Alzheimer's & Cognition

Sleeping too much or too little can lead to cognitive decline over time, but new research suggests there could be a sleep time “sweet spot” that stabilizes cognitive function.

JGI/Tom Grill/Getty Images

In a longitudinal study, investigators found older adults who slept less than 4.5 hours or more than 6.5 hours a night reported significant cognitive decline over time, but cognitive scores for those with sleep duration in between that range remained stable.

“This really suggests that there’s this middle range, a ‘sweet spot,’ where your sleep is really optimal,” lead author Brendan Lucey, MD, MSCI, associate professor of neurology and director of the Washington University Sleep Medicine Center, St. Louis, said in an interview.

The study, published online Oct. 20, 2021, in the journal Brain, is part of a growing body of research that seeks to determine if sleep can be used as a marker of Alzheimer’s disease progression.
 

A complex relationship

Studies suggest a strong relationship between sleep patterns and Alzheimer’s disease, which affects nearly 6 million Americans. The challenge, Dr. Lucey said, is unwinding the complex links between sleep, AD, and cognitive function.

An earlier study by Dr. Lucey and colleagues found that poor sleep quality is associated with early signs of AD, and a report published in September found that elderly people who slept less than 6 hours a night had a greater burden of amyloid-beta, a hallmark sign of AD.

For this new study, researchers monitored sleep-wake activity over 4-6 nights in 100 participants who underwent annual cognitive assessments and clinical studies, including APOE genotyping, as part of a longitudinal study at the Knight Alzheimer Disease Research Center at Washington University.

Participants also provided cerebrospinal fluid (CSF) total tau and amyloid-beta 42 and wore a small EEG device on their forehead while they slept.

The majority of participants had a clinical dementia rating (CDR) score of 0, indicating no cognitive impairment. Twelve individuals had a CDR greater than 0, with most reporting mild cognitive impairment.

As expected, CSF analysis showed greater evidence of AD pathology in those with a baseline CDR greater than 0.

Changes in cognitive function were measured using a Preclinical Alzheimer Cognitive Composite (PACC) score, a composite of results from a neuropsychological testing battery that included the Free and Cued Selective Reminding Test, the Logical Memory Delayed Recall Test from the Wechsler Memory Scale–Revised, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale–Revised, and the Mini-Mental State Examination.

Researchers found an upside-down U-shaped relationship between PACC scores and sleep duration, with dramatic cognitive decline in those who slept less than 4.5 hours or more than 6.5 hours a night (P < .001 for both).

The U-shaped relationship was also found with measures of sleep phases, including time spent in rapid eye movement and in non-REM sleep (P < .001 for both).

The findings persisted even after controlling for confounders that can affect sleep and cognition, such as age, CSF total tau/amyloid-beta ₄₂ ratio, apo E four-allele carrier status, years of education, and sex.

Understanding how sleep changes at different stages of AD could help researchers determine if sleep can be used as a marker of disease progression, Dr. Lucey said. That could lead to interventions to slow that process.

“We’re not at the point yet where we can say that we need to monitor someone’s sleep time and then do an intervention to see if it would improve their risk for cognitive decline,” said Dr. Lucey, who plans to repeat this sleep study with the same cohort to track changes in sleep patterns and cognitive function over time. “But that’s a question I’m very excited to try to answer.”
 

A component of cognitive health

Commenting on the findings for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, noted that the study adds to a body of evidence linking sleep and cognition, especially how sleep quality can optimize brain function.

“We’ve seen previous research that’s shown poor sleep contributes to dementia risk, as well as research showing sleep duration may play a role in cognition,” she said.

“We also need studies that look at sleep as an intervention for cognitive health,” Dr. Snyder said. “Sleep is an important aspect of our overall health. Clinicians should have conversations with their patients about sleep as part of standard discussions about their health habits and wellness.”

The study was funded by the National Institutes of Health, the American Sleep Medicine Foundation, the Roger and Paula Riney Fund, and the Daniel J. Brennan, MD Fund. Dr. Lucey consults for Merck and Eli Lilly. Dr. Snyder has disclosed no relevant financial relationships.

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

Sleeping too much or too little can lead to cognitive decline over time, but new research suggests there could be a sleep time “sweet spot” that stabilizes cognitive function.

JGI/Tom Grill/Getty Images

In a longitudinal study, investigators found older adults who slept less than 4.5 hours or more than 6.5 hours a night reported significant cognitive decline over time, but cognitive scores for those with sleep duration in between that range remained stable.

“This really suggests that there’s this middle range, a ‘sweet spot,’ where your sleep is really optimal,” lead author Brendan Lucey, MD, MSCI, associate professor of neurology and director of the Washington University Sleep Medicine Center, St. Louis, said in an interview.

The study, published online Oct. 20, 2021, in the journal Brain, is part of a growing body of research that seeks to determine if sleep can be used as a marker of Alzheimer’s disease progression.
 

A complex relationship

Studies suggest a strong relationship between sleep patterns and Alzheimer’s disease, which affects nearly 6 million Americans. The challenge, Dr. Lucey said, is unwinding the complex links between sleep, AD, and cognitive function.

An earlier study by Dr. Lucey and colleagues found that poor sleep quality is associated with early signs of AD, and a report published in September found that elderly people who slept less than 6 hours a night had a greater burden of amyloid-beta, a hallmark sign of AD.

For this new study, researchers monitored sleep-wake activity over 4-6 nights in 100 participants who underwent annual cognitive assessments and clinical studies, including APOE genotyping, as part of a longitudinal study at the Knight Alzheimer Disease Research Center at Washington University.

Participants also provided cerebrospinal fluid (CSF) total tau and amyloid-beta 42 and wore a small EEG device on their forehead while they slept.

The majority of participants had a clinical dementia rating (CDR) score of 0, indicating no cognitive impairment. Twelve individuals had a CDR greater than 0, with most reporting mild cognitive impairment.

As expected, CSF analysis showed greater evidence of AD pathology in those with a baseline CDR greater than 0.

Changes in cognitive function were measured using a Preclinical Alzheimer Cognitive Composite (PACC) score, a composite of results from a neuropsychological testing battery that included the Free and Cued Selective Reminding Test, the Logical Memory Delayed Recall Test from the Wechsler Memory Scale–Revised, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale–Revised, and the Mini-Mental State Examination.

Researchers found an upside-down U-shaped relationship between PACC scores and sleep duration, with dramatic cognitive decline in those who slept less than 4.5 hours or more than 6.5 hours a night (P < .001 for both).

The U-shaped relationship was also found with measures of sleep phases, including time spent in rapid eye movement and in non-REM sleep (P < .001 for both).

The findings persisted even after controlling for confounders that can affect sleep and cognition, such as age, CSF total tau/amyloid-beta ₄₂ ratio, apo E four-allele carrier status, years of education, and sex.

Understanding how sleep changes at different stages of AD could help researchers determine if sleep can be used as a marker of disease progression, Dr. Lucey said. That could lead to interventions to slow that process.

“We’re not at the point yet where we can say that we need to monitor someone’s sleep time and then do an intervention to see if it would improve their risk for cognitive decline,” said Dr. Lucey, who plans to repeat this sleep study with the same cohort to track changes in sleep patterns and cognitive function over time. “But that’s a question I’m very excited to try to answer.”
 

A component of cognitive health

Commenting on the findings for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, noted that the study adds to a body of evidence linking sleep and cognition, especially how sleep quality can optimize brain function.

“We’ve seen previous research that’s shown poor sleep contributes to dementia risk, as well as research showing sleep duration may play a role in cognition,” she said.

“We also need studies that look at sleep as an intervention for cognitive health,” Dr. Snyder said. “Sleep is an important aspect of our overall health. Clinicians should have conversations with their patients about sleep as part of standard discussions about their health habits and wellness.”

The study was funded by the National Institutes of Health, the American Sleep Medicine Foundation, the Roger and Paula Riney Fund, and the Daniel J. Brennan, MD Fund. Dr. Lucey consults for Merck and Eli Lilly. Dr. Snyder has disclosed no relevant financial relationships.

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

Sleeping too much or too little can lead to cognitive decline over time, but new research suggests there could be a sleep time “sweet spot” that stabilizes cognitive function.

JGI/Tom Grill/Getty Images

In a longitudinal study, investigators found older adults who slept less than 4.5 hours or more than 6.5 hours a night reported significant cognitive decline over time, but cognitive scores for those with sleep duration in between that range remained stable.

“This really suggests that there’s this middle range, a ‘sweet spot,’ where your sleep is really optimal,” lead author Brendan Lucey, MD, MSCI, associate professor of neurology and director of the Washington University Sleep Medicine Center, St. Louis, said in an interview.

The study, published online Oct. 20, 2021, in the journal Brain, is part of a growing body of research that seeks to determine if sleep can be used as a marker of Alzheimer’s disease progression.
 

A complex relationship

Studies suggest a strong relationship between sleep patterns and Alzheimer’s disease, which affects nearly 6 million Americans. The challenge, Dr. Lucey said, is unwinding the complex links between sleep, AD, and cognitive function.

An earlier study by Dr. Lucey and colleagues found that poor sleep quality is associated with early signs of AD, and a report published in September found that elderly people who slept less than 6 hours a night had a greater burden of amyloid-beta, a hallmark sign of AD.

For this new study, researchers monitored sleep-wake activity over 4-6 nights in 100 participants who underwent annual cognitive assessments and clinical studies, including APOE genotyping, as part of a longitudinal study at the Knight Alzheimer Disease Research Center at Washington University.

Participants also provided cerebrospinal fluid (CSF) total tau and amyloid-beta 42 and wore a small EEG device on their forehead while they slept.

The majority of participants had a clinical dementia rating (CDR) score of 0, indicating no cognitive impairment. Twelve individuals had a CDR greater than 0, with most reporting mild cognitive impairment.

As expected, CSF analysis showed greater evidence of AD pathology in those with a baseline CDR greater than 0.

Changes in cognitive function were measured using a Preclinical Alzheimer Cognitive Composite (PACC) score, a composite of results from a neuropsychological testing battery that included the Free and Cued Selective Reminding Test, the Logical Memory Delayed Recall Test from the Wechsler Memory Scale–Revised, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale–Revised, and the Mini-Mental State Examination.

Researchers found an upside-down U-shaped relationship between PACC scores and sleep duration, with dramatic cognitive decline in those who slept less than 4.5 hours or more than 6.5 hours a night (P < .001 for both).

The U-shaped relationship was also found with measures of sleep phases, including time spent in rapid eye movement and in non-REM sleep (P < .001 for both).

The findings persisted even after controlling for confounders that can affect sleep and cognition, such as age, CSF total tau/amyloid-beta ₄₂ ratio, apo E four-allele carrier status, years of education, and sex.

Understanding how sleep changes at different stages of AD could help researchers determine if sleep can be used as a marker of disease progression, Dr. Lucey said. That could lead to interventions to slow that process.

“We’re not at the point yet where we can say that we need to monitor someone’s sleep time and then do an intervention to see if it would improve their risk for cognitive decline,” said Dr. Lucey, who plans to repeat this sleep study with the same cohort to track changes in sleep patterns and cognitive function over time. “But that’s a question I’m very excited to try to answer.”
 

A component of cognitive health

Commenting on the findings for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, noted that the study adds to a body of evidence linking sleep and cognition, especially how sleep quality can optimize brain function.

“We’ve seen previous research that’s shown poor sleep contributes to dementia risk, as well as research showing sleep duration may play a role in cognition,” she said.

“We also need studies that look at sleep as an intervention for cognitive health,” Dr. Snyder said. “Sleep is an important aspect of our overall health. Clinicians should have conversations with their patients about sleep as part of standard discussions about their health habits and wellness.”

The study was funded by the National Institutes of Health, the American Sleep Medicine Foundation, the Roger and Paula Riney Fund, and the Daniel J. Brennan, MD Fund. Dr. Lucey consults for Merck and Eli Lilly. Dr. Snyder has disclosed no relevant financial relationships.

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

Sleeping too much or too little can lead to cognitive decline over time, but new research suggests there could be a sleep time “sweet spot” that stabilizes cognitive function.

In a longitudinal study, investigators found older adults who slept less than 4.5 hours or more than 6.5 hours a night reported significant cognitive decline over time, but cognitive scores for those with sleep duration in between that range remained stable.

“This really suggests that there’s this middle range, a ‘sweet spot,’ where your sleep is really optimal,” said lead author Brendan Lucey, MD, MSCI, associate professor of neurology and director of the Washington University Sleep Medicine Center, St. Louis.

The study, published online Oct. 20 in Brain, is part of a growing body of research that seeks to determine if sleep can be used as a marker of Alzheimer’s disease progression.
 

A complex relationship

Studies suggest a strong relationship between sleep patterns and Alzheimer’s disease, which affects nearly 6 million Americans. The challenge, Dr. Lucey said, is unwinding the complex links between sleep, Alzheimer’s disease, and cognitive function.

An earlier study by Dr. Lucey and colleagues found that poor sleep quality is associated with early signs of Alzheimer’s disease, and a report published in September found that elderly people who slept less than 6 hours a night had a greater burden of amyloid beta, a hallmark sign of Alzheimer’s disease.

For this new study, researchers monitored sleep-wake activity over 4-6 nights in 100 participants who underwent annual cognitive assessments and clinical studies, including APOE genotyping, as part of a longitudinal study at the Knight Alzheimer Disease Research Center at Washington University. Participants also provided cerebrospinal fluid (CSF) total tau and amyloid-beta42 and wore a small EEG device on their forehead while they slept.

The majority of participants had a clinical dementia rating (CDR) score of 0, indicating no cognitive impairment. Twelve individuals had a CDR >0, with most reporting mild cognitive impairment.

As expected, CSF analysis showed greater evidence of Alzheimer’s disease pathology in those with a baseline CDR greater than 0.

Changes in cognitive function were measured using a Preclinical Alzheimer Cognitive Composite (PACC) score, a composite of results from a neuropsychological testing battery that included the Free and Cued Selective Reminding Test, the Logical Memory Delayed Recall Test from the Wechsler Memory Scale-Revised, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale-Revised, and the Mini-Mental State Examination.

Researchers found an upside-down U-shaped relationship between PACC scores and sleep duration, with dramatic cognitive decline in those who slept less than 4.5 hours or more than 6.5 hours a night (P < .001 for both). The U-shaped relationship was also found with measures of sleep phases, including time spent in rapid eye movement and in non-REM sleep (P < .001 for both).

The findings persisted even after controlling for confounders that can affect sleep and cognition, such as age, CSF total tau/amyloid-beta-42 ratio, APOE ε4 allele carrier status, years of education, and sex.

Understanding how sleep changes at different stages of Alzheimer’s disease could help researchers determine if sleep can be used as a marker of disease progression, Dr. Lucey said. That could lead to interventions to slow that process.

“We’re not at the point yet where we can say that we need to monitor someone’s sleep time and then do an intervention to see if it would improve their risk for cognitive decline,” said Dr. Lucey, who plans to repeat this sleep study with the same cohort to track changes in sleep patterns and cognitive function over time. “But that’s a question I’m very excited to try to answer.”
 

A component of cognitive health

Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, noted that the study adds to a body of evidence linking sleep and cognition, especially how sleep quality can optimize brain function.

“We’ve seen previous research that’s shown poor sleep contributes to dementia risk, as well as research showing sleep duration may play a role in cognition,” she said.

“We also need studies that look at sleep as an intervention for cognitive health,” Dr. Snyder said. “Sleep is an important aspect of our overall health. Clinicians should have conversations with their patients about sleep as part of standard discussions about their health habits and wellness.”

The study was funded by the National Institutes of Health, the American Sleep Medicine Foundation, the Roger and Paula Riney Fund, and the Daniel J. Brennan, MD Fund. Dr. Lucey consults for Merck and Eli Lilly. Dr. Snyder has disclosed no relevant financial relationships. Full disclosures are included in the original article.

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

Sleeping too much or too little can lead to cognitive decline over time, but new research suggests there could be a sleep time “sweet spot” that stabilizes cognitive function.

In a longitudinal study, investigators found older adults who slept less than 4.5 hours or more than 6.5 hours a night reported significant cognitive decline over time, but cognitive scores for those with sleep duration in between that range remained stable.

“This really suggests that there’s this middle range, a ‘sweet spot,’ where your sleep is really optimal,” said lead author Brendan Lucey, MD, MSCI, associate professor of neurology and director of the Washington University Sleep Medicine Center, St. Louis.

The study, published online Oct. 20 in Brain, is part of a growing body of research that seeks to determine if sleep can be used as a marker of Alzheimer’s disease progression.
 

A complex relationship

Studies suggest a strong relationship between sleep patterns and Alzheimer’s disease, which affects nearly 6 million Americans. The challenge, Dr. Lucey said, is unwinding the complex links between sleep, Alzheimer’s disease, and cognitive function.

An earlier study by Dr. Lucey and colleagues found that poor sleep quality is associated with early signs of Alzheimer’s disease, and a report published in September found that elderly people who slept less than 6 hours a night had a greater burden of amyloid beta, a hallmark sign of Alzheimer’s disease.

