Literature Review

Mental disorders in early life are associated with a significantly increased risk of dementia in later years.

Results of a large, longitudinal, population-based study show that individuals hospitalized for a mental health disorder had a fourfold increased relative risk (RR) for developing dementia, compared with those who were not hospitalized with a mental illness.

In addition, those with dementia plus a mental disorder developed dementia almost 6 years earlier than those without a mental illness.

The findings were consistent among men and women, in patients with early- and late-onset dementia, in those with Alzheimer’s and non-Alzheimer’s dementia, and across all mental health disorders – and remained so after accounting for pre-existing physical illness and socioeconomic factors.

“Dementia is not typically treated until later in life, but our study suggests that we need to be thinking about dementia prevention much earlier in the life course,” study investigator Leah Richmond-Rakerd, PhD, assistant professor, department of psychology, University of Michigan, said in an interview.

“Supporting young people’s mental health could be a window of opportunity to help reduce the burden of dementia in older adults,” she said.

The findings were published online Feb. 16.
 

Underappreciated risk factor

“Recognition of the outsized influence of dementia on later-life functioning has fueled research into modifiable risk factors and prevention targets,” the investigators write.

Previous research suggests mental disorders may “comprise an underappreciated category of modifiable risk factors.” However, those studies focused primarily on midlife and older individuals, not on capturing mental disorders during young adulthood, which is the time of “peak prevalence,” they add. In addition, most studies have not explored the full range of mental disorders.

Dr. Richmond-Rakerd noted that it is well known that mental health disorders peak in adolescence and young adulthood – and are treatable.

“If the same people who have mental disorders when they are young tend to develop dementia when they are older, that would mean that preventing mental health problems in younger people might reduce or delay the burden of dementia in older people,” she said.

The investigators assessed records from the New Zealand Integrated Data Infrastructure, which is a de-identified register that includes the entire New Zealand population. They also examined information about hospitalizations and diagnoses from records kept by the New Zealand Ministry of Health.

The researchers followed 1,711,386 individuals born between 1928 and 1967 (50.6% men, aged 21 to 60 years at baseline) for 30 years. The population was subdivided into age groups based on birth years: 1928-1937 (14.8%), 1938-1947 (20.85%), 1948-1957 (29.35%), and 1958-1967 (35.1%).
 

Earlier onset

During the study period, 3.8% of individuals were identified as having a mental disorder, and 2% were identified as having dementia. Similar percentages of men and women had a mental disorder, and similar percentages had dementia.

Dementia was “over-represented” among participants with versus without a mental disorder (6.1% vs. 1.8%). This finding held across all age groups.

Those diagnosed with a mental disorder were also more likely to develop dementia, compared with their peers without a mental disorder (RR, 3.51; 95% confidence interval, 3.39-3.64), which is a larger association than that between physical diseases and dementia (RR, 1.19; 95% CI, 1.16-1.21).

These associations were present in both sexes and in all age groups, although the associations were stronger in more recently born cohorts.

A sixfold higher risk for dementia remained even after adjusting for pre-existing physical illnesses (HR, 6.49; 95% CI, 6.25-6.73); and the elevated risk was evident across different lengths of follow-up from the index mental disorder.

When the researchers focused specifically on individuals diagnosed with dementia, they found that those diagnosed with a mental disorder developed dementia a mean of 5.60 years earlier than those without a mental disorder diagnosis – an association observed across both sexes and all age groups.

“Individuals diagnosed with psychotic, substance use, mood, neurotic, and all other mental disorders and who engaged in self-harm were all more likely than those without a mental disorder to be diagnosed with subsequent dementia, even after accounting for their physical disease histories,” the investigators write.

Although there was a link between mental disorders in both Alzheimer’s and non-Alzheimer’s dementias, the association was larger in non-Alzheimer’s.

The researchers note that the study has several limitations, including the fact that it was conducted in New Zealand and therefore the results may not be generalizable to other regions. In addition, inpatient hospital records do not capture less severe mental disorder cases treated in the outpatient setting.

Dr. Richmond-Rakerd suggested several potential mechanisms that could account for the link between mental illness and dementia, including poor lifestyle choices and metabolic side effects associated with some psychiatric medications.

“There could also be shared risk factors for both mental disorders and dementia, such as shared genetics, or individuals may experience a lifelong brain vulnerability that shows up as mental health problems earlier in life and shows up as dementia later in life,” she said.
 

An important risk factor

Commenting for this article, Ken Duckworth, MD, chief medical officer of the National Alliance on Mental Illness, said a major strength of the study was its longitudinal scope and large population size.

He described the study as allowing clinicians to “watch the movie,” as opposed to looking at a “snapshot” of data.

“Although you can learn things from snapshots, a large, comprehensive public health system looking at 30 years of claims – something not possible in the U.S. because of our more fragmented health care system – offers more insight,” said Dr. Duckworth, who was not involved with the research.

The investigators are “painting a picture of a correlation of risk, and to me, that’s the beginning of further inquiry,” he added. “Would preventive efforts targeting dementia, such as exercise and socialization, be helpful? It’s a great study that raises these interesting questions.”

Also commenting in an interview, Claire Sexton, DPhil, director of scientific programs and outreach at the Alzheimer’s Association, said the study “adds a wealth of data to our understanding” of mental disorders as a dementia risk factor.

However, the study was observational, so “the findings cannot imply causation, [and just] because someone has depression, that does not mean they will go on to develop Alzheimer’s,” said Dr. Sexton, who also was not involved with the research.

Still, “these data support the idea that taking care of one’s mental health is incredibly important for overall wellbeing. For providers, it’s important to have mental health evaluation be a part of your patient’s regular checkups,” she added.

Dr. Richmond-Rakerd noted that even if mental health conditions are not a causal risk factor for dementia, “the presence of a mental health problem is still an important indicator of risk. Mental health providers may wish to target other risk factors for dementia that are more common in individuals with mental health conditions, such as social disconnection.”

The study was funded by grants from the National Institute on Aging, the U.K. Medical Research Council, the National Institute of Child Health and Development through the Duke Population Research Center, and the National Institute on Aging through the Center for Advancing Sociodemographic and Economic Study of Alzheimer’s Disease and Related Dementias. Dr. Richmond-Rakerd reports no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Sexton and Dr. Duckworth report no relevant financial relationships.

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

Mental disorders in early life are associated with a significantly increased risk of dementia in later years.

Results of a large, longitudinal, population-based study show that individuals hospitalized for a mental health disorder had a fourfold increased relative risk (RR) for developing dementia, compared with those who were not hospitalized with a mental illness.

In addition, those with dementia plus a mental disorder developed dementia almost 6 years earlier than those without a mental illness.

The findings were consistent among men and women, in patients with early- and late-onset dementia, in those with Alzheimer’s and non-Alzheimer’s dementia, and across all mental health disorders – and remained so after accounting for pre-existing physical illness and socioeconomic factors.

“Dementia is not typically treated until later in life, but our study suggests that we need to be thinking about dementia prevention much earlier in the life course,” study investigator Leah Richmond-Rakerd, PhD, assistant professor, department of psychology, University of Michigan, said in an interview.

“Supporting young people’s mental health could be a window of opportunity to help reduce the burden of dementia in older adults,” she said.

The findings were published online Feb. 16.
 

Underappreciated risk factor

“Recognition of the outsized influence of dementia on later-life functioning has fueled research into modifiable risk factors and prevention targets,” the investigators write.

Previous research suggests mental disorders may “comprise an underappreciated category of modifiable risk factors.” However, those studies focused primarily on midlife and older individuals, not on capturing mental disorders during young adulthood, which is the time of “peak prevalence,” they add. In addition, most studies have not explored the full range of mental disorders.

Dr. Richmond-Rakerd noted that it is well known that mental health disorders peak in adolescence and young adulthood – and are treatable.

“If the same people who have mental disorders when they are young tend to develop dementia when they are older, that would mean that preventing mental health problems in younger people might reduce or delay the burden of dementia in older people,” she said.

The investigators assessed records from the New Zealand Integrated Data Infrastructure, which is a de-identified register that includes the entire New Zealand population. They also examined information about hospitalizations and diagnoses from records kept by the New Zealand Ministry of Health.

The researchers followed 1,711,386 individuals born between 1928 and 1967 (50.6% men, aged 21 to 60 years at baseline) for 30 years. The population was subdivided into age groups based on birth years: 1928-1937 (14.8%), 1938-1947 (20.85%), 1948-1957 (29.35%), and 1958-1967 (35.1%).
 

Earlier onset

During the study period, 3.8% of individuals were identified as having a mental disorder, and 2% were identified as having dementia. Similar percentages of men and women had a mental disorder, and similar percentages had dementia.

Dementia was “over-represented” among participants with versus without a mental disorder (6.1% vs. 1.8%). This finding held across all age groups.

Those diagnosed with a mental disorder were also more likely to develop dementia, compared with their peers without a mental disorder (RR, 3.51; 95% confidence interval, 3.39-3.64), which is a larger association than that between physical diseases and dementia (RR, 1.19; 95% CI, 1.16-1.21).

These associations were present in both sexes and in all age groups, although the associations were stronger in more recently born cohorts.

A sixfold higher risk for dementia remained even after adjusting for pre-existing physical illnesses (HR, 6.49; 95% CI, 6.25-6.73); and the elevated risk was evident across different lengths of follow-up from the index mental disorder.

When the researchers focused specifically on individuals diagnosed with dementia, they found that those diagnosed with a mental disorder developed dementia a mean of 5.60 years earlier than those without a mental disorder diagnosis – an association observed across both sexes and all age groups.

“Individuals diagnosed with psychotic, substance use, mood, neurotic, and all other mental disorders and who engaged in self-harm were all more likely than those without a mental disorder to be diagnosed with subsequent dementia, even after accounting for their physical disease histories,” the investigators write.

Although there was a link between mental disorders in both Alzheimer’s and non-Alzheimer’s dementias, the association was larger in non-Alzheimer’s.

The researchers note that the study has several limitations, including the fact that it was conducted in New Zealand and therefore the results may not be generalizable to other regions. In addition, inpatient hospital records do not capture less severe mental disorder cases treated in the outpatient setting.

Dr. Richmond-Rakerd suggested several potential mechanisms that could account for the link between mental illness and dementia, including poor lifestyle choices and metabolic side effects associated with some psychiatric medications.

“There could also be shared risk factors for both mental disorders and dementia, such as shared genetics, or individuals may experience a lifelong brain vulnerability that shows up as mental health problems earlier in life and shows up as dementia later in life,” she said.
 

An important risk factor

Commenting for this article, Ken Duckworth, MD, chief medical officer of the National Alliance on Mental Illness, said a major strength of the study was its longitudinal scope and large population size.

He described the study as allowing clinicians to “watch the movie,” as opposed to looking at a “snapshot” of data.

“Although you can learn things from snapshots, a large, comprehensive public health system looking at 30 years of claims – something not possible in the U.S. because of our more fragmented health care system – offers more insight,” said Dr. Duckworth, who was not involved with the research.

The investigators are “painting a picture of a correlation of risk, and to me, that’s the beginning of further inquiry,” he added. “Would preventive efforts targeting dementia, such as exercise and socialization, be helpful? It’s a great study that raises these interesting questions.”

Also commenting in an interview, Claire Sexton, DPhil, director of scientific programs and outreach at the Alzheimer’s Association, said the study “adds a wealth of data to our understanding” of mental disorders as a dementia risk factor.

However, the study was observational, so “the findings cannot imply causation, [and just] because someone has depression, that does not mean they will go on to develop Alzheimer’s,” said Dr. Sexton, who also was not involved with the research.

Still, “these data support the idea that taking care of one’s mental health is incredibly important for overall wellbeing. For providers, it’s important to have mental health evaluation be a part of your patient’s regular checkups,” she added.

Dr. Richmond-Rakerd noted that even if mental health conditions are not a causal risk factor for dementia, “the presence of a mental health problem is still an important indicator of risk. Mental health providers may wish to target other risk factors for dementia that are more common in individuals with mental health conditions, such as social disconnection.”

The study was funded by grants from the National Institute on Aging, the U.K. Medical Research Council, the National Institute of Child Health and Development through the Duke Population Research Center, and the National Institute on Aging through the Center for Advancing Sociodemographic and Economic Study of Alzheimer’s Disease and Related Dementias. Dr. Richmond-Rakerd reports no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Sexton and Dr. Duckworth report no relevant financial relationships.

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

Mental disorders in early life are associated with a significantly increased risk of dementia in later years.

Results of a large, longitudinal, population-based study show that individuals hospitalized for a mental health disorder had a fourfold increased relative risk (RR) for developing dementia, compared with those who were not hospitalized with a mental illness.

In addition, those with dementia plus a mental disorder developed dementia almost 6 years earlier than those without a mental illness.

The findings were consistent among men and women, in patients with early- and late-onset dementia, in those with Alzheimer’s and non-Alzheimer’s dementia, and across all mental health disorders – and remained so after accounting for pre-existing physical illness and socioeconomic factors.

“Dementia is not typically treated until later in life, but our study suggests that we need to be thinking about dementia prevention much earlier in the life course,” study investigator Leah Richmond-Rakerd, PhD, assistant professor, department of psychology, University of Michigan, said in an interview.

“Supporting young people’s mental health could be a window of opportunity to help reduce the burden of dementia in older adults,” she said.

The findings were published online Feb. 16.
 

Underappreciated risk factor

“Recognition of the outsized influence of dementia on later-life functioning has fueled research into modifiable risk factors and prevention targets,” the investigators write.

Previous research suggests mental disorders may “comprise an underappreciated category of modifiable risk factors.” However, those studies focused primarily on midlife and older individuals, not on capturing mental disorders during young adulthood, which is the time of “peak prevalence,” they add. In addition, most studies have not explored the full range of mental disorders.

Dr. Richmond-Rakerd noted that it is well known that mental health disorders peak in adolescence and young adulthood – and are treatable.

“If the same people who have mental disorders when they are young tend to develop dementia when they are older, that would mean that preventing mental health problems in younger people might reduce or delay the burden of dementia in older people,” she said.

The investigators assessed records from the New Zealand Integrated Data Infrastructure, which is a de-identified register that includes the entire New Zealand population. They also examined information about hospitalizations and diagnoses from records kept by the New Zealand Ministry of Health.

The researchers followed 1,711,386 individuals born between 1928 and 1967 (50.6% men, aged 21 to 60 years at baseline) for 30 years. The population was subdivided into age groups based on birth years: 1928-1937 (14.8%), 1938-1947 (20.85%), 1948-1957 (29.35%), and 1958-1967 (35.1%).
 

Earlier onset

During the study period, 3.8% of individuals were identified as having a mental disorder, and 2% were identified as having dementia. Similar percentages of men and women had a mental disorder, and similar percentages had dementia.

Dementia was “over-represented” among participants with versus without a mental disorder (6.1% vs. 1.8%). This finding held across all age groups.

