. Caplan, MD, professor of neurology at Harvard University and senior neurologist at Beth Israel Deaconess Medical Center, Boston, said that “recovery and rehab are going to be the next frontier in stroke neurology, because there has to be a limitation in the present emphasis on acute care.”
Some patients do not receive acute care on time, and current treatment is not curative, added Dr. Caplan, who was not involved with the research.
Little scientific attention has been paid to how doctors can enhance recovery after stroke, what interventions delay recovery, and what the natural history of recovery is, he said. “This is a very nice study about that.”
Although the study’s methodology was sound, there were some limitations, including that strokes and underlying brain lesions were heterogeneous and that the study population was relatively small, Dr. Caplan said.
He added that “it’s a difficult study to do” and that it is difficult to organize participants into homogeneous groups.
Another limitation cited was lack of long-term follow-up that could indicate whether training provided sustained improvements in walking.
“It would be nice to revisit the same people later and see if their walking has improved, if they’re doing it differently, and if their subjective responses are different,” said Dr. Caplan.
In addition, the study did not examine whether the interventions made it easier for participants to walk with other people or to socialize more. “It may be that it really requires some time for them to gain confidence and for them to integrate that into their social network,” Dr. Caplan said.
“I would call it a proof-of-principle study, not a final study,” he noted. “It’s a study that shows that you can scientifically study rehab” and indicates the possible methodology that could be used.
The study was funded by the Stroke Association. Dr. Collett and Dr. Caplan have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, suggests new research backed by imaging data.
In secondary analysis of a previous study, training enabled both “good” and “limited” walkers to increase travel distance during a 2-minute walk. However, for “dual-task” walking, good walkers improved their distance by approximately 10 m after training, whereas limited walkers improved by only 1 m. Brain imaging showed increased brain activity in the limited walkers, which could reduce cognitive resources available for performing a second task while walking.
These findings, which were published online May 30 in Clinical Rehabilitation, may explain the apparent lack of superiority, shown previously, of dual-task training compared with single-task training for patients with stroke and impaired walking ability, researchers noted.
“Imaging data were consistent with our hypothesis that walking automaticity might explain these results,” said lead author Johnny Collett, PhD, senior clinical research fellow at Oxford Brookes University, United Kingdom.
At baseline, participants who walked slowly had increased resting state connectivity between contralesional M1 and cortical areas associated with conscious gait control.
“In response to the intervention, we found increased connectivity with the precuneus in those who walked slowly at baseline, an adaptation that might support walking in more complex situations,” Dr. Collett said.
Benefits questioned
After stroke, many patients have difficulty walking while performing a second task, such as holding a conversation. Training in dual-task walking has provided uncertain benefits, according to clinical research.
In healthy individuals, walking is believed to be a largely automatic process that requires minimal executive resources. Previous studies have suggested that a certain minimum walking speed is required to enable automatic control of walking in the brain.
“We know that those with better walking ability after stroke are better able to cope with additional cognitive loads while walking,” said Dr. Collett. “Here, we proposed that increased automatic gait control may provide a mechanism whereby executive resources are freed up to attend to additional tasks,” he added.
The investigators further hypothesized that greater walking speed is required for automatic gait control. To test these hypotheses, they analyzed data from a previously conducted randomized trial of single- and dual-task walking interventions.
Trial participants were aged 18 years or older, had survived a stroke that had occurred at least 6 months before enrollment, had reduced 2-minute walk distance relative to their peers, and had no comorbid neurologic or psychologic disorders.
Over 10 weeks, participants underwent 20 sessions that included 30 minutes of walking on a treadmill. They were randomly assigned to undergo single-task walking or dual-task walking. The latter incorporated cognitive tasks as distractions.
Good versus limited walkers
In the current study, investigators analyzed various assessments that had been conducted at baseline and after completion of the training sessions, including distance on 2-minute walks with and without a distracting task. In addition, participants underwent imaging with functional near-infrared spectroscopy (fNIRS) and fMRI.
Using previous research as a basis, the researchers defined good walking speed as 0.8 m/sec. They categorized all participants, regardless of their intervention assignments, as having good walking capacity (0.8 m/sec or more) or limited walking capacity (less than 0.79 m/sec).
A total of 50 participants enrolled in the study (mean age, 62 years), and 45 completed the interventions. Of those who completed the interventions, 22 were randomly assigned to undergo single-task training, and 23 were assigned to dual-task training.
The researchers categorized 21 participants as having good walking capacity and 24 as having limited walking capacity. Participants in each category were divided approximately evenly between treatment assignments.
Barthel index score, which assesses functional independence, was higher in the group of good walkers.
Increased travel distance
Results showed that after the interventions, distance traveled during the single-task 2-minute walk increased by 8.9 m for good walkers and by 5.3 m for limited walkers. For the dual-task 2-minute walk, the distance traveled increased by 10.4 m among good walkers and by 1.3 m for limited walkers. Change from baseline on the dual-task walk was not significant for limited walkers.
There was no significant difference between good walkers and limited walkers in their perceptions of participation in community walking. Neither group increased its walking activity significantly following the interventions.
At baseline, limited walkers, in comparison with good walkers, had significantly greater activation in the contralesional hemisphere during dual-task walking, which consisted of incorporating a planning task.
In contrast, for many good walkers, there was a decrease in activation during dual-task walking. Activation in the contralesional hemisphere correlated negatively with dual-task 2-minute walk distance.
The researchers also found a negative correlation between activation and dual-task 2-minute walk distance when the second task was the Stroop task.
Initial step
“The original trial was never designed or powered to compare groups formed by walking speed or test our automaticity hypothesis, and the results need to be viewed within this context,” said Dr. Collett. The small sample size did not allow the researchers to detect small effects of the intervention, especially in the imaging data, he added.
It also prevented the investigators from comparing limited walking and good walking groups according to whether they underwent the single-task or dual-task intervention, “which would be a superior way to investigate our hypotheses,” Dr. Collett said.
“The result of this study should be seen as exploratory, with further investigation needed,” he noted.
Helping stroke survivors to walk in the community is challenging, and new interventions that enable them to navigate complex surroundings need to be designed, said Dr. Collett. “Research is required to better understand the conscious and automatic contribution to gait control, especially with neurological impairment,” he added.
Overall, “our results suggest that improving automatic walking may be an initial step to improve capacity to respond to more complex walking interventions. However, [future] trials are required to test this,” he concluded.
The next frontier?
Commenting on the findings, Louis R. Caplan, MD, professor of neurology at Harvard University and senior neurologist at Beth Israel Deaconess Medical Center, Boston, said that “recovery and rehab are going to be the next frontier in stroke neurology, because there has to be a limitation in the present emphasis on acute care.”
Some patients do not receive acute care on time, and current treatment is not curative, added Dr. Caplan, who was not involved with the research.
Little scientific attention has been paid to how doctors can enhance recovery after stroke, what interventions delay recovery, and what the natural history of recovery is, he said. “This is a very nice study about that.”
Although the study’s methodology was sound, there were some limitations, including that strokes and underlying brain lesions were heterogeneous and that the study population was relatively small, Dr. Caplan said.
He added that “it’s a difficult study to do” and that it is difficult to organize participants into homogeneous groups.
Another limitation cited was lack of long-term follow-up that could indicate whether training provided sustained improvements in walking.
“It would be nice to revisit the same people later and see if their walking has improved, if they’re doing it differently, and if their subjective responses are different,” said Dr. Caplan.
In addition, the study did not examine whether the interventions made it easier for participants to walk with other people or to socialize more. “It may be that it really requires some time for them to gain confidence and for them to integrate that into their social network,” Dr. Caplan said.
“I would call it a proof-of-principle study, not a final study,” he noted. “It’s a study that shows that you can scientifically study rehab” and indicates the possible methodology that could be used.
The study was funded by the Stroke Association. Dr. Collett and Dr. Caplan have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
From Clinical Rehabilitation
Default EMR settings can influence opioid prescribing
Background: The opioid crisis is in the forefront as a public health emergency and there are concerns regarding addiction stemming from opioid prescriptions written in the acute setting, such as the ED and hospitals.
Study design: Quality improvement project, randomized.
Setting: Two large EDs in San Francisco and Oakland, Calif.