For this new study, researchers monitored sleep-wake activity over 4-6 nights in 100 participants who underwent annual cognitive assessments and clinical studies, including APOE genotyping, as part of a longitudinal study at the Knight Alzheimer Disease Research Center at Washington University. Participants also provided cerebrospinal fluid (CSF) total tau and amyloid-beta42 and wore a small EEG device on their forehead while they slept.

The majority of participants had a clinical dementia rating (CDR) score of 0, indicating no cognitive impairment. Twelve individuals had a CDR >0, with most reporting mild cognitive impairment.

As expected, CSF analysis showed greater evidence of Alzheimer’s disease pathology in those with a baseline CDR greater than 0.

Changes in cognitive function were measured using a Preclinical Alzheimer Cognitive Composite (PACC) score, a composite of results from a neuropsychological testing battery that included the Free and Cued Selective Reminding Test, the Logical Memory Delayed Recall Test from the Wechsler Memory Scale-Revised, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale-Revised, and the Mini-Mental State Examination.

Researchers found an upside-down U-shaped relationship between PACC scores and sleep duration, with dramatic cognitive decline in those who slept less than 4.5 hours or more than 6.5 hours a night (P < .001 for both). The U-shaped relationship was also found with measures of sleep phases, including time spent in rapid eye movement and in non-REM sleep (P < .001 for both).

The findings persisted even after controlling for confounders that can affect sleep and cognition, such as age, CSF total tau/amyloid-beta-42 ratio, APOE ε4 allele carrier status, years of education, and sex.

Understanding how sleep changes at different stages of Alzheimer’s disease could help researchers determine if sleep can be used as a marker of disease progression, Dr. Lucey said. That could lead to interventions to slow that process.

“We’re not at the point yet where we can say that we need to monitor someone’s sleep time and then do an intervention to see if it would improve their risk for cognitive decline,” said Dr. Lucey, who plans to repeat this sleep study with the same cohort to track changes in sleep patterns and cognitive function over time. “But that’s a question I’m very excited to try to answer.”
 

A component of cognitive health

Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, noted that the study adds to a body of evidence linking sleep and cognition, especially how sleep quality can optimize brain function.

“We’ve seen previous research that’s shown poor sleep contributes to dementia risk, as well as research showing sleep duration may play a role in cognition,” she said.

“We also need studies that look at sleep as an intervention for cognitive health,” Dr. Snyder said. “Sleep is an important aspect of our overall health. Clinicians should have conversations with their patients about sleep as part of standard discussions about their health habits and wellness.”

The study was funded by the National Institutes of Health, the American Sleep Medicine Foundation, the Roger and Paula Riney Fund, and the Daniel J. Brennan, MD Fund. Dr. Lucey consults for Merck and Eli Lilly. Dr. Snyder has disclosed no relevant financial relationships. Full disclosures are included in the original article.

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

Sleeping too much or too little can lead to cognitive decline over time, but new research suggests there could be a sleep time “sweet spot” that stabilizes cognitive function.

In a longitudinal study, investigators found older adults who slept less than 4.5 hours or more than 6.5 hours a night reported significant cognitive decline over time, but cognitive scores for those with sleep duration in between that range remained stable.

“This really suggests that there’s this middle range, a ‘sweet spot,’ where your sleep is really optimal,” said lead author Brendan Lucey, MD, MSCI, associate professor of neurology and director of the Washington University Sleep Medicine Center, St. Louis.

The study, published online Oct. 20 in Brain, is part of a growing body of research that seeks to determine if sleep can be used as a marker of Alzheimer’s disease progression.
 

A complex relationship

Studies suggest a strong relationship between sleep patterns and Alzheimer’s disease, which affects nearly 6 million Americans. The challenge, Dr. Lucey said, is unwinding the complex links between sleep, Alzheimer’s disease, and cognitive function.

An earlier study by Dr. Lucey and colleagues found that poor sleep quality is associated with early signs of Alzheimer’s disease, and a report published in September found that elderly people who slept less than 6 hours a night had a greater burden of amyloid beta, a hallmark sign of Alzheimer’s disease.

For this new study, researchers monitored sleep-wake activity over 4-6 nights in 100 participants who underwent annual cognitive assessments and clinical studies, including APOE genotyping, as part of a longitudinal study at the Knight Alzheimer Disease Research Center at Washington University. Participants also provided cerebrospinal fluid (CSF) total tau and amyloid-beta42 and wore a small EEG device on their forehead while they slept.

The majority of participants had a clinical dementia rating (CDR) score of 0, indicating no cognitive impairment. Twelve individuals had a CDR >0, with most reporting mild cognitive impairment.

As expected, CSF analysis showed greater evidence of Alzheimer’s disease pathology in those with a baseline CDR greater than 0.

Changes in cognitive function were measured using a Preclinical Alzheimer Cognitive Composite (PACC) score, a composite of results from a neuropsychological testing battery that included the Free and Cued Selective Reminding Test, the Logical Memory Delayed Recall Test from the Wechsler Memory Scale-Revised, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale-Revised, and the Mini-Mental State Examination.

Researchers found an upside-down U-shaped relationship between PACC scores and sleep duration, with dramatic cognitive decline in those who slept less than 4.5 hours or more than 6.5 hours a night (P < .001 for both). The U-shaped relationship was also found with measures of sleep phases, including time spent in rapid eye movement and in non-REM sleep (P < .001 for both).

The findings persisted even after controlling for confounders that can affect sleep and cognition, such as age, CSF total tau/amyloid-beta-42 ratio, APOE ε4 allele carrier status, years of education, and sex.

Understanding how sleep changes at different stages of Alzheimer’s disease could help researchers determine if sleep can be used as a marker of disease progression, Dr. Lucey said. That could lead to interventions to slow that process.

“We’re not at the point yet where we can say that we need to monitor someone’s sleep time and then do an intervention to see if it would improve their risk for cognitive decline,” said Dr. Lucey, who plans to repeat this sleep study with the same cohort to track changes in sleep patterns and cognitive function over time. “But that’s a question I’m very excited to try to answer.”
 

A component of cognitive health

Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, noted that the study adds to a body of evidence linking sleep and cognition, especially how sleep quality can optimize brain function.

“We’ve seen previous research that’s shown poor sleep contributes to dementia risk, as well as research showing sleep duration may play a role in cognition,” she said.

“We also need studies that look at sleep as an intervention for cognitive health,” Dr. Snyder said. “Sleep is an important aspect of our overall health. Clinicians should have conversations with their patients about sleep as part of standard discussions about their health habits and wellness.”

The study was funded by the National Institutes of Health, the American Sleep Medicine Foundation, the Roger and Paula Riney Fund, and the Daniel J. Brennan, MD Fund. Dr. Lucey consults for Merck and Eli Lilly. Dr. Snyder has disclosed no relevant financial relationships. Full disclosures are included in the original article.

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

Near-infrared light delivered to the brain using a specially designed helmet appears to improve memory, motor function, and processing skills in cognitively healthy older adults, in new findings that suggest potential benefit in patients with dementia.

Studies in animals and people have shown “many positive effects” with near-infrared transcranial photobiomodulation therapy (PBM-T), study investigator Paul Chazot, PhD, department of biosciences, Durham University, United Kingdom, told this news organization.

For example, PBM-T has been shown to increase blood circulation (which keeps the brain well oxygenated), boost mitochondria function in neurons, protect neurons from oxidative stress, and help maintain neuronal connectivity, Dr. Chazot explained.

PBM-T has also been shown to reduce amyloid and phosphorylated tau load, pathological signs of Alzheimer’s disease.

“All these in combination improve memory performance and mobility,” Dr. Chazot said.

The study was published online October 18 in Photobiomodulation, Photomedicine and Laser Surgery. 
 

Promising early data

In the study, 14 healthy adults, aged 45 to 70 years, received 6 minutes of transcranial PBM-T twice daily at a wavelength of 1,068 nanometers over 4 weeks. PBM-T was delivered via a helmet that comprised 14 air-cooled light emitting diode panel arrays. A control group of 13 adults used a sham PBM-T helmet.

Before and after active and sham treatment, all participants completed the automated neuropsychological assessment metrics (ANAM) – a computer-based tool designed to detect speed and accuracy of attention, memory, and thinking ability.

According to the research team, compared with sham PBM-T, those receiving active PBM-T showed significant improvement in motor function (finger tapping), working memory, delayed memory, and brain processing speed, the research team reports. No adverse effects were reported.

“This study complements our other recent studies, which showed improvement in memory performance with no obvious side effects,” said Dr. Chazot.

“While this is a pilot study and more research is needed, there are promising indications that therapy involving infrared light might also be beneficial for people living with dementia, and this is worth exploring,” Dr. Chazot added in a news release.

The PBM-T helmet was devised by first author Gordon Dougal, MBChB, of Maculume in the U.K., and a general practitioner based in Durham.

A recent study by Mr. Dougal, Dr. Chazot, and collaborators in the United States provides early evidence that PBM-T can improve memory in adults with dementia.

In that study, 39 patients received 6 minutes of PBM-T twice a day for 8 weeks, alongside a control group of 17 patients who received sham PBM-T.

After 8 weeks, there was about a 20% improvement in Mini-Mental State Exam (MMSE) scores in the active PBM-T group compared with roughly a 6% improvement in the control group, the researchers report in the journal Cureus.
 

More research needed

Reached for comment, Rebecca Edelmayer, PhD, Alzheimer’s Association senior director of scientific engagement, said using light to stimulate the brain is “an emerging technology.”

“However, this is a very small study in healthy volunteers, therefore we don’t know from this work alone if this approach would work as an intervention or reduce [the] risk of cognitive decline,” Dr. Edelmayer told this news organization.

“That being said, we’re starting to see companies looking at similar, noninvasive methods of stimulating the brain. For example, brain stimulation devices have been applied to other neurodegenerative diseases like Parkinson’s to try to prevent degeneration of brain cells,” Dr. Edelmayer noted. 

She said more research is needed to understand how photobiomodulation might be used as a therapy or prevention for cognitive decline and dementia.

“Specifically, we need to understand what parts of the brain need to be targeted and at what point(s) in the disease course this treatment would be most impactful. If proven to be effective, this could possibly be part of an approach that’s combined with other treatments, like drugs and lifestyle interventions,” said Dr. Edelmayer.

The Alzheimer’s Association is funding a number of projects looking at noninvasive treatments for Alzheimer’s disease, including two clinical trials looking at deep brain stimulation and photobiomodulation.

Maculume provided funding for the study. Mr. Dougal is a majority shareholder in the company, which manufactures the helmet device used in the study. Dr. Chazot, study co-authors, and Dr. Edelmayer have disclosed no relevant financial relationships.

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

Near-infrared light delivered to the brain using a specially designed helmet appears to improve memory, motor function, and processing skills in cognitively healthy older adults, in new findings that suggest potential benefit in patients with dementia.

Studies in animals and people have shown “many positive effects” with near-infrared transcranial photobiomodulation therapy (PBM-T), study investigator Paul Chazot, PhD, department of biosciences, Durham University, United Kingdom, told this news organization.

For example, PBM-T has been shown to increase blood circulation (which keeps the brain well oxygenated), boost mitochondria function in neurons, protect neurons from oxidative stress, and help maintain neuronal connectivity, Dr. Chazot explained.

PBM-T has also been shown to reduce amyloid and phosphorylated tau load, pathological signs of Alzheimer’s disease.

“All these in combination improve memory performance and mobility,” Dr. Chazot said.

The study was published online October 18 in Photobiomodulation, Photomedicine and Laser Surgery. 
 

Promising early data

In the study, 14 healthy adults, aged 45 to 70 years, received 6 minutes of transcranial PBM-T twice daily at a wavelength of 1,068 nanometers over 4 weeks. PBM-T was delivered via a helmet that comprised 14 air-cooled light emitting diode panel arrays. A control group of 13 adults used a sham PBM-T helmet.

Before and after active and sham treatment, all participants completed the automated neuropsychological assessment metrics (ANAM) – a computer-based tool designed to detect speed and accuracy of attention, memory, and thinking ability.

According to the research team, compared with sham PBM-T, those receiving active PBM-T showed significant improvement in motor function (finger tapping), working memory, delayed memory, and brain processing speed, the research team reports. No adverse effects were reported.

“This study complements our other recent studies, which showed improvement in memory performance with no obvious side effects,” said Dr. Chazot.

“While this is a pilot study and more research is needed, there are promising indications that therapy involving infrared light might also be beneficial for people living with dementia, and this is worth exploring,” Dr. Chazot added in a news release.

The PBM-T helmet was devised by first author Gordon Dougal, MBChB, of Maculume in the U.K., and a general practitioner based in Durham.

A recent study by Mr. Dougal, Dr. Chazot, and collaborators in the United States provides early evidence that PBM-T can improve memory in adults with dementia.

In that study, 39 patients received 6 minutes of PBM-T twice a day for 8 weeks, alongside a control group of 17 patients who received sham PBM-T.

After 8 weeks, there was about a 20% improvement in Mini-Mental State Exam (MMSE) scores in the active PBM-T group compared with roughly a 6% improvement in the control group, the researchers report in the journal Cureus.
 

More research needed

Reached for comment, Rebecca Edelmayer, PhD, Alzheimer’s Association senior director of scientific engagement, said using light to stimulate the brain is “an emerging technology.”

“However, this is a very small study in healthy volunteers, therefore we don’t know from this work alone if this approach would work as an intervention or reduce [the] risk of cognitive decline,” Dr. Edelmayer told this news organization.

“That being said, we’re starting to see companies looking at similar, noninvasive methods of stimulating the brain. For example, brain stimulation devices have been applied to other neurodegenerative diseases like Parkinson’s to try to prevent degeneration of brain cells,” Dr. Edelmayer noted. 

She said more research is needed to understand how photobiomodulation might be used as a therapy or prevention for cognitive decline and dementia.

“Specifically, we need to understand what parts of the brain need to be targeted and at what point(s) in the disease course this treatment would be most impactful. If proven to be effective, this could possibly be part of an approach that’s combined with other treatments, like drugs and lifestyle interventions,” said Dr. Edelmayer.

The Alzheimer’s Association is funding a number of projects looking at noninvasive treatments for Alzheimer’s disease, including two clinical trials looking at deep brain stimulation and photobiomodulation.

Maculume provided funding for the study. Mr. Dougal is a majority shareholder in the company, which manufactures the helmet device used in the study. Dr. Chazot, study co-authors, and Dr. Edelmayer have disclosed no relevant financial relationships.

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

Near-infrared light delivered to the brain using a specially designed helmet appears to improve memory, motor function, and processing skills in cognitively healthy older adults, in new findings that suggest potential benefit in patients with dementia.

Studies in animals and people have shown “many positive effects” with near-infrared transcranial photobiomodulation therapy (PBM-T), study investigator Paul Chazot, PhD, department of biosciences, Durham University, United Kingdom, told this news organization.

For example, PBM-T has been shown to increase blood circulation (which keeps the brain well oxygenated), boost mitochondria function in neurons, protect neurons from oxidative stress, and help maintain neuronal connectivity, Dr. Chazot explained.

PBM-T has also been shown to reduce amyloid and phosphorylated tau load, pathological signs of Alzheimer’s disease.

“All these in combination improve memory performance and mobility,” Dr. Chazot said.

The study was published online October 18 in Photobiomodulation, Photomedicine and Laser Surgery. 
 

Promising early data

In the study, 14 healthy adults, aged 45 to 70 years, received 6 minutes of transcranial PBM-T twice daily at a wavelength of 1,068 nanometers over 4 weeks. PBM-T was delivered via a helmet that comprised 14 air-cooled light emitting diode panel arrays. A control group of 13 adults used a sham PBM-T helmet.

Before and after active and sham treatment, all participants completed the automated neuropsychological assessment metrics (ANAM) – a computer-based tool designed to detect speed and accuracy of attention, memory, and thinking ability.

According to the research team, compared with sham PBM-T, those receiving active PBM-T showed significant improvement in motor function (finger tapping), working memory, delayed memory, and brain processing speed, the research team reports. No adverse effects were reported.

“This study complements our other recent studies, which showed improvement in memory performance with no obvious side effects,” said Dr. Chazot.

“While this is a pilot study and more research is needed, there are promising indications that therapy involving infrared light might also be beneficial for people living with dementia, and this is worth exploring,” Dr. Chazot added in a news release.

The PBM-T helmet was devised by first author Gordon Dougal, MBChB, of Maculume in the U.K., and a general practitioner based in Durham.

A recent study by Mr. Dougal, Dr. Chazot, and collaborators in the United States provides early evidence that PBM-T can improve memory in adults with dementia.

In that study, 39 patients received 6 minutes of PBM-T twice a day for 8 weeks, alongside a control group of 17 patients who received sham PBM-T.

After 8 weeks, there was about a 20% improvement in Mini-Mental State Exam (MMSE) scores in the active PBM-T group compared with roughly a 6% improvement in the control group, the researchers report in the journal Cureus.
 