Those diagnosed with a mental disorder were also more likely to develop dementia, compared with their peers without a mental disorder (RR, 3.51; 95% confidence interval, 3.39-3.64), which is a larger association than that between physical diseases and dementia (RR, 1.19; 95% CI, 1.16-1.21).

These associations were present in both sexes and in all age groups, although the associations were stronger in more recently born cohorts.

A sixfold higher risk for dementia remained even after adjusting for pre-existing physical illnesses (HR, 6.49; 95% CI, 6.25-6.73); and the elevated risk was evident across different lengths of follow-up from the index mental disorder.

When the researchers focused specifically on individuals diagnosed with dementia, they found that those diagnosed with a mental disorder developed dementia a mean of 5.60 years earlier than those without a mental disorder diagnosis – an association observed across both sexes and all age groups.

“Individuals diagnosed with psychotic, substance use, mood, neurotic, and all other mental disorders and who engaged in self-harm were all more likely than those without a mental disorder to be diagnosed with subsequent dementia, even after accounting for their physical disease histories,” the investigators write.

Although there was a link between mental disorders in both Alzheimer’s and non-Alzheimer’s dementias, the association was larger in non-Alzheimer’s.

The researchers note that the study has several limitations, including the fact that it was conducted in New Zealand and therefore the results may not be generalizable to other regions. In addition, inpatient hospital records do not capture less severe mental disorder cases treated in the outpatient setting.

Dr. Richmond-Rakerd suggested several potential mechanisms that could account for the link between mental illness and dementia, including poor lifestyle choices and metabolic side effects associated with some psychiatric medications.

“There could also be shared risk factors for both mental disorders and dementia, such as shared genetics, or individuals may experience a lifelong brain vulnerability that shows up as mental health problems earlier in life and shows up as dementia later in life,” she said.
 

An important risk factor

Commenting for this article, Ken Duckworth, MD, chief medical officer of the National Alliance on Mental Illness, said a major strength of the study was its longitudinal scope and large population size.

He described the study as allowing clinicians to “watch the movie,” as opposed to looking at a “snapshot” of data.

“Although you can learn things from snapshots, a large, comprehensive public health system looking at 30 years of claims – something not possible in the U.S. because of our more fragmented health care system – offers more insight,” said Dr. Duckworth, who was not involved with the research.

The investigators are “painting a picture of a correlation of risk, and to me, that’s the beginning of further inquiry,” he added. “Would preventive efforts targeting dementia, such as exercise and socialization, be helpful? It’s a great study that raises these interesting questions.”

Also commenting in an interview, Claire Sexton, DPhil, director of scientific programs and outreach at the Alzheimer’s Association, said the study “adds a wealth of data to our understanding” of mental disorders as a dementia risk factor.

However, the study was observational, so “the findings cannot imply causation, [and just] because someone has depression, that does not mean they will go on to develop Alzheimer’s,” said Dr. Sexton, who also was not involved with the research.

Still, “these data support the idea that taking care of one’s mental health is incredibly important for overall wellbeing. For providers, it’s important to have mental health evaluation be a part of your patient’s regular checkups,” she added.

Dr. Richmond-Rakerd noted that even if mental health conditions are not a causal risk factor for dementia, “the presence of a mental health problem is still an important indicator of risk. Mental health providers may wish to target other risk factors for dementia that are more common in individuals with mental health conditions, such as social disconnection.”

The study was funded by grants from the National Institute on Aging, the U.K. Medical Research Council, the National Institute of Child Health and Development through the Duke Population Research Center, and the National Institute on Aging through the Center for Advancing Sociodemographic and Economic Study of Alzheimer’s Disease and Related Dementias. Dr. Richmond-Rakerd reports no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Sexton and Dr. Duckworth report no relevant financial relationships.

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

For the first time, neuroscientists have recorded the brain activity of a dying person, revealing a brain wave pattern similar to that seen when memories are recalled. Although only a single case study, researchers say the recording raises the possibility that as we die, our lives really do flash before our eyes.

“The same neurophysiological activity patterns that occur in our brains when we dream, remember, meditate, concentrate – these same patterns also appear just before we die,” study investigator Ajmal Zemmar, MD, PhD, assistant professor of neurosurgery at the University of Louisville (Ky.), said in an interview.

The research was published online Feb. 22, 2022, in the Frontiers in Aging Neuroscience.
 

Accidental finding

The recording of brain activity was captured inadvertently in 2016 when neuroscientists used continuous EEG to detect and treat seizures in an 87-year-old man who had developed epilepsy after a traumatic brain injury, While undergoing the EEG, the patient had a cardiac arrest and died.

In the 30 seconds before and after blood flow to the brain stopped, the EEG showed an increase in gamma oscillations. These are brain waves known to be involved in high cognitive functions, including conscious perception and memory flashbacks.

Researchers also noted changes in alpha, theta, delta, and beta wave activity just before and just after cardiac arrest, and that changes in one type modulated changes in others. That suggests a coordinated rhythm, which further suggests the activity is more than just the firing of neurons as they die.

“When you observe this and you observe the rhythmic oscillation, you are inclined to think this may be a coordinated activity pattern of the brain rather than a mere discharge when the brain dies,” Dr. Zemmar said.

Although they’ve had the data since 2016, Dr. Zemmar and colleagues held off on publishing in the hopes of finding similar recordings in other individuals. That their 5-year search yielded no results illustrates just how difficult a study like this is to conduct, Dr. Zemmar noted. “We’re trying to figure out how to do this in a predictable way, but obtaining datasets like this is going to be challenging,” he said.

Although Dr. Zemmar was unable to find recordings of activity in the dying brains of other humans, he did find a similar study conducted with rats in 2013. In that research, investigators reported a surge of brain activity in rats just prior to and immediately after experimental cardiac arrest. Changes in high- and low-frequency brain waves mirrored those documented in the current case study.
 

Bringing a picture together

Commenting on the new study, George Mashour, MD, PhD, professor and chair of anesthesiology and professor of neurosurgery and pharmacology at the University of Michigan, Ann Arbor, said the results are eerily similar to a 2013 study that he coauthored.

Although the current research is just a single case study, Dr. Mashour said when taken with his team’s findings in rats and other work, the new findings are “starting to put a picture together of what might be going on in the dying brain.”

“They were able to record throughout the process of cardiac arrest and death and what they found was strikingly similar to what we found in our highly controlled animal study,” said Dr. Mashour, who is also the founding director of the Center for Consciousness Science at the University of Michigan.

“There was a surge of higher-frequency activity and there was coherence across different parts of the brain,” he added. “That suggests that what we found in the rigorous controlled setting of a laboratory actually translates to humans who are undergoing the clinical process of dying.”

What remains unclear is whether this brain activity explains the near-death experiences described in the literature, which include “life recall” of memories, Dr. Mashour said. “This higher-frequency surge that’s happening around the time of death, is that correlated with experiencing something like this near-death experience? Or is it just a neural feature that can just as easily happen in an unconscious brain?”

The study was funded by the Heidi Demetriades Foundation, the ETH Zürich Foundation, and the Henan Provincial People’s Hospital Outstanding Talents Founding Grant Project. Dr. Zemmar and Dr. Mashour disclosed no relevant financial relationships.

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

For the first time, neuroscientists have recorded the brain activity of a dying person, revealing a brain wave pattern similar to that seen when memories are recalled. Although only a single case study, researchers say the recording raises the possibility that as we die, our lives really do flash before our eyes.

“The same neurophysiological activity patterns that occur in our brains when we dream, remember, meditate, concentrate – these same patterns also appear just before we die,” study investigator Ajmal Zemmar, MD, PhD, assistant professor of neurosurgery at the University of Louisville (Ky.), said in an interview.

The research was published online Feb. 22, 2022, in the Frontiers in Aging Neuroscience.
 

Accidental finding

The recording of brain activity was captured inadvertently in 2016 when neuroscientists used continuous EEG to detect and treat seizures in an 87-year-old man who had developed epilepsy after a traumatic brain injury, While undergoing the EEG, the patient had a cardiac arrest and died.

In the 30 seconds before and after blood flow to the brain stopped, the EEG showed an increase in gamma oscillations. These are brain waves known to be involved in high cognitive functions, including conscious perception and memory flashbacks.

Researchers also noted changes in alpha, theta, delta, and beta wave activity just before and just after cardiac arrest, and that changes in one type modulated changes in others. That suggests a coordinated rhythm, which further suggests the activity is more than just the firing of neurons as they die.

“When you observe this and you observe the rhythmic oscillation, you are inclined to think this may be a coordinated activity pattern of the brain rather than a mere discharge when the brain dies,” Dr. Zemmar said.

Although they’ve had the data since 2016, Dr. Zemmar and colleagues held off on publishing in the hopes of finding similar recordings in other individuals. That their 5-year search yielded no results illustrates just how difficult a study like this is to conduct, Dr. Zemmar noted. “We’re trying to figure out how to do this in a predictable way, but obtaining datasets like this is going to be challenging,” he said.

Although Dr. Zemmar was unable to find recordings of activity in the dying brains of other humans, he did find a similar study conducted with rats in 2013. In that research, investigators reported a surge of brain activity in rats just prior to and immediately after experimental cardiac arrest. Changes in high- and low-frequency brain waves mirrored those documented in the current case study.
 

Bringing a picture together

Commenting on the new study, George Mashour, MD, PhD, professor and chair of anesthesiology and professor of neurosurgery and pharmacology at the University of Michigan, Ann Arbor, said the results are eerily similar to a 2013 study that he coauthored.

Although the current research is just a single case study, Dr. Mashour said when taken with his team’s findings in rats and other work, the new findings are “starting to put a picture together of what might be going on in the dying brain.”

“They were able to record throughout the process of cardiac arrest and death and what they found was strikingly similar to what we found in our highly controlled animal study,” said Dr. Mashour, who is also the founding director of the Center for Consciousness Science at the University of Michigan.

“There was a surge of higher-frequency activity and there was coherence across different parts of the brain,” he added. “That suggests that what we found in the rigorous controlled setting of a laboratory actually translates to humans who are undergoing the clinical process of dying.”

What remains unclear is whether this brain activity explains the near-death experiences described in the literature, which include “life recall” of memories, Dr. Mashour said. “This higher-frequency surge that’s happening around the time of death, is that correlated with experiencing something like this near-death experience? Or is it just a neural feature that can just as easily happen in an unconscious brain?”

The study was funded by the Heidi Demetriades Foundation, the ETH Zürich Foundation, and the Henan Provincial People’s Hospital Outstanding Talents Founding Grant Project. Dr. Zemmar and Dr. Mashour disclosed no relevant financial relationships.

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

For the first time, neuroscientists have recorded the brain activity of a dying person, revealing a brain wave pattern similar to that seen when memories are recalled. Although only a single case study, researchers say the recording raises the possibility that as we die, our lives really do flash before our eyes.

“The same neurophysiological activity patterns that occur in our brains when we dream, remember, meditate, concentrate – these same patterns also appear just before we die,” study investigator Ajmal Zemmar, MD, PhD, assistant professor of neurosurgery at the University of Louisville (Ky.), said in an interview.

The research was published online Feb. 22, 2022, in the Frontiers in Aging Neuroscience.
 

Accidental finding

The recording of brain activity was captured inadvertently in 2016 when neuroscientists used continuous EEG to detect and treat seizures in an 87-year-old man who had developed epilepsy after a traumatic brain injury, While undergoing the EEG, the patient had a cardiac arrest and died.

In the 30 seconds before and after blood flow to the brain stopped, the EEG showed an increase in gamma oscillations. These are brain waves known to be involved in high cognitive functions, including conscious perception and memory flashbacks.

Researchers also noted changes in alpha, theta, delta, and beta wave activity just before and just after cardiac arrest, and that changes in one type modulated changes in others. That suggests a coordinated rhythm, which further suggests the activity is more than just the firing of neurons as they die.

“When you observe this and you observe the rhythmic oscillation, you are inclined to think this may be a coordinated activity pattern of the brain rather than a mere discharge when the brain dies,” Dr. Zemmar said.

Although they’ve had the data since 2016, Dr. Zemmar and colleagues held off on publishing in the hopes of finding similar recordings in other individuals. That their 5-year search yielded no results illustrates just how difficult a study like this is to conduct, Dr. Zemmar noted. “We’re trying to figure out how to do this in a predictable way, but obtaining datasets like this is going to be challenging,” he said.

Although Dr. Zemmar was unable to find recordings of activity in the dying brains of other humans, he did find a similar study conducted with rats in 2013. In that research, investigators reported a surge of brain activity in rats just prior to and immediately after experimental cardiac arrest. Changes in high- and low-frequency brain waves mirrored those documented in the current case study.
 

Bringing a picture together

Commenting on the new study, George Mashour, MD, PhD, professor and chair of anesthesiology and professor of neurosurgery and pharmacology at the University of Michigan, Ann Arbor, said the results are eerily similar to a 2013 study that he coauthored.

Although the current research is just a single case study, Dr. Mashour said when taken with his team’s findings in rats and other work, the new findings are “starting to put a picture together of what might be going on in the dying brain.”

“They were able to record throughout the process of cardiac arrest and death and what they found was strikingly similar to what we found in our highly controlled animal study,” said Dr. Mashour, who is also the founding director of the Center for Consciousness Science at the University of Michigan.

“There was a surge of higher-frequency activity and there was coherence across different parts of the brain,” he added. “That suggests that what we found in the rigorous controlled setting of a laboratory actually translates to humans who are undergoing the clinical process of dying.”

What remains unclear is whether this brain activity explains the near-death experiences described in the literature, which include “life recall” of memories, Dr. Mashour said. “This higher-frequency surge that’s happening around the time of death, is that correlated with experiencing something like this near-death experience? Or is it just a neural feature that can just as easily happen in an unconscious brain?”

The study was funded by the Heidi Demetriades Foundation, the ETH Zürich Foundation, and the Henan Provincial People’s Hospital Outstanding Talents Founding Grant Project. Dr. Zemmar and Dr. Mashour disclosed no relevant financial relationships.

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

Anti–calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies are effective for patients with chronic migraine and medication overuse headache regardless of detoxification strategy, according to investigators.

Abruptly discontinuing overused analgesics with health care provider oversight – a frequently resource-intensive and challenging process – is no more effective for controlling medication overuse headache than simply advising patients to stop, reported lead author Umberto Pensato, MD, of the University of Bologna, Italy, and colleagues.

“[C]urrently, the abrupt discontinuation of the overused painkiller(s), accompanied by the start of a pharmacological preventive therapy, is the most recommended strategy [for medication overuse headache],” the investigators wrote in Cephalalgia. “While painkiller(s) withdrawal could be accomplished on an outpatient basis in most cases, an in-hospital setting may be required to achieve successful discontinuation in a subgroup of patients with medication overuse headache, further weighing on individual and hospital costs. Additionally hampering this approach, the abrupt discontinuation of the overused painkiller(s) invariably results in disabling withdrawal symptoms for up to 2 weeks, including a transitory worsening of headache, the so-called ‘rebound headache.’ ”
 

Inpatient or outpatient: Does it matter?