Synopsis: In five 4-week blocks, the prepopulated opioid dispense quantities were altered on a block randomized treatment schedule without prior knowledge by the prescribing practitioners with the default dispense quantities of 5, 10, 15, and null (prescriber determined dispense quantity). Opiates included oxycodone, oxycodone/acetaminophen, and hydrocodone/acetaminophen. The primary outcome was number of opioid tablets prescribed at discharge from the ED. In this study, a total of 104 health care professionals issued 4,320 opioid study prescriptions. With use of linear regression, an increase of 0.19 tablets prescribed was found for each tablet increase in default quantity. When comparing default pairs – that is, 5 versus 15 tablets – a lower default was associated with a lower number of pills prescribed in more than half of the comparisons. Limitations of this study include a small sample of EDs, and local prescribing patterns can vary greatly for opioid prescriptions written. In addition, the reasons for the prescriptions were not noted.
Bottom line: Default EMR opioid quantity settings can be used to decrease the quantity of opioids prescribed.
Citation: Montoy JCC et al. Association of default electronic medical record settings with health care professional patterns of opioid prescribing in emergency departments: A randomized quality improvement study. JAMA Intern Med. 2020;180(4):487-93.
Dr. Wang is a hospitalist and associate professor of medicine at University of Texas Health, San Antonio.
Background: The opioid crisis is in the forefront as a public health emergency and there are concerns regarding addiction stemming from opioid prescriptions written in the acute setting, such as the ED and hospitals.
Study design: Quality improvement project, randomized.
Setting: Two large EDs in San Francisco and Oakland, Calif.
Synopsis: In five 4-week blocks, the prepopulated opioid dispense quantities were altered on a block randomized treatment schedule without prior knowledge by the prescribing practitioners with the default dispense quantities of 5, 10, 15, and null (prescriber determined dispense quantity). Opiates included oxycodone, oxycodone/acetaminophen, and hydrocodone/acetaminophen. The primary outcome was number of opioid tablets prescribed at discharge from the ED. In this study, a total of 104 health care professionals issued 4,320 opioid study prescriptions. With use of linear regression, an increase of 0.19 tablets prescribed was found for each tablet increase in default quantity. When comparing default pairs – that is, 5 versus 15 tablets – a lower default was associated with a lower number of pills prescribed in more than half of the comparisons. Limitations of this study include a small sample of EDs, and local prescribing patterns can vary greatly for opioid prescriptions written. In addition, the reasons for the prescriptions were not noted.
Bottom line: Default EMR opioid quantity settings can be used to decrease the quantity of opioids prescribed.
Citation: Montoy JCC et al. Association of default electronic medical record settings with health care professional patterns of opioid prescribing in emergency departments: A randomized quality improvement study. JAMA Intern Med. 2020;180(4):487-93.
Dr. Wang is a hospitalist and associate professor of medicine at University of Texas Health, San Antonio.
Background: The opioid crisis is in the forefront as a public health emergency and there are concerns regarding addiction stemming from opioid prescriptions written in the acute setting, such as the ED and hospitals.
Study design: Quality improvement project, randomized.
Setting: Two large EDs in San Francisco and Oakland, Calif.
Synopsis: In five 4-week blocks, the prepopulated opioid dispense quantities were altered on a block randomized treatment schedule without prior knowledge by the prescribing practitioners with the default dispense quantities of 5, 10, 15, and null (prescriber determined dispense quantity). Opiates included oxycodone, oxycodone/acetaminophen, and hydrocodone/acetaminophen. The primary outcome was number of opioid tablets prescribed at discharge from the ED. In this study, a total of 104 health care professionals issued 4,320 opioid study prescriptions. With use of linear regression, an increase of 0.19 tablets prescribed was found for each tablet increase in default quantity. When comparing default pairs – that is, 5 versus 15 tablets – a lower default was associated with a lower number of pills prescribed in more than half of the comparisons. Limitations of this study include a small sample of EDs, and local prescribing patterns can vary greatly for opioid prescriptions written. In addition, the reasons for the prescriptions were not noted.
Bottom line: Default EMR opioid quantity settings can be used to decrease the quantity of opioids prescribed.
Citation: Montoy JCC et al. Association of default electronic medical record settings with health care professional patterns of opioid prescribing in emergency departments: A randomized quality improvement study. JAMA Intern Med. 2020;180(4):487-93.
Dr. Wang is a hospitalist and associate professor of medicine at University of Texas Health, San Antonio.
Hearing loss tied to decline in physical functioning
published online in JAMA Network Open.
Hearing loss is associated with slower gait and, in particular, worse balance, the data suggest.
“Because hearing impairment is amenable to prevention and management, it potentially serves as a target for interventions to slow physical decline with aging,” the researchers said.
To examine how hearing impairment relates to physical function in older adults, Pablo Martinez-Amezcua, MD, PhD, MHS, a researcher in the department of epidemiology at Johns Hopkins University, Baltimore, and colleagues analyzed data from the ongoing Atherosclerosis Risk in Communities (ARIC) study.
ARIC initially enrolled more than 15,000 adults in Maryland, Minnesota, Mississippi, and North Carolina between 1987 and 1989. In the present study, the researchers focused on data from 2,956 participants who attended a study visit between 2016 and 2017, during which researchers assessed their hearing using pure tone audiometry.
Hearing-study participants had an average age of 79 years, about 58% were women, and 80% were White. Approximately 33% of the participants had normal hearing, 40% had mild hearing impairment, 23% had moderate hearing impairment, and 4% had severe hearing impairment.
Participants had also undergone assessment of physical functioning at study visits between 2011 and 2019, including a fast-paced 2-minute walk test to measure their walking endurance. Another assessment, the Short Physical Performance Battery (SPPB), tests balance, gait speed, and chair stands (seated participants stand up and sit back down five times as quickly as possible while their arms are crossed).
Dr. Martinez-Amezcua and colleagues found that severe hearing impairment was associated with a lower average SPPB score compared with normal hearing in a regression analysis. Specifically, compared with those with normal hearing, participants with severe hearing impairment were more likely to have low scores on the SPPB (odds ratio, 2.72), balance (OR, 2.72), and gait speed (OR, 2.16).
However, hearing impairment was not significantly associated with the chair stand test results. The researchers note that chair stands may rely more on strength, whereas balance and gait speed may rely more on coordination and movement.
The team also found that people with worse hearing tended to walk a shorter distance during the 2-minute walk test. Compared with participants with normal hearing, participants with moderate hearing impairment walked 2.81 meters less and those with severe hearing impairment walked 5.31 meters less on average, after adjustment for variables including age, sex, and health conditions.
Participants with hearing impairment also tended to have faster declines in physical function over time.
Various mechanisms could explain associations between hearing and physical function, the authors said. For example, an underlying condition such as cardiovascular disease might affect both hearing and physical function. Damage to the inner ear could affect vestibular and auditory systems at the same time. In addition, hearing impairment may relate to cognition, depression, or social isolation, which could influence physical activity.
“Age-related hearing loss is traditionally seen as a barrier for communication,” Dr. Martinez-Amezcua told this news organization. “In the past decade, research on the consequences of hearing loss has identified it as a risk factor for cognitive decline and dementia. Our findings contribute to our understanding of other negative outcomes associated with hearing loss.”
Randomized clinical trials are the best way to assess whether addressing hearing loss might improve physical function, Dr. Martinez-Amezcua said. “Currently there is one clinical trial (ACHIEVE) that will, among other outcomes, study the impact of hearing aids on cognitive and physical function,” he said.
Although interventions may not reverse hearing loss, hearing rehabilitation strategies, including hearing aids and cochlear implants, may help, he added. Educating caregivers and changing a person’s environment can also reduce the effects hearing loss has on daily life, Dr. Martinez-Amezcua said.
“We rely so much in our sense of vision for activities of daily living that we tend to underestimate how important hearing is, and the consequences of hearing loss go beyond having trouble communicating with someone,” he said.
This study and prior research “raise the intriguing idea that hearing may provide essential information to the neural circuits underpinning movement in our environment and that correction for hearing loss may help promote physical well-being,” Willa D. Brenowitz, PhD, MPH, and Margaret I. Wallhagen, PhD, GNP-BC, both at the University of California, San Francisco, wrote in an accompanying commentary. “While this hypothesis is appealing and warrants further investigation, there are multiple other potential explanations of such an association, including potential sources of bias that may affect observational studies such as this one.”
Beyond treating hearing loss, interventions such as physical therapy or tai chi may benefit patients, they suggested.