More research needed

Reached for comment, Rebecca Edelmayer, PhD, Alzheimer’s Association senior director of scientific engagement, said using light to stimulate the brain is “an emerging technology.”

“However, this is a very small study in healthy volunteers, therefore we don’t know from this work alone if this approach would work as an intervention or reduce [the] risk of cognitive decline,” Dr. Edelmayer told this news organization.

“That being said, we’re starting to see companies looking at similar, noninvasive methods of stimulating the brain. For example, brain stimulation devices have been applied to other neurodegenerative diseases like Parkinson’s to try to prevent degeneration of brain cells,” Dr. Edelmayer noted. 

She said more research is needed to understand how photobiomodulation might be used as a therapy or prevention for cognitive decline and dementia.

“Specifically, we need to understand what parts of the brain need to be targeted and at what point(s) in the disease course this treatment would be most impactful. If proven to be effective, this could possibly be part of an approach that’s combined with other treatments, like drugs and lifestyle interventions,” said Dr. Edelmayer.

The Alzheimer’s Association is funding a number of projects looking at noninvasive treatments for Alzheimer’s disease, including two clinical trials looking at deep brain stimulation and photobiomodulation.

Maculume provided funding for the study. Mr. Dougal is a majority shareholder in the company, which manufactures the helmet device used in the study. Dr. Chazot, study co-authors, and Dr. Edelmayer have disclosed no relevant financial relationships.

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

The U.S. Food and Drug Administration has given marketing clearance to CognICA, an artificial intelligence–powered integrated cognitive assessment for the early detection of dementia.

Developed by Cognetivity Neurosciences, CognICA is a 5-minute, computerized cognitive assessment that is completed using an iPad. The test offers several advantages over traditional pen-and-paper–based cognitive tests, the company said in a news release.

“These include its high sensitivity to early-stage cognitive impairment, avoidance of cultural or educational bias, and absence of learning effect upon repeat testing,” the company notes.

Because the test runs on a computer, it can support remote, self-administered testing at scale and is geared toward seamless integration with existing electronic health record systems, they add.

According to the latest Alzheimer’s Disease Facts and Figures, published by the Alzheimer’s Association, more than 6 million Americans are now living with Alzheimer’s disease. That number is projected to increase to 12.7 million by 2050.

“We’re excited about the opportunity to revolutionize the way cognitive impairment is assessed and managed in the U.S. and make a positive impact on the health and wellbeing of millions of Americans,” Sina Habibi, PhD, cofounder and CEO of Cognetivity, said in the news release.

The test has already received European regulatory approval as a CE-marked medical device and has been deployed in both primary and specialist clinical care in the U.K.’s National Health Service.

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

The U.S. Food and Drug Administration has given marketing clearance to CognICA, an artificial intelligence–powered integrated cognitive assessment for the early detection of dementia.

Developed by Cognetivity Neurosciences, CognICA is a 5-minute, computerized cognitive assessment that is completed using an iPad. The test offers several advantages over traditional pen-and-paper–based cognitive tests, the company said in a news release.

“These include its high sensitivity to early-stage cognitive impairment, avoidance of cultural or educational bias, and absence of learning effect upon repeat testing,” the company notes.

Because the test runs on a computer, it can support remote, self-administered testing at scale and is geared toward seamless integration with existing electronic health record systems, they add.

According to the latest Alzheimer’s Disease Facts and Figures, published by the Alzheimer’s Association, more than 6 million Americans are now living with Alzheimer’s disease. That number is projected to increase to 12.7 million by 2050.

“We’re excited about the opportunity to revolutionize the way cognitive impairment is assessed and managed in the U.S. and make a positive impact on the health and wellbeing of millions of Americans,” Sina Habibi, PhD, cofounder and CEO of Cognetivity, said in the news release.

The test has already received European regulatory approval as a CE-marked medical device and has been deployed in both primary and specialist clinical care in the U.K.’s National Health Service.

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

The U.S. Food and Drug Administration has given marketing clearance to CognICA, an artificial intelligence–powered integrated cognitive assessment for the early detection of dementia.

Developed by Cognetivity Neurosciences, CognICA is a 5-minute, computerized cognitive assessment that is completed using an iPad. The test offers several advantages over traditional pen-and-paper–based cognitive tests, the company said in a news release.

“These include its high sensitivity to early-stage cognitive impairment, avoidance of cultural or educational bias, and absence of learning effect upon repeat testing,” the company notes.

Because the test runs on a computer, it can support remote, self-administered testing at scale and is geared toward seamless integration with existing electronic health record systems, they add.

According to the latest Alzheimer’s Disease Facts and Figures, published by the Alzheimer’s Association, more than 6 million Americans are now living with Alzheimer’s disease. That number is projected to increase to 12.7 million by 2050.

“We’re excited about the opportunity to revolutionize the way cognitive impairment is assessed and managed in the U.S. and make a positive impact on the health and wellbeing of millions of Americans,” Sina Habibi, PhD, cofounder and CEO of Cognetivity, said in the news release.

The test has already received European regulatory approval as a CE-marked medical device and has been deployed in both primary and specialist clinical care in the U.K.’s National Health Service.

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

Dementia remains a major cause of disability in older adults. In addition, it places a strain on family members and other caregivers taking care of these patients.

It is estimated that by the year 2060, 13.9 million Americans over the age of 65 will be diagnosed with dementia. Few good treatments are currently available.

Earlier this year, the American Psychological Association (APA) Task Force issued clinical guidelines “for the Evaluation of Dementia and Age-Related Cognitive Change.” While these 16 guidelines are aimed at psychologists, primary care doctors are often the first ones to evaluate a patient who may have dementia. As a family physician, I find having these guidelines especially helpful.
 

Neuropsychiatric testing and defining severity and type

This new guidance places emphasis on neuropsychiatric testing and defining the severity and type of dementia present.

Over the past 2 decades, diagnoses of mild neurocognitive disorders have increased, and this, in part, is due to diagnosing these problems earlier and with greater precision. It is also important to know that biomarkers are being increasingly researched, and it is imperative that we stay current with this research.

Cognitive decline may also occur with the coexistence of other mental health disorders, such as depression, so it is important that we screen for these as well. This is often difficult given the behavioral changes that can arise in dementia, but, as primary care doctors, we must differentiate these to treat our patients appropriately.
 

Informed consent

Informed consent can become an issue with patients with dementia. It must be assessed whether the patient has the capacity to make an informed decision and can competently communicate that decision.

The diagnosis of dementia alone does not preclude a patient from giving informed consent. A patient’s mental capacity must be determined, and if they are not capable of making an informed decision, the person legally responsible for giving informed consent on behalf of the patient must be identified.

Patients with dementia often have other medical comorbidities and take several medications. It is imperative to keep accurate medical records and medication lists. Sometimes, patients with dementia cannot provide this information. If that is the case, every attempt should be made to obtain records from every possible source.
 

Cultural competence

The guidelines also stress that there may be cultural differences when applying neuropsychiatric tests. It is our duty to maintain cultural competence and understand these differences. We all need to work to ensure we control our biases, and it is suggested that we review relevant evidence-based literature.

While ageism is common in our society, it shouldn’t be in our practices. For these reasons, outreach in at-risk populations is very important.
 

Pertinent data

The guidelines also suggest obtaining all possible information in our evaluation, especially when the patient is unable to give it to us.

Often, as primary care physicians, we refer these patients to other providers, and we should be providing all pertinent data to those we are referring these patients to. If all information is not available at the time of evaluation, follow-up visits should be scheduled.

If possible, family members should be present at the time of visit. They often provide valuable information regarding the extent and progression of the decline. Also, they know how the patient is functioning in the home setting and how much assistance they need with activities of daily living.
 

Caretaker support

Another important factor to consider is caretaker burnout. Caretakers are often under a lot of stress and have high rates of depression. It is important to provide them with education and support, as well as resources that may be available to them. For some, accepting the diagnosis that their loved one has dementia may be a struggle.

As doctors treating dementia patients, we need to know the resources that are available to assist dementia patients and their families. There are many local organizations that can help.

Also, research into dementia is ongoing and we need to stay current. The diagnosis of dementia should be made as early as possible using appropriate screening tools. The sooner the diagnosis is made, the quicker interventions can be started and the family members, as well as the patient, can come to accept the diagnosis.

As the population ages, we can expect the demands of dementia to rise as well. Primary care doctors are in a unique position to diagnose dementia once it starts to appear.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].

Dementia remains a major cause of disability in older adults. In addition, it places a strain on family members and other caregivers taking care of these patients.

It is estimated that by the year 2060, 13.9 million Americans over the age of 65 will be diagnosed with dementia. Few good treatments are currently available.

Earlier this year, the American Psychological Association (APA) Task Force issued clinical guidelines “for the Evaluation of Dementia and Age-Related Cognitive Change.” While these 16 guidelines are aimed at psychologists, primary care doctors are often the first ones to evaluate a patient who may have dementia. As a family physician, I find having these guidelines especially helpful.
 

Neuropsychiatric testing and defining severity and type

This new guidance places emphasis on neuropsychiatric testing and defining the severity and type of dementia present.

Over the past 2 decades, diagnoses of mild neurocognitive disorders have increased, and this, in part, is due to diagnosing these problems earlier and with greater precision. It is also important to know that biomarkers are being increasingly researched, and it is imperative that we stay current with this research.

Cognitive decline may also occur with the coexistence of other mental health disorders, such as depression, so it is important that we screen for these as well. This is often difficult given the behavioral changes that can arise in dementia, but, as primary care doctors, we must differentiate these to treat our patients appropriately.
 

Informed consent

Informed consent can become an issue with patients with dementia. It must be assessed whether the patient has the capacity to make an informed decision and can competently communicate that decision.

The diagnosis of dementia alone does not preclude a patient from giving informed consent. A patient’s mental capacity must be determined, and if they are not capable of making an informed decision, the person legally responsible for giving informed consent on behalf of the patient must be identified.

Patients with dementia often have other medical comorbidities and take several medications. It is imperative to keep accurate medical records and medication lists. Sometimes, patients with dementia cannot provide this information. If that is the case, every attempt should be made to obtain records from every possible source.
 

Cultural competence

The guidelines also stress that there may be cultural differences when applying neuropsychiatric tests. It is our duty to maintain cultural competence and understand these differences. We all need to work to ensure we control our biases, and it is suggested that we review relevant evidence-based literature.

While ageism is common in our society, it shouldn’t be in our practices. For these reasons, outreach in at-risk populations is very important.
 

Pertinent data

The guidelines also suggest obtaining all possible information in our evaluation, especially when the patient is unable to give it to us.

Often, as primary care physicians, we refer these patients to other providers, and we should be providing all pertinent data to those we are referring these patients to. If all information is not available at the time of evaluation, follow-up visits should be scheduled.

If possible, family members should be present at the time of visit. They often provide valuable information regarding the extent and progression of the decline. Also, they know how the patient is functioning in the home setting and how much assistance they need with activities of daily living.
 

Caretaker support

Another important factor to consider is caretaker burnout. Caretakers are often under a lot of stress and have high rates of depression. It is important to provide them with education and support, as well as resources that may be available to them. For some, accepting the diagnosis that their loved one has dementia may be a struggle.

As doctors treating dementia patients, we need to know the resources that are available to assist dementia patients and their families. There are many local organizations that can help.

Also, research into dementia is ongoing and we need to stay current. The diagnosis of dementia should be made as early as possible using appropriate screening tools. The sooner the diagnosis is made, the quicker interventions can be started and the family members, as well as the patient, can come to accept the diagnosis.

As the population ages, we can expect the demands of dementia to rise as well. Primary care doctors are in a unique position to diagnose dementia once it starts to appear.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].

Dementia remains a major cause of disability in older adults. In addition, it places a strain on family members and other caregivers taking care of these patients.

It is estimated that by the year 2060, 13.9 million Americans over the age of 65 will be diagnosed with dementia. Few good treatments are currently available.

Earlier this year, the American Psychological Association (APA) Task Force issued clinical guidelines “for the Evaluation of Dementia and Age-Related Cognitive Change.” While these 16 guidelines are aimed at psychologists, primary care doctors are often the first ones to evaluate a patient who may have dementia. As a family physician, I find having these guidelines especially helpful.
 

Neuropsychiatric testing and defining severity and type

This new guidance places emphasis on neuropsychiatric testing and defining the severity and type of dementia present.

Over the past 2 decades, diagnoses of mild neurocognitive disorders have increased, and this, in part, is due to diagnosing these problems earlier and with greater precision. It is also important to know that biomarkers are being increasingly researched, and it is imperative that we stay current with this research.

Cognitive decline may also occur with the coexistence of other mental health disorders, such as depression, so it is important that we screen for these as well. This is often difficult given the behavioral changes that can arise in dementia, but, as primary care doctors, we must differentiate these to treat our patients appropriately.
 

Informed consent

Informed consent can become an issue with patients with dementia. It must be assessed whether the patient has the capacity to make an informed decision and can competently communicate that decision.

The diagnosis of dementia alone does not preclude a patient from giving informed consent. A patient’s mental capacity must be determined, and if they are not capable of making an informed decision, the person legally responsible for giving informed consent on behalf of the patient must be identified.

Patients with dementia often have other medical comorbidities and take several medications. It is imperative to keep accurate medical records and medication lists. Sometimes, patients with dementia cannot provide this information. If that is the case, every attempt should be made to obtain records from every possible source.
 

Cultural competence

The guidelines also stress that there may be cultural differences when applying neuropsychiatric tests. It is our duty to maintain cultural competence and understand these differences. We all need to work to ensure we control our biases, and it is suggested that we review relevant evidence-based literature.

While ageism is common in our society, it shouldn’t be in our practices. For these reasons, outreach in at-risk populations is very important.
 

Pertinent data

The guidelines also suggest obtaining all possible information in our evaluation, especially when the patient is unable to give it to us.

Often, as primary care physicians, we refer these patients to other providers, and we should be providing all pertinent data to those we are referring these patients to. If all information is not available at the time of evaluation, follow-up visits should be scheduled.

If possible, family members should be present at the time of visit. They often provide valuable information regarding the extent and progression of the decline. Also, they know how the patient is functioning in the home setting and how much assistance they need with activities of daily living.
 

Caretaker support

Another important factor to consider is caretaker burnout. Caretakers are often under a lot of stress and have high rates of depression. It is important to provide them with education and support, as well as resources that may be available to them. For some, accepting the diagnosis that their loved one has dementia may be a struggle.

As doctors treating dementia patients, we need to know the resources that are available to assist dementia patients and their families. There are many local organizations that can help.

Also, research into dementia is ongoing and we need to stay current. The diagnosis of dementia should be made as early as possible using appropriate screening tools. The sooner the diagnosis is made, the quicker interventions can be started and the family members, as well as the patient, can come to accept the diagnosis.

As the population ages, we can expect the demands of dementia to rise as well. Primary care doctors are in a unique position to diagnose dementia once it starts to appear.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].

I recently saw a 62-year-old patient who had been struggling in her job at a law firm. She had been one of the top paralegals for over a decade, but recently had received a poor job performance. She told me she was forgetting things and was worried she might be developing dementia. Fortunately her problem stemmed from sleep apnea, and resolved with continuous positive airway pressure (CPAP) therapy.

Wallace and Bucks performed a meta analysis of 42 studies of memory in patients with sleep apnea and found sleep apnea patients were impaired when compared to healthy controls on verbal episodic memory (immediate recall, delayed recall, learning, and recognition) and visuospatial episodic memory (immediate and delayed recall).¹ A meta-analysis by Olaithe and associates found an improvement in executive function in patients with sleep apnea who were treated with CPAP.² I think this is worth considering especially in your patients who have subjective memory disturbances and do not appear to have a mild cognitive impairment or dementia.

About 15 years ago I saw a 74-year-old man for nocturia. He had seen two urologists and had a transurethral resection of the prostate (TURP) without any real change in his nocturia. I trialed him on all sorts of medications, and he seemed to improve temporarily a little on trazodone (went from seven episodes a night to four).

Eventually, after several years, I sent him for a sleep study. He had severe sleep apnea (Apnea Hypopnea Index, 65; O₂ saturations as low as 60%). With treatment, his nocturia resolved. He went from seven episodes to two each night.

Zhou and colleagues performed a meta-analysis of 13 studies looking at the association of sleep apnea with nocturia.³ They found that men with sleep apnea have a high incidence of nocturia.

Miyazato and colleagues looked at the effect of CPAP treatment on nighttime urine production in patients with obstructive sleep apnea.⁴ In this small study of 40 patients, mean nighttime voiding episodes decreased from 2.1 to 1.2 (P < .01).

I have seen several patients with night sweats who ended up having sleep apnea. These patients have had a resolution of their night sweats with sleep apnea treatment.

Arnardottir and colleagues found that obstructive sleep apnea was associated with frequent nocturnal sweating.⁵ They found that 31% of men and 33% of women with OSA had nocturnal sweating, compared with about 10% of the general population.