According to Dr. Pensato and colleagues, early evidence suggests that previous painkiller withdrawal does not impact the efficacy of anti-CGRPs for medication overuse headache, yet relevant data remain scarce. To address this knowledge gap, they conducted a prospective, real-world study exploring the relationship between detoxification and outcomes after starting anti-CGRP therapy.

Out of 401 patients enrolled based on initiation of erenumab or galcanezumab, 111 satisfied inclusion criteria, including diagnosis of chronic migraine and medication overuse headache, at least 28 days of analgesic usage and headache days per month in the preceding 3 months, and other factors. Of these 111 patients, 83 underwent in-hospital detox, while the remaining 28 patients, who declined detox based on personal reasons or COVID-19–related bed shortage, were advised to discontinue overused medication on an outpatient basis (without oversight).

The primary endpoint was medication overuse headache responder rate after 3 months, as defined by ICHD-3 diagnostic criteria. Secondary endpoints included 6-item headache impact test (HIT-6), monthly headache days (MHD), migraine disability assessment score (MIDAS), mean pain intensity (MPI), monthly pain medication intake (MPMI), baseline predictors of response/refractoriness, and safety.

Three months after starting anti-CGRP therapy, 59% of patients had resolution of medication overuse headache, including 57% in the inpatient detox group and 64% in the outpatient group, a difference that was not statistically significant (P = .4788). Approximately half of the patients (51%) had at least 50% reduction in monthly headache days; although the rate was numerically lower in the inpatient group compared with the outpatient group, the difference was again not significant (51% vs. 54%; P = .8393).

“Our results support the emerging evidence that anti-CGRP drugs may be effective in these patients irrespective of the detoxification program,” the investigators concluded. “Further studies are needed to definitively confirm these results, potentially leading to a paradigm shift in the management of medication overuse headache.”
 

Abrupt or gradual detox?

According to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews, the study was hampered by two major design limitations.

“The biggest problem I see is that the two groups were treated very differently for their detoxification,” Dr. Rapoport said. “One group was detoxified abruptly in the hospital, so the authors were sure that the patients were off acute-care medication before they started their preventives. The other group was advised to stop their medication on an outpatient basis. The issue is that we have no follow-up as to whether the outpatients did or did not abruptly detoxify. A bigger issue was that the two groups were not randomized so there are many other variables that may have come into consideration.”

Still, Dr. Rapoport, a past president of the International Headache Society (IHS), noted that the findings strengthen a growing body of evidence supporting the efficacy of monoclonal antibodies for medication overuse headache regardless of detoxification strategy. He cited a 2020 study by Carlsen and colleagues conducted at the Danish Headache Center in Copenhagen, which reported similar medication overuse headache outcomes across three randomized cohorts whether they received preventive therapy with detoxification, preventive therapy without detoxification, or detoxification followed 2 months later by preventive therapy.

“What I have noticed since we have had monoclonal antibodies in our armamentarium is that these drugs work very well even when the patient has not fully detoxified,” Dr. Rapoport said. “What I do with my patients is not teach them how to detoxify now, but simply educate them to take fewer acute care medications as their headaches get better from the monoclonal antibodies; they should try to take fewer acute care medications for milder, shorter headaches, and just let them go away on their own. Previous research suggests that even when a patient is not educated at all about medication overuse headache and the reason for detoxification, monoclonal antibodies still work in the presence of medication overuse headache, and improve it.”

The investigators disclosed relationships with Allergan, Novartis, Teva, and others. Dr. Rapoport is on the speakers bureau for AbbVie.

Anti–calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies are effective for patients with chronic migraine and medication overuse headache regardless of detoxification strategy, according to investigators.

Abruptly discontinuing overused analgesics with health care provider oversight – a frequently resource-intensive and challenging process – is no more effective for controlling medication overuse headache than simply advising patients to stop, reported lead author Umberto Pensato, MD, of the University of Bologna, Italy, and colleagues.

“[C]urrently, the abrupt discontinuation of the overused painkiller(s), accompanied by the start of a pharmacological preventive therapy, is the most recommended strategy [for medication overuse headache],” the investigators wrote in Cephalalgia. “While painkiller(s) withdrawal could be accomplished on an outpatient basis in most cases, an in-hospital setting may be required to achieve successful discontinuation in a subgroup of patients with medication overuse headache, further weighing on individual and hospital costs. Additionally hampering this approach, the abrupt discontinuation of the overused painkiller(s) invariably results in disabling withdrawal symptoms for up to 2 weeks, including a transitory worsening of headache, the so-called ‘rebound headache.’ ”
 

Inpatient or outpatient: Does it matter?

According to Dr. Pensato and colleagues, early evidence suggests that previous painkiller withdrawal does not impact the efficacy of anti-CGRPs for medication overuse headache, yet relevant data remain scarce. To address this knowledge gap, they conducted a prospective, real-world study exploring the relationship between detoxification and outcomes after starting anti-CGRP therapy.

Out of 401 patients enrolled based on initiation of erenumab or galcanezumab, 111 satisfied inclusion criteria, including diagnosis of chronic migraine and medication overuse headache, at least 28 days of analgesic usage and headache days per month in the preceding 3 months, and other factors. Of these 111 patients, 83 underwent in-hospital detox, while the remaining 28 patients, who declined detox based on personal reasons or COVID-19–related bed shortage, were advised to discontinue overused medication on an outpatient basis (without oversight).

The primary endpoint was medication overuse headache responder rate after 3 months, as defined by ICHD-3 diagnostic criteria. Secondary endpoints included 6-item headache impact test (HIT-6), monthly headache days (MHD), migraine disability assessment score (MIDAS), mean pain intensity (MPI), monthly pain medication intake (MPMI), baseline predictors of response/refractoriness, and safety.

Three months after starting anti-CGRP therapy, 59% of patients had resolution of medication overuse headache, including 57% in the inpatient detox group and 64% in the outpatient group, a difference that was not statistically significant (P = .4788). Approximately half of the patients (51%) had at least 50% reduction in monthly headache days; although the rate was numerically lower in the inpatient group compared with the outpatient group, the difference was again not significant (51% vs. 54%; P = .8393).

“Our results support the emerging evidence that anti-CGRP drugs may be effective in these patients irrespective of the detoxification program,” the investigators concluded. “Further studies are needed to definitively confirm these results, potentially leading to a paradigm shift in the management of medication overuse headache.”
 

Abrupt or gradual detox?

According to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews, the study was hampered by two major design limitations.

“The biggest problem I see is that the two groups were treated very differently for their detoxification,” Dr. Rapoport said. “One group was detoxified abruptly in the hospital, so the authors were sure that the patients were off acute-care medication before they started their preventives. The other group was advised to stop their medication on an outpatient basis. The issue is that we have no follow-up as to whether the outpatients did or did not abruptly detoxify. A bigger issue was that the two groups were not randomized so there are many other variables that may have come into consideration.”

Still, Dr. Rapoport, a past president of the International Headache Society (IHS), noted that the findings strengthen a growing body of evidence supporting the efficacy of monoclonal antibodies for medication overuse headache regardless of detoxification strategy. He cited a 2020 study by Carlsen and colleagues conducted at the Danish Headache Center in Copenhagen, which reported similar medication overuse headache outcomes across three randomized cohorts whether they received preventive therapy with detoxification, preventive therapy without detoxification, or detoxification followed 2 months later by preventive therapy.

“What I have noticed since we have had monoclonal antibodies in our armamentarium is that these drugs work very well even when the patient has not fully detoxified,” Dr. Rapoport said. “What I do with my patients is not teach them how to detoxify now, but simply educate them to take fewer acute care medications as their headaches get better from the monoclonal antibodies; they should try to take fewer acute care medications for milder, shorter headaches, and just let them go away on their own. Previous research suggests that even when a patient is not educated at all about medication overuse headache and the reason for detoxification, monoclonal antibodies still work in the presence of medication overuse headache, and improve it.”

The investigators disclosed relationships with Allergan, Novartis, Teva, and others. Dr. Rapoport is on the speakers bureau for AbbVie.

Anti–calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies are effective for patients with chronic migraine and medication overuse headache regardless of detoxification strategy, according to investigators.

Abruptly discontinuing overused analgesics with health care provider oversight – a frequently resource-intensive and challenging process – is no more effective for controlling medication overuse headache than simply advising patients to stop, reported lead author Umberto Pensato, MD, of the University of Bologna, Italy, and colleagues.

“[C]urrently, the abrupt discontinuation of the overused painkiller(s), accompanied by the start of a pharmacological preventive therapy, is the most recommended strategy [for medication overuse headache],” the investigators wrote in Cephalalgia. “While painkiller(s) withdrawal could be accomplished on an outpatient basis in most cases, an in-hospital setting may be required to achieve successful discontinuation in a subgroup of patients with medication overuse headache, further weighing on individual and hospital costs. Additionally hampering this approach, the abrupt discontinuation of the overused painkiller(s) invariably results in disabling withdrawal symptoms for up to 2 weeks, including a transitory worsening of headache, the so-called ‘rebound headache.’ ”
 

Inpatient or outpatient: Does it matter?

According to Dr. Pensato and colleagues, early evidence suggests that previous painkiller withdrawal does not impact the efficacy of anti-CGRPs for medication overuse headache, yet relevant data remain scarce. To address this knowledge gap, they conducted a prospective, real-world study exploring the relationship between detoxification and outcomes after starting anti-CGRP therapy.

Out of 401 patients enrolled based on initiation of erenumab or galcanezumab, 111 satisfied inclusion criteria, including diagnosis of chronic migraine and medication overuse headache, at least 28 days of analgesic usage and headache days per month in the preceding 3 months, and other factors. Of these 111 patients, 83 underwent in-hospital detox, while the remaining 28 patients, who declined detox based on personal reasons or COVID-19–related bed shortage, were advised to discontinue overused medication on an outpatient basis (without oversight).

The primary endpoint was medication overuse headache responder rate after 3 months, as defined by ICHD-3 diagnostic criteria. Secondary endpoints included 6-item headache impact test (HIT-6), monthly headache days (MHD), migraine disability assessment score (MIDAS), mean pain intensity (MPI), monthly pain medication intake (MPMI), baseline predictors of response/refractoriness, and safety.

Three months after starting anti-CGRP therapy, 59% of patients had resolution of medication overuse headache, including 57% in the inpatient detox group and 64% in the outpatient group, a difference that was not statistically significant (P = .4788). Approximately half of the patients (51%) had at least 50% reduction in monthly headache days; although the rate was numerically lower in the inpatient group compared with the outpatient group, the difference was again not significant (51% vs. 54%; P = .8393).

“Our results support the emerging evidence that anti-CGRP drugs may be effective in these patients irrespective of the detoxification program,” the investigators concluded. “Further studies are needed to definitively confirm these results, potentially leading to a paradigm shift in the management of medication overuse headache.”
 

Abrupt or gradual detox?

According to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews, the study was hampered by two major design limitations.

“The biggest problem I see is that the two groups were treated very differently for their detoxification,” Dr. Rapoport said. “One group was detoxified abruptly in the hospital, so the authors were sure that the patients were off acute-care medication before they started their preventives. The other group was advised to stop their medication on an outpatient basis. The issue is that we have no follow-up as to whether the outpatients did or did not abruptly detoxify. A bigger issue was that the two groups were not randomized so there are many other variables that may have come into consideration.”

Still, Dr. Rapoport, a past president of the International Headache Society (IHS), noted that the findings strengthen a growing body of evidence supporting the efficacy of monoclonal antibodies for medication overuse headache regardless of detoxification strategy. He cited a 2020 study by Carlsen and colleagues conducted at the Danish Headache Center in Copenhagen, which reported similar medication overuse headache outcomes across three randomized cohorts whether they received preventive therapy with detoxification, preventive therapy without detoxification, or detoxification followed 2 months later by preventive therapy.

“What I have noticed since we have had monoclonal antibodies in our armamentarium is that these drugs work very well even when the patient has not fully detoxified,” Dr. Rapoport said. “What I do with my patients is not teach them how to detoxify now, but simply educate them to take fewer acute care medications as their headaches get better from the monoclonal antibodies; they should try to take fewer acute care medications for milder, shorter headaches, and just let them go away on their own. Previous research suggests that even when a patient is not educated at all about medication overuse headache and the reason for detoxification, monoclonal antibodies still work in the presence of medication overuse headache, and improve it.”

The investigators disclosed relationships with Allergan, Novartis, Teva, and others. Dr. Rapoport is on the speakers bureau for AbbVie.

New research shows that men in their 20s and 30s have worse survival from many different types of brain tumors than women of the same age. And, researchers say, it’s not exactly clear why.

Differences in treatment may mediate some of the association, but biologic sex itself appears to be a stronger risk factor for death, according to the study published online Feb. 8 in Cancer.

The excess in male deaths is “concerning, and we need more clinical data and more biological tumor data within each histologic type of brain tumor to understand why these young adult men who would be otherwise healthy are dying of these brain tumors,” study author Lindsay Williams, PhD, MPH, with the division of epidemiology and clinical research, University of Minnesota, Minneapolis, told this news organization.

Central nervous system tumors rank among the top five cancers diagnosed in young adults aged 20-39 years.

Dr. Williams and her colleagues previously showed that men are more likely to develop brain tumors. Their latest study shows that men die more frequently from brain tumors as well.

Using the National Cancer Database, they identified 47,560 young adults aged 20-39 (47% male) diagnosed with a CNS tumor between 2004 and 2016.

After adjusting for relevant factors, males had a 47% increased risk of dying after a brain tumor diagnosis compared with females (hazard ratio, 1.47; 95% confidence interval, 1.41-1.53).

Males had significantly worse overall survival than females for all CNS tumors combined and for nine of 16 histologic types – namely, diffuse astrocytoma (HR, 1.30), anaplastic astrocytoma (HR, 1.25), glioblastoma (HR, 1.14), oligodendroglioma (HR, 1.37), oligoastrocytic tumors (HR, 1.22), ependymal tumors (HR, 1.29), other malignant gliomas (HR, 1.43), neuronal and mixed neuronal-glial tumors (HR, 1.52), and meningioma (HR, 2.01; all P < .05).

The researchers identified no histologies where females had worse survival.

Five-year survival differed between females and males by at least 5% for all histologies combined (83.2% female and 71.2% male) as well as for diffuse astrocytoma (75.1% vs. 68.5%), anaplastic astrocytoma (63.5% vs. 57.5%), oligoastrocytic tumors (80.2% vs. 74.7%), other malignant gliomas (74.1% vs. 64.9%), and germ cell tumors (92.4% vs. 86.5%).