Because many changes occur during older age, it can be difficult to understand which factor is influencing another, Dr. Brenowitz said in an interview. There are potentially relevant mechanisms through which hearing could affect cognition and physical functioning. Still another explanation could be that some people are “aging in a faster way” than others, Dr. Brenowitz said.
Dr. Martinez-Amezcua and a coauthor disclosed receiving sponsorship from the Cochlear Center for Hearing and Public Health. Another author, Frank R. Lin, MD, PhD, directs the research center, which is partly funded by a philanthropic gift from Cochlear to the Johns Hopkins Bloomberg School of Public Health. Dr. Lin also disclosed personal fees from Frequency Therapeutics and Caption Call. One author serves on a scientific advisory board for Shoebox and Good Machine Studio.
Dr. Wallhagen has served on the board of trustees of the Hearing Loss Association of America and is a member of the board of the Hearing Loss Association of America–California. Dr. Wallhagen also received funding for a pilot project on the impact of hearing loss on communication in the context of chronic serious illness from the National Palliative Care Research Center outside the submitted work.
A version of this article first appeared on Medscape.com.
published online in JAMA Network Open.
Hearing loss is associated with slower gait and, in particular, worse balance, the data suggest.
“Because hearing impairment is amenable to prevention and management, it potentially serves as a target for interventions to slow physical decline with aging,” the researchers said.
To examine how hearing impairment relates to physical function in older adults, Pablo Martinez-Amezcua, MD, PhD, MHS, a researcher in the department of epidemiology at Johns Hopkins University, Baltimore, and colleagues analyzed data from the ongoing Atherosclerosis Risk in Communities (ARIC) study.
ARIC initially enrolled more than 15,000 adults in Maryland, Minnesota, Mississippi, and North Carolina between 1987 and 1989. In the present study, the researchers focused on data from 2,956 participants who attended a study visit between 2016 and 2017, during which researchers assessed their hearing using pure tone audiometry.
Hearing-study participants had an average age of 79 years, about 58% were women, and 80% were White. Approximately 33% of the participants had normal hearing, 40% had mild hearing impairment, 23% had moderate hearing impairment, and 4% had severe hearing impairment.
Participants had also undergone assessment of physical functioning at study visits between 2011 and 2019, including a fast-paced 2-minute walk test to measure their walking endurance. Another assessment, the Short Physical Performance Battery (SPPB), tests balance, gait speed, and chair stands (seated participants stand up and sit back down five times as quickly as possible while their arms are crossed).
Dr. Martinez-Amezcua and colleagues found that severe hearing impairment was associated with a lower average SPPB score compared with normal hearing in a regression analysis. Specifically, compared with those with normal hearing, participants with severe hearing impairment were more likely to have low scores on the SPPB (odds ratio, 2.72), balance (OR, 2.72), and gait speed (OR, 2.16).
However, hearing impairment was not significantly associated with the chair stand test results. The researchers note that chair stands may rely more on strength, whereas balance and gait speed may rely more on coordination and movement.
The team also found that people with worse hearing tended to walk a shorter distance during the 2-minute walk test. Compared with participants with normal hearing, participants with moderate hearing impairment walked 2.81 meters less and those with severe hearing impairment walked 5.31 meters less on average, after adjustment for variables including age, sex, and health conditions.
Participants with hearing impairment also tended to have faster declines in physical function over time.
Various mechanisms could explain associations between hearing and physical function, the authors said. For example, an underlying condition such as cardiovascular disease might affect both hearing and physical function. Damage to the inner ear could affect vestibular and auditory systems at the same time. In addition, hearing impairment may relate to cognition, depression, or social isolation, which could influence physical activity.
“Age-related hearing loss is traditionally seen as a barrier for communication,” Dr. Martinez-Amezcua told this news organization. “In the past decade, research on the consequences of hearing loss has identified it as a risk factor for cognitive decline and dementia. Our findings contribute to our understanding of other negative outcomes associated with hearing loss.”
Randomized clinical trials are the best way to assess whether addressing hearing loss might improve physical function, Dr. Martinez-Amezcua said. “Currently there is one clinical trial (ACHIEVE) that will, among other outcomes, study the impact of hearing aids on cognitive and physical function,” he said.
Although interventions may not reverse hearing loss, hearing rehabilitation strategies, including hearing aids and cochlear implants, may help, he added. Educating caregivers and changing a person’s environment can also reduce the effects hearing loss has on daily life, Dr. Martinez-Amezcua said.
“We rely so much in our sense of vision for activities of daily living that we tend to underestimate how important hearing is, and the consequences of hearing loss go beyond having trouble communicating with someone,” he said.
This study and prior research “raise the intriguing idea that hearing may provide essential information to the neural circuits underpinning movement in our environment and that correction for hearing loss may help promote physical well-being,” Willa D. Brenowitz, PhD, MPH, and Margaret I. Wallhagen, PhD, GNP-BC, both at the University of California, San Francisco, wrote in an accompanying commentary. “While this hypothesis is appealing and warrants further investigation, there are multiple other potential explanations of such an association, including potential sources of bias that may affect observational studies such as this one.”
Beyond treating hearing loss, interventions such as physical therapy or tai chi may benefit patients, they suggested.
Because many changes occur during older age, it can be difficult to understand which factor is influencing another, Dr. Brenowitz said in an interview. There are potentially relevant mechanisms through which hearing could affect cognition and physical functioning. Still another explanation could be that some people are “aging in a faster way” than others, Dr. Brenowitz said.
Dr. Martinez-Amezcua and a coauthor disclosed receiving sponsorship from the Cochlear Center for Hearing and Public Health. Another author, Frank R. Lin, MD, PhD, directs the research center, which is partly funded by a philanthropic gift from Cochlear to the Johns Hopkins Bloomberg School of Public Health. Dr. Lin also disclosed personal fees from Frequency Therapeutics and Caption Call. One author serves on a scientific advisory board for Shoebox and Good Machine Studio.
Dr. Wallhagen has served on the board of trustees of the Hearing Loss Association of America and is a member of the board of the Hearing Loss Association of America–California. Dr. Wallhagen also received funding for a pilot project on the impact of hearing loss on communication in the context of chronic serious illness from the National Palliative Care Research Center outside the submitted work.
A version of this article first appeared on Medscape.com.
published online in JAMA Network Open.
Hearing loss is associated with slower gait and, in particular, worse balance, the data suggest.
“Because hearing impairment is amenable to prevention and management, it potentially serves as a target for interventions to slow physical decline with aging,” the researchers said.
To examine how hearing impairment relates to physical function in older adults, Pablo Martinez-Amezcua, MD, PhD, MHS, a researcher in the department of epidemiology at Johns Hopkins University, Baltimore, and colleagues analyzed data from the ongoing Atherosclerosis Risk in Communities (ARIC) study.
ARIC initially enrolled more than 15,000 adults in Maryland, Minnesota, Mississippi, and North Carolina between 1987 and 1989. In the present study, the researchers focused on data from 2,956 participants who attended a study visit between 2016 and 2017, during which researchers assessed their hearing using pure tone audiometry.
Hearing-study participants had an average age of 79 years, about 58% were women, and 80% were White. Approximately 33% of the participants had normal hearing, 40% had mild hearing impairment, 23% had moderate hearing impairment, and 4% had severe hearing impairment.
Participants had also undergone assessment of physical functioning at study visits between 2011 and 2019, including a fast-paced 2-minute walk test to measure their walking endurance. Another assessment, the Short Physical Performance Battery (SPPB), tests balance, gait speed, and chair stands (seated participants stand up and sit back down five times as quickly as possible while their arms are crossed).
Dr. Martinez-Amezcua and colleagues found that severe hearing impairment was associated with a lower average SPPB score compared with normal hearing in a regression analysis. Specifically, compared with those with normal hearing, participants with severe hearing impairment were more likely to have low scores on the SPPB (odds ratio, 2.72), balance (OR, 2.72), and gait speed (OR, 2.16).
However, hearing impairment was not significantly associated with the chair stand test results. The researchers note that chair stands may rely more on strength, whereas balance and gait speed may rely more on coordination and movement.
The team also found that people with worse hearing tended to walk a shorter distance during the 2-minute walk test. Compared with participants with normal hearing, participants with moderate hearing impairment walked 2.81 meters less and those with severe hearing impairment walked 5.31 meters less on average, after adjustment for variables including age, sex, and health conditions.
Participants with hearing impairment also tended to have faster declines in physical function over time.