When the OSA patients were treated with positive airway pressure, the prevalence of nocturnal sweating decreased to 11.5%, which is similar to general population numbers. Given how common both sleep apnea and night sweats are, this is an important consideration as you evaluate night sweats.

I have seen many patients who have had atrial fibrillation and sleep apnea. Shapira-Daniels and colleagues did a prospective study of 188 patients with atrial fibrillation without a history of sleep apnea who were referred for ablation.⁶ All patients had home sleep studies, and testing was consistent with sleep apnea in 82% of patients.

Kanagala and associates found that patients with untreated sleep apnea had a greater chance of recurrent atrial fibrillation after cardioversion.⁷ Recurrence of atrial fibrillation at 12 months was 82% in untreated OSA patients, higher than the 42% recurrence in the treated OSA group (P = .013) and the 53% recurrence in control patients.

I think sleep apnea evaluation should be strongly considered in patients with atrial fibrillation and should be done before referral for ablations.

Pearl: Consider sleep apnea as a possible cause of or contributing factor to the common primary care problems of cognitive concerns, nocturia, night sweats, and atrial fibrillation.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as 3rd-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Wallace A and Bucks RS. Memory and obstructive sleep apnea: a meta-analysis. Sleep. 2013;36(2):203. Epub 2013 Feb 1.

2. Olaithe M and Bucks RS. Executive dysfunction in OSA before and after treatment: a meta-analysis. Sleep. 2013;36(9):1297. Epub 2013 Sep 1.

3. Zhou J et al. Association between obstructive sleep apnea syndrome and nocturia: a meta-analysis. Sleep Breath. 2020 Dec;24(4):1293-8.

4. Miyauchi Y et al. Effect of the continuous positive airway pressure on the nocturnal urine volume or night-time frequency in patients with obstructive sleep apnea syndrome. Urology 2015;85:333.

5. Arnardottir ES et al. Nocturnal sweating–a common symptom of obstructive sleep apnoea: the Icelandic sleep apnoea cohort. BMJ Open. 2013 May 14;3(5):e002795. BMJ Open 2013;3:e002795

6. Shapira-Daniels A et al. Prevalence of undiagnosed sleep apnea in patients with atrial fibrillation and its impact on therapy. JACC Clin Electrophysiol. 2020;6(12):1499. Epub 2020 Aug 12.

7. Kanagala R et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003;107(20):2589. Epub 2003 May 12.

I recently saw a 62-year-old patient who had been struggling in her job at a law firm. She had been one of the top paralegals for over a decade, but recently had received a poor job performance. She told me she was forgetting things and was worried she might be developing dementia. Fortunately her problem stemmed from sleep apnea, and resolved with continuous positive airway pressure (CPAP) therapy.

Wallace and Bucks performed a meta analysis of 42 studies of memory in patients with sleep apnea and found sleep apnea patients were impaired when compared to healthy controls on verbal episodic memory (immediate recall, delayed recall, learning, and recognition) and visuospatial episodic memory (immediate and delayed recall).¹ A meta-analysis by Olaithe and associates found an improvement in executive function in patients with sleep apnea who were treated with CPAP.² I think this is worth considering especially in your patients who have subjective memory disturbances and do not appear to have a mild cognitive impairment or dementia.

About 15 years ago I saw a 74-year-old man for nocturia. He had seen two urologists and had a transurethral resection of the prostate (TURP) without any real change in his nocturia. I trialed him on all sorts of medications, and he seemed to improve temporarily a little on trazodone (went from seven episodes a night to four).

Eventually, after several years, I sent him for a sleep study. He had severe sleep apnea (Apnea Hypopnea Index, 65; O₂ saturations as low as 60%). With treatment, his nocturia resolved. He went from seven episodes to two each night.

Zhou and colleagues performed a meta-analysis of 13 studies looking at the association of sleep apnea with nocturia.³ They found that men with sleep apnea have a high incidence of nocturia.

Miyazato and colleagues looked at the effect of CPAP treatment on nighttime urine production in patients with obstructive sleep apnea.⁴ In this small study of 40 patients, mean nighttime voiding episodes decreased from 2.1 to 1.2 (P < .01).

I have seen several patients with night sweats who ended up having sleep apnea. These patients have had a resolution of their night sweats with sleep apnea treatment.

Arnardottir and colleagues found that obstructive sleep apnea was associated with frequent nocturnal sweating.⁵ They found that 31% of men and 33% of women with OSA had nocturnal sweating, compared with about 10% of the general population.

When the OSA patients were treated with positive airway pressure, the prevalence of nocturnal sweating decreased to 11.5%, which is similar to general population numbers. Given how common both sleep apnea and night sweats are, this is an important consideration as you evaluate night sweats.

I have seen many patients who have had atrial fibrillation and sleep apnea. Shapira-Daniels and colleagues did a prospective study of 188 patients with atrial fibrillation without a history of sleep apnea who were referred for ablation.⁶ All patients had home sleep studies, and testing was consistent with sleep apnea in 82% of patients.

Kanagala and associates found that patients with untreated sleep apnea had a greater chance of recurrent atrial fibrillation after cardioversion.⁷ Recurrence of atrial fibrillation at 12 months was 82% in untreated OSA patients, higher than the 42% recurrence in the treated OSA group (P = .013) and the 53% recurrence in control patients.

I think sleep apnea evaluation should be strongly considered in patients with atrial fibrillation and should be done before referral for ablations.

Pearl: Consider sleep apnea as a possible cause of or contributing factor to the common primary care problems of cognitive concerns, nocturia, night sweats, and atrial fibrillation.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as 3rd-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Wallace A and Bucks RS. Memory and obstructive sleep apnea: a meta-analysis. Sleep. 2013;36(2):203. Epub 2013 Feb 1.

2. Olaithe M and Bucks RS. Executive dysfunction in OSA before and after treatment: a meta-analysis. Sleep. 2013;36(9):1297. Epub 2013 Sep 1.

3. Zhou J et al. Association between obstructive sleep apnea syndrome and nocturia: a meta-analysis. Sleep Breath. 2020 Dec;24(4):1293-8.

4. Miyauchi Y et al. Effect of the continuous positive airway pressure on the nocturnal urine volume or night-time frequency in patients with obstructive sleep apnea syndrome. Urology 2015;85:333.

5. Arnardottir ES et al. Nocturnal sweating–a common symptom of obstructive sleep apnoea: the Icelandic sleep apnoea cohort. BMJ Open. 2013 May 14;3(5):e002795. BMJ Open 2013;3:e002795

6. Shapira-Daniels A et al. Prevalence of undiagnosed sleep apnea in patients with atrial fibrillation and its impact on therapy. JACC Clin Electrophysiol. 2020;6(12):1499. Epub 2020 Aug 12.

7. Kanagala R et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003;107(20):2589. Epub 2003 May 12.

I recently saw a 62-year-old patient who had been struggling in her job at a law firm. She had been one of the top paralegals for over a decade, but recently had received a poor job performance. She told me she was forgetting things and was worried she might be developing dementia. Fortunately her problem stemmed from sleep apnea, and resolved with continuous positive airway pressure (CPAP) therapy.

Wallace and Bucks performed a meta analysis of 42 studies of memory in patients with sleep apnea and found sleep apnea patients were impaired when compared to healthy controls on verbal episodic memory (immediate recall, delayed recall, learning, and recognition) and visuospatial episodic memory (immediate and delayed recall).¹ A meta-analysis by Olaithe and associates found an improvement in executive function in patients with sleep apnea who were treated with CPAP.² I think this is worth considering especially in your patients who have subjective memory disturbances and do not appear to have a mild cognitive impairment or dementia.

About 15 years ago I saw a 74-year-old man for nocturia. He had seen two urologists and had a transurethral resection of the prostate (TURP) without any real change in his nocturia. I trialed him on all sorts of medications, and he seemed to improve temporarily a little on trazodone (went from seven episodes a night to four).

Eventually, after several years, I sent him for a sleep study. He had severe sleep apnea (Apnea Hypopnea Index, 65; O₂ saturations as low as 60%). With treatment, his nocturia resolved. He went from seven episodes to two each night.

Zhou and colleagues performed a meta-analysis of 13 studies looking at the association of sleep apnea with nocturia.³ They found that men with sleep apnea have a high incidence of nocturia.

Miyazato and colleagues looked at the effect of CPAP treatment on nighttime urine production in patients with obstructive sleep apnea.⁴ In this small study of 40 patients, mean nighttime voiding episodes decreased from 2.1 to 1.2 (P < .01).

I have seen several patients with night sweats who ended up having sleep apnea. These patients have had a resolution of their night sweats with sleep apnea treatment.

Arnardottir and colleagues found that obstructive sleep apnea was associated with frequent nocturnal sweating.⁵ They found that 31% of men and 33% of women with OSA had nocturnal sweating, compared with about 10% of the general population.

When the OSA patients were treated with positive airway pressure, the prevalence of nocturnal sweating decreased to 11.5%, which is similar to general population numbers. Given how common both sleep apnea and night sweats are, this is an important consideration as you evaluate night sweats.

I have seen many patients who have had atrial fibrillation and sleep apnea. Shapira-Daniels and colleagues did a prospective study of 188 patients with atrial fibrillation without a history of sleep apnea who were referred for ablation.⁶ All patients had home sleep studies, and testing was consistent with sleep apnea in 82% of patients.

Kanagala and associates found that patients with untreated sleep apnea had a greater chance of recurrent atrial fibrillation after cardioversion.⁷ Recurrence of atrial fibrillation at 12 months was 82% in untreated OSA patients, higher than the 42% recurrence in the treated OSA group (P = .013) and the 53% recurrence in control patients.

I think sleep apnea evaluation should be strongly considered in patients with atrial fibrillation and should be done before referral for ablations.

Pearl: Consider sleep apnea as a possible cause of or contributing factor to the common primary care problems of cognitive concerns, nocturia, night sweats, and atrial fibrillation.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as 3rd-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Wallace A and Bucks RS. Memory and obstructive sleep apnea: a meta-analysis. Sleep. 2013;36(2):203. Epub 2013 Feb 1.

2. Olaithe M and Bucks RS. Executive dysfunction in OSA before and after treatment: a meta-analysis. Sleep. 2013;36(9):1297. Epub 2013 Sep 1.

3. Zhou J et al. Association between obstructive sleep apnea syndrome and nocturia: a meta-analysis. Sleep Breath. 2020 Dec;24(4):1293-8.

4. Miyauchi Y et al. Effect of the continuous positive airway pressure on the nocturnal urine volume or night-time frequency in patients with obstructive sleep apnea syndrome. Urology 2015;85:333.

5. Arnardottir ES et al. Nocturnal sweating–a common symptom of obstructive sleep apnoea: the Icelandic sleep apnoea cohort. BMJ Open. 2013 May 14;3(5):e002795. BMJ Open 2013;3:e002795

6. Shapira-Daniels A et al. Prevalence of undiagnosed sleep apnea in patients with atrial fibrillation and its impact on therapy. JACC Clin Electrophysiol. 2020;6(12):1499. Epub 2020 Aug 12.

7. Kanagala R et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003;107(20):2589. Epub 2003 May 12.

Risk for Alzheimer’s disease (AD) and susceptibility to severe COVID-19 share a common genetic mechanism involved in the immune response to viruses, investigators report. The findings could lead to new treatment targets to slow progression and severity of both diseases.

Investigators found that a single genetic variant in the oligoadenylate synthetase 1 (OAS1) gene increases the risk for AD and that related variants in the same gene increase the likelihood of severe COVID-19 outcomes.

“These findings may allow us to identify new drug targets to slow progression of both diseases and reduce their severity,” Dervis Salih, PhD, senior research associate, UK Dementia Research Institute, University College London, said in an interview.

“Our work also suggests new approaches to treat both diseases with the same drugs,” Dr. Salih added.

The study was published online Oct. 7 in Brain.
 

Shared genetic network

The OAS1 gene is expressed in microglia, a type of immune cell that makes up around 10% of all cells in the brain.

In earlier work, investigators found evidence suggesting a link between the OAS1 gene and AD, but the function of the gene in microglia was unknown.

To further investigate the gene’s link to AD, they sequenced genetic data from 2,547 people – half with AD, and half without.

The genotyping analysis confirmed that the single-nucleotide polymorphism (SNP) rs1131454 within OAS1 is significantly associated with AD.

Given that the same OAS1 locus has recently been linked with severe COVID-19 outcomes, the researchers investigated four variants on the OAS1 gene.

Results indicate that SNPs within OAS1 associated with AD also show linkage to SNP variants associated with critical illness in COVID-19.

The rs1131454 (risk allele A) and rs4766676 (risk allele T) are associated with AD, and rs10735079 (risk allele A) and rs6489867 (risk allele T) are associated with critical illness with COVID-19, the investigators reported. All of these risk alleles dampen expression of OAS1.

“This study also provides strong new evidence that interferon signaling by the innate immune system plays a substantial role in the progression of Alzheimer’s,” said Dr. Salih.

“Identifying this shared genetic network in innate immune cells will allow us with future work to identify new biomarkers to track disease progression and also predict disease risk better for both disorders,” he added.
 

‘Fascinating’ link

In a statement from the UK nonprofit organization, Science Media Center, Kenneth Baillie, MBChB, with the University of Edinburgh, said this study builds on a discovery he and his colleagues made last year that OAS1 variants are associated with severe COVID-19.

“In the ISARIC4C study, we recently found that this is probably due to a change in the way cell membranes detect viruses, but this mechanism doesn’t explain the fascinating association with Alzheimer’s disease reported in this new work,” Dr. Baillie said.

“It is often the case that the same gene can have different roles in different parts of the body. Importantly, it doesn’t mean that having COVID-19 has any effect on your risk of Alzheimer’s,” he added.

Also weighing in on the new study, Jonathan Schott, MD, professor of neurology, University College London, noted that dementia is the “main preexisting health condition associated with COVID-19 mortality, accounting for about one in four deaths from COVID-19 between March and June 2020.

“While some of this excessive mortality may relate to people with dementia being overrepresented in care homes, which were particularly hard hit by the pandemic, or due to general increased vulnerability to infections, there have been questions as to whether there are common factors that might increase susceptibility both to developing dementia and to dying from COVID-19,” Dr. Schott explained.

This “elegant paper” provides evidence for the latter, “suggesting a common genetic mechanism both for Alzheimer’s disease and for severe COVID-19 infection,” Dr. Schott said.

“The identification of a genetic risk factor and elucidation of inflammatory pathways through which it may increase risk has important implications for our understanding of both diseases, with potential implications for novel treatments,” he added.

The study was funded by the UK Dementia Research Institute. The authors have disclosed no relevant financial relationships. Dr. Schott serves as chief medical officer for Alzheimer’s Research UK and is clinical adviser to the UK Dementia Research Institute. Dr. Baillie has disclosed no relevant financial relationships.

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

Risk for Alzheimer’s disease (AD) and susceptibility to severe COVID-19 share a common genetic mechanism involved in the immune response to viruses, investigators report. The findings could lead to new treatment targets to slow progression and severity of both diseases.

Investigators found that a single genetic variant in the oligoadenylate synthetase 1 (OAS1) gene increases the risk for AD and that related variants in the same gene increase the likelihood of severe COVID-19 outcomes.

“These findings may allow us to identify new drug targets to slow progression of both diseases and reduce their severity,” Dervis Salih, PhD, senior research associate, UK Dementia Research Institute, University College London, said in an interview.

“Our work also suggests new approaches to treat both diseases with the same drugs,” Dr. Salih added.

The study was published online Oct. 7 in Brain.
 

Shared genetic network

The OAS1 gene is expressed in microglia, a type of immune cell that makes up around 10% of all cells in the brain.

In earlier work, investigators found evidence suggesting a link between the OAS1 gene and AD, but the function of the gene in microglia was unknown.

To further investigate the gene’s link to AD, they sequenced genetic data from 2,547 people – half with AD, and half without.

The genotyping analysis confirmed that the single-nucleotide polymorphism (SNP) rs1131454 within OAS1 is significantly associated with AD.

Given that the same OAS1 locus has recently been linked with severe COVID-19 outcomes, the researchers investigated four variants on the OAS1 gene.

Results indicate that SNPs within OAS1 associated with AD also show linkage to SNP variants associated with critical illness in COVID-19.

The rs1131454 (risk allele A) and rs4766676 (risk allele T) are associated with AD, and rs10735079 (risk allele A) and rs6489867 (risk allele T) are associated with critical illness with COVID-19, the investigators reported. All of these risk alleles dampen expression of OAS1.

“This study also provides strong new evidence that interferon signaling by the innate immune system plays a substantial role in the progression of Alzheimer’s,” said Dr. Salih.

“Identifying this shared genetic network in innate immune cells will allow us with future work to identify new biomarkers to track disease progression and also predict disease risk better for both disorders,” he added.
 

‘Fascinating’ link

In a statement from the UK nonprofit organization, Science Media Center, Kenneth Baillie, MBChB, with the University of Edinburgh, said this study builds on a discovery he and his colleagues made last year that OAS1 variants are associated with severe COVID-19.