The researchers estimated that had survival in men been equal to that of women over the study period, 20% of total deaths and 34% of male deaths could have been avoided.

They say future population-based studies are needed to confirm these findings and determine whether tumor biology or responses to therapy are driving forces of the observed male excess in death from brain tumors.

“We cannot discount the role of sex differences in diagnosis, treatment, or behavioral risk factors that may underlie the better survival for women after a brain tumor diagnosis,” they write. 

“Hopefully, our research will increase awareness of sex differences in brain tumor outcomes in young adults and encourage other researchers with similar datasets to look at this same question and see if they observe a similar trend,” Dr. Williams said in an interview.

The study was supported by the National Cancer Institute. Dr. Williams has no relevant disclosures. One author, Christopher L. Moertel, MD, is chief medical officer for OX2 Therapeutics, has stock in OX2 Therapeutics, and reports patents relevant to his relationship with OX2 Therapeutics.

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

New research shows that men in their 20s and 30s have worse survival from many different types of brain tumors than women of the same age. And, researchers say, it’s not exactly clear why.

Differences in treatment may mediate some of the association, but biologic sex itself appears to be a stronger risk factor for death, according to the study published online Feb. 8 in Cancer.

The excess in male deaths is “concerning, and we need more clinical data and more biological tumor data within each histologic type of brain tumor to understand why these young adult men who would be otherwise healthy are dying of these brain tumors,” study author Lindsay Williams, PhD, MPH, with the division of epidemiology and clinical research, University of Minnesota, Minneapolis, told this news organization.

Central nervous system tumors rank among the top five cancers diagnosed in young adults aged 20-39 years.

Dr. Williams and her colleagues previously showed that men are more likely to develop brain tumors. Their latest study shows that men die more frequently from brain tumors as well.

Using the National Cancer Database, they identified 47,560 young adults aged 20-39 (47% male) diagnosed with a CNS tumor between 2004 and 2016.

After adjusting for relevant factors, males had a 47% increased risk of dying after a brain tumor diagnosis compared with females (hazard ratio, 1.47; 95% confidence interval, 1.41-1.53).

Males had significantly worse overall survival than females for all CNS tumors combined and for nine of 16 histologic types – namely, diffuse astrocytoma (HR, 1.30), anaplastic astrocytoma (HR, 1.25), glioblastoma (HR, 1.14), oligodendroglioma (HR, 1.37), oligoastrocytic tumors (HR, 1.22), ependymal tumors (HR, 1.29), other malignant gliomas (HR, 1.43), neuronal and mixed neuronal-glial tumors (HR, 1.52), and meningioma (HR, 2.01; all P < .05).

The researchers identified no histologies where females had worse survival.

Five-year survival differed between females and males by at least 5% for all histologies combined (83.2% female and 71.2% male) as well as for diffuse astrocytoma (75.1% vs. 68.5%), anaplastic astrocytoma (63.5% vs. 57.5%), oligoastrocytic tumors (80.2% vs. 74.7%), other malignant gliomas (74.1% vs. 64.9%), and germ cell tumors (92.4% vs. 86.5%).

The researchers estimated that had survival in men been equal to that of women over the study period, 20% of total deaths and 34% of male deaths could have been avoided.

They say future population-based studies are needed to confirm these findings and determine whether tumor biology or responses to therapy are driving forces of the observed male excess in death from brain tumors.

“We cannot discount the role of sex differences in diagnosis, treatment, or behavioral risk factors that may underlie the better survival for women after a brain tumor diagnosis,” they write. 

“Hopefully, our research will increase awareness of sex differences in brain tumor outcomes in young adults and encourage other researchers with similar datasets to look at this same question and see if they observe a similar trend,” Dr. Williams said in an interview.

The study was supported by the National Cancer Institute. Dr. Williams has no relevant disclosures. One author, Christopher L. Moertel, MD, is chief medical officer for OX2 Therapeutics, has stock in OX2 Therapeutics, and reports patents relevant to his relationship with OX2 Therapeutics.

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

New research shows that men in their 20s and 30s have worse survival from many different types of brain tumors than women of the same age. And, researchers say, it’s not exactly clear why.

Differences in treatment may mediate some of the association, but biologic sex itself appears to be a stronger risk factor for death, according to the study published online Feb. 8 in Cancer.

The excess in male deaths is “concerning, and we need more clinical data and more biological tumor data within each histologic type of brain tumor to understand why these young adult men who would be otherwise healthy are dying of these brain tumors,” study author Lindsay Williams, PhD, MPH, with the division of epidemiology and clinical research, University of Minnesota, Minneapolis, told this news organization.

Central nervous system tumors rank among the top five cancers diagnosed in young adults aged 20-39 years.

Dr. Williams and her colleagues previously showed that men are more likely to develop brain tumors. Their latest study shows that men die more frequently from brain tumors as well.

Using the National Cancer Database, they identified 47,560 young adults aged 20-39 (47% male) diagnosed with a CNS tumor between 2004 and 2016.

After adjusting for relevant factors, males had a 47% increased risk of dying after a brain tumor diagnosis compared with females (hazard ratio, 1.47; 95% confidence interval, 1.41-1.53).

Males had significantly worse overall survival than females for all CNS tumors combined and for nine of 16 histologic types – namely, diffuse astrocytoma (HR, 1.30), anaplastic astrocytoma (HR, 1.25), glioblastoma (HR, 1.14), oligodendroglioma (HR, 1.37), oligoastrocytic tumors (HR, 1.22), ependymal tumors (HR, 1.29), other malignant gliomas (HR, 1.43), neuronal and mixed neuronal-glial tumors (HR, 1.52), and meningioma (HR, 2.01; all P < .05).

The researchers identified no histologies where females had worse survival.

Five-year survival differed between females and males by at least 5% for all histologies combined (83.2% female and 71.2% male) as well as for diffuse astrocytoma (75.1% vs. 68.5%), anaplastic astrocytoma (63.5% vs. 57.5%), oligoastrocytic tumors (80.2% vs. 74.7%), other malignant gliomas (74.1% vs. 64.9%), and germ cell tumors (92.4% vs. 86.5%).

The researchers estimated that had survival in men been equal to that of women over the study period, 20% of total deaths and 34% of male deaths could have been avoided.

They say future population-based studies are needed to confirm these findings and determine whether tumor biology or responses to therapy are driving forces of the observed male excess in death from brain tumors.

“We cannot discount the role of sex differences in diagnosis, treatment, or behavioral risk factors that may underlie the better survival for women after a brain tumor diagnosis,” they write. 

“Hopefully, our research will increase awareness of sex differences in brain tumor outcomes in young adults and encourage other researchers with similar datasets to look at this same question and see if they observe a similar trend,” Dr. Williams said in an interview.

The study was supported by the National Cancer Institute. Dr. Williams has no relevant disclosures. One author, Christopher L. Moertel, MD, is chief medical officer for OX2 Therapeutics, has stock in OX2 Therapeutics, and reports patents relevant to his relationship with OX2 Therapeutics.

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

A high level of education, superior academic performance, and excellent written language skills may predict the reversal of mild cognitive impairment (MCI) to normal cognitive function, new research shows.

The investigators found individuals with these factors, which are all markers of cognitive reserve, had a significantly greater chance of reversion from MCI to normal cognition (NC) than progression from MCI to dementia.

In a cohort study of more than 600 women aged 75 years or older, about a third of those with MCI reverted to NC at some point during follow-up, which sends “an encouraging message,” study author Suzanne Tyas, PhD, associate professor, University of Waterloo (Ont.), said in an interview.

“That’s a positive thing for people to keep in mind when they’re thinking about prognosis. Some of these novel characteristics we’ve identified might be useful in thinking about how likely a particular patient might be to improve versus decline cognitively,” Dr. Tyas added.

The findings were published online Feb. 4, 2022, in the journal Neurology.
 

Highly educated cohort

As the population ages, the number of individuals experiencing age-related conditions, including dementia, increases. There is no cure for most dementia types so prevention is key – and preventing dementia requires understanding its risk factors, Dr. Tyas noted.

The analysis included participants from the Nun Study, a longitudinal study of aging and cognition among members of the School Sisters of Notre Dame in the United States. All were 75 and older at baseline, which was from 1991 to 1993; about 14.5% were older than 90 years.

Participants were generally highly educated, with 84.5% attaining an undergraduate or graduate degree. They also had a similar socioeconomic status, level of social supports, marital and reproductive history, and alcohol and tobacco use.

Researchers examined cognitive function at baseline and then about annually until death or end of the 12th round of assessments. They used five measures from the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery to categorize subjects into NC, MCI, or dementia: Delayed Word Recall, Verbal Fluency, Boston Naming, Constructional Praxis, and the Mini-Mental State Exam.

The current analysis focused on the 619 participants with data on apolipoprotein E (apo E) epsilon-4 genotyping and education. From convent archives, investigators also had access to the nuns’ early high school academic performance in English, Latin, algebra, and geometry.

“Typically we only have data for [overall] education. But I know from teaching that there’s a difference between people who just pass my courses and graduate with a university degree versus those who really excel,” Dr. Tyas said.

The researchers also assessed handwriting samples from before the participants entered the religious order. From these, they scored “idea density,” which is the number of ideas contained in the writing and “grammatical complexity,” which includes structure, use of clauses, subclauses, and so on.
 

Dementia not inevitable

Results showed 472 of the 619 participants had MCI during the study period. About 30.3% of these showed at least one reverse transition from MCI to NC during a mean follow-up of 8.6 years; 83.9% went on to develop dementia.

This shows converting from MCI to NC occurs relatively frequently, Dr. Tyas noted.

“This is encouraging because some people think that if they have a diagnosis of MCI they are inevitably going to decline to dementia,” she added.

The researchers also used complicated modeling of transition rates over time between NC, MCI, and dementia and adjusted for participants who died. They estimated relative risk of reversion versus progression for age, apo E, and potential cognitive reserve indicators.

Not surprisingly, younger age (90 years or less) and absence of apo E epsilon-4 allele contributed to a significantly higher rate for reversion from MCI to NC versus progression from MCI to dementia.

However, although age and apo E are known risk factors for dementia, these have not been examined in the context of whether individuals with MCI are more likely to improve or decline, said Dr. Tyas.

Higher educational attainment, the traditional indicator of cognitive reserve, was associated with a significantly higher relative risk for reversion from MCI to NC versus progression from MCI to dementia (RR, 2.6) for a bachelor’s degree versus less education.

There was a greater RR for even higher education after adjusting for age and apo E epsilon-4 status.
 

Language skills key

Interestingly, the investigators also found a significant association with good grades in high school English but not other subjects (RR for higher vs. lower English grades, 1.83; 95% confidence interval, 1.07-3.14).

In addition, they found both characteristics of written language skills (idea density and grammatical complexity) were significant predictors of conversion to NC.

“Those with high levels of idea density were four times more likely to improve to normal cognition than progress to dementia, and the effect was even stronger for grammatical structure. Those individuals with higher levels were almost six times more likely to improve than decline,” Dr. Tyas reported.

The RR for higher versus lower idea density was 3.93 (95% CI, 1.3-11.9) and the RR for higher versus lower grammatical complexity was 5.78 (95% CI, 1.56-21.42).

These new results could be useful when planning future clinical trials, Dr. Tyas noted. “MCI in some people is going to improve even without any treatment, and this should be taken into consideration when recruiting participants to a study and when interpreting the results.

“You don’t want something to look like it’s a benefit of the treatment when in fact these individuals would have just reverted on their own,” she added.
 

Research implications

Commenting on the findings, Claire Sexton, DPhil, director of scientific programs and outreach at the Alzheimer’s Association, noted that, in “this study of highly educated, older women,” transitions from MCI to NC “were about equally common” as transitions from MCI to dementia.

“As advances are made in early detection of dementia, and treatments are developed and marketed for people living with MCI, this article’s findings are important to inform discussions of prognosis with patients and [to the] design of clinical trials,” Dr. Sexton said.

The study was funded by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada. Funding for the Nun Study at the University of Kentucky was provided by the U.S. National Institute of Aging and the Kleberg Foundation. Dr. Tyas has disclosed no relevant financial relationships.

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

A high level of education, superior academic performance, and excellent written language skills may predict the reversal of mild cognitive impairment (MCI) to normal cognitive function, new research shows.

The investigators found individuals with these factors, which are all markers of cognitive reserve, had a significantly greater chance of reversion from MCI to normal cognition (NC) than progression from MCI to dementia.

In a cohort study of more than 600 women aged 75 years or older, about a third of those with MCI reverted to NC at some point during follow-up, which sends “an encouraging message,” study author Suzanne Tyas, PhD, associate professor, University of Waterloo (Ont.), said in an interview.

“That’s a positive thing for people to keep in mind when they’re thinking about prognosis. Some of these novel characteristics we’ve identified might be useful in thinking about how likely a particular patient might be to improve versus decline cognitively,” Dr. Tyas added.

The findings were published online Feb. 4, 2022, in the journal Neurology.
 

Highly educated cohort

As the population ages, the number of individuals experiencing age-related conditions, including dementia, increases. There is no cure for most dementia types so prevention is key – and preventing dementia requires understanding its risk factors, Dr. Tyas noted.

The analysis included participants from the Nun Study, a longitudinal study of aging and cognition among members of the School Sisters of Notre Dame in the United States. All were 75 and older at baseline, which was from 1991 to 1993; about 14.5% were older than 90 years.

Participants were generally highly educated, with 84.5% attaining an undergraduate or graduate degree. They also had a similar socioeconomic status, level of social supports, marital and reproductive history, and alcohol and tobacco use.

Researchers examined cognitive function at baseline and then about annually until death or end of the 12th round of assessments. They used five measures from the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery to categorize subjects into NC, MCI, or dementia: Delayed Word Recall, Verbal Fluency, Boston Naming, Constructional Praxis, and the Mini-Mental State Exam.

The current analysis focused on the 619 participants with data on apolipoprotein E (apo E) epsilon-4 genotyping and education. From convent archives, investigators also had access to the nuns’ early high school academic performance in English, Latin, algebra, and geometry.

“Typically we only have data for [overall] education. But I know from teaching that there’s a difference between people who just pass my courses and graduate with a university degree versus those who really excel,” Dr. Tyas said.

The researchers also assessed handwriting samples from before the participants entered the religious order. From these, they scored “idea density,” which is the number of ideas contained in the writing and “grammatical complexity,” which includes structure, use of clauses, subclauses, and so on.
 

Dementia not inevitable

Results showed 472 of the 619 participants had MCI during the study period. About 30.3% of these showed at least one reverse transition from MCI to NC during a mean follow-up of 8.6 years; 83.9% went on to develop dementia.

This shows converting from MCI to NC occurs relatively frequently, Dr. Tyas noted.

“This is encouraging because some people think that if they have a diagnosis of MCI they are inevitably going to decline to dementia,” she added.