Various mechanisms could explain associations between hearing and physical function, the authors said. For example, an underlying condition such as cardiovascular disease might affect both hearing and physical function. Damage to the inner ear could affect vestibular and auditory systems at the same time. In addition, hearing impairment may relate to cognition, depression, or social isolation, which could influence physical activity.
“Age-related hearing loss is traditionally seen as a barrier for communication,” Dr. Martinez-Amezcua told this news organization. “In the past decade, research on the consequences of hearing loss has identified it as a risk factor for cognitive decline and dementia. Our findings contribute to our understanding of other negative outcomes associated with hearing loss.”
Randomized clinical trials are the best way to assess whether addressing hearing loss might improve physical function, Dr. Martinez-Amezcua said. “Currently there is one clinical trial (ACHIEVE) that will, among other outcomes, study the impact of hearing aids on cognitive and physical function,” he said.
Although interventions may not reverse hearing loss, hearing rehabilitation strategies, including hearing aids and cochlear implants, may help, he added. Educating caregivers and changing a person’s environment can also reduce the effects hearing loss has on daily life, Dr. Martinez-Amezcua said.
“We rely so much in our sense of vision for activities of daily living that we tend to underestimate how important hearing is, and the consequences of hearing loss go beyond having trouble communicating with someone,” he said.
This study and prior research “raise the intriguing idea that hearing may provide essential information to the neural circuits underpinning movement in our environment and that correction for hearing loss may help promote physical well-being,” Willa D. Brenowitz, PhD, MPH, and Margaret I. Wallhagen, PhD, GNP-BC, both at the University of California, San Francisco, wrote in an accompanying commentary. “While this hypothesis is appealing and warrants further investigation, there are multiple other potential explanations of such an association, including potential sources of bias that may affect observational studies such as this one.”
Beyond treating hearing loss, interventions such as physical therapy or tai chi may benefit patients, they suggested.
Because many changes occur during older age, it can be difficult to understand which factor is influencing another, Dr. Brenowitz said in an interview. There are potentially relevant mechanisms through which hearing could affect cognition and physical functioning. Still another explanation could be that some people are “aging in a faster way” than others, Dr. Brenowitz said.
Dr. Martinez-Amezcua and a coauthor disclosed receiving sponsorship from the Cochlear Center for Hearing and Public Health. Another author, Frank R. Lin, MD, PhD, directs the research center, which is partly funded by a philanthropic gift from Cochlear to the Johns Hopkins Bloomberg School of Public Health. Dr. Lin also disclosed personal fees from Frequency Therapeutics and Caption Call. One author serves on a scientific advisory board for Shoebox and Good Machine Studio.
Dr. Wallhagen has served on the board of trustees of the Hearing Loss Association of America and is a member of the board of the Hearing Loss Association of America–California. Dr. Wallhagen also received funding for a pilot project on the impact of hearing loss on communication in the context of chronic serious illness from the National Palliative Care Research Center outside the submitted work.
A version of this article first appeared on Medscape.com.
FDA fast-tracks lecanemab for Alzheimer’s disease
Lecanemab (formerly BAN2401) is a humanized monoclonal antibody that selectively binds to large, soluble aggregated Abeta protofibrils. The antibody was developed following the discovery of a mutation in amyloid precursor protein that leads to a form of Alzheimer’s disease that is marked by particularly high levels of Abeta protofibrils.
“As such, lecanemab may have the potential to have an effect on disease pathology and to slow down the progression of the disease,” Eisai and Biogen said in a joint news release.
The breakthrough therapy designation for lecanemab is based on results of a randomized, double-blind, phase 2b proof-of-concept study published April 17 in Alzheimer’s Research & Therapy.
The study enrolled 856 patients with mild cognitive impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease with confirmed presence of amyloid pathology.
At the highest doses, treatment with lecanemab led to a reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints.
Phase 3 testing underway
In March, Eisai and Biogen completed enrollment in a phase 3 study designed to confirm the safety and efficacy of lecanemab in patients with symptomatic early Alzheimer’s disease.
The CLARITY AD study includes 1,795 patients with early Alzheimer’s disease, and initial results are expected by the end of September 2022. The core study will compare lecanemab against placebo on the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 18 months. The study will also evaluate the long-term safety and tolerability of lecanemab in the extension phase and whether the long-term effects of lecanemab, as measured by the CDR-SB at the end of the core study, are maintained over time.
Additionally, the phase 3 AHEAD 3-45 clinical study is currently exploring lecanemab in adults with preclinical Alzheimer’s disease (clinically normal but with intermediate or elevated brain amyloid).
On June 7, the FDA – amid significant controversy – approved aducanumab (Aduhelm), the first anti-amyloid agent for the treatment Alzheimer’s disease, disregarding the recommendation by its own advisory panel not to approve the drug. Three members of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee subsequently resigned in protest following the agency’s approval of aducanumab.
In addition, the high-profile consumer advocacy group Public Citizen sent a letter to the secretary of the U.S. Department of Health & Human Services demanding the removal of three FDA officials, including acting FDA Commissioner Janet Woodcock, MD.
A version of this article first appeared on Medscape.com.
Lecanemab (formerly BAN2401) is a humanized monoclonal antibody that selectively binds to large, soluble aggregated Abeta protofibrils. The antibody was developed following the discovery of a mutation in amyloid precursor protein that leads to a form of Alzheimer’s disease that is marked by particularly high levels of Abeta protofibrils.
“As such, lecanemab may have the potential to have an effect on disease pathology and to slow down the progression of the disease,” Eisai and Biogen said in a joint news release.
The breakthrough therapy designation for lecanemab is based on results of a randomized, double-blind, phase 2b proof-of-concept study published April 17 in Alzheimer’s Research & Therapy.
The study enrolled 856 patients with mild cognitive impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease with confirmed presence of amyloid pathology.
At the highest doses, treatment with lecanemab led to a reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints.
Phase 3 testing underway
In March, Eisai and Biogen completed enrollment in a phase 3 study designed to confirm the safety and efficacy of lecanemab in patients with symptomatic early Alzheimer’s disease.
The CLARITY AD study includes 1,795 patients with early Alzheimer’s disease, and initial results are expected by the end of September 2022. The core study will compare lecanemab against placebo on the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 18 months. The study will also evaluate the long-term safety and tolerability of lecanemab in the extension phase and whether the long-term effects of lecanemab, as measured by the CDR-SB at the end of the core study, are maintained over time.
Additionally, the phase 3 AHEAD 3-45 clinical study is currently exploring lecanemab in adults with preclinical Alzheimer’s disease (clinically normal but with intermediate or elevated brain amyloid).
On June 7, the FDA – amid significant controversy – approved aducanumab (Aduhelm), the first anti-amyloid agent for the treatment Alzheimer’s disease, disregarding the recommendation by its own advisory panel not to approve the drug. Three members of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee subsequently resigned in protest following the agency’s approval of aducanumab.
In addition, the high-profile consumer advocacy group Public Citizen sent a letter to the secretary of the U.S. Department of Health & Human Services demanding the removal of three FDA officials, including acting FDA Commissioner Janet Woodcock, MD.
A version of this article first appeared on Medscape.com.
Lecanemab (formerly BAN2401) is a humanized monoclonal antibody that selectively binds to large, soluble aggregated Abeta protofibrils. The antibody was developed following the discovery of a mutation in amyloid precursor protein that leads to a form of Alzheimer’s disease that is marked by particularly high levels of Abeta protofibrils.
“As such, lecanemab may have the potential to have an effect on disease pathology and to slow down the progression of the disease,” Eisai and Biogen said in a joint news release.
The breakthrough therapy designation for lecanemab is based on results of a randomized, double-blind, phase 2b proof-of-concept study published April 17 in Alzheimer’s Research & Therapy.
The study enrolled 856 patients with mild cognitive impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease with confirmed presence of amyloid pathology.
At the highest doses, treatment with lecanemab led to a reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints.
Phase 3 testing underway
In March, Eisai and Biogen completed enrollment in a phase 3 study designed to confirm the safety and efficacy of lecanemab in patients with symptomatic early Alzheimer’s disease.
The CLARITY AD study includes 1,795 patients with early Alzheimer’s disease, and initial results are expected by the end of September 2022. The core study will compare lecanemab against placebo on the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 18 months. The study will also evaluate the long-term safety and tolerability of lecanemab in the extension phase and whether the long-term effects of lecanemab, as measured by the CDR-SB at the end of the core study, are maintained over time.