“In the ISARIC4C study, we recently found that this is probably due to a change in the way cell membranes detect viruses, but this mechanism doesn’t explain the fascinating association with Alzheimer’s disease reported in this new work,” Dr. Baillie said.

“It is often the case that the same gene can have different roles in different parts of the body. Importantly, it doesn’t mean that having COVID-19 has any effect on your risk of Alzheimer’s,” he added.

Also weighing in on the new study, Jonathan Schott, MD, professor of neurology, University College London, noted that dementia is the “main preexisting health condition associated with COVID-19 mortality, accounting for about one in four deaths from COVID-19 between March and June 2020.

“While some of this excessive mortality may relate to people with dementia being overrepresented in care homes, which were particularly hard hit by the pandemic, or due to general increased vulnerability to infections, there have been questions as to whether there are common factors that might increase susceptibility both to developing dementia and to dying from COVID-19,” Dr. Schott explained.

This “elegant paper” provides evidence for the latter, “suggesting a common genetic mechanism both for Alzheimer’s disease and for severe COVID-19 infection,” Dr. Schott said.

“The identification of a genetic risk factor and elucidation of inflammatory pathways through which it may increase risk has important implications for our understanding of both diseases, with potential implications for novel treatments,” he added.

The study was funded by the UK Dementia Research Institute. The authors have disclosed no relevant financial relationships. Dr. Schott serves as chief medical officer for Alzheimer’s Research UK and is clinical adviser to the UK Dementia Research Institute. Dr. Baillie has disclosed no relevant financial relationships.

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

Risk for Alzheimer’s disease (AD) and susceptibility to severe COVID-19 share a common genetic mechanism involved in the immune response to viruses, investigators report. The findings could lead to new treatment targets to slow progression and severity of both diseases.

Investigators found that a single genetic variant in the oligoadenylate synthetase 1 (OAS1) gene increases the risk for AD and that related variants in the same gene increase the likelihood of severe COVID-19 outcomes.

“These findings may allow us to identify new drug targets to slow progression of both diseases and reduce their severity,” Dervis Salih, PhD, senior research associate, UK Dementia Research Institute, University College London, said in an interview.

“Our work also suggests new approaches to treat both diseases with the same drugs,” Dr. Salih added.

The study was published online Oct. 7 in Brain.
 

Shared genetic network

The OAS1 gene is expressed in microglia, a type of immune cell that makes up around 10% of all cells in the brain.

In earlier work, investigators found evidence suggesting a link between the OAS1 gene and AD, but the function of the gene in microglia was unknown.

To further investigate the gene’s link to AD, they sequenced genetic data from 2,547 people – half with AD, and half without.

The genotyping analysis confirmed that the single-nucleotide polymorphism (SNP) rs1131454 within OAS1 is significantly associated with AD.

Given that the same OAS1 locus has recently been linked with severe COVID-19 outcomes, the researchers investigated four variants on the OAS1 gene.

Results indicate that SNPs within OAS1 associated with AD also show linkage to SNP variants associated with critical illness in COVID-19.

The rs1131454 (risk allele A) and rs4766676 (risk allele T) are associated with AD, and rs10735079 (risk allele A) and rs6489867 (risk allele T) are associated with critical illness with COVID-19, the investigators reported. All of these risk alleles dampen expression of OAS1.

“This study also provides strong new evidence that interferon signaling by the innate immune system plays a substantial role in the progression of Alzheimer’s,” said Dr. Salih.

“Identifying this shared genetic network in innate immune cells will allow us with future work to identify new biomarkers to track disease progression and also predict disease risk better for both disorders,” he added.
 

‘Fascinating’ link

In a statement from the UK nonprofit organization, Science Media Center, Kenneth Baillie, MBChB, with the University of Edinburgh, said this study builds on a discovery he and his colleagues made last year that OAS1 variants are associated with severe COVID-19.

“In the ISARIC4C study, we recently found that this is probably due to a change in the way cell membranes detect viruses, but this mechanism doesn’t explain the fascinating association with Alzheimer’s disease reported in this new work,” Dr. Baillie said.

“It is often the case that the same gene can have different roles in different parts of the body. Importantly, it doesn’t mean that having COVID-19 has any effect on your risk of Alzheimer’s,” he added.

Also weighing in on the new study, Jonathan Schott, MD, professor of neurology, University College London, noted that dementia is the “main preexisting health condition associated with COVID-19 mortality, accounting for about one in four deaths from COVID-19 between March and June 2020.

“While some of this excessive mortality may relate to people with dementia being overrepresented in care homes, which were particularly hard hit by the pandemic, or due to general increased vulnerability to infections, there have been questions as to whether there are common factors that might increase susceptibility both to developing dementia and to dying from COVID-19,” Dr. Schott explained.

This “elegant paper” provides evidence for the latter, “suggesting a common genetic mechanism both for Alzheimer’s disease and for severe COVID-19 infection,” Dr. Schott said.

“The identification of a genetic risk factor and elucidation of inflammatory pathways through which it may increase risk has important implications for our understanding of both diseases, with potential implications for novel treatments,” he added.

The study was funded by the UK Dementia Research Institute. The authors have disclosed no relevant financial relationships. Dr. Schott serves as chief medical officer for Alzheimer’s Research UK and is clinical adviser to the UK Dementia Research Institute. Dr. Baillie has disclosed no relevant financial relationships.

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

A drug approved to treat constipation appears to improve cognitive impairment and boost brain activity for patients with mental illness, new research suggests.

In a randomized controlled trial, 44 healthy individuals were assigned to receive the selective serotonin-4 (5-HT4) receptor agonist prucalopride (Motegrity) or placebo for 1 week.

After 6 days, the active-treatment group performed significantly better on memory tests than the participants who received placebo. In addition, the drug increased activity in brain areas related to cognition.

“What we’re hoping is...these agents may be able to help those with cognitive impairment as part of their mental illness,” lead author Angharad N. de Cates, a clinical DPhil student in the department of psychiatry, University of Oxford, Oxford, United Kingdom, told meeting attendees.

“Currently, we’re looking to see if we can translate our finding a step further and do a similar study in those with depression,” Ms. de Cates added.

The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress and were simultaneously published in Translational Psychiatry.
 

“Exciting early evidence”

“Even when the low mood associated with depression is well-treated with conventional antidepressants, many patients continue to experience problems with their memory,” co-investigator Susannah Murphy, PhD, a senior research fellow at the University of Oxford, said in a release.

“Our study provides exciting early evidence in humans of a new approach that might be a helpful way to treat these residual cognitive symptoms,” Dr. Murphy added.

Preclinical and animal studies suggest that the 5-HT4 receptor is a promising treatment target for cognitive impairment in individuals with psychiatric disorders, although studies in humans have been limited by the adverse effects of early agents.

“We’ve had our eye on this receptor for a while,” explained de Cates, inasmuch as the animal data “have been so good.”

However, she said in an interview that “a lack of safe human agents made translation tricky.”

As previously reported, prucalopride, a selective high-affinity 5-HT4 partial agonist, was approved in 2018 by the U.S. Food and Drug Administration for the treatment of chronic idiopathic constipation.

The current researchers note that the drug has “good brain penetration,” which “allowed us to investigate 5-HT4-receptor agonism in humans.”

Having previously shown that a single dose of the drug has “pro-cognitive effects,” the investigators conducted the new trial in 44 healthy participants. All were randomly assigned in a 1:1 ratio to receive either prucalopride 1 mg for 7 days or placebo.

In accordance with enrollment criteria, patients were 18 to 36 years of age, right-handed, and were not pregnant or breastfeeding. Participants’ body mass index was 18 to 30 kg/m², and they had no contraindications to the study drug. The two treatment groups were well balanced; the participants who received placebo were significantly more likely to be nonnative English speakers (P = .02).

On day 6 of treatment administration, all participants underwent 3T MRI.

Before undergoing imaging, the participants were presented with eight emotionally neutral images of animals or landscapes and were asked to indicate whether or not the images were of animals. The task was then repeated with the eight familiar images and eight novel ones.

During the scan, participants were shown the same images or eight novel images and were again asked whether or not the images contained an animal. They were also instructed to try to remember the images for a subsequent memory task. In that task, the eight original images, 48 novel images, and 27 “distractor” images were presented.
 

Better memory

In the pre-scan assessment, results showed no significant differences in the ability of members of the prucalopride and placebo groups to identify images as being familiar or different.

However, taking prucalopride was associated with significantly improved memory performance in the post-scan recall task.

Compared to the placebo group, participants in the prucalopride group were more accurate in selecting images as familiar vs distractors (P = .029) and in distinguishing images as familiar, novel, or distractors (P = .035).

Functional MRI revealed increased activity in the left and right hippocampus in response to both novel and familiar images among the participants in the prucalopride group in comparison with those in the placebo group.

There was also increased activity in the right angular gyrus in the prucalopride group in comparison with the placebo group in response to familiar images (P < .005).

“Clinically, angular gyri lesions cause language dysfunction, low mood, and poor memory and can mimic dementia or pseudodementia,” the investigators write. They note that the right angular gyrus “shows significantly decreased activity” in mild cognitive impairment.

“Therefore, the increased activity seen in the right angular gyrus following prucalopride administration in our study is consistent with the pro-cognitive behavioural effects we observed,” they add.

Ms. De Cates noted that the dose used in their study was lower than the 2 mg given for constipation.

“At the low dose, there were no differences in side effects between groups and no withdrawals from the prucalopride group for side effects. We are going to try increasing the dose in our next study actually, as we don’t have PET data to tell us what the optimal dose for binding at the receptor should be,” said Ms. de Cates.

“In safety studies, the dose was trialled in healthy volunteers at 4 mg, which was found to be safe, although perhaps less well tolerated than 2 mg,” she said.
 

Generalizable findings?

Commenting on the research, Vibe G. Frøkjær, MD, adjunct professor, department of psychology, Copenhagen University, Denmark, said the study “highlights a very interesting and much needed potential for repurposing drugs to help cognitive dysfunction.”

He noted that cognitive dysfunction is often associated with psychiatric disorders -- even in states of remission.

“Importantly, as the authors also state, it will be vital to translate these findings from healthy populations into clinical populations,” said Dr. Frøkjær, who was not involved in the research.

“It will also be important to understand if prucalopride adds to the effects of existing antidepressant treatments or can be used as a stand-alone therapy,” he added.

The study was funded by the NIHR Oxford Health Biomedical Research Center and by the Wellcome Center for Integrative Neuroscience. Ms. De Cates has received a travel grant from the Royal College of Psychiatrists/Gatsby Foundation and support from Wellcome. The other authors have relationships with P1vital Ltd, Janssen Pharmaceuticals, Sage Therapeutics, Pfizer, Zogenix, Compass Pathways, and Lundbeck.

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

A drug approved to treat constipation appears to improve cognitive impairment and boost brain activity for patients with mental illness, new research suggests.

In a randomized controlled trial, 44 healthy individuals were assigned to receive the selective serotonin-4 (5-HT4) receptor agonist prucalopride (Motegrity) or placebo for 1 week.

After 6 days, the active-treatment group performed significantly better on memory tests than the participants who received placebo. In addition, the drug increased activity in brain areas related to cognition.

“What we’re hoping is...these agents may be able to help those with cognitive impairment as part of their mental illness,” lead author Angharad N. de Cates, a clinical DPhil student in the department of psychiatry, University of Oxford, Oxford, United Kingdom, told meeting attendees.

“Currently, we’re looking to see if we can translate our finding a step further and do a similar study in those with depression,” Ms. de Cates added.

The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress and were simultaneously published in Translational Psychiatry.
 

“Exciting early evidence”

“Even when the low mood associated with depression is well-treated with conventional antidepressants, many patients continue to experience problems with their memory,” co-investigator Susannah Murphy, PhD, a senior research fellow at the University of Oxford, said in a release.

“Our study provides exciting early evidence in humans of a new approach that might be a helpful way to treat these residual cognitive symptoms,” Dr. Murphy added.

Preclinical and animal studies suggest that the 5-HT4 receptor is a promising treatment target for cognitive impairment in individuals with psychiatric disorders, although studies in humans have been limited by the adverse effects of early agents.

“We’ve had our eye on this receptor for a while,” explained de Cates, inasmuch as the animal data “have been so good.”

However, she said in an interview that “a lack of safe human agents made translation tricky.”

As previously reported, prucalopride, a selective high-affinity 5-HT4 partial agonist, was approved in 2018 by the U.S. Food and Drug Administration for the treatment of chronic idiopathic constipation.

The current researchers note that the drug has “good brain penetration,” which “allowed us to investigate 5-HT4-receptor agonism in humans.”

Having previously shown that a single dose of the drug has “pro-cognitive effects,” the investigators conducted the new trial in 44 healthy participants. All were randomly assigned in a 1:1 ratio to receive either prucalopride 1 mg for 7 days or placebo.

In accordance with enrollment criteria, patients were 18 to 36 years of age, right-handed, and were not pregnant or breastfeeding. Participants’ body mass index was 18 to 30 kg/m², and they had no contraindications to the study drug. The two treatment groups were well balanced; the participants who received placebo were significantly more likely to be nonnative English speakers (P = .02).

On day 6 of treatment administration, all participants underwent 3T MRI.

Before undergoing imaging, the participants were presented with eight emotionally neutral images of animals or landscapes and were asked to indicate whether or not the images were of animals. The task was then repeated with the eight familiar images and eight novel ones.

During the scan, participants were shown the same images or eight novel images and were again asked whether or not the images contained an animal. They were also instructed to try to remember the images for a subsequent memory task. In that task, the eight original images, 48 novel images, and 27 “distractor” images were presented.
 

Better memory

In the pre-scan assessment, results showed no significant differences in the ability of members of the prucalopride and placebo groups to identify images as being familiar or different.

However, taking prucalopride was associated with significantly improved memory performance in the post-scan recall task.

Compared to the placebo group, participants in the prucalopride group were more accurate in selecting images as familiar vs distractors (P = .029) and in distinguishing images as familiar, novel, or distractors (P = .035).

Functional MRI revealed increased activity in the left and right hippocampus in response to both novel and familiar images among the participants in the prucalopride group in comparison with those in the placebo group.

There was also increased activity in the right angular gyrus in the prucalopride group in comparison with the placebo group in response to familiar images (P < .005).

“Clinically, angular gyri lesions cause language dysfunction, low mood, and poor memory and can mimic dementia or pseudodementia,” the investigators write. They note that the right angular gyrus “shows significantly decreased activity” in mild cognitive impairment.

“Therefore, the increased activity seen in the right angular gyrus following prucalopride administration in our study is consistent with the pro-cognitive behavioural effects we observed,” they add.

Ms. De Cates noted that the dose used in their study was lower than the 2 mg given for constipation.

“At the low dose, there were no differences in side effects between groups and no withdrawals from the prucalopride group for side effects. We are going to try increasing the dose in our next study actually, as we don’t have PET data to tell us what the optimal dose for binding at the receptor should be,” said Ms. de Cates.

“In safety studies, the dose was trialled in healthy volunteers at 4 mg, which was found to be safe, although perhaps less well tolerated than 2 mg,” she said.
 

Generalizable findings?

Commenting on the research, Vibe G. Frøkjær, MD, adjunct professor, department of psychology, Copenhagen University, Denmark, said the study “highlights a very interesting and much needed potential for repurposing drugs to help cognitive dysfunction.”

He noted that cognitive dysfunction is often associated with psychiatric disorders -- even in states of remission.

“Importantly, as the authors also state, it will be vital to translate these findings from healthy populations into clinical populations,” said Dr. Frøkjær, who was not involved in the research.

“It will also be important to understand if prucalopride adds to the effects of existing antidepressant treatments or can be used as a stand-alone therapy,” he added.

The study was funded by the NIHR Oxford Health Biomedical Research Center and by the Wellcome Center for Integrative Neuroscience. Ms. De Cates has received a travel grant from the Royal College of Psychiatrists/Gatsby Foundation and support from Wellcome. The other authors have relationships with P1vital Ltd, Janssen Pharmaceuticals, Sage Therapeutics, Pfizer, Zogenix, Compass Pathways, and Lundbeck.

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

A drug approved to treat constipation appears to improve cognitive impairment and boost brain activity for patients with mental illness, new research suggests.

In a randomized controlled trial, 44 healthy individuals were assigned to receive the selective serotonin-4 (5-HT4) receptor agonist prucalopride (Motegrity) or placebo for 1 week.

After 6 days, the active-treatment group performed significantly better on memory tests than the participants who received placebo. In addition, the drug increased activity in brain areas related to cognition.

“What we’re hoping is...these agents may be able to help those with cognitive impairment as part of their mental illness,” lead author Angharad N. de Cates, a clinical DPhil student in the department of psychiatry, University of Oxford, Oxford, United Kingdom, told meeting attendees.

“Currently, we’re looking to see if we can translate our finding a step further and do a similar study in those with depression,” Ms. de Cates added.

The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress and were simultaneously published in Translational Psychiatry.
 