The researchers also used complicated modeling of transition rates over time between NC, MCI, and dementia and adjusted for participants who died. They estimated relative risk of reversion versus progression for age, apo E, and potential cognitive reserve indicators.

Not surprisingly, younger age (90 years or less) and absence of apo E epsilon-4 allele contributed to a significantly higher rate for reversion from MCI to NC versus progression from MCI to dementia.

However, although age and apo E are known risk factors for dementia, these have not been examined in the context of whether individuals with MCI are more likely to improve or decline, said Dr. Tyas.

Higher educational attainment, the traditional indicator of cognitive reserve, was associated with a significantly higher relative risk for reversion from MCI to NC versus progression from MCI to dementia (RR, 2.6) for a bachelor’s degree versus less education.

There was a greater RR for even higher education after adjusting for age and apo E epsilon-4 status.
 

Language skills key

Interestingly, the investigators also found a significant association with good grades in high school English but not other subjects (RR for higher vs. lower English grades, 1.83; 95% confidence interval, 1.07-3.14).

In addition, they found both characteristics of written language skills (idea density and grammatical complexity) were significant predictors of conversion to NC.

“Those with high levels of idea density were four times more likely to improve to normal cognition than progress to dementia, and the effect was even stronger for grammatical structure. Those individuals with higher levels were almost six times more likely to improve than decline,” Dr. Tyas reported.

The RR for higher versus lower idea density was 3.93 (95% CI, 1.3-11.9) and the RR for higher versus lower grammatical complexity was 5.78 (95% CI, 1.56-21.42).

These new results could be useful when planning future clinical trials, Dr. Tyas noted. “MCI in some people is going to improve even without any treatment, and this should be taken into consideration when recruiting participants to a study and when interpreting the results.

“You don’t want something to look like it’s a benefit of the treatment when in fact these individuals would have just reverted on their own,” she added.
 

Research implications

Commenting on the findings, Claire Sexton, DPhil, director of scientific programs and outreach at the Alzheimer’s Association, noted that, in “this study of highly educated, older women,” transitions from MCI to NC “were about equally common” as transitions from MCI to dementia.

“As advances are made in early detection of dementia, and treatments are developed and marketed for people living with MCI, this article’s findings are important to inform discussions of prognosis with patients and [to the] design of clinical trials,” Dr. Sexton said.

The study was funded by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada. Funding for the Nun Study at the University of Kentucky was provided by the U.S. National Institute of Aging and the Kleberg Foundation. Dr. Tyas has disclosed no relevant financial relationships.

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

A high level of education, superior academic performance, and excellent written language skills may predict the reversal of mild cognitive impairment (MCI) to normal cognitive function, new research shows.

The investigators found individuals with these factors, which are all markers of cognitive reserve, had a significantly greater chance of reversion from MCI to normal cognition (NC) than progression from MCI to dementia.

In a cohort study of more than 600 women aged 75 years or older, about a third of those with MCI reverted to NC at some point during follow-up, which sends “an encouraging message,” study author Suzanne Tyas, PhD, associate professor, University of Waterloo (Ont.), said in an interview.

“That’s a positive thing for people to keep in mind when they’re thinking about prognosis. Some of these novel characteristics we’ve identified might be useful in thinking about how likely a particular patient might be to improve versus decline cognitively,” Dr. Tyas added.

The findings were published online Feb. 4, 2022, in the journal Neurology.
 

Highly educated cohort

As the population ages, the number of individuals experiencing age-related conditions, including dementia, increases. There is no cure for most dementia types so prevention is key – and preventing dementia requires understanding its risk factors, Dr. Tyas noted.

The analysis included participants from the Nun Study, a longitudinal study of aging and cognition among members of the School Sisters of Notre Dame in the United States. All were 75 and older at baseline, which was from 1991 to 1993; about 14.5% were older than 90 years.

Participants were generally highly educated, with 84.5% attaining an undergraduate or graduate degree. They also had a similar socioeconomic status, level of social supports, marital and reproductive history, and alcohol and tobacco use.

Researchers examined cognitive function at baseline and then about annually until death or end of the 12th round of assessments. They used five measures from the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery to categorize subjects into NC, MCI, or dementia: Delayed Word Recall, Verbal Fluency, Boston Naming, Constructional Praxis, and the Mini-Mental State Exam.

The current analysis focused on the 619 participants with data on apolipoprotein E (apo E) epsilon-4 genotyping and education. From convent archives, investigators also had access to the nuns’ early high school academic performance in English, Latin, algebra, and geometry.

“Typically we only have data for [overall] education. But I know from teaching that there’s a difference between people who just pass my courses and graduate with a university degree versus those who really excel,” Dr. Tyas said.

The researchers also assessed handwriting samples from before the participants entered the religious order. From these, they scored “idea density,” which is the number of ideas contained in the writing and “grammatical complexity,” which includes structure, use of clauses, subclauses, and so on.
 

Dementia not inevitable

Results showed 472 of the 619 participants had MCI during the study period. About 30.3% of these showed at least one reverse transition from MCI to NC during a mean follow-up of 8.6 years; 83.9% went on to develop dementia.

This shows converting from MCI to NC occurs relatively frequently, Dr. Tyas noted.

“This is encouraging because some people think that if they have a diagnosis of MCI they are inevitably going to decline to dementia,” she added.

The researchers also used complicated modeling of transition rates over time between NC, MCI, and dementia and adjusted for participants who died. They estimated relative risk of reversion versus progression for age, apo E, and potential cognitive reserve indicators.

Not surprisingly, younger age (90 years or less) and absence of apo E epsilon-4 allele contributed to a significantly higher rate for reversion from MCI to NC versus progression from MCI to dementia.

However, although age and apo E are known risk factors for dementia, these have not been examined in the context of whether individuals with MCI are more likely to improve or decline, said Dr. Tyas.

Higher educational attainment, the traditional indicator of cognitive reserve, was associated with a significantly higher relative risk for reversion from MCI to NC versus progression from MCI to dementia (RR, 2.6) for a bachelor’s degree versus less education.

There was a greater RR for even higher education after adjusting for age and apo E epsilon-4 status.
 

Language skills key

Interestingly, the investigators also found a significant association with good grades in high school English but not other subjects (RR for higher vs. lower English grades, 1.83; 95% confidence interval, 1.07-3.14).

In addition, they found both characteristics of written language skills (idea density and grammatical complexity) were significant predictors of conversion to NC.

“Those with high levels of idea density were four times more likely to improve to normal cognition than progress to dementia, and the effect was even stronger for grammatical structure. Those individuals with higher levels were almost six times more likely to improve than decline,” Dr. Tyas reported.

The RR for higher versus lower idea density was 3.93 (95% CI, 1.3-11.9) and the RR for higher versus lower grammatical complexity was 5.78 (95% CI, 1.56-21.42).

These new results could be useful when planning future clinical trials, Dr. Tyas noted. “MCI in some people is going to improve even without any treatment, and this should be taken into consideration when recruiting participants to a study and when interpreting the results.

“You don’t want something to look like it’s a benefit of the treatment when in fact these individuals would have just reverted on their own,” she added.
 

Research implications

Commenting on the findings, Claire Sexton, DPhil, director of scientific programs and outreach at the Alzheimer’s Association, noted that, in “this study of highly educated, older women,” transitions from MCI to NC “were about equally common” as transitions from MCI to dementia.

“As advances are made in early detection of dementia, and treatments are developed and marketed for people living with MCI, this article’s findings are important to inform discussions of prognosis with patients and [to the] design of clinical trials,” Dr. Sexton said.

The study was funded by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada. Funding for the Nun Study at the University of Kentucky was provided by the U.S. National Institute of Aging and the Kleberg Foundation. Dr. Tyas has disclosed no relevant financial relationships.

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

The International League Against Epilepsy (ILAE) has issued recommendations for treating depression in patients with epilepsy.

The new guidance highlights the high prevalence of depression among patients with epilepsy while offering the first systematic approach to treatment, reported lead author Marco Mula, MD, PhD, of Atkinson Morley Regional Neuroscience Centre at St George’s University Hospital, London, and colleagues.

“Despite evidence that depression represents a frequently encountered comorbidity [among patients with epilepsy], data on the treatment of depression in epilepsy [are] still limited and recommendations rely mostly on individual clinical experience and expertise,” the investigators wrote in Epilepsia.

Recommendations cover first-line treatment of unipolar depression in epilepsy without other psychiatric disorders.

For patients with mild depression, the guidance supports psychological intervention without pharmacologic therapy; however, if the patient wishes to use medication, has had a positive response to medication in the past, or nonpharmacologic treatments have previously failed or are unavailable, then SSRIs should be considered first-choice therapy. For moderate to severe depression, SSRIs are the first choice, according to Dr. Mula and colleagues.

“It has to be acknowledged that there is considerable debate in the psychiatric literature about the treatment of mild depression in adults,” the investigators noted. “A patient-level meta-analysis pointed out that the magnitude of benefit of antidepressant medications compared with placebo increases with severity of depression symptoms and it may be minimal or nonexistent, on average, in patients with mild or moderate symptoms.”

If a patient does not respond to first-line therapy, then venlafaxine should be considered, according to the guidance. When a patient does respond to therapy, treatment should be continued for at least 6 months, and when residual symptoms persist, treatment should be continued until resolution.

“In people with depression it is established that around two-thirds of patients do not achieve full remission with first-line treatment,” Dr. Mula and colleagues wrote. “In people with epilepsy, current data show that up to 50% of patients do not achieve full remission from depression. For this reason, augmentation strategies are often needed. They should be adopted by psychiatrists, neuropsychiatrists, or mental health professionals familiar with such therapeutic strategies.”

Beyond these key recommendations, the guidance covers a range of additional topics, including other pharmacologic options, medication discontinuation strategies, electroconvulsive therapy, light therapy, exercise training, vagus nerve stimulation, and repetitive transcranial magnetic stimulation.
 

Useful advice that counters common misconceptions

According to Jacqueline A. French, MD, a professor at NYU Langone Medical Center, Dr. Mula and colleagues are “top notch,” and their recommendations “hit every nail on the head.”

Dr. French, chief medical officer of The Epilepsy Foundation, emphasized the importance of the publication, which addresses two common misconceptions within the medical community: First, that standard antidepressants are insufficient to treat depression in patients with epilepsy, and second, that antidepressants may trigger seizures.

“The first purpose [of the publication] is to say, yes, these antidepressants do work,” Dr. French said, “and no, they don’t worsen seizures, and you can use them safely, and they are appropriate to use.”

Dr. French explained that managing depression remains a practice gap among epileptologists and neurologists because it is a diagnosis that doesn’t traditionally fall into their purview, yet many patients with epilepsy forgo visiting their primary care providers, who more frequently diagnose and manage depression. Dr. French agreed with the guidance that epilepsy specialists should fill this gap.

“We need to at least be able to take people through their first antidepressant, even though we were not trained to be psychiatrists,” Dr. French said. “That’s part of the best care of our patients.”

Imad Najm, MD, director of the Charles Shor Epilepsy Center, Cleveland Clinic, said the recommendations are a step forward in the field, as they are supported by clinical data, instead of just clinical experience and expertise.

Still, Dr. Najm noted that more work is needed to stratify risk of depression in epilepsy and evaluate a possible causal relationship between epilepsy therapies and depression.

He went on to emphasizes the scale of issue at hand, and the stakes involved.

“Depression, anxiety, and psychosis affect a large number of patients with epilepsy,” Dr. Najm said. “Clinical screening and recognition of these comorbidities leads to the institution of treatment options and significant improvement in quality of life. Mental health professionals should be an integral part of any comprehensive epilepsy center.”

The investigators disclosed relationships with Esai, UCB, Elsevier, and others. Dr. French is indirectly involved with multiple pharmaceutical companies developing epilepsy drugs through her role as director of The Epilepsy Study Consortium, a nonprofit organization. Dr. Najm reported no conflicts of interest.

The International League Against Epilepsy (ILAE) has issued recommendations for treating depression in patients with epilepsy.

The new guidance highlights the high prevalence of depression among patients with epilepsy while offering the first systematic approach to treatment, reported lead author Marco Mula, MD, PhD, of Atkinson Morley Regional Neuroscience Centre at St George’s University Hospital, London, and colleagues.

“Despite evidence that depression represents a frequently encountered comorbidity [among patients with epilepsy], data on the treatment of depression in epilepsy [are] still limited and recommendations rely mostly on individual clinical experience and expertise,” the investigators wrote in Epilepsia.

Recommendations cover first-line treatment of unipolar depression in epilepsy without other psychiatric disorders.

For patients with mild depression, the guidance supports psychological intervention without pharmacologic therapy; however, if the patient wishes to use medication, has had a positive response to medication in the past, or nonpharmacologic treatments have previously failed or are unavailable, then SSRIs should be considered first-choice therapy. For moderate to severe depression, SSRIs are the first choice, according to Dr. Mula and colleagues.

“It has to be acknowledged that there is considerable debate in the psychiatric literature about the treatment of mild depression in adults,” the investigators noted. “A patient-level meta-analysis pointed out that the magnitude of benefit of antidepressant medications compared with placebo increases with severity of depression symptoms and it may be minimal or nonexistent, on average, in patients with mild or moderate symptoms.”

If a patient does not respond to first-line therapy, then venlafaxine should be considered, according to the guidance. When a patient does respond to therapy, treatment should be continued for at least 6 months, and when residual symptoms persist, treatment should be continued until resolution.

“In people with depression it is established that around two-thirds of patients do not achieve full remission with first-line treatment,” Dr. Mula and colleagues wrote. “In people with epilepsy, current data show that up to 50% of patients do not achieve full remission from depression. For this reason, augmentation strategies are often needed. They should be adopted by psychiatrists, neuropsychiatrists, or mental health professionals familiar with such therapeutic strategies.”

Beyond these key recommendations, the guidance covers a range of additional topics, including other pharmacologic options, medication discontinuation strategies, electroconvulsive therapy, light therapy, exercise training, vagus nerve stimulation, and repetitive transcranial magnetic stimulation.
 

Useful advice that counters common misconceptions

According to Jacqueline A. French, MD, a professor at NYU Langone Medical Center, Dr. Mula and colleagues are “top notch,” and their recommendations “hit every nail on the head.”

Dr. French, chief medical officer of The Epilepsy Foundation, emphasized the importance of the publication, which addresses two common misconceptions within the medical community: First, that standard antidepressants are insufficient to treat depression in patients with epilepsy, and second, that antidepressants may trigger seizures.

“The first purpose [of the publication] is to say, yes, these antidepressants do work,” Dr. French said, “and no, they don’t worsen seizures, and you can use them safely, and they are appropriate to use.”

Dr. French explained that managing depression remains a practice gap among epileptologists and neurologists because it is a diagnosis that doesn’t traditionally fall into their purview, yet many patients with epilepsy forgo visiting their primary care providers, who more frequently diagnose and manage depression. Dr. French agreed with the guidance that epilepsy specialists should fill this gap.