Additionally, the phase 3 AHEAD 3-45 clinical study is currently exploring lecanemab in adults with preclinical Alzheimer’s disease (clinically normal but with intermediate or elevated brain amyloid).
On June 7, the FDA – amid significant controversy – approved aducanumab (Aduhelm), the first anti-amyloid agent for the treatment Alzheimer’s disease, disregarding the recommendation by its own advisory panel not to approve the drug. Three members of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee subsequently resigned in protest following the agency’s approval of aducanumab.
In addition, the high-profile consumer advocacy group Public Citizen sent a letter to the secretary of the U.S. Department of Health & Human Services demanding the removal of three FDA officials, including acting FDA Commissioner Janet Woodcock, MD.
A version of this article first appeared on Medscape.com.
Profound brain changes found in patients who died of COVID-19
The most comprehensive molecular study to date of brain tissue from people who died of COVID-19 provides clear evidence that SARS-CoV-2 causes profound molecular changes in the brain, despite no molecular trace of the virus in brain tissue.
“The signature the virus leaves in the brain speaks of strong inflammation and disrupted brain circuits and resembles signatures the field has observed in Alzheimer’s or other neurodegenerative diseases,” senior author Tony Wyss-Coray, PhD, professor of neurology and neurological sciences, Stanford (Calif.) University, told this news organization.
The study was published online June 21 in Nature.
Signs of distress
“We know that up to a third of SARS-CoV-2-infected people show brain symptoms including brain fog, memory problems, and fatigue, and a growing number of people have such symptoms long after they [have] seemingly recovered from virus infection,” said Dr. Wyss-Coray.
“However, we have very little understanding of how the virus causes these symptoms and what its effects are on the brain at a molecular level,” he added.
Using single-cell RNA sequencing, the researchers profiled the transcriptomes of 65,309 nuclei isolated from frontal cortex and choroid plexus samples from eight patients who died of COVID-19 and 14 controls who died of other causes.
There was no molecular evidence of SARS-CoV-2 in brain tissue samples from the patients who died of COVID-19.
Yet, “we were very surprised to learn that no matter which type of cell we studied (different types of nerve cells, immune cells, or different support cells in the brain) there were prominent changes” compared with brain tissue samples from controls who died of other causes, said Dr. Wyss-Coray.
The changes in the COVID-19 brains showed signatures of inflammation, abnormal nerve cell communication, and chronic neurodegeneration.
“Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression,” the researchers report.
“Viral infection appears to trigger inflammatory responses throughout the body that may cause inflammatory signaling across the blood–brain barrier, which in turn could ‘trip off’ neuroinflammation in the brain,” Dr. Wyss-Coray said.
The findings may help explain the brain fog, fatigue, and other neurological and psychiatric symptoms of long COVID.
“While we studied only brains from people who died of COVID-19, we believe it is likely that similar, but hopefully weaker, signs of inflammation and chronic neurodegeneration will be found in COVID-19 survivors, especially those with chronic brain symptoms,” Dr. Wyss-Coray said.
This research was funded by the Nomis Foundation, the National Institutes of Health, Nan Fung Life Sciences, the Wu Tsai Neurosciences Institute and the Stanford Alzheimer’s Disease Research Center. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The most comprehensive molecular study to date of brain tissue from people who died of COVID-19 provides clear evidence that SARS-CoV-2 causes profound molecular changes in the brain, despite no molecular trace of the virus in brain tissue.
“The signature the virus leaves in the brain speaks of strong inflammation and disrupted brain circuits and resembles signatures the field has observed in Alzheimer’s or other neurodegenerative diseases,” senior author Tony Wyss-Coray, PhD, professor of neurology and neurological sciences, Stanford (Calif.) University, told this news organization.
The study was published online June 21 in Nature.
Signs of distress
“We know that up to a third of SARS-CoV-2-infected people show brain symptoms including brain fog, memory problems, and fatigue, and a growing number of people have such symptoms long after they [have] seemingly recovered from virus infection,” said Dr. Wyss-Coray.
“However, we have very little understanding of how the virus causes these symptoms and what its effects are on the brain at a molecular level,” he added.
Using single-cell RNA sequencing, the researchers profiled the transcriptomes of 65,309 nuclei isolated from frontal cortex and choroid plexus samples from eight patients who died of COVID-19 and 14 controls who died of other causes.
There was no molecular evidence of SARS-CoV-2 in brain tissue samples from the patients who died of COVID-19.
Yet, “we were very surprised to learn that no matter which type of cell we studied (different types of nerve cells, immune cells, or different support cells in the brain) there were prominent changes” compared with brain tissue samples from controls who died of other causes, said Dr. Wyss-Coray.
The changes in the COVID-19 brains showed signatures of inflammation, abnormal nerve cell communication, and chronic neurodegeneration.
“Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression,” the researchers report.
“Viral infection appears to trigger inflammatory responses throughout the body that may cause inflammatory signaling across the blood–brain barrier, which in turn could ‘trip off’ neuroinflammation in the brain,” Dr. Wyss-Coray said.
The findings may help explain the brain fog, fatigue, and other neurological and psychiatric symptoms of long COVID.
“While we studied only brains from people who died of COVID-19, we believe it is likely that similar, but hopefully weaker, signs of inflammation and chronic neurodegeneration will be found in COVID-19 survivors, especially those with chronic brain symptoms,” Dr. Wyss-Coray said.
This research was funded by the Nomis Foundation, the National Institutes of Health, Nan Fung Life Sciences, the Wu Tsai Neurosciences Institute and the Stanford Alzheimer’s Disease Research Center. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The most comprehensive molecular study to date of brain tissue from people who died of COVID-19 provides clear evidence that SARS-CoV-2 causes profound molecular changes in the brain, despite no molecular trace of the virus in brain tissue.
“The signature the virus leaves in the brain speaks of strong inflammation and disrupted brain circuits and resembles signatures the field has observed in Alzheimer’s or other neurodegenerative diseases,” senior author Tony Wyss-Coray, PhD, professor of neurology and neurological sciences, Stanford (Calif.) University, told this news organization.
The study was published online June 21 in Nature.
Signs of distress
“We know that up to a third of SARS-CoV-2-infected people show brain symptoms including brain fog, memory problems, and fatigue, and a growing number of people have such symptoms long after they [have] seemingly recovered from virus infection,” said Dr. Wyss-Coray.
“However, we have very little understanding of how the virus causes these symptoms and what its effects are on the brain at a molecular level,” he added.
Using single-cell RNA sequencing, the researchers profiled the transcriptomes of 65,309 nuclei isolated from frontal cortex and choroid plexus samples from eight patients who died of COVID-19 and 14 controls who died of other causes.
There was no molecular evidence of SARS-CoV-2 in brain tissue samples from the patients who died of COVID-19.
Yet, “we were very surprised to learn that no matter which type of cell we studied (different types of nerve cells, immune cells, or different support cells in the brain) there were prominent changes” compared with brain tissue samples from controls who died of other causes, said Dr. Wyss-Coray.
The changes in the COVID-19 brains showed signatures of inflammation, abnormal nerve cell communication, and chronic neurodegeneration.
“Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression,” the researchers report.
“Viral infection appears to trigger inflammatory responses throughout the body that may cause inflammatory signaling across the blood–brain barrier, which in turn could ‘trip off’ neuroinflammation in the brain,” Dr. Wyss-Coray said.
The findings may help explain the brain fog, fatigue, and other neurological and psychiatric symptoms of long COVID.
“While we studied only brains from people who died of COVID-19, we believe it is likely that similar, but hopefully weaker, signs of inflammation and chronic neurodegeneration will be found in COVID-19 survivors, especially those with chronic brain symptoms,” Dr. Wyss-Coray said.
This research was funded by the Nomis Foundation, the National Institutes of Health, Nan Fung Life Sciences, the Wu Tsai Neurosciences Institute and the Stanford Alzheimer’s Disease Research Center. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Guidance provided for telepsychiatry in tardive dyskinesia
Expert panel reviewed best practices in 2020 while pandemic limited in-person visits
Tardive dyskinesia (TD) can be reasonably managed through telemedicine, but it should be employed as part of a hybrid strategy that ideally includes an office visit at the time of diagnosis and yearly intervals thereafter, according to an expert who spoke at a meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
In psychiatry in general and in TD specifically, telepsychiatry is useful, but “is not a one-size-fits-all approach,” according to Rif S. El-Mallakh, MD, director of the mood disorder research program at the University of Louisville (Ky.).