“Exciting early evidence”

“Even when the low mood associated with depression is well-treated with conventional antidepressants, many patients continue to experience problems with their memory,” co-investigator Susannah Murphy, PhD, a senior research fellow at the University of Oxford, said in a release.

“Our study provides exciting early evidence in humans of a new approach that might be a helpful way to treat these residual cognitive symptoms,” Dr. Murphy added.

Preclinical and animal studies suggest that the 5-HT4 receptor is a promising treatment target for cognitive impairment in individuals with psychiatric disorders, although studies in humans have been limited by the adverse effects of early agents.

“We’ve had our eye on this receptor for a while,” explained de Cates, inasmuch as the animal data “have been so good.”

However, she said in an interview that “a lack of safe human agents made translation tricky.”

As previously reported, prucalopride, a selective high-affinity 5-HT4 partial agonist, was approved in 2018 by the U.S. Food and Drug Administration for the treatment of chronic idiopathic constipation.

The current researchers note that the drug has “good brain penetration,” which “allowed us to investigate 5-HT4-receptor agonism in humans.”

Having previously shown that a single dose of the drug has “pro-cognitive effects,” the investigators conducted the new trial in 44 healthy participants. All were randomly assigned in a 1:1 ratio to receive either prucalopride 1 mg for 7 days or placebo.

In accordance with enrollment criteria, patients were 18 to 36 years of age, right-handed, and were not pregnant or breastfeeding. Participants’ body mass index was 18 to 30 kg/m², and they had no contraindications to the study drug. The two treatment groups were well balanced; the participants who received placebo were significantly more likely to be nonnative English speakers (P = .02).

On day 6 of treatment administration, all participants underwent 3T MRI.

Before undergoing imaging, the participants were presented with eight emotionally neutral images of animals or landscapes and were asked to indicate whether or not the images were of animals. The task was then repeated with the eight familiar images and eight novel ones.

During the scan, participants were shown the same images or eight novel images and were again asked whether or not the images contained an animal. They were also instructed to try to remember the images for a subsequent memory task. In that task, the eight original images, 48 novel images, and 27 “distractor” images were presented.
 

Better memory

In the pre-scan assessment, results showed no significant differences in the ability of members of the prucalopride and placebo groups to identify images as being familiar or different.

However, taking prucalopride was associated with significantly improved memory performance in the post-scan recall task.

Compared to the placebo group, participants in the prucalopride group were more accurate in selecting images as familiar vs distractors (P = .029) and in distinguishing images as familiar, novel, or distractors (P = .035).

Functional MRI revealed increased activity in the left and right hippocampus in response to both novel and familiar images among the participants in the prucalopride group in comparison with those in the placebo group.

There was also increased activity in the right angular gyrus in the prucalopride group in comparison with the placebo group in response to familiar images (P < .005).

“Clinically, angular gyri lesions cause language dysfunction, low mood, and poor memory and can mimic dementia or pseudodementia,” the investigators write. They note that the right angular gyrus “shows significantly decreased activity” in mild cognitive impairment.

“Therefore, the increased activity seen in the right angular gyrus following prucalopride administration in our study is consistent with the pro-cognitive behavioural effects we observed,” they add.

Ms. De Cates noted that the dose used in their study was lower than the 2 mg given for constipation.

“At the low dose, there were no differences in side effects between groups and no withdrawals from the prucalopride group for side effects. We are going to try increasing the dose in our next study actually, as we don’t have PET data to tell us what the optimal dose for binding at the receptor should be,” said Ms. de Cates.

“In safety studies, the dose was trialled in healthy volunteers at 4 mg, which was found to be safe, although perhaps less well tolerated than 2 mg,” she said.
 

Generalizable findings?

Commenting on the research, Vibe G. Frøkjær, MD, adjunct professor, department of psychology, Copenhagen University, Denmark, said the study “highlights a very interesting and much needed potential for repurposing drugs to help cognitive dysfunction.”

He noted that cognitive dysfunction is often associated with psychiatric disorders -- even in states of remission.

“Importantly, as the authors also state, it will be vital to translate these findings from healthy populations into clinical populations,” said Dr. Frøkjær, who was not involved in the research.

“It will also be important to understand if prucalopride adds to the effects of existing antidepressant treatments or can be used as a stand-alone therapy,” he added.

The study was funded by the NIHR Oxford Health Biomedical Research Center and by the Wellcome Center for Integrative Neuroscience. Ms. De Cates has received a travel grant from the Royal College of Psychiatrists/Gatsby Foundation and support from Wellcome. The other authors have relationships with P1vital Ltd, Janssen Pharmaceuticals, Sage Therapeutics, Pfizer, Zogenix, Compass Pathways, and Lundbeck.

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

Methylphenidate is safe and effective for treating apathy in patients with Alzheimer’s disease (AD), new research suggests.

Dundanim/shutterstock.com

Results from a phase 3 randomized trial showed that, after 6 months of treatment, mean score on the Neuropsychiatric Inventory (NPI) apathy subscale decreased by 4.5 points for patients who received methylphenidate vs. a decrease of 3.1 points for those who received placebo.

In addition, the safety profile showed no significant between-group differences.

“Methylphenidate offers a treatment approach providing a modest but potentially clinically significant benefit for patients and caregivers,” said the investigators, led by Jacobo E. Mintzer, MD, MBA, professor of health studies at the Medical University of South Carolina in Charleston.

The findings were published online Sept. 27 in JAMA Neurology.
 

Common problem

Apathy, which is common among patients with AD, is associated with increased risk for mortality, financial burden, and caregiver burden. No treatment has proved effective for apathy in this population.

Two trials of methylphenidate, a catecholaminergic agent, have provided preliminary evidence of efficacy. Findings from the Apathy in Dementia Methylphenidate trial (ADMET) suggested the drug was associated with improved cognition and few adverse events. However, both trials had small patient populations and short durations.

The current investigators conducted ADMET 2, a 6-month, phase 3 trial, to investigate methylphenidate further. They recruited 200 patients (mean age, 76 years; 66% men; 90% White) at nine clinical centers that specialized in dementia care in the United States and one in Canada.

Eligible patients had a diagnosis of possible or probable AD and a Mini-Mental State Examination (MMSE) score between 10 and 28. They also had clinically significant apathy for at least 4 weeks and an available caregiver who spent more than 10 hours a week with the patient.

The researchers randomly assigned patients to receive methylphenidate (n = 99) or placebo (n = 101). For 3 days, participants in the active group received 10 mg/day of methylphenidate. After that point, they received 20 mg/day of methylphenidate for the rest of the study.

Patients in both treatment groups were given the same number of identical-appearing capsules each day.

In-person follow-up visits took place monthly for 6 months. Participants also were contacted by telephone at days 15, 45, and 75 after treatment assignment.

Participants underwent cognitive testing at baseline and at 2, 4, and 6 months. The battery of tests included the MMSE, Hopkins Verbal Learning Test, and Wechsler Adult Intelligence Scale – Revised Digit Span.

The trial’s two primary outcomes were mean change in NPI apathy score from baseline to 6 months and the odds of an improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC) between baseline and 6 months.

Significant change on either outcome was to be considered a signal of effective treatment.
 

Treatment-specific benefit

Ten patients in the methylphenidate group and seven in the placebo group withdrew during the study.

Mean MMSE score at baseline was 19.2 in the methylphenidate group vs. 18.5 in the placebo group, indicating moderately severe dementia. Mean baseline score on the NPI apathy subscale was 8.0 vs. 7.6, respectively.

In an adjusted, longitudinal model, mean between-group difference in change in NPI apathy score at 6 months was –1.25 (P = .002). The mean NPI apathy score decreased by 4.5 points in the methylphenidate group vs. 3.1 points in the placebo group.

The largest change in apathy score occurred during the first 2 months of treatment. At 6 months, 27% of the methylphenidate group vs. 14% of the placebo group had an NPI apathy score of 0.

In addition, 43.8% of the methylphenidate group had improvement on the ADCS-CGIC compared with 35.2% of the placebo group. The odds ratio (OR) for improvement on ADCS-CGIC for methylphenidate vs. placebo was 1.90 (P = .07).

There was also a strong association between score improvement on the NPI apathy subscale and improvement on the ADCS-CGIC subscale (OR, 2.95; P = .002).

“It is important to note that there were no group differences in any of the cognitive measures, suggesting that the effect of the treatment is specific to the treatment of apathy and not a secondary effect of improvement in cognition,” the researchers wrote.

In all, 17 serious adverse events occurred in the methylphenidate group and 10 occurred in the placebo group. However, all events were found to be hospitalizations for events not related to treatment.
 

‘Enduring effect’

Commenting on the findings, Jeffrey L. Cummings, MD, ScD, professor of brain sciences at the University of Nevada, Las Vegas, noted that the reduction in NPI apathy subscale score of more than 50% was clinically meaningful.

A more robust outcome on the ADCS-CGIC would have been desirable, he added, although that instrument is not designed specifically for apathy.

Methylphenidate’s effect on apathy observed at 2 months and remaining stable throughout the study makes it appear to be “an enduring effect, and not something that the patient accommodates to,” said Dr. Cummings, who was not involved with the research. Such a change may manifest itself in a patient’s greater willingness to help voluntarily with housework or to suggest going for a walk, he noted.

“These are not dramatic changes in cognition, of course, but they are changes in initiative and that is very important,” Dr. Cummings said. Decreased apathy also may improve quality of life for the patient’s caregiver, he added.

Overall, the findings raise the question of whether the Food and Drug Administration should recognize apathy as an indication for which drugs can be approved, said Dr. Cummings.

“For me, that would be the next major step in this line of investigation,” he concluded.

The study was funded by the National Institute on Aging. Dr. Mintzer has served as an adviser to Praxis Bioresearch and Cerevel Therapeutics on matters unrelated to this study. Dr. Cummings is the author of the Neuropsychiatric Inventory but does not receive payments for it from academic trials such as ADMET 2.
 

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

Methylphenidate is safe and effective for treating apathy in patients with Alzheimer’s disease (AD), new research suggests.

Dundanim/shutterstock.com

Results from a phase 3 randomized trial showed that, after 6 months of treatment, mean score on the Neuropsychiatric Inventory (NPI) apathy subscale decreased by 4.5 points for patients who received methylphenidate vs. a decrease of 3.1 points for those who received placebo.

In addition, the safety profile showed no significant between-group differences.

“Methylphenidate offers a treatment approach providing a modest but potentially clinically significant benefit for patients and caregivers,” said the investigators, led by Jacobo E. Mintzer, MD, MBA, professor of health studies at the Medical University of South Carolina in Charleston.

The findings were published online Sept. 27 in JAMA Neurology.
 

Common problem

Apathy, which is common among patients with AD, is associated with increased risk for mortality, financial burden, and caregiver burden. No treatment has proved effective for apathy in this population.

Two trials of methylphenidate, a catecholaminergic agent, have provided preliminary evidence of efficacy. Findings from the Apathy in Dementia Methylphenidate trial (ADMET) suggested the drug was associated with improved cognition and few adverse events. However, both trials had small patient populations and short durations.

The current investigators conducted ADMET 2, a 6-month, phase 3 trial, to investigate methylphenidate further. They recruited 200 patients (mean age, 76 years; 66% men; 90% White) at nine clinical centers that specialized in dementia care in the United States and one in Canada.

Eligible patients had a diagnosis of possible or probable AD and a Mini-Mental State Examination (MMSE) score between 10 and 28. They also had clinically significant apathy for at least 4 weeks and an available caregiver who spent more than 10 hours a week with the patient.

The researchers randomly assigned patients to receive methylphenidate (n = 99) or placebo (n = 101). For 3 days, participants in the active group received 10 mg/day of methylphenidate. After that point, they received 20 mg/day of methylphenidate for the rest of the study.

Patients in both treatment groups were given the same number of identical-appearing capsules each day.

In-person follow-up visits took place monthly for 6 months. Participants also were contacted by telephone at days 15, 45, and 75 after treatment assignment.

Participants underwent cognitive testing at baseline and at 2, 4, and 6 months. The battery of tests included the MMSE, Hopkins Verbal Learning Test, and Wechsler Adult Intelligence Scale – Revised Digit Span.

The trial’s two primary outcomes were mean change in NPI apathy score from baseline to 6 months and the odds of an improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC) between baseline and 6 months.

Significant change on either outcome was to be considered a signal of effective treatment.
 

Treatment-specific benefit

Ten patients in the methylphenidate group and seven in the placebo group withdrew during the study.

Mean MMSE score at baseline was 19.2 in the methylphenidate group vs. 18.5 in the placebo group, indicating moderately severe dementia. Mean baseline score on the NPI apathy subscale was 8.0 vs. 7.6, respectively.

In an adjusted, longitudinal model, mean between-group difference in change in NPI apathy score at 6 months was –1.25 (P = .002). The mean NPI apathy score decreased by 4.5 points in the methylphenidate group vs. 3.1 points in the placebo group.

The largest change in apathy score occurred during the first 2 months of treatment. At 6 months, 27% of the methylphenidate group vs. 14% of the placebo group had an NPI apathy score of 0.

In addition, 43.8% of the methylphenidate group had improvement on the ADCS-CGIC compared with 35.2% of the placebo group. The odds ratio (OR) for improvement on ADCS-CGIC for methylphenidate vs. placebo was 1.90 (P = .07).

There was also a strong association between score improvement on the NPI apathy subscale and improvement on the ADCS-CGIC subscale (OR, 2.95; P = .002).

“It is important to note that there were no group differences in any of the cognitive measures, suggesting that the effect of the treatment is specific to the treatment of apathy and not a secondary effect of improvement in cognition,” the researchers wrote.

In all, 17 serious adverse events occurred in the methylphenidate group and 10 occurred in the placebo group. However, all events were found to be hospitalizations for events not related to treatment.
 

‘Enduring effect’

Commenting on the findings, Jeffrey L. Cummings, MD, ScD, professor of brain sciences at the University of Nevada, Las Vegas, noted that the reduction in NPI apathy subscale score of more than 50% was clinically meaningful.

A more robust outcome on the ADCS-CGIC would have been desirable, he added, although that instrument is not designed specifically for apathy.

Methylphenidate’s effect on apathy observed at 2 months and remaining stable throughout the study makes it appear to be “an enduring effect, and not something that the patient accommodates to,” said Dr. Cummings, who was not involved with the research. Such a change may manifest itself in a patient’s greater willingness to help voluntarily with housework or to suggest going for a walk, he noted.

“These are not dramatic changes in cognition, of course, but they are changes in initiative and that is very important,” Dr. Cummings said. Decreased apathy also may improve quality of life for the patient’s caregiver, he added.

Overall, the findings raise the question of whether the Food and Drug Administration should recognize apathy as an indication for which drugs can be approved, said Dr. Cummings.

“For me, that would be the next major step in this line of investigation,” he concluded.

The study was funded by the National Institute on Aging. Dr. Mintzer has served as an adviser to Praxis Bioresearch and Cerevel Therapeutics on matters unrelated to this study. Dr. Cummings is the author of the Neuropsychiatric Inventory but does not receive payments for it from academic trials such as ADMET 2.
 

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

Methylphenidate is safe and effective for treating apathy in patients with Alzheimer’s disease (AD), new research suggests.

Dundanim/shutterstock.com

Results from a phase 3 randomized trial showed that, after 6 months of treatment, mean score on the Neuropsychiatric Inventory (NPI) apathy subscale decreased by 4.5 points for patients who received methylphenidate vs. a decrease of 3.1 points for those who received placebo.

In addition, the safety profile showed no significant between-group differences.

“Methylphenidate offers a treatment approach providing a modest but potentially clinically significant benefit for patients and caregivers,” said the investigators, led by Jacobo E. Mintzer, MD, MBA, professor of health studies at the Medical University of South Carolina in Charleston.

The findings were published online Sept. 27 in JAMA Neurology.
 

Common problem

Apathy, which is common among patients with AD, is associated with increased risk for mortality, financial burden, and caregiver burden. No treatment has proved effective for apathy in this population.

Two trials of methylphenidate, a catecholaminergic agent, have provided preliminary evidence of efficacy. Findings from the Apathy in Dementia Methylphenidate trial (ADMET) suggested the drug was associated with improved cognition and few adverse events. However, both trials had small patient populations and short durations.

The current investigators conducted ADMET 2, a 6-month, phase 3 trial, to investigate methylphenidate further. They recruited 200 patients (mean age, 76 years; 66% men; 90% White) at nine clinical centers that specialized in dementia care in the United States and one in Canada.

Eligible patients had a diagnosis of possible or probable AD and a Mini-Mental State Examination (MMSE) score between 10 and 28. They also had clinically significant apathy for at least 4 weeks and an available caregiver who spent more than 10 hours a week with the patient.

The researchers randomly assigned patients to receive methylphenidate (n = 99) or placebo (n = 101). For 3 days, participants in the active group received 10 mg/day of methylphenidate. After that point, they received 20 mg/day of methylphenidate for the rest of the study.

Patients in both treatment groups were given the same number of identical-appearing capsules each day.