“We need to at least be able to take people through their first antidepressant, even though we were not trained to be psychiatrists,” Dr. French said. “That’s part of the best care of our patients.”

Imad Najm, MD, director of the Charles Shor Epilepsy Center, Cleveland Clinic, said the recommendations are a step forward in the field, as they are supported by clinical data, instead of just clinical experience and expertise.

Still, Dr. Najm noted that more work is needed to stratify risk of depression in epilepsy and evaluate a possible causal relationship between epilepsy therapies and depression.

He went on to emphasizes the scale of issue at hand, and the stakes involved.

“Depression, anxiety, and psychosis affect a large number of patients with epilepsy,” Dr. Najm said. “Clinical screening and recognition of these comorbidities leads to the institution of treatment options and significant improvement in quality of life. Mental health professionals should be an integral part of any comprehensive epilepsy center.”

The investigators disclosed relationships with Esai, UCB, Elsevier, and others. Dr. French is indirectly involved with multiple pharmaceutical companies developing epilepsy drugs through her role as director of The Epilepsy Study Consortium, a nonprofit organization. Dr. Najm reported no conflicts of interest.

The International League Against Epilepsy (ILAE) has issued recommendations for treating depression in patients with epilepsy.

The new guidance highlights the high prevalence of depression among patients with epilepsy while offering the first systematic approach to treatment, reported lead author Marco Mula, MD, PhD, of Atkinson Morley Regional Neuroscience Centre at St George’s University Hospital, London, and colleagues.

“Despite evidence that depression represents a frequently encountered comorbidity [among patients with epilepsy], data on the treatment of depression in epilepsy [are] still limited and recommendations rely mostly on individual clinical experience and expertise,” the investigators wrote in Epilepsia.

Recommendations cover first-line treatment of unipolar depression in epilepsy without other psychiatric disorders.

For patients with mild depression, the guidance supports psychological intervention without pharmacologic therapy; however, if the patient wishes to use medication, has had a positive response to medication in the past, or nonpharmacologic treatments have previously failed or are unavailable, then SSRIs should be considered first-choice therapy. For moderate to severe depression, SSRIs are the first choice, according to Dr. Mula and colleagues.

“It has to be acknowledged that there is considerable debate in the psychiatric literature about the treatment of mild depression in adults,” the investigators noted. “A patient-level meta-analysis pointed out that the magnitude of benefit of antidepressant medications compared with placebo increases with severity of depression symptoms and it may be minimal or nonexistent, on average, in patients with mild or moderate symptoms.”

If a patient does not respond to first-line therapy, then venlafaxine should be considered, according to the guidance. When a patient does respond to therapy, treatment should be continued for at least 6 months, and when residual symptoms persist, treatment should be continued until resolution.

“In people with depression it is established that around two-thirds of patients do not achieve full remission with first-line treatment,” Dr. Mula and colleagues wrote. “In people with epilepsy, current data show that up to 50% of patients do not achieve full remission from depression. For this reason, augmentation strategies are often needed. They should be adopted by psychiatrists, neuropsychiatrists, or mental health professionals familiar with such therapeutic strategies.”

Beyond these key recommendations, the guidance covers a range of additional topics, including other pharmacologic options, medication discontinuation strategies, electroconvulsive therapy, light therapy, exercise training, vagus nerve stimulation, and repetitive transcranial magnetic stimulation.
 

Useful advice that counters common misconceptions

According to Jacqueline A. French, MD, a professor at NYU Langone Medical Center, Dr. Mula and colleagues are “top notch,” and their recommendations “hit every nail on the head.”

Dr. French, chief medical officer of The Epilepsy Foundation, emphasized the importance of the publication, which addresses two common misconceptions within the medical community: First, that standard antidepressants are insufficient to treat depression in patients with epilepsy, and second, that antidepressants may trigger seizures.

“The first purpose [of the publication] is to say, yes, these antidepressants do work,” Dr. French said, “and no, they don’t worsen seizures, and you can use them safely, and they are appropriate to use.”

Dr. French explained that managing depression remains a practice gap among epileptologists and neurologists because it is a diagnosis that doesn’t traditionally fall into their purview, yet many patients with epilepsy forgo visiting their primary care providers, who more frequently diagnose and manage depression. Dr. French agreed with the guidance that epilepsy specialists should fill this gap.

“We need to at least be able to take people through their first antidepressant, even though we were not trained to be psychiatrists,” Dr. French said. “That’s part of the best care of our patients.”

Imad Najm, MD, director of the Charles Shor Epilepsy Center, Cleveland Clinic, said the recommendations are a step forward in the field, as they are supported by clinical data, instead of just clinical experience and expertise.

Still, Dr. Najm noted that more work is needed to stratify risk of depression in epilepsy and evaluate a possible causal relationship between epilepsy therapies and depression.

He went on to emphasizes the scale of issue at hand, and the stakes involved.

“Depression, anxiety, and psychosis affect a large number of patients with epilepsy,” Dr. Najm said. “Clinical screening and recognition of these comorbidities leads to the institution of treatment options and significant improvement in quality of life. Mental health professionals should be an integral part of any comprehensive epilepsy center.”

The investigators disclosed relationships with Esai, UCB, Elsevier, and others. Dr. French is indirectly involved with multiple pharmaceutical companies developing epilepsy drugs through her role as director of The Epilepsy Study Consortium, a nonprofit organization. Dr. Najm reported no conflicts of interest.

Cluster headache attacks induced by either pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) or vasoactive intestinal polypeptide (VIP) do not lead to changes in plasma levels of calcitonin gene-related peptide (CGRP) or markers of mast cell activation such as tryptase and histamine, a new study has found.

“Whether cluster headache attacks provoked by CGRP and PACAP38/VIP are mediated by distinct signaling pathways will be worth investigating in forthcoming studies,” wrote Lanfranco Pellesi, MD, of the Danish Headache Center at the University of Copenhagen, and his coauthors. The study was published in Cephalalgia.

To assess how these biochemical variables might contribute to cluster headache attacks, the researchers launched a randomized, double-blind trial of data from 44 Danish participants with cluster headache. The average age of the patients was 38 years; 14 had active episodic cluster headache, 15 had episodic cluster headache in remission, and 15 had chronic cluster headache.

All patients received a continuous infusion of either PACAP38 (10 pmol/kg per minute) or VIP (8 pmol/kg per minute) over a 20-minute period, using a time- and volume-controlled infusion pump. Blood was collected for analysis at fixed time points, including at baseline, at the end of the infusion, 10 minutes after the infusion, and 70 minutes after the infusion. Technical problems led to missing values in 285 out of 1,144 planned plasma samples.

PACAP38 infusion resulted in a cluster headache attack in 13 of the 44 participants and VIP induced an attack in 12 of the 44. No differences in plasma CGRP (P = .7074), tryptase (P = .6673), and histamine (P = .4792) levels were found between patients who developed attacks and those who did not, and the plasma concentrations did not differ among the various blood-drawing time points.

There was also no difference in plasma CGRP levels between patients with active episodic cluster headache, those with episodic cluster headache in remission, and those with chronic cluster headache. After post hoc analysis, plasma tryptase and plasma histamine levels were similar among the three cluster headache patient groups.

The final link to the cluster headache puzzle has not yet been found

“We know a lot about cluster headache: how it presents, how we can stop it acutely, and how we can stop it preventively. But we don’t know everything about all the neurotransmitters involved, the triggers that start an attack, or the causes of pain,” Alan Rapoport, MD, professor of neurology at the University of California, Los Angeles (UCLA), and past president of the International Headache Society, said in an interview. “This study was performed to find the answer to a small piece of the puzzle. Is CGRP the missing link for patients who begin a cluster attack, or should we be looking elsewhere?

“I would be cautious and say it appears that it doesn’t seem to be related, but further studies may show something different,” he added. “The reason for my qualification: There is a monoclonal antibody [galcanezumab], which grabs CGRP and prevents it from docking on its receptor, that has been approved for preventive treatment of episodic cluster headache. When you have episodic cluster, go into a cluster period, and take galcanezumab, it could and should decrease the number of attacks that you would ordinarily have had. That means it is related somewhat. But it certainly doesn’t work for everyone, so more investigations like this are needed.”

“What’s important about this study is that it opens up the possibility that there is another way into the cluster attack that could be operationalized for therapeutic purposes,” Peter Goadsby, MD, PhD, professor of neurology at UCLA and president of the American Headache Society, said in an interview.

When asked about the authors’ stated interest in investigating “if monoclonal antibodies targeting the CGRP pathway prevent PACAP38- or VIP-induced cluster headache attacks” as a follow-up, Dr. Goadsby strongly backed the idea. “If I sound excited about actually exploring whether that was a useful treatment or not, it’s because cluster headache is a dreadful condition. And the sooner you could work out whether it was useful or put the money into something else, well, that’s where I’d go.

“I think the principle here of doing experimental medicine, getting into human work with targets like this at the earliest possible time, is something that is not done as often as would be appropriate,” he added. “There is not enough investment, in my view, in early phase experimental work, which really just gets to that next step. Broadly speaking, the encouragement and support of experimental medicine is crucial to developing new therapies.”

The authors recognized their study’s potential limitations, including it’s being an exploratory study with results that should be interpreted cautiously. They acknowledged discrepancies with previous studies of plasma CGRP during cluster headache attacks, offering “different methodologies, including intra-assay differences and the location of blood sampling” as a possible reason. They also explained that some of the data are missing “completely at random” due to their policy of discarding all observations with incomplete laboratory measurements, adding that the impact on their sample size was “only modest.”

“In spite of these limitations,” Dr. Rapoport said, “this is an excellent study that shows us that PACAP38- and VIP-induced cluster headache attacks are not associated with alterations in plasma CGRP or in histamine and tryptase.”

Regarding potential conflicts of interest, one author reported being employed at the testing lab where the histamine measurements were conducted, as did another author who serves as the lab’s scientific adviser. A third author reported receiving personal fees from various pharmaceutical companies.

Cluster headache attacks induced by either pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) or vasoactive intestinal polypeptide (VIP) do not lead to changes in plasma levels of calcitonin gene-related peptide (CGRP) or markers of mast cell activation such as tryptase and histamine, a new study has found.

“Whether cluster headache attacks provoked by CGRP and PACAP38/VIP are mediated by distinct signaling pathways will be worth investigating in forthcoming studies,” wrote Lanfranco Pellesi, MD, of the Danish Headache Center at the University of Copenhagen, and his coauthors. The study was published in Cephalalgia.

To assess how these biochemical variables might contribute to cluster headache attacks, the researchers launched a randomized, double-blind trial of data from 44 Danish participants with cluster headache. The average age of the patients was 38 years; 14 had active episodic cluster headache, 15 had episodic cluster headache in remission, and 15 had chronic cluster headache.

All patients received a continuous infusion of either PACAP38 (10 pmol/kg per minute) or VIP (8 pmol/kg per minute) over a 20-minute period, using a time- and volume-controlled infusion pump. Blood was collected for analysis at fixed time points, including at baseline, at the end of the infusion, 10 minutes after the infusion, and 70 minutes after the infusion. Technical problems led to missing values in 285 out of 1,144 planned plasma samples.

PACAP38 infusion resulted in a cluster headache attack in 13 of the 44 participants and VIP induced an attack in 12 of the 44. No differences in plasma CGRP (P = .7074), tryptase (P = .6673), and histamine (P = .4792) levels were found between patients who developed attacks and those who did not, and the plasma concentrations did not differ among the various blood-drawing time points.

There was also no difference in plasma CGRP levels between patients with active episodic cluster headache, those with episodic cluster headache in remission, and those with chronic cluster headache. After post hoc analysis, plasma tryptase and plasma histamine levels were similar among the three cluster headache patient groups.

The final link to the cluster headache puzzle has not yet been found

“We know a lot about cluster headache: how it presents, how we can stop it acutely, and how we can stop it preventively. But we don’t know everything about all the neurotransmitters involved, the triggers that start an attack, or the causes of pain,” Alan Rapoport, MD, professor of neurology at the University of California, Los Angeles (UCLA), and past president of the International Headache Society, said in an interview. “This study was performed to find the answer to a small piece of the puzzle. Is CGRP the missing link for patients who begin a cluster attack, or should we be looking elsewhere?

“I would be cautious and say it appears that it doesn’t seem to be related, but further studies may show something different,” he added. “The reason for my qualification: There is a monoclonal antibody [galcanezumab], which grabs CGRP and prevents it from docking on its receptor, that has been approved for preventive treatment of episodic cluster headache. When you have episodic cluster, go into a cluster period, and take galcanezumab, it could and should decrease the number of attacks that you would ordinarily have had. That means it is related somewhat. But it certainly doesn’t work for everyone, so more investigations like this are needed.”

“What’s important about this study is that it opens up the possibility that there is another way into the cluster attack that could be operationalized for therapeutic purposes,” Peter Goadsby, MD, PhD, professor of neurology at UCLA and president of the American Headache Society, said in an interview.

When asked about the authors’ stated interest in investigating “if monoclonal antibodies targeting the CGRP pathway prevent PACAP38- or VIP-induced cluster headache attacks” as a follow-up, Dr. Goadsby strongly backed the idea. “If I sound excited about actually exploring whether that was a useful treatment or not, it’s because cluster headache is a dreadful condition. And the sooner you could work out whether it was useful or put the money into something else, well, that’s where I’d go.

“I think the principle here of doing experimental medicine, getting into human work with targets like this at the earliest possible time, is something that is not done as often as would be appropriate,” he added. “There is not enough investment, in my view, in early phase experimental work, which really just gets to that next step. Broadly speaking, the encouragement and support of experimental medicine is crucial to developing new therapies.”

The authors recognized their study’s potential limitations, including it’s being an exploratory study with results that should be interpreted cautiously. They acknowledged discrepancies with previous studies of plasma CGRP during cluster headache attacks, offering “different methodologies, including intra-assay differences and the location of blood sampling” as a possible reason. They also explained that some of the data are missing “completely at random” due to their policy of discarding all observations with incomplete laboratory measurements, adding that the impact on their sample size was “only modest.”

“In spite of these limitations,” Dr. Rapoport said, “this is an excellent study that shows us that PACAP38- and VIP-induced cluster headache attacks are not associated with alterations in plasma CGRP or in histamine and tryptase.”

Regarding potential conflicts of interest, one author reported being employed at the testing lab where the histamine measurements were conducted, as did another author who serves as the lab’s scientific adviser. A third author reported receiving personal fees from various pharmaceutical companies.

Cluster headache attacks induced by either pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) or vasoactive intestinal polypeptide (VIP) do not lead to changes in plasma levels of calcitonin gene-related peptide (CGRP) or markers of mast cell activation such as tryptase and histamine, a new study has found.