Telepsychiatry was already growing as a strategy to expand psychiatric services to communities with limited resources in mental health when the COVID-19 pandemic arrived. Dependence on this type of patient care then exploded out of necessity but in advance of how it might best be applied in specific circumstances.
Best practices panel convened in 2020
The project to develop best practices in TD began in July 2020, when the pandemic was still limiting normal clinician-patient interactions. It was expected from the beginning that recommendations would be applicable to postpandemic circumstances.
There is no reason to expect the forces driving the growth of telepsychiatry, which include convenience of patients and efficiency for clinicians, to dissipate once the pandemic resolves, Dr. El-Mallakh said at the virtual meeting, sponsored by MedscapeLive.
, which consisted of six neurologists, three psychiatrists, and three psychiatric nurse practitioners. The goal was to gather information about the current practice of TD diagnosis and treatment in real-world settings.
With the information on current practices providing a baseline, a virtual roundtable was then convened to develop best-practices recommendations. The deliberations were performed on the basis of expert opinion. There were no statistical methods applied to data collected from the qualitative interviews.
Four key points in recommendations
The panel agreed on four key points: an in-person visit is preferred for initial evaluation and diagnosis; when applied for the evaluation of TD, telepsychiatry should include video; virtual visits cannot completely replace in-person visits; and patients with TD should be evaluated in person at least once per year.
In addition, the panelists recommended specific steps aimed at maximizing the quality of the virtual visit, including confirming that patients have appropriate equipment for video and audio communication. It is also important to recognize that patients or caregivers may require instruction on how to set up the equipment.
Prior to a telemedicine visit, it is appropriate to provide patients with a checklist that includes instructions on adequate lighting and audio. In addition, patient expectations about the goals and processes in the video should be explained.
“Instructional videos prior to the visit might be helpful,” Dr. El-Mallakh said.
Immediately prior to each visit, visual and audio quality should be verified. This allows technical issues, if any, to be resolved.
For the evaluation of TD, the ability to adequately observe body movements is crucial but can pose a challenge in telepsychiatry. To capture hyperkinetic movements and functional impairments with adequate clarity, it might be necessary to engage caregivers to hold the camera or otherwise help the clinician gain an adequate view. Clinicians should consider the limitations of telepsychiatry.
In addition to the challenges of a differential diagnosis for TD that should include such entities as parkinsonism and other drug-induced movement disorders, Dr. El-Mallakh cautioned, “comorbidities add another layer of complexity to TD diagnosis.”
Some in-office visits recommended
It is this complexity that led to the recommendation for an in-person evaluation for new-onset TD, although the expert panel did not characterize an initial in-office visit as mandatory.
Once a diagnosis of TD is established, telepsychiatry can be an efficient strategy for education and for confirming that treatments remain effective. However, Dr. El-Mallakh pointed out that patients can and often do have more than one drug-induced movement disorder at the time of diagnosis or develop additional clinical issues over time.
According to the expert panel, telepsychiatry should not be considered an adequate strategy to manage TD by itself, but “it can be an important component” of care of these patients if used judiciously.
“We have all come to recognize the benefits of telepsychiatry and some of the limitations,” said Jonathan M. Meyer, MD, clinical professor of psychiatry, University of California, San Diego. An author or coauthor of several articles on TD, including a recent study of patient awareness of TD symptoms while on vesicular monoamine transporter 2 inhibitors, Dr. Meyer identified technical problems as among the limitations.
“For movement disorders in particular, low bandwidth, poor video quality and lighting, and inadequate visualization of the trunk and limbs all present issues in diagnosing TD, scoring its severity, and differentiating it from other movement disorders,” he said.
“Nonetheless, I agree with the panel conclusions that in many instances, a video visit can be used to diagnose TD, assess severity, and monitor changes in symptoms over time,” he added, but he did express caution.
“For cases where the diagnosis is in doubt or where comorbid disorders require physical assessment, an in-person examination should be performed before embarking on any TD treatment strategy,” Dr. Meyer said.
MedscapeLive and this news organization are owned by the same parent company. Dr. El-Mallakh has ties with Allergan, Janssen, Lundbeck, Otsuka, Takeda, Teva, and Neurocrine Biosciences, which provided funding for this expert panel and summary. Dr. Meyer has ties with Acadia, Alkermes, Allergan, Merck, Neurocrine, Otsuka, Sunovion, and Teva.
Expert panel reviewed best practices in 2020 while pandemic limited in-person visits
Expert panel reviewed best practices in 2020 while pandemic limited in-person visits
Tardive dyskinesia (TD) can be reasonably managed through telemedicine, but it should be employed as part of a hybrid strategy that ideally includes an office visit at the time of diagnosis and yearly intervals thereafter, according to an expert who spoke at a meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
In psychiatry in general and in TD specifically, telepsychiatry is useful, but “is not a one-size-fits-all approach,” according to Rif S. El-Mallakh, MD, director of the mood disorder research program at the University of Louisville (Ky.).
Telepsychiatry was already growing as a strategy to expand psychiatric services to communities with limited resources in mental health when the COVID-19 pandemic arrived. Dependence on this type of patient care then exploded out of necessity but in advance of how it might best be applied in specific circumstances.
Best practices panel convened in 2020
The project to develop best practices in TD began in July 2020, when the pandemic was still limiting normal clinician-patient interactions. It was expected from the beginning that recommendations would be applicable to postpandemic circumstances.
There is no reason to expect the forces driving the growth of telepsychiatry, which include convenience of patients and efficiency for clinicians, to dissipate once the pandemic resolves, Dr. El-Mallakh said at the virtual meeting, sponsored by MedscapeLive.
, which consisted of six neurologists, three psychiatrists, and three psychiatric nurse practitioners. The goal was to gather information about the current practice of TD diagnosis and treatment in real-world settings.
With the information on current practices providing a baseline, a virtual roundtable was then convened to develop best-practices recommendations. The deliberations were performed on the basis of expert opinion. There were no statistical methods applied to data collected from the qualitative interviews.
Four key points in recommendations
The panel agreed on four key points: an in-person visit is preferred for initial evaluation and diagnosis; when applied for the evaluation of TD, telepsychiatry should include video; virtual visits cannot completely replace in-person visits; and patients with TD should be evaluated in person at least once per year.
In addition, the panelists recommended specific steps aimed at maximizing the quality of the virtual visit, including confirming that patients have appropriate equipment for video and audio communication. It is also important to recognize that patients or caregivers may require instruction on how to set up the equipment.
Prior to a telemedicine visit, it is appropriate to provide patients with a checklist that includes instructions on adequate lighting and audio. In addition, patient expectations about the goals and processes in the video should be explained.
“Instructional videos prior to the visit might be helpful,” Dr. El-Mallakh said.
Immediately prior to each visit, visual and audio quality should be verified. This allows technical issues, if any, to be resolved.
For the evaluation of TD, the ability to adequately observe body movements is crucial but can pose a challenge in telepsychiatry. To capture hyperkinetic movements and functional impairments with adequate clarity, it might be necessary to engage caregivers to hold the camera or otherwise help the clinician gain an adequate view. Clinicians should consider the limitations of telepsychiatry.
In addition to the challenges of a differential diagnosis for TD that should include such entities as parkinsonism and other drug-induced movement disorders, Dr. El-Mallakh cautioned, “comorbidities add another layer of complexity to TD diagnosis.”
Some in-office visits recommended
It is this complexity that led to the recommendation for an in-person evaluation for new-onset TD, although the expert panel did not characterize an initial in-office visit as mandatory.
Once a diagnosis of TD is established, telepsychiatry can be an efficient strategy for education and for confirming that treatments remain effective. However, Dr. El-Mallakh pointed out that patients can and often do have more than one drug-induced movement disorder at the time of diagnosis or develop additional clinical issues over time.
According to the expert panel, telepsychiatry should not be considered an adequate strategy to manage TD by itself, but “it can be an important component” of care of these patients if used judiciously.
“We have all come to recognize the benefits of telepsychiatry and some of the limitations,” said Jonathan M. Meyer, MD, clinical professor of psychiatry, University of California, San Diego. An author or coauthor of several articles on TD, including a recent study of patient awareness of TD symptoms while on vesicular monoamine transporter 2 inhibitors, Dr. Meyer identified technical problems as among the limitations.