In-person follow-up visits took place monthly for 6 months. Participants also were contacted by telephone at days 15, 45, and 75 after treatment assignment.

Participants underwent cognitive testing at baseline and at 2, 4, and 6 months. The battery of tests included the MMSE, Hopkins Verbal Learning Test, and Wechsler Adult Intelligence Scale – Revised Digit Span.

The trial’s two primary outcomes were mean change in NPI apathy score from baseline to 6 months and the odds of an improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC) between baseline and 6 months.

Significant change on either outcome was to be considered a signal of effective treatment.
 

Treatment-specific benefit

Ten patients in the methylphenidate group and seven in the placebo group withdrew during the study.

Mean MMSE score at baseline was 19.2 in the methylphenidate group vs. 18.5 in the placebo group, indicating moderately severe dementia. Mean baseline score on the NPI apathy subscale was 8.0 vs. 7.6, respectively.

In an adjusted, longitudinal model, mean between-group difference in change in NPI apathy score at 6 months was –1.25 (P = .002). The mean NPI apathy score decreased by 4.5 points in the methylphenidate group vs. 3.1 points in the placebo group.

The largest change in apathy score occurred during the first 2 months of treatment. At 6 months, 27% of the methylphenidate group vs. 14% of the placebo group had an NPI apathy score of 0.

In addition, 43.8% of the methylphenidate group had improvement on the ADCS-CGIC compared with 35.2% of the placebo group. The odds ratio (OR) for improvement on ADCS-CGIC for methylphenidate vs. placebo was 1.90 (P = .07).

There was also a strong association between score improvement on the NPI apathy subscale and improvement on the ADCS-CGIC subscale (OR, 2.95; P = .002).

“It is important to note that there were no group differences in any of the cognitive measures, suggesting that the effect of the treatment is specific to the treatment of apathy and not a secondary effect of improvement in cognition,” the researchers wrote.

In all, 17 serious adverse events occurred in the methylphenidate group and 10 occurred in the placebo group. However, all events were found to be hospitalizations for events not related to treatment.
 

‘Enduring effect’

Commenting on the findings, Jeffrey L. Cummings, MD, ScD, professor of brain sciences at the University of Nevada, Las Vegas, noted that the reduction in NPI apathy subscale score of more than 50% was clinically meaningful.

A more robust outcome on the ADCS-CGIC would have been desirable, he added, although that instrument is not designed specifically for apathy.

Methylphenidate’s effect on apathy observed at 2 months and remaining stable throughout the study makes it appear to be “an enduring effect, and not something that the patient accommodates to,” said Dr. Cummings, who was not involved with the research. Such a change may manifest itself in a patient’s greater willingness to help voluntarily with housework or to suggest going for a walk, he noted.

“These are not dramatic changes in cognition, of course, but they are changes in initiative and that is very important,” Dr. Cummings said. Decreased apathy also may improve quality of life for the patient’s caregiver, he added.

Overall, the findings raise the question of whether the Food and Drug Administration should recognize apathy as an indication for which drugs can be approved, said Dr. Cummings.

“For me, that would be the next major step in this line of investigation,” he concluded.

The study was funded by the National Institute on Aging. Dr. Mintzer has served as an adviser to Praxis Bioresearch and Cerevel Therapeutics on matters unrelated to this study. Dr. Cummings is the author of the Neuropsychiatric Inventory but does not receive payments for it from academic trials such as ADMET 2.
 

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

CASE Sluggish, weak, and incoherent

Mr. O, age 24, who has a history of schizophrenia and obesity, presents to the emergency department (ED) for altered mental status (AMS). His mother reports that he has been sluggish, weak, incoherent, had no appetite, and that on the day before admission, he was drinking excessive amounts of water and urinating every 10 minutes.

HISTORY Multiple ineffective antipsychotics

Mr. O was diagnosed with schizophrenia at age 21 and struggled with medication adherence, which resulted in multiple hospitalizations for stabilization. Trials of haloperidol, risperidone, paliperidone palmitate, and valproic acid had been ineffective. At the time of admission, his psychotropic medication regimen is fluphenazine decanoate, 25 mg injection every 2 weeks; clozapine, 50 mg/d; lithium carbonate, 300 mg twice a day; benztropine, 2 mg every night; and trazodone, 50 mg every night.

EVALUATION Fever, tachycardia, and diabetic ketoacidosis

Upon arrival to the ED, Mr. O is obtunded, unable to follow commands, and does not respond to painful stimuli. On physical exam, he has a fever of 38.4°C (reference range 35.1°C to 37.9°C); tachycardia with a heart rate of 142 beats per minute (bpm) (reference range 60 to 100); tachypnea with a respiratory rate of 35 breaths per minute (reference range 12 to 20); a blood pressure of 116/76 mmHg (reference range 90/60 to 130/80); and hypoxemia with an oxygen saturation of 90% on room air (reference range 94% to 100%).

Mr. O is admitted to the hospital and his laboratory workup indicates diabetic ketoacidosis (DKA), with a glucose of 1,700 mg/dL; anion gap of 30 (reference range 4 to 12 mmol/L); pH 7.04 (reference range 7.32 to 7.42); serum bicarbonate 6 (reference range 20 to 24 mEq/L); beta-hydroxybutyrate 11.04 (reference range 0 to 0.27 mmol/L); urine ketones, serum osmolality 407 (reference range 280 to 300 mOsm/kg); and an elevated white blood cell count of 18.4 (reference range 4.5 to 11.0 × 10⁹/L). A CT scan of the head is negative for acute pathology.

Initially, all psychotropic medications are held. On Day 3 of hospitalization, psychiatry is consulted and clozapine, 50 mg/d; lithium, 300 mg/d; and benztropine, 1 mg at night, are restarted; however, fluphenazine decanoate and trazodone are held. The team recommends IV haloperidol, 2 mg as needed for agitation; however, it is never administered.

Imaging rules out deep vein thrombosis, cardiac dysfunction, and stroke, but a CT chest scan is notable for bilateral lung infiltrates, which suggests aspiration pneumonia.

Mr. O is diagnosed with diabetes, complicated by DKA, and is treated in the intensive care unit (ICU). Despite resolution of the DKA, he remains altered with fever and tachycardia.

Continue to: On Day 6 of hospitalization...

On Day 6 of hospitalization, Mr. O continues to be tachycardic and obtunded with nuchal rigidity. The team decides to transfer Mr. O to another hospital for a higher level of care and continued workup of his persistent AMS.

Immediately upon arrival at the second hospital, infectious disease and neurology teams are consulted for further evaluation. Mr. O’s AMS continues despite no clear signs of infection or other neurologic insults.

[polldaddy:10930631]

The authors’ observations

Based on Mr. O’s psychiatric history and laboratory results, the first medical team concluded his initial AMS was likely secondary to DKA; however, the AMS continued after the DKA resolved. At the second hospital, Mr. O’s treatment team continued to dig for answers.

EVALUATION Exploring the differential diagnosis

At the second hospital, Mr. O is admitted to the ICU with fever (37.8°C), tachycardia (120 bpm), tachypnea, withdrawal from painful stimuli, decreased reflexes, and muscle rigidity, including clenched jaw. The differential diagnoses include meningitis, sepsis from aspiration pneumonia, severe metabolic encephalopathy with prolonged recovery, central pontine myelinolysis, anoxic brain injury, and subclinical seizures.

Empiric vancomycin, 1.75 g every 12 hours; ceftriaxone, 2 g/d; and acyclovir, 900 mg every 8 hours are started for meningoencephalitis, and all psychotropic medications are discontinued. Case reports have documented a relationship between hyperglycemic hyperosmolar syndrome (HHS) and malignant hyperthermia in rare cases¹; however, HHS is ruled out based on Mr. O’s laboratory results.A lumbar puncture and imaging rules out CNS infection. Antibiotic treatment is narrowed to ampicillin-sulbactam due to Mr. O’s prior CT chest showing concern for aspiration pneumonia. An MRI of the brain rules out central pontine myelinolysis, acute stroke, and anoxic brain injury, and an EEG shows nonspecific encephalopathy. On Day 10 of hospitalization, a neurologic exam shows flaccid paralysis and bilateral clonus, and Mr. O is mute. On Day 14 of hospitalization, his fever resolves, and his blood cultures are negative. On Day 15 of hospitalization, Mr. O’s creatine kinase (CK) level is elevated at 1,308 U/L (reference range 26 to 192 U/L), suggesting rhabdomyolysis.

Continue to: Given the neurologic exam findings...

Given the neurologic exam findings, and the limited evidence of infection, the differential diagnosis for Mr. O’s AMS is broadened to include catatonia, neuroleptic malignant syndrome (NMS), serotonin syndrome, and autoimmune encephalitis. The psychiatry team evaluates Mr. O for catatonia. He scores 14 on the Bush-Francis Catatonia Rating Scale, with findings of immobility/stupor, mutism, staring, autonomic instability, and withdrawal indicating the presence of catatonia.²

The authors’ observations

When Mr. O was transferred to the second hospital, the primary concern was to rule out meningitis due to his unstable vitals, obtunded mental state, and nuchal rigidity. A comprehensive infectious workup, including lumbar puncture, was imperative because infection can not only lead to AMS, but also precipitate episodes of DKA. Mr. O’s persistently abnormal vital signs indicated an underlying process may have been missed by focusing on treating DKA.

TREATMENT Finally, the diagnosis is established

A lorazepam challenge is performed, and Mr. O receives 4 mg of lorazepam over 24 hours with little change in his catatonia symptoms. Given his persistent fever, tachycardia, and an elevated CK levels in the context of recent exposure to antipsychotic medications, Mr. O is diagnosed with NMS (Table 1^3,4 ) and is started on bromocriptine, 5 mg 3 times daily.

[polldaddy:10930632]

The authors’ observations

Mr. O’s complicated medical state—starting with DKA, halting the use of antipsychotic medications, and the suspicion of catatonia due to his history of schizophrenia—all distracted from the ultimate diagnosis of NMS as the cause of his enduring AMS and autonomic instability. Catatonia and NMS have overlapping symptomatology, including rigidity, autonomic instability, and stupor, which make the diagnosis of either condition complicated. A positive lorazepam test to diagnose catatonia is defined as a marked reduction in catatonia symptoms (typically a 50% reduction) as measured on a standardized rating scale.⁵ However, a negative lorazepam challenge does not definitely rule out catatonia because some cases are resistant to benzodiazepines.⁶

NMS risk factors relevant in this case include male sex, young age, acute medical illness, dehydration, and exposure to multiple psychotropic medications, including 2 antipsychotics, clozapine and fluphenazine.⁷ DKA is especially pertinent due to its acute onset and cause of significant dehydration. NMS can occur at any point of antipsychotic exposure, although the risk is highest during the initial weeks of treatment and during dosage changes. Unfortunately, Mr. O’s treatment team was unable to determine whether his medication had been recently changed, so it is not known what role this may have played in the development of NMS. Although first-generation antipsychotics are considered more likely to cause NMS, second-generation antipsychotics (SGAs) dominate the treatment of schizophrenia and bipolar disorder, and these medications also can cause NMS.⁸ As occurred in this case, long-acting injectable antipsychotics can be easily forgotten when not administered in the hospital, and their presence in the body persists for weeks. For example, the half-life of fluphenazine decanoate is approximately 10 days, and the half-life of haloperidol decanoate is 21 days.⁹

Continue to: OUTCOME Improvement with bromocriptine

After 4 days of bromocriptine, 5 mg 3 times daily, Mr. O is more alert, able to say “hello,” and can follow 1-step commands. By Day 26 of hospitalization, his CK levels decrease to 296 U/L, his CSF autoimmune panel is negative, and he is able to participate in physical therapy. After failing multiple swallow tests, Mr. O requires a percutaneous endoscopic gastrostomy (PEG) tube. He is discharged from the hospital to a long-term acute care facility with the plan to taper bromocriptine and restart a psychotropic regimen with his outpatient psychiatrist. At the time of discharge, he is able to sit at the edge of the bed independently, state his name, and respond to questions with multiple-word answers.

[polldaddy:10930633]

The authors’ observations

The most common pharmacologic treatments for NMS are dantrolene, bromocriptine, benzodiazepines (lorazepam or diazepam), and amantadine.³ Mild cases of NMS should be treated with discontinuation of all antipsychotics, supportive care, and benzodiazepines.³ Bromocriptine or amantadine are more appropriate for moderate cases and dantrolene for severe cases of NMS.³ All antipsychotics should be discontinued while a patient is experiencing an episode of NMS; however, once the NMS has resolved, clinicians must thoroughly evaluate the risks and benefits of restarting antipsychotic medication. After a patient has experienced an episode of NMS, clinicians generally should avoid prescribing the agent(s) that caused NMS and long-acting injections, and slowly titrate a low-potency SGA such as quetiapine.¹⁰Table 2^3,11,12 outlines the pharmacologic treatment of NMS.

Bottom Line

Neuroleptic malignant syndrome (NMS) should always be part of the differential diagnosis in patients with mental illness and altered mental status. The risk of NMS is especially high in patients with acute medical illness and exposure to antipsychotic medications.

Related Resource

• Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.

Drug Brand Names

Acyclovir • Zovirax
Amantadine • Gocovri
Ampicillin-sulbactam • Unasyn
Aripiprazole • Abilify Maintena
Benztropine • Cogentin
Bromocriptine • Cycloset, Parlodel
Ceftriaxone • Rocephin
Clozapine • Clozaril
Dantrolene • Dantrium
Diazepam • Valium
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Valproate sodium • Depakote
Trazodone • Oleptro
Vancomycin • Vancocin

CASE Sluggish, weak, and incoherent

Mr. O, age 24, who has a history of schizophrenia and obesity, presents to the emergency department (ED) for altered mental status (AMS). His mother reports that he has been sluggish, weak, incoherent, had no appetite, and that on the day before admission, he was drinking excessive amounts of water and urinating every 10 minutes.

HISTORY Multiple ineffective antipsychotics

Mr. O was diagnosed with schizophrenia at age 21 and struggled with medication adherence, which resulted in multiple hospitalizations for stabilization. Trials of haloperidol, risperidone, paliperidone palmitate, and valproic acid had been ineffective. At the time of admission, his psychotropic medication regimen is fluphenazine decanoate, 25 mg injection every 2 weeks; clozapine, 50 mg/d; lithium carbonate, 300 mg twice a day; benztropine, 2 mg every night; and trazodone, 50 mg every night.

EVALUATION Fever, tachycardia, and diabetic ketoacidosis

Upon arrival to the ED, Mr. O is obtunded, unable to follow commands, and does not respond to painful stimuli. On physical exam, he has a fever of 38.4°C (reference range 35.1°C to 37.9°C); tachycardia with a heart rate of 142 beats per minute (bpm) (reference range 60 to 100); tachypnea with a respiratory rate of 35 breaths per minute (reference range 12 to 20); a blood pressure of 116/76 mmHg (reference range 90/60 to 130/80); and hypoxemia with an oxygen saturation of 90% on room air (reference range 94% to 100%).

Mr. O is admitted to the hospital and his laboratory workup indicates diabetic ketoacidosis (DKA), with a glucose of 1,700 mg/dL; anion gap of 30 (reference range 4 to 12 mmol/L); pH 7.04 (reference range 7.32 to 7.42); serum bicarbonate 6 (reference range 20 to 24 mEq/L); beta-hydroxybutyrate 11.04 (reference range 0 to 0.27 mmol/L); urine ketones, serum osmolality 407 (reference range 280 to 300 mOsm/kg); and an elevated white blood cell count of 18.4 (reference range 4.5 to 11.0 × 10⁹/L). A CT scan of the head is negative for acute pathology.

Initially, all psychotropic medications are held. On Day 3 of hospitalization, psychiatry is consulted and clozapine, 50 mg/d; lithium, 300 mg/d; and benztropine, 1 mg at night, are restarted; however, fluphenazine decanoate and trazodone are held. The team recommends IV haloperidol, 2 mg as needed for agitation; however, it is never administered.

Imaging rules out deep vein thrombosis, cardiac dysfunction, and stroke, but a CT chest scan is notable for bilateral lung infiltrates, which suggests aspiration pneumonia.

Mr. O is diagnosed with diabetes, complicated by DKA, and is treated in the intensive care unit (ICU). Despite resolution of the DKA, he remains altered with fever and tachycardia.

Continue to: On Day 6 of hospitalization...

On Day 6 of hospitalization, Mr. O continues to be tachycardic and obtunded with nuchal rigidity. The team decides to transfer Mr. O to another hospital for a higher level of care and continued workup of his persistent AMS.

Immediately upon arrival at the second hospital, infectious disease and neurology teams are consulted for further evaluation. Mr. O’s AMS continues despite no clear signs of infection or other neurologic insults.

[polldaddy:10930631]

The authors’ observations

Based on Mr. O’s psychiatric history and laboratory results, the first medical team concluded his initial AMS was likely secondary to DKA; however, the AMS continued after the DKA resolved. At the second hospital, Mr. O’s treatment team continued to dig for answers.