“Whether cluster headache attacks provoked by CGRP and PACAP38/VIP are mediated by distinct signaling pathways will be worth investigating in forthcoming studies,” wrote Lanfranco Pellesi, MD, of the Danish Headache Center at the University of Copenhagen, and his coauthors. The study was published in Cephalalgia.

To assess how these biochemical variables might contribute to cluster headache attacks, the researchers launched a randomized, double-blind trial of data from 44 Danish participants with cluster headache. The average age of the patients was 38 years; 14 had active episodic cluster headache, 15 had episodic cluster headache in remission, and 15 had chronic cluster headache.

All patients received a continuous infusion of either PACAP38 (10 pmol/kg per minute) or VIP (8 pmol/kg per minute) over a 20-minute period, using a time- and volume-controlled infusion pump. Blood was collected for analysis at fixed time points, including at baseline, at the end of the infusion, 10 minutes after the infusion, and 70 minutes after the infusion. Technical problems led to missing values in 285 out of 1,144 planned plasma samples.

PACAP38 infusion resulted in a cluster headache attack in 13 of the 44 participants and VIP induced an attack in 12 of the 44. No differences in plasma CGRP (P = .7074), tryptase (P = .6673), and histamine (P = .4792) levels were found between patients who developed attacks and those who did not, and the plasma concentrations did not differ among the various blood-drawing time points.

There was also no difference in plasma CGRP levels between patients with active episodic cluster headache, those with episodic cluster headache in remission, and those with chronic cluster headache. After post hoc analysis, plasma tryptase and plasma histamine levels were similar among the three cluster headache patient groups.

The final link to the cluster headache puzzle has not yet been found

“We know a lot about cluster headache: how it presents, how we can stop it acutely, and how we can stop it preventively. But we don’t know everything about all the neurotransmitters involved, the triggers that start an attack, or the causes of pain,” Alan Rapoport, MD, professor of neurology at the University of California, Los Angeles (UCLA), and past president of the International Headache Society, said in an interview. “This study was performed to find the answer to a small piece of the puzzle. Is CGRP the missing link for patients who begin a cluster attack, or should we be looking elsewhere?

“I would be cautious and say it appears that it doesn’t seem to be related, but further studies may show something different,” he added. “The reason for my qualification: There is a monoclonal antibody [galcanezumab], which grabs CGRP and prevents it from docking on its receptor, that has been approved for preventive treatment of episodic cluster headache. When you have episodic cluster, go into a cluster period, and take galcanezumab, it could and should decrease the number of attacks that you would ordinarily have had. That means it is related somewhat. But it certainly doesn’t work for everyone, so more investigations like this are needed.”

“What’s important about this study is that it opens up the possibility that there is another way into the cluster attack that could be operationalized for therapeutic purposes,” Peter Goadsby, MD, PhD, professor of neurology at UCLA and president of the American Headache Society, said in an interview.

When asked about the authors’ stated interest in investigating “if monoclonal antibodies targeting the CGRP pathway prevent PACAP38- or VIP-induced cluster headache attacks” as a follow-up, Dr. Goadsby strongly backed the idea. “If I sound excited about actually exploring whether that was a useful treatment or not, it’s because cluster headache is a dreadful condition. And the sooner you could work out whether it was useful or put the money into something else, well, that’s where I’d go.

“I think the principle here of doing experimental medicine, getting into human work with targets like this at the earliest possible time, is something that is not done as often as would be appropriate,” he added. “There is not enough investment, in my view, in early phase experimental work, which really just gets to that next step. Broadly speaking, the encouragement and support of experimental medicine is crucial to developing new therapies.”

The authors recognized their study’s potential limitations, including it’s being an exploratory study with results that should be interpreted cautiously. They acknowledged discrepancies with previous studies of plasma CGRP during cluster headache attacks, offering “different methodologies, including intra-assay differences and the location of blood sampling” as a possible reason. They also explained that some of the data are missing “completely at random” due to their policy of discarding all observations with incomplete laboratory measurements, adding that the impact on their sample size was “only modest.”

“In spite of these limitations,” Dr. Rapoport said, “this is an excellent study that shows us that PACAP38- and VIP-induced cluster headache attacks are not associated with alterations in plasma CGRP or in histamine and tryptase.”

Regarding potential conflicts of interest, one author reported being employed at the testing lab where the histamine measurements were conducted, as did another author who serves as the lab’s scientific adviser. A third author reported receiving personal fees from various pharmaceutical companies.

The newly approved insomnia drug daridorexant (Quviviq) improves sleep onset in adults, new phase 3 data suggest.  In the first of two studies, a 50-mg dose of daridorexant was associated with a reduction in latency to persistent sleep (LPS) of 11.7 minutes at month 3 versus placebo. The drug also was associated with improved daytime function.

Based on these results, the Food and Drug Administration approved daridorexant for the treatment of insomnia in adults earlier in January.

“The study shows that it is a really good drug that works differently from most other drugs,” said Emmanuel Mignot, MD, PhD, professor of sleep medicine at Stanford (Calif.) University. “It’s more specific to sleep,” Dr. Mignot added.

The findings were published in the February issue of The Lancet Neurology.
 

Two trials, three doses

Daridorexant is a dual orexin receptor antagonist intended to reduce excessive wakefulness. The investigators hypothesized that, because of its therapeutic target, the drug would not cause sleepiness on the morning after administration.

To examine daridorexant’s safety and efficacy, the researchers conducted two double-blind, parallel-group, phase 3 trials. Eligible participants were aged 18 years or older, had moderate to severe insomnia disorder, and had a self-reported history of disturbed sleep at least 3 nights per week for at least 3 months before screening.

In study 1, investigators randomly assigned participants in groups of equal size to daridorexant 25 mg, 50 mg, or placebo. In study 2, participants were randomly assigned to daridorexant 10 mg, 25 mg, or placebo.

During a placebo run-in period, participants underwent polysomnography on two consecutive nights to define baseline values. At the end of months 1 and 3 of the treatment period, participants again underwent 2 nights of polysomnography. A final night of polysomnography occurred during the placebo run-out period.

Self-assessments included the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). This questionnaire, to which participants responded daily, is designed to measure the daytime impairments related to insomnia. The IDSIQ questions focus on sleepiness, mood, alertness, and cognition.

The study’s primary endpoints were change from baseline in wake after sleep onset (WASO) and LPS at months 1 and 3. Secondary endpoints were change from baseline in self-reported total sleep time and change in the IDSIQ sleepiness domain score at months 1 and 3.

The investigators enrolled 930 participants in study 1 and 924 in study 2. In each study, more than two-thirds of participants were women, 39% were aged 65 or older, and demographic and baseline characteristics were similar between treatment groups.
 

Dose-dependent effects

At month 1 in study 1, WASO was reduced by 22.8 minutes (P < .0001) in patients who received the 50-mg dose and by 12.2 minutes (P < .0001) in the 25-mg dose. At month 3, WASO was reduced by 18.3 minutes (P < .0001) in those assigned to 50 mg and by 11.9 minutes (P < .0001) in those assigned to 25 mg.

LPS was reduced by 11.4 minutes (P < .0001) at month 1 and by 11.7 minutes (P < .0001) at month 3 with the 50-mg dose versus placebo. LPS was reduced by 8.3 minutes (P = .0005) at month 1 and by 7.6 minutes (P = .0015) at month 3 with the 25-mg dose versus placebo.

At both time points, self-reported total sleep time was significantly increased and the IDSIQ sleepiness score significantly improved with the 50-mg dose. The 25-mg dose was associated with significant improvements in self-reported total sleep time at both time points, but not with significant improvements in IDSIQ sleepiness score.

In study 2, the 25-mg dose was associated with significant reductions in WASO at month 1 (11.6 minutes, P = .0001) and month 3 (10.3 minutes, P = .0028) compared with placebo. The 25-mg dose was not associated with significant differences in LPS at either time point, however.

Similarly, the 25-mg dose was associated with improvements in self-reported total sleep time, but not with the IDSIQ sleepiness score. The 10-mg dose was not associated with improvements on any endpoint compared with placebo.
 

Longer studies needed

In an accompanying editorial, Kai Spiegelhalder, PhD, University of Freiburg, Germany, and colleagues pointed out that although insomnia disorder is defined by self-reported difficulty initiating or maintaining sleep, none of the primary or secondary endpoints in these trials addressed these symptoms.

However, Dr. Mignot noted the use of the IDSIQ scale is the most interesting aspect of the study. Although difficulty with concentration and mood impairment are major symptoms of insomnia, they are often neglected. “This drug was reversing the daytime impairment that insomniacs have,” said Dr. Mignot. “We now need to systematically study people not only for the effect on sleep, but also that it makes them feel better the day after.”

He added that most of the current hypnotics were not developed to treat insomnia. Daridorexant, in contrast, targets the wake-promoting orexin system. “It works more selectively on sleep and not on other things. Most of the other sleeping pills have more complex effects on the brain,” Dr. Mignot said.

Commenting on the study, John Winkelman, MD, PhD, professor of psychiatry at Harvard Medical School, Boston, said the low prevalence of side effects associated with daridorexant was remarkable. “This is not what most of the benzodiazepine receptor agonists looked like,” said Dr. Winkelman, who was not involved with the research.

Many insomnia drugs affect transmitter systems that are widespread in the brain, thus provoking side effects. But orexin-receptor antagonists “don’t seem to produce a lot of side effects,” he noted.

Although the study duration was reasonable, longer studies will be necessary, he added. “And it would be nice to see comparative data. Prescribers want to see some context.” said Dr. Winkelman.

The study was funded by Idorsia Pharmaceuticals. Dr. Mignot reported receiving research or clinical trial funding from Axsome, Jazz Pharmaceuticals, Avadel, Apple, Huami, Sunovion, and Takeda. He has also received consulting fees or speakers’ conference reimbursement from Idorsia, Centessa Pharmaceuticals, Jazz Pharmaceuticals, Avadel, Dreem, and Takeda. Dr. Winkelman has consulted for Idorsia and has participated in investigator-initiated studies supported by Merck.

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

The newly approved insomnia drug daridorexant (Quviviq) improves sleep onset in adults, new phase 3 data suggest.  In the first of two studies, a 50-mg dose of daridorexant was associated with a reduction in latency to persistent sleep (LPS) of 11.7 minutes at month 3 versus placebo. The drug also was associated with improved daytime function.

Based on these results, the Food and Drug Administration approved daridorexant for the treatment of insomnia in adults earlier in January.

“The study shows that it is a really good drug that works differently from most other drugs,” said Emmanuel Mignot, MD, PhD, professor of sleep medicine at Stanford (Calif.) University. “It’s more specific to sleep,” Dr. Mignot added.

The findings were published in the February issue of The Lancet Neurology.
 

Two trials, three doses

Daridorexant is a dual orexin receptor antagonist intended to reduce excessive wakefulness. The investigators hypothesized that, because of its therapeutic target, the drug would not cause sleepiness on the morning after administration.

To examine daridorexant’s safety and efficacy, the researchers conducted two double-blind, parallel-group, phase 3 trials. Eligible participants were aged 18 years or older, had moderate to severe insomnia disorder, and had a self-reported history of disturbed sleep at least 3 nights per week for at least 3 months before screening.

In study 1, investigators randomly assigned participants in groups of equal size to daridorexant 25 mg, 50 mg, or placebo. In study 2, participants were randomly assigned to daridorexant 10 mg, 25 mg, or placebo.

During a placebo run-in period, participants underwent polysomnography on two consecutive nights to define baseline values. At the end of months 1 and 3 of the treatment period, participants again underwent 2 nights of polysomnography. A final night of polysomnography occurred during the placebo run-out period.

Self-assessments included the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). This questionnaire, to which participants responded daily, is designed to measure the daytime impairments related to insomnia. The IDSIQ questions focus on sleepiness, mood, alertness, and cognition.

The study’s primary endpoints were change from baseline in wake after sleep onset (WASO) and LPS at months 1 and 3. Secondary endpoints were change from baseline in self-reported total sleep time and change in the IDSIQ sleepiness domain score at months 1 and 3.

The investigators enrolled 930 participants in study 1 and 924 in study 2. In each study, more than two-thirds of participants were women, 39% were aged 65 or older, and demographic and baseline characteristics were similar between treatment groups.
 

Dose-dependent effects

At month 1 in study 1, WASO was reduced by 22.8 minutes (P < .0001) in patients who received the 50-mg dose and by 12.2 minutes (P < .0001) in the 25-mg dose. At month 3, WASO was reduced by 18.3 minutes (P < .0001) in those assigned to 50 mg and by 11.9 minutes (P < .0001) in those assigned to 25 mg.

LPS was reduced by 11.4 minutes (P < .0001) at month 1 and by 11.7 minutes (P < .0001) at month 3 with the 50-mg dose versus placebo. LPS was reduced by 8.3 minutes (P = .0005) at month 1 and by 7.6 minutes (P = .0015) at month 3 with the 25-mg dose versus placebo.

At both time points, self-reported total sleep time was significantly increased and the IDSIQ sleepiness score significantly improved with the 50-mg dose. The 25-mg dose was associated with significant improvements in self-reported total sleep time at both time points, but not with significant improvements in IDSIQ sleepiness score.

In study 2, the 25-mg dose was associated with significant reductions in WASO at month 1 (11.6 minutes, P = .0001) and month 3 (10.3 minutes, P = .0028) compared with placebo. The 25-mg dose was not associated with significant differences in LPS at either time point, however.

Similarly, the 25-mg dose was associated with improvements in self-reported total sleep time, but not with the IDSIQ sleepiness score. The 10-mg dose was not associated with improvements on any endpoint compared with placebo.
 

Longer studies needed

In an accompanying editorial, Kai Spiegelhalder, PhD, University of Freiburg, Germany, and colleagues pointed out that although insomnia disorder is defined by self-reported difficulty initiating or maintaining sleep, none of the primary or secondary endpoints in these trials addressed these symptoms.

However, Dr. Mignot noted the use of the IDSIQ scale is the most interesting aspect of the study. Although difficulty with concentration and mood impairment are major symptoms of insomnia, they are often neglected. “This drug was reversing the daytime impairment that insomniacs have,” said Dr. Mignot. “We now need to systematically study people not only for the effect on sleep, but also that it makes them feel better the day after.”

He added that most of the current hypnotics were not developed to treat insomnia. Daridorexant, in contrast, targets the wake-promoting orexin system. “It works more selectively on sleep and not on other things. Most of the other sleeping pills have more complex effects on the brain,” Dr. Mignot said.

Commenting on the study, John Winkelman, MD, PhD, professor of psychiatry at Harvard Medical School, Boston, said the low prevalence of side effects associated with daridorexant was remarkable. “This is not what most of the benzodiazepine receptor agonists looked like,” said Dr. Winkelman, who was not involved with the research.

Many insomnia drugs affect transmitter systems that are widespread in the brain, thus provoking side effects. But orexin-receptor antagonists “don’t seem to produce a lot of side effects,” he noted.