“For movement disorders in particular, low bandwidth, poor video quality and lighting, and inadequate visualization of the trunk and limbs all present issues in diagnosing TD, scoring its severity, and differentiating it from other movement disorders,” he said.
“Nonetheless, I agree with the panel conclusions that in many instances, a video visit can be used to diagnose TD, assess severity, and monitor changes in symptoms over time,” he added, but he did express caution.
“For cases where the diagnosis is in doubt or where comorbid disorders require physical assessment, an in-person examination should be performed before embarking on any TD treatment strategy,” Dr. Meyer said.
MedscapeLive and this news organization are owned by the same parent company. Dr. El-Mallakh has ties with Allergan, Janssen, Lundbeck, Otsuka, Takeda, Teva, and Neurocrine Biosciences, which provided funding for this expert panel and summary. Dr. Meyer has ties with Acadia, Alkermes, Allergan, Merck, Neurocrine, Otsuka, Sunovion, and Teva.
Tardive dyskinesia (TD) can be reasonably managed through telemedicine, but it should be employed as part of a hybrid strategy that ideally includes an office visit at the time of diagnosis and yearly intervals thereafter, according to an expert who spoke at a meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
In psychiatry in general and in TD specifically, telepsychiatry is useful, but “is not a one-size-fits-all approach,” according to Rif S. El-Mallakh, MD, director of the mood disorder research program at the University of Louisville (Ky.).
Telepsychiatry was already growing as a strategy to expand psychiatric services to communities with limited resources in mental health when the COVID-19 pandemic arrived. Dependence on this type of patient care then exploded out of necessity but in advance of how it might best be applied in specific circumstances.
Best practices panel convened in 2020
The project to develop best practices in TD began in July 2020, when the pandemic was still limiting normal clinician-patient interactions. It was expected from the beginning that recommendations would be applicable to postpandemic circumstances.
There is no reason to expect the forces driving the growth of telepsychiatry, which include convenience of patients and efficiency for clinicians, to dissipate once the pandemic resolves, Dr. El-Mallakh said at the virtual meeting, sponsored by MedscapeLive.
, which consisted of six neurologists, three psychiatrists, and three psychiatric nurse practitioners. The goal was to gather information about the current practice of TD diagnosis and treatment in real-world settings.
With the information on current practices providing a baseline, a virtual roundtable was then convened to develop best-practices recommendations. The deliberations were performed on the basis of expert opinion. There were no statistical methods applied to data collected from the qualitative interviews.
Four key points in recommendations
The panel agreed on four key points: an in-person visit is preferred for initial evaluation and diagnosis; when applied for the evaluation of TD, telepsychiatry should include video; virtual visits cannot completely replace in-person visits; and patients with TD should be evaluated in person at least once per year.
In addition, the panelists recommended specific steps aimed at maximizing the quality of the virtual visit, including confirming that patients have appropriate equipment for video and audio communication. It is also important to recognize that patients or caregivers may require instruction on how to set up the equipment.
Prior to a telemedicine visit, it is appropriate to provide patients with a checklist that includes instructions on adequate lighting and audio. In addition, patient expectations about the goals and processes in the video should be explained.
“Instructional videos prior to the visit might be helpful,” Dr. El-Mallakh said.
Immediately prior to each visit, visual and audio quality should be verified. This allows technical issues, if any, to be resolved.
For the evaluation of TD, the ability to adequately observe body movements is crucial but can pose a challenge in telepsychiatry. To capture hyperkinetic movements and functional impairments with adequate clarity, it might be necessary to engage caregivers to hold the camera or otherwise help the clinician gain an adequate view. Clinicians should consider the limitations of telepsychiatry.
In addition to the challenges of a differential diagnosis for TD that should include such entities as parkinsonism and other drug-induced movement disorders, Dr. El-Mallakh cautioned, “comorbidities add another layer of complexity to TD diagnosis.”
Some in-office visits recommended
It is this complexity that led to the recommendation for an in-person evaluation for new-onset TD, although the expert panel did not characterize an initial in-office visit as mandatory.
Once a diagnosis of TD is established, telepsychiatry can be an efficient strategy for education and for confirming that treatments remain effective. However, Dr. El-Mallakh pointed out that patients can and often do have more than one drug-induced movement disorder at the time of diagnosis or develop additional clinical issues over time.
According to the expert panel, telepsychiatry should not be considered an adequate strategy to manage TD by itself, but “it can be an important component” of care of these patients if used judiciously.
“We have all come to recognize the benefits of telepsychiatry and some of the limitations,” said Jonathan M. Meyer, MD, clinical professor of psychiatry, University of California, San Diego. An author or coauthor of several articles on TD, including a recent study of patient awareness of TD symptoms while on vesicular monoamine transporter 2 inhibitors, Dr. Meyer identified technical problems as among the limitations.
“For movement disorders in particular, low bandwidth, poor video quality and lighting, and inadequate visualization of the trunk and limbs all present issues in diagnosing TD, scoring its severity, and differentiating it from other movement disorders,” he said.
“Nonetheless, I agree with the panel conclusions that in many instances, a video visit can be used to diagnose TD, assess severity, and monitor changes in symptoms over time,” he added, but he did express caution.
“For cases where the diagnosis is in doubt or where comorbid disorders require physical assessment, an in-person examination should be performed before embarking on any TD treatment strategy,” Dr. Meyer said.
MedscapeLive and this news organization are owned by the same parent company. Dr. El-Mallakh has ties with Allergan, Janssen, Lundbeck, Otsuka, Takeda, Teva, and Neurocrine Biosciences, which provided funding for this expert panel and summary. Dr. Meyer has ties with Acadia, Alkermes, Allergan, Merck, Neurocrine, Otsuka, Sunovion, and Teva.
FROM CP/AACP PSYCHIATRY UPDATE
FDA leader explains rationale leading to controversial Alzheimer’s drug approval
, including the release of several internal documents.
In a letter sent to members of the FDA’s Center for Drug Evaluation Research (CDER), CDER Director Patrizia Cavazzoni, MD, noted that in view of the “fierce public debate” that erupted immediately following the drug’s approval, she felt compelled to explain how the agency came to its decision.
Also publicly released today on the FDA’s updated aducanumab landing page was “the first set of review memos,” for the drug.
“We’re releasing these documents with the intent of informing public discourse – providing interested parties with the opportunity to explore the data that helped shape our decision to grant accelerated approval,” Dr. Cavazzoni wrote. “The rest of the approval package will be released over the next several days,” she added.
Immediate backlash
The FDA’s June 7 approval of aducanumab was met with instant backlash. In November 2020, the agency’s Peripheral and Central Nervous System Drugs Advisory Committee voted nearly unanimously to not vote in favor of approval because of a lack of evidence proving its efficacy.
Since the drug was approved, three of the advisory committee’s members resigned in protest. In addition, the high-profile consumer advocacy group Public Citizen sent a letter to the secretary of the U.S. Department of Health & Human Services demanding the removal of three FDA officials, including acting FDA Commissioner Janet Woodcock, MD.
In its letter, the group noted that the FDA’s decision “showed a stunning disregard for science, eviscerated the agency’s standards for approving new drugs, and ranks as one of the most irresponsible and egregious decisions in the history of the agency.”
Even the Alzheimer’s Association, which was a staunch supporter of the drug throughout its development process and applauded its approval, expressed outrage over its more than $56,000-a-year cost to patients and called the price “simply unacceptable” in a statement.
In the June 23 letter, the CDER director noted, “this was one of the most complex applications in recent history” and admitted that deliberations were lengthy and difficult.
“It’s also not surprising, in fact it was to be expected, that there would be different viewpoints about the data, including dissenting opinions about the approval decision,” Dr. Cavazzoni wrote.
However, this “is what scientific debate is all about, and while difficult at times, it should be celebrated,” she added. “Please know that every opinion was heard, and the approval is a direct reflection of this open and robust scientific and regulatory debate.”
Accelerated approval pathway
Documents newly posted to the FDA’s aducanumab landing page include CDER’s Office of Neurology’s Summary Review Memorandum, which includes details on the basis for the approval; the Concurrence Memorandum from the director of CDER’s Office of New Drugs; and the Concurrence Memorandum from Dr. Cavazzoni.