EVALUATION Exploring the differential diagnosis

At the second hospital, Mr. O is admitted to the ICU with fever (37.8°C), tachycardia (120 bpm), tachypnea, withdrawal from painful stimuli, decreased reflexes, and muscle rigidity, including clenched jaw. The differential diagnoses include meningitis, sepsis from aspiration pneumonia, severe metabolic encephalopathy with prolonged recovery, central pontine myelinolysis, anoxic brain injury, and subclinical seizures.

Empiric vancomycin, 1.75 g every 12 hours; ceftriaxone, 2 g/d; and acyclovir, 900 mg every 8 hours are started for meningoencephalitis, and all psychotropic medications are discontinued. Case reports have documented a relationship between hyperglycemic hyperosmolar syndrome (HHS) and malignant hyperthermia in rare cases¹; however, HHS is ruled out based on Mr. O’s laboratory results.A lumbar puncture and imaging rules out CNS infection. Antibiotic treatment is narrowed to ampicillin-sulbactam due to Mr. O’s prior CT chest showing concern for aspiration pneumonia. An MRI of the brain rules out central pontine myelinolysis, acute stroke, and anoxic brain injury, and an EEG shows nonspecific encephalopathy. On Day 10 of hospitalization, a neurologic exam shows flaccid paralysis and bilateral clonus, and Mr. O is mute. On Day 14 of hospitalization, his fever resolves, and his blood cultures are negative. On Day 15 of hospitalization, Mr. O’s creatine kinase (CK) level is elevated at 1,308 U/L (reference range 26 to 192 U/L), suggesting rhabdomyolysis.

Continue to: Given the neurologic exam findings...

Given the neurologic exam findings, and the limited evidence of infection, the differential diagnosis for Mr. O’s AMS is broadened to include catatonia, neuroleptic malignant syndrome (NMS), serotonin syndrome, and autoimmune encephalitis. The psychiatry team evaluates Mr. O for catatonia. He scores 14 on the Bush-Francis Catatonia Rating Scale, with findings of immobility/stupor, mutism, staring, autonomic instability, and withdrawal indicating the presence of catatonia.²

The authors’ observations

When Mr. O was transferred to the second hospital, the primary concern was to rule out meningitis due to his unstable vitals, obtunded mental state, and nuchal rigidity. A comprehensive infectious workup, including lumbar puncture, was imperative because infection can not only lead to AMS, but also precipitate episodes of DKA. Mr. O’s persistently abnormal vital signs indicated an underlying process may have been missed by focusing on treating DKA.

TREATMENT Finally, the diagnosis is established

A lorazepam challenge is performed, and Mr. O receives 4 mg of lorazepam over 24 hours with little change in his catatonia symptoms. Given his persistent fever, tachycardia, and an elevated CK levels in the context of recent exposure to antipsychotic medications, Mr. O is diagnosed with NMS (Table 1^3,4 ) and is started on bromocriptine, 5 mg 3 times daily.

[polldaddy:10930632]

The authors’ observations

Mr. O’s complicated medical state—starting with DKA, halting the use of antipsychotic medications, and the suspicion of catatonia due to his history of schizophrenia—all distracted from the ultimate diagnosis of NMS as the cause of his enduring AMS and autonomic instability. Catatonia and NMS have overlapping symptomatology, including rigidity, autonomic instability, and stupor, which make the diagnosis of either condition complicated. A positive lorazepam test to diagnose catatonia is defined as a marked reduction in catatonia symptoms (typically a 50% reduction) as measured on a standardized rating scale.⁵ However, a negative lorazepam challenge does not definitely rule out catatonia because some cases are resistant to benzodiazepines.⁶

NMS risk factors relevant in this case include male sex, young age, acute medical illness, dehydration, and exposure to multiple psychotropic medications, including 2 antipsychotics, clozapine and fluphenazine.⁷ DKA is especially pertinent due to its acute onset and cause of significant dehydration. NMS can occur at any point of antipsychotic exposure, although the risk is highest during the initial weeks of treatment and during dosage changes. Unfortunately, Mr. O’s treatment team was unable to determine whether his medication had been recently changed, so it is not known what role this may have played in the development of NMS. Although first-generation antipsychotics are considered more likely to cause NMS, second-generation antipsychotics (SGAs) dominate the treatment of schizophrenia and bipolar disorder, and these medications also can cause NMS.⁸ As occurred in this case, long-acting injectable antipsychotics can be easily forgotten when not administered in the hospital, and their presence in the body persists for weeks. For example, the half-life of fluphenazine decanoate is approximately 10 days, and the half-life of haloperidol decanoate is 21 days.⁹

Continue to: OUTCOME Improvement with bromocriptine

After 4 days of bromocriptine, 5 mg 3 times daily, Mr. O is more alert, able to say “hello,” and can follow 1-step commands. By Day 26 of hospitalization, his CK levels decrease to 296 U/L, his CSF autoimmune panel is negative, and he is able to participate in physical therapy. After failing multiple swallow tests, Mr. O requires a percutaneous endoscopic gastrostomy (PEG) tube. He is discharged from the hospital to a long-term acute care facility with the plan to taper bromocriptine and restart a psychotropic regimen with his outpatient psychiatrist. At the time of discharge, he is able to sit at the edge of the bed independently, state his name, and respond to questions with multiple-word answers.

[polldaddy:10930633]

The authors’ observations

The most common pharmacologic treatments for NMS are dantrolene, bromocriptine, benzodiazepines (lorazepam or diazepam), and amantadine.³ Mild cases of NMS should be treated with discontinuation of all antipsychotics, supportive care, and benzodiazepines.³ Bromocriptine or amantadine are more appropriate for moderate cases and dantrolene for severe cases of NMS.³ All antipsychotics should be discontinued while a patient is experiencing an episode of NMS; however, once the NMS has resolved, clinicians must thoroughly evaluate the risks and benefits of restarting antipsychotic medication. After a patient has experienced an episode of NMS, clinicians generally should avoid prescribing the agent(s) that caused NMS and long-acting injections, and slowly titrate a low-potency SGA such as quetiapine.¹⁰Table 2^3,11,12 outlines the pharmacologic treatment of NMS.

Bottom Line

Neuroleptic malignant syndrome (NMS) should always be part of the differential diagnosis in patients with mental illness and altered mental status. The risk of NMS is especially high in patients with acute medical illness and exposure to antipsychotic medications.

Related Resource

• Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.

Drug Brand Names

Acyclovir • Zovirax
Amantadine • Gocovri
Ampicillin-sulbactam • Unasyn
Aripiprazole • Abilify Maintena
Benztropine • Cogentin
Bromocriptine • Cycloset, Parlodel
Ceftriaxone • Rocephin
Clozapine • Clozaril
Dantrolene • Dantrium
Diazepam • Valium
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Valproate sodium • Depakote
Trazodone • Oleptro
Vancomycin • Vancocin

CASE Sluggish, weak, and incoherent

Mr. O, age 24, who has a history of schizophrenia and obesity, presents to the emergency department (ED) for altered mental status (AMS). His mother reports that he has been sluggish, weak, incoherent, had no appetite, and that on the day before admission, he was drinking excessive amounts of water and urinating every 10 minutes.

HISTORY Multiple ineffective antipsychotics

Mr. O was diagnosed with schizophrenia at age 21 and struggled with medication adherence, which resulted in multiple hospitalizations for stabilization. Trials of haloperidol, risperidone, paliperidone palmitate, and valproic acid had been ineffective. At the time of admission, his psychotropic medication regimen is fluphenazine decanoate, 25 mg injection every 2 weeks; clozapine, 50 mg/d; lithium carbonate, 300 mg twice a day; benztropine, 2 mg every night; and trazodone, 50 mg every night.

EVALUATION Fever, tachycardia, and diabetic ketoacidosis

Upon arrival to the ED, Mr. O is obtunded, unable to follow commands, and does not respond to painful stimuli. On physical exam, he has a fever of 38.4°C (reference range 35.1°C to 37.9°C); tachycardia with a heart rate of 142 beats per minute (bpm) (reference range 60 to 100); tachypnea with a respiratory rate of 35 breaths per minute (reference range 12 to 20); a blood pressure of 116/76 mmHg (reference range 90/60 to 130/80); and hypoxemia with an oxygen saturation of 90% on room air (reference range 94% to 100%).

Mr. O is admitted to the hospital and his laboratory workup indicates diabetic ketoacidosis (DKA), with a glucose of 1,700 mg/dL; anion gap of 30 (reference range 4 to 12 mmol/L); pH 7.04 (reference range 7.32 to 7.42); serum bicarbonate 6 (reference range 20 to 24 mEq/L); beta-hydroxybutyrate 11.04 (reference range 0 to 0.27 mmol/L); urine ketones, serum osmolality 407 (reference range 280 to 300 mOsm/kg); and an elevated white blood cell count of 18.4 (reference range 4.5 to 11.0 × 10⁹/L). A CT scan of the head is negative for acute pathology.

Initially, all psychotropic medications are held. On Day 3 of hospitalization, psychiatry is consulted and clozapine, 50 mg/d; lithium, 300 mg/d; and benztropine, 1 mg at night, are restarted; however, fluphenazine decanoate and trazodone are held. The team recommends IV haloperidol, 2 mg as needed for agitation; however, it is never administered.

Imaging rules out deep vein thrombosis, cardiac dysfunction, and stroke, but a CT chest scan is notable for bilateral lung infiltrates, which suggests aspiration pneumonia.

Mr. O is diagnosed with diabetes, complicated by DKA, and is treated in the intensive care unit (ICU). Despite resolution of the DKA, he remains altered with fever and tachycardia.

Continue to: On Day 6 of hospitalization...

On Day 6 of hospitalization, Mr. O continues to be tachycardic and obtunded with nuchal rigidity. The team decides to transfer Mr. O to another hospital for a higher level of care and continued workup of his persistent AMS.

Immediately upon arrival at the second hospital, infectious disease and neurology teams are consulted for further evaluation. Mr. O’s AMS continues despite no clear signs of infection or other neurologic insults.

[polldaddy:10930631]

The authors’ observations

Based on Mr. O’s psychiatric history and laboratory results, the first medical team concluded his initial AMS was likely secondary to DKA; however, the AMS continued after the DKA resolved. At the second hospital, Mr. O’s treatment team continued to dig for answers.

EVALUATION Exploring the differential diagnosis

At the second hospital, Mr. O is admitted to the ICU with fever (37.8°C), tachycardia (120 bpm), tachypnea, withdrawal from painful stimuli, decreased reflexes, and muscle rigidity, including clenched jaw. The differential diagnoses include meningitis, sepsis from aspiration pneumonia, severe metabolic encephalopathy with prolonged recovery, central pontine myelinolysis, anoxic brain injury, and subclinical seizures.

Empiric vancomycin, 1.75 g every 12 hours; ceftriaxone, 2 g/d; and acyclovir, 900 mg every 8 hours are started for meningoencephalitis, and all psychotropic medications are discontinued. Case reports have documented a relationship between hyperglycemic hyperosmolar syndrome (HHS) and malignant hyperthermia in rare cases¹; however, HHS is ruled out based on Mr. O’s laboratory results.A lumbar puncture and imaging rules out CNS infection. Antibiotic treatment is narrowed to ampicillin-sulbactam due to Mr. O’s prior CT chest showing concern for aspiration pneumonia. An MRI of the brain rules out central pontine myelinolysis, acute stroke, and anoxic brain injury, and an EEG shows nonspecific encephalopathy. On Day 10 of hospitalization, a neurologic exam shows flaccid paralysis and bilateral clonus, and Mr. O is mute. On Day 14 of hospitalization, his fever resolves, and his blood cultures are negative. On Day 15 of hospitalization, Mr. O’s creatine kinase (CK) level is elevated at 1,308 U/L (reference range 26 to 192 U/L), suggesting rhabdomyolysis.

Continue to: Given the neurologic exam findings...

Given the neurologic exam findings, and the limited evidence of infection, the differential diagnosis for Mr. O’s AMS is broadened to include catatonia, neuroleptic malignant syndrome (NMS), serotonin syndrome, and autoimmune encephalitis. The psychiatry team evaluates Mr. O for catatonia. He scores 14 on the Bush-Francis Catatonia Rating Scale, with findings of immobility/stupor, mutism, staring, autonomic instability, and withdrawal indicating the presence of catatonia.²

The authors’ observations

When Mr. O was transferred to the second hospital, the primary concern was to rule out meningitis due to his unstable vitals, obtunded mental state, and nuchal rigidity. A comprehensive infectious workup, including lumbar puncture, was imperative because infection can not only lead to AMS, but also precipitate episodes of DKA. Mr. O’s persistently abnormal vital signs indicated an underlying process may have been missed by focusing on treating DKA.

TREATMENT Finally, the diagnosis is established

A lorazepam challenge is performed, and Mr. O receives 4 mg of lorazepam over 24 hours with little change in his catatonia symptoms. Given his persistent fever, tachycardia, and an elevated CK levels in the context of recent exposure to antipsychotic medications, Mr. O is diagnosed with NMS (Table 1^3,4 ) and is started on bromocriptine, 5 mg 3 times daily.

[polldaddy:10930632]

The authors’ observations

Mr. O’s complicated medical state—starting with DKA, halting the use of antipsychotic medications, and the suspicion of catatonia due to his history of schizophrenia—all distracted from the ultimate diagnosis of NMS as the cause of his enduring AMS and autonomic instability. Catatonia and NMS have overlapping symptomatology, including rigidity, autonomic instability, and stupor, which make the diagnosis of either condition complicated. A positive lorazepam test to diagnose catatonia is defined as a marked reduction in catatonia symptoms (typically a 50% reduction) as measured on a standardized rating scale.⁵ However, a negative lorazepam challenge does not definitely rule out catatonia because some cases are resistant to benzodiazepines.⁶

NMS risk factors relevant in this case include male sex, young age, acute medical illness, dehydration, and exposure to multiple psychotropic medications, including 2 antipsychotics, clozapine and fluphenazine.⁷ DKA is especially pertinent due to its acute onset and cause of significant dehydration. NMS can occur at any point of antipsychotic exposure, although the risk is highest during the initial weeks of treatment and during dosage changes. Unfortunately, Mr. O’s treatment team was unable to determine whether his medication had been recently changed, so it is not known what role this may have played in the development of NMS. Although first-generation antipsychotics are considered more likely to cause NMS, second-generation antipsychotics (SGAs) dominate the treatment of schizophrenia and bipolar disorder, and these medications also can cause NMS.⁸ As occurred in this case, long-acting injectable antipsychotics can be easily forgotten when not administered in the hospital, and their presence in the body persists for weeks. For example, the half-life of fluphenazine decanoate is approximately 10 days, and the half-life of haloperidol decanoate is 21 days.⁹

Continue to: OUTCOME Improvement with bromocriptine

After 4 days of bromocriptine, 5 mg 3 times daily, Mr. O is more alert, able to say “hello,” and can follow 1-step commands. By Day 26 of hospitalization, his CK levels decrease to 296 U/L, his CSF autoimmune panel is negative, and he is able to participate in physical therapy. After failing multiple swallow tests, Mr. O requires a percutaneous endoscopic gastrostomy (PEG) tube. He is discharged from the hospital to a long-term acute care facility with the plan to taper bromocriptine and restart a psychotropic regimen with his outpatient psychiatrist. At the time of discharge, he is able to sit at the edge of the bed independently, state his name, and respond to questions with multiple-word answers.

[polldaddy:10930633]

The authors’ observations

The most common pharmacologic treatments for NMS are dantrolene, bromocriptine, benzodiazepines (lorazepam or diazepam), and amantadine.³ Mild cases of NMS should be treated with discontinuation of all antipsychotics, supportive care, and benzodiazepines.³ Bromocriptine or amantadine are more appropriate for moderate cases and dantrolene for severe cases of NMS.³ All antipsychotics should be discontinued while a patient is experiencing an episode of NMS; however, once the NMS has resolved, clinicians must thoroughly evaluate the risks and benefits of restarting antipsychotic medication. After a patient has experienced an episode of NMS, clinicians generally should avoid prescribing the agent(s) that caused NMS and long-acting injections, and slowly titrate a low-potency SGA such as quetiapine.¹⁰Table 2^3,11,12 outlines the pharmacologic treatment of NMS.

Bottom Line

Neuroleptic malignant syndrome (NMS) should always be part of the differential diagnosis in patients with mental illness and altered mental status. The risk of NMS is especially high in patients with acute medical illness and exposure to antipsychotic medications.

Related Resource

• Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.

Drug Brand Names

Acyclovir • Zovirax
Amantadine • Gocovri
Ampicillin-sulbactam • Unasyn
Aripiprazole • Abilify Maintena
Benztropine • Cogentin
Bromocriptine • Cycloset, Parlodel
Ceftriaxone • Rocephin
Clozapine • Clozaril
Dantrolene • Dantrium
Diazepam • Valium
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Valproate sodium • Depakote
Trazodone • Oleptro
Vancomycin • Vancocin