“The remaining scientific review documents in the Aduhelm action package are not yet available but will be made available to the public as soon as the internal process of review and redaction is complete,” the FDA noted on its site.
In the document FDA’s Decision to Approve New Treatment for Alzheimer’s Disease, Dr. Cavazzoni noted that the “highly complex” data included in the submission package for the drug “left residual uncertainties regarding clinical benefit.”
However, after listening to the patient community and reviewing all the data, the FDA chose to use the Accelerated Approval pathway, deciding that the potential benefit to patients outweighed the drug’s risks.
Of two phase 3 trials, only one met its primary endpoint. However, in all trials, including earlier studies, “Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion,” Dr. Cavazzoni wrote.
“It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline,” she added.
Dr. Cavazzoni noted that although the Advisory Committee did not agree that clinical benefit from one trial meeting its primary endpoint was enough for approval, “the option of Accelerated Approval was not discussed” at that time.
This type of approval “is based on a surrogate or intermediate clinical endpoint, in this case reduction of amyloid plaque in the brain” and requires post-approval studies to verify clinical benefit.
Dr. Cavazzoni added that the drug could still be removed from the market if its confirmatory trial does not verify this type of benefit.
A version of this article first appeared on Medscape.com.
, including the release of several internal documents.
In a letter sent to members of the FDA’s Center for Drug Evaluation Research (CDER), CDER Director Patrizia Cavazzoni, MD, noted that in view of the “fierce public debate” that erupted immediately following the drug’s approval, she felt compelled to explain how the agency came to its decision.
Also publicly released today on the FDA’s updated aducanumab landing page was “the first set of review memos,” for the drug.
“We’re releasing these documents with the intent of informing public discourse – providing interested parties with the opportunity to explore the data that helped shape our decision to grant accelerated approval,” Dr. Cavazzoni wrote. “The rest of the approval package will be released over the next several days,” she added.
Immediate backlash
The FDA’s June 7 approval of aducanumab was met with instant backlash. In November 2020, the agency’s Peripheral and Central Nervous System Drugs Advisory Committee voted nearly unanimously to not vote in favor of approval because of a lack of evidence proving its efficacy.
Since the drug was approved, three of the advisory committee’s members resigned in protest. In addition, the high-profile consumer advocacy group Public Citizen sent a letter to the secretary of the U.S. Department of Health & Human Services demanding the removal of three FDA officials, including acting FDA Commissioner Janet Woodcock, MD.
In its letter, the group noted that the FDA’s decision “showed a stunning disregard for science, eviscerated the agency’s standards for approving new drugs, and ranks as one of the most irresponsible and egregious decisions in the history of the agency.”
Even the Alzheimer’s Association, which was a staunch supporter of the drug throughout its development process and applauded its approval, expressed outrage over its more than $56,000-a-year cost to patients and called the price “simply unacceptable” in a statement.
In the June 23 letter, the CDER director noted, “this was one of the most complex applications in recent history” and admitted that deliberations were lengthy and difficult.
“It’s also not surprising, in fact it was to be expected, that there would be different viewpoints about the data, including dissenting opinions about the approval decision,” Dr. Cavazzoni wrote.
However, this “is what scientific debate is all about, and while difficult at times, it should be celebrated,” she added. “Please know that every opinion was heard, and the approval is a direct reflection of this open and robust scientific and regulatory debate.”
Accelerated approval pathway
Documents newly posted to the FDA’s aducanumab landing page include CDER’s Office of Neurology’s Summary Review Memorandum, which includes details on the basis for the approval; the Concurrence Memorandum from the director of CDER’s Office of New Drugs; and the Concurrence Memorandum from Dr. Cavazzoni.
“The remaining scientific review documents in the Aduhelm action package are not yet available but will be made available to the public as soon as the internal process of review and redaction is complete,” the FDA noted on its site.
In the document FDA’s Decision to Approve New Treatment for Alzheimer’s Disease, Dr. Cavazzoni noted that the “highly complex” data included in the submission package for the drug “left residual uncertainties regarding clinical benefit.”
However, after listening to the patient community and reviewing all the data, the FDA chose to use the Accelerated Approval pathway, deciding that the potential benefit to patients outweighed the drug’s risks.
Of two phase 3 trials, only one met its primary endpoint. However, in all trials, including earlier studies, “Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion,” Dr. Cavazzoni wrote.
“It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline,” she added.
Dr. Cavazzoni noted that although the Advisory Committee did not agree that clinical benefit from one trial meeting its primary endpoint was enough for approval, “the option of Accelerated Approval was not discussed” at that time.
This type of approval “is based on a surrogate or intermediate clinical endpoint, in this case reduction of amyloid plaque in the brain” and requires post-approval studies to verify clinical benefit.
Dr. Cavazzoni added that the drug could still be removed from the market if its confirmatory trial does not verify this type of benefit.
A version of this article first appeared on Medscape.com.
, including the release of several internal documents.
In a letter sent to members of the FDA’s Center for Drug Evaluation Research (CDER), CDER Director Patrizia Cavazzoni, MD, noted that in view of the “fierce public debate” that erupted immediately following the drug’s approval, she felt compelled to explain how the agency came to its decision.
Also publicly released today on the FDA’s updated aducanumab landing page was “the first set of review memos,” for the drug.
“We’re releasing these documents with the intent of informing public discourse – providing interested parties with the opportunity to explore the data that helped shape our decision to grant accelerated approval,” Dr. Cavazzoni wrote. “The rest of the approval package will be released over the next several days,” she added.
Immediate backlash
The FDA’s June 7 approval of aducanumab was met with instant backlash. In November 2020, the agency’s Peripheral and Central Nervous System Drugs Advisory Committee voted nearly unanimously to not vote in favor of approval because of a lack of evidence proving its efficacy.
Since the drug was approved, three of the advisory committee’s members resigned in protest. In addition, the high-profile consumer advocacy group Public Citizen sent a letter to the secretary of the U.S. Department of Health & Human Services demanding the removal of three FDA officials, including acting FDA Commissioner Janet Woodcock, MD.
In its letter, the group noted that the FDA’s decision “showed a stunning disregard for science, eviscerated the agency’s standards for approving new drugs, and ranks as one of the most irresponsible and egregious decisions in the history of the agency.”
Even the Alzheimer’s Association, which was a staunch supporter of the drug throughout its development process and applauded its approval, expressed outrage over its more than $56,000-a-year cost to patients and called the price “simply unacceptable” in a statement.
In the June 23 letter, the CDER director noted, “this was one of the most complex applications in recent history” and admitted that deliberations were lengthy and difficult.
“It’s also not surprising, in fact it was to be expected, that there would be different viewpoints about the data, including dissenting opinions about the approval decision,” Dr. Cavazzoni wrote.
However, this “is what scientific debate is all about, and while difficult at times, it should be celebrated,” she added. “Please know that every opinion was heard, and the approval is a direct reflection of this open and robust scientific and regulatory debate.”
Accelerated approval pathway
Documents newly posted to the FDA’s aducanumab landing page include CDER’s Office of Neurology’s Summary Review Memorandum, which includes details on the basis for the approval; the Concurrence Memorandum from the director of CDER’s Office of New Drugs; and the Concurrence Memorandum from Dr. Cavazzoni.
“The remaining scientific review documents in the Aduhelm action package are not yet available but will be made available to the public as soon as the internal process of review and redaction is complete,” the FDA noted on its site.
In the document FDA’s Decision to Approve New Treatment for Alzheimer’s Disease, Dr. Cavazzoni noted that the “highly complex” data included in the submission package for the drug “left residual uncertainties regarding clinical benefit.”
However, after listening to the patient community and reviewing all the data, the FDA chose to use the Accelerated Approval pathway, deciding that the potential benefit to patients outweighed the drug’s risks.
Of two phase 3 trials, only one met its primary endpoint. However, in all trials, including earlier studies, “Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion,” Dr. Cavazzoni wrote.
“It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline,” she added.
Dr. Cavazzoni noted that although the Advisory Committee did not agree that clinical benefit from one trial meeting its primary endpoint was enough for approval, “the option of Accelerated Approval was not discussed” at that time.
This type of approval “is based on a surrogate or intermediate clinical endpoint, in this case reduction of amyloid plaque in the brain” and requires post-approval studies to verify clinical benefit.
Dr. Cavazzoni added that the drug could still be removed from the market if its confirmatory trial does not verify this type of benefit.
A version of this article first appeared on Medscape.com.