Although the study duration was reasonable, longer studies will be necessary, he added. “And it would be nice to see comparative data. Prescribers want to see some context.” said Dr. Winkelman.

The study was funded by Idorsia Pharmaceuticals. Dr. Mignot reported receiving research or clinical trial funding from Axsome, Jazz Pharmaceuticals, Avadel, Apple, Huami, Sunovion, and Takeda. He has also received consulting fees or speakers’ conference reimbursement from Idorsia, Centessa Pharmaceuticals, Jazz Pharmaceuticals, Avadel, Dreem, and Takeda. Dr. Winkelman has consulted for Idorsia and has participated in investigator-initiated studies supported by Merck.

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

The newly approved insomnia drug daridorexant (Quviviq) improves sleep onset in adults, new phase 3 data suggest.  In the first of two studies, a 50-mg dose of daridorexant was associated with a reduction in latency to persistent sleep (LPS) of 11.7 minutes at month 3 versus placebo. The drug also was associated with improved daytime function.

Based on these results, the Food and Drug Administration approved daridorexant for the treatment of insomnia in adults earlier in January.

“The study shows that it is a really good drug that works differently from most other drugs,” said Emmanuel Mignot, MD, PhD, professor of sleep medicine at Stanford (Calif.) University. “It’s more specific to sleep,” Dr. Mignot added.

The findings were published in the February issue of The Lancet Neurology.
 

Two trials, three doses

Daridorexant is a dual orexin receptor antagonist intended to reduce excessive wakefulness. The investigators hypothesized that, because of its therapeutic target, the drug would not cause sleepiness on the morning after administration.

To examine daridorexant’s safety and efficacy, the researchers conducted two double-blind, parallel-group, phase 3 trials. Eligible participants were aged 18 years or older, had moderate to severe insomnia disorder, and had a self-reported history of disturbed sleep at least 3 nights per week for at least 3 months before screening.

In study 1, investigators randomly assigned participants in groups of equal size to daridorexant 25 mg, 50 mg, or placebo. In study 2, participants were randomly assigned to daridorexant 10 mg, 25 mg, or placebo.

During a placebo run-in period, participants underwent polysomnography on two consecutive nights to define baseline values. At the end of months 1 and 3 of the treatment period, participants again underwent 2 nights of polysomnography. A final night of polysomnography occurred during the placebo run-out period.

Self-assessments included the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). This questionnaire, to which participants responded daily, is designed to measure the daytime impairments related to insomnia. The IDSIQ questions focus on sleepiness, mood, alertness, and cognition.

The study’s primary endpoints were change from baseline in wake after sleep onset (WASO) and LPS at months 1 and 3. Secondary endpoints were change from baseline in self-reported total sleep time and change in the IDSIQ sleepiness domain score at months 1 and 3.

The investigators enrolled 930 participants in study 1 and 924 in study 2. In each study, more than two-thirds of participants were women, 39% were aged 65 or older, and demographic and baseline characteristics were similar between treatment groups.
 

Dose-dependent effects

At month 1 in study 1, WASO was reduced by 22.8 minutes (P < .0001) in patients who received the 50-mg dose and by 12.2 minutes (P < .0001) in the 25-mg dose. At month 3, WASO was reduced by 18.3 minutes (P < .0001) in those assigned to 50 mg and by 11.9 minutes (P < .0001) in those assigned to 25 mg.

LPS was reduced by 11.4 minutes (P < .0001) at month 1 and by 11.7 minutes (P < .0001) at month 3 with the 50-mg dose versus placebo. LPS was reduced by 8.3 minutes (P = .0005) at month 1 and by 7.6 minutes (P = .0015) at month 3 with the 25-mg dose versus placebo.

At both time points, self-reported total sleep time was significantly increased and the IDSIQ sleepiness score significantly improved with the 50-mg dose. The 25-mg dose was associated with significant improvements in self-reported total sleep time at both time points, but not with significant improvements in IDSIQ sleepiness score.

In study 2, the 25-mg dose was associated with significant reductions in WASO at month 1 (11.6 minutes, P = .0001) and month 3 (10.3 minutes, P = .0028) compared with placebo. The 25-mg dose was not associated with significant differences in LPS at either time point, however.

Similarly, the 25-mg dose was associated with improvements in self-reported total sleep time, but not with the IDSIQ sleepiness score. The 10-mg dose was not associated with improvements on any endpoint compared with placebo.
 

Longer studies needed

In an accompanying editorial, Kai Spiegelhalder, PhD, University of Freiburg, Germany, and colleagues pointed out that although insomnia disorder is defined by self-reported difficulty initiating or maintaining sleep, none of the primary or secondary endpoints in these trials addressed these symptoms.

However, Dr. Mignot noted the use of the IDSIQ scale is the most interesting aspect of the study. Although difficulty with concentration and mood impairment are major symptoms of insomnia, they are often neglected. “This drug was reversing the daytime impairment that insomniacs have,” said Dr. Mignot. “We now need to systematically study people not only for the effect on sleep, but also that it makes them feel better the day after.”

He added that most of the current hypnotics were not developed to treat insomnia. Daridorexant, in contrast, targets the wake-promoting orexin system. “It works more selectively on sleep and not on other things. Most of the other sleeping pills have more complex effects on the brain,” Dr. Mignot said.

Commenting on the study, John Winkelman, MD, PhD, professor of psychiatry at Harvard Medical School, Boston, said the low prevalence of side effects associated with daridorexant was remarkable. “This is not what most of the benzodiazepine receptor agonists looked like,” said Dr. Winkelman, who was not involved with the research.

Many insomnia drugs affect transmitter systems that are widespread in the brain, thus provoking side effects. But orexin-receptor antagonists “don’t seem to produce a lot of side effects,” he noted.

Although the study duration was reasonable, longer studies will be necessary, he added. “And it would be nice to see comparative data. Prescribers want to see some context.” said Dr. Winkelman.

The study was funded by Idorsia Pharmaceuticals. Dr. Mignot reported receiving research or clinical trial funding from Axsome, Jazz Pharmaceuticals, Avadel, Apple, Huami, Sunovion, and Takeda. He has also received consulting fees or speakers’ conference reimbursement from Idorsia, Centessa Pharmaceuticals, Jazz Pharmaceuticals, Avadel, Dreem, and Takeda. Dr. Winkelman has consulted for Idorsia and has participated in investigator-initiated studies supported by Merck.

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

Dairy intake may increase risk of Parkinson’s disease in men, according to investigators. Men of European ancestry with a genetic marker predicting dairy consumption had significantly greater risk of Parkinson’s disease than individuals without the marker, suggesting a causal relationship between dairy intake and Parkinson’s disease, lead author Cloé Domenighetti, MSc, a PhD student at UVSQ, Université Paris Sud, and colleagues reported.

“Previous studies highlighted dairy intake as a risk factor of Parkinson’s disease,” the investigators wrote in Movement Disorders. “A meta-analysis of prospective studies reported a 40% increased Parkinson’s disease risk in participants with the highest intake. It is unclear whether the association is causal or explained by confounding or reverse causation, given the long prodromal phase of Parkinson’s disease.”
 

A Mendelian randomization study

The investigators evaluated this link by comparing 9,823 cases of Parkinson’s disease with 8,376 controls, all individuals of European ancestry from the Courage-Parkinson’s disease consortium, comprising 23 studies. Data were analyzed by two-sample Mendelian randomization, a technique that uses genotype to predict behavior, thereby replacing conventional methods of capturing behavior, such as questionnaires. In this case, the investigators screened all participants for rs4988235, a single-nucleotide polymorphism (SNP) upstream of the lactase gene that is well documented to predict dairy intake among individuals of European ancestry.

“Mendelian randomization uses genetic variants associated with exposures as instrumental variables to estimate causal relationships between exposures and outcomes,” the investigators wrote. “Mendelian randomization analyses are less likely to be biased by confounding or reverse causation than observational studies if a set of assumptions are met.”

The approach uncovered a significant association between rs4988235 and Parkinson’s disease, with a 70% increase in disease risk per one serving of dairy per day (odds ratio, 1.70; 95% confidence interval, 1.12-2.60; P = .013). Further analysis revealed that this finding was driven by men, who had a 2.5-fold increased risk of Parkinson’s disease per one serving per day (OR, 2.50; 95% CI, 1.37-4.56; P = .003) versus women, among whom there was no significant association (OR, 1.04; 95% CI, 0.56-1.92; P = .91). No significant associations were observed among individuals grouped by age or Parkinson’s disease duration.

“Our findings suggest that dairy intake increases Parkinson’s disease risk,” the investigators concluded. “Therefore, diets with limited milk intake (e.g., Mediterranean diet) may be beneficial with respect to Parkinson’s disease.”
 

Further evidence supporting a link between diet and Parkinson’s disease

According to Silke Appel-Cresswell, MD, Marg Meikle Professor for Parkinson’s Research at the University of British Columbia, Vancouver, the findings align with previous prospective cohort studies demonstrating an increased risk of Parkinson’s disease with greater consumption of dairy.

“What the current study adds,” Dr. Appel-Cresswell said, “is a complementary approach to assess the association where the risk of reverse causation and of confounding are minimized. Like in some of the previous studies, the authors find sex differences with an increased risk for men but not women.”

Dr. Appel-Cresswell noted that an increasing body of evidence supports a link between diet and Parkinson’s disease, including a study of her own published last year, which showed later onset of Parkinson’s disease among individuals with a Mediterranean-style diet.

“We are accumulating evidence for a role of diet (or more broadly, the food exposome) for the risk to develop Parkinson’s disease,” Dr. Appel-Cresswell said, noting that “key pieces are still missing, including mechanisms underlying associations, clinical trials in individuals with established Parkinson’s disease and – eventually – preventive interventions. This research is urgently needed and analyses will need to take sex differences and a large range of potential other factors into account.”
 

A ‘modest’ contributing factor?

Vikas Kotagal, MD, associate professor of neurology at the University of Michigan, Ann Arbor, offered a perspective on the study methodology, and suggested that a causal link between dairy intake and Parkinson’s disease, if present, is likely minimal.

“Limitations to the study include the fact that participants weren’t actually asked or tested for how much dairy they truly consumed,” Dr. Kotagal said*. “Their dairy intake was estimated based on their genetic background – there are certainly many assumptions baked into this analytic approach which may or may not be true. It is also worth noting the fact that this causal association was seen in men and not women, suggesting that even if dairy intake was truly causal, it is likely to be a modest contributing factor and not a significant cause of Parkinson’s disease in the broader population in general.”

Still, Dr. Kotagal agreed with Dr. Appel-Cresswell that underlying mechanisms need further investigation.

“The biggest takeaway here is to heighten the urgency for researchers and funders to explore whether factors that might cluster with dairy intake – including pesticide exposure in milk or even the make-up of bacterial populations in different peoples’ intestines – might deserve closer scrutiny as a missing link connecting dairy consumption to increased Parkinson’s disease risk,” Dr. Kotagal said.
 

Dietary advice

Considering all available evidence, Dr. Appel-Cresswell offered some dietary advice with benefits that may extend beyond prevention of Parkinson’s disease.

“From a clinical point of view, I suggest to limit dairy intake to a moderate amount,” she said. “Mediterranean diets so far have the best supporting evidence for a lower Parkinson’s disease risk, although data is lacking for benefits in established Parkinson’s disease. Given the low risk of the Mediterranean diet and the established benefits for a host of other medical conditions, this is generally a safe and delicious recommendation whether one is living with Parkinson’s or not.”

The study was supported by the European Union Joint Program for Neurodegenerative Disease Research, the National Centre of Excellence in Research on Parkinson’s Disease, the National Institutes of Health, and others. The investigators disclosed additional relationships with Astellas Pharma, Sanofi, Pfizer, and others. Dr. Kotagal and Dr. Appel-Cresswell reported no relevant conflicts of interest.

*Correction, 2/10/22: An earlier version of this article misstated Dr. Kotagal's name in certain instances, including a photo caption.

Dairy intake may increase risk of Parkinson’s disease in men, according to investigators. Men of European ancestry with a genetic marker predicting dairy consumption had significantly greater risk of Parkinson’s disease than individuals without the marker, suggesting a causal relationship between dairy intake and Parkinson’s disease, lead author Cloé Domenighetti, MSc, a PhD student at UVSQ, Université Paris Sud, and colleagues reported.

“Previous studies highlighted dairy intake as a risk factor of Parkinson’s disease,” the investigators wrote in Movement Disorders. “A meta-analysis of prospective studies reported a 40% increased Parkinson’s disease risk in participants with the highest intake. It is unclear whether the association is causal or explained by confounding or reverse causation, given the long prodromal phase of Parkinson’s disease.”
 

A Mendelian randomization study

The investigators evaluated this link by comparing 9,823 cases of Parkinson’s disease with 8,376 controls, all individuals of European ancestry from the Courage-Parkinson’s disease consortium, comprising 23 studies. Data were analyzed by two-sample Mendelian randomization, a technique that uses genotype to predict behavior, thereby replacing conventional methods of capturing behavior, such as questionnaires. In this case, the investigators screened all participants for rs4988235, a single-nucleotide polymorphism (SNP) upstream of the lactase gene that is well documented to predict dairy intake among individuals of European ancestry.

“Mendelian randomization uses genetic variants associated with exposures as instrumental variables to estimate causal relationships between exposures and outcomes,” the investigators wrote. “Mendelian randomization analyses are less likely to be biased by confounding or reverse causation than observational studies if a set of assumptions are met.”

The approach uncovered a significant association between rs4988235 and Parkinson’s disease, with a 70% increase in disease risk per one serving of dairy per day (odds ratio, 1.70; 95% confidence interval, 1.12-2.60; P = .013). Further analysis revealed that this finding was driven by men, who had a 2.5-fold increased risk of Parkinson’s disease per one serving per day (OR, 2.50; 95% CI, 1.37-4.56; P = .003) versus women, among whom there was no significant association (OR, 1.04; 95% CI, 0.56-1.92; P = .91). No significant associations were observed among individuals grouped by age or Parkinson’s disease duration.

“Our findings suggest that dairy intake increases Parkinson’s disease risk,” the investigators concluded. “Therefore, diets with limited milk intake (e.g., Mediterranean diet) may be beneficial with respect to Parkinson’s disease.”
 

Further evidence supporting a link between diet and Parkinson’s disease

According to Silke Appel-Cresswell, MD, Marg Meikle Professor for Parkinson’s Research at the University of British Columbia, Vancouver, the findings align with previous prospective cohort studies demonstrating an increased risk of Parkinson’s disease with greater consumption of dairy.

“What the current study adds,” Dr. Appel-Cresswell said, “is a complementary approach to assess the association where the risk of reverse causation and of confounding are minimized. Like in some of the previous studies, the authors find sex differences with an increased risk for men but not women.”

Dr. Appel-Cresswell noted that an increasing body of evidence supports a link between diet and Parkinson’s disease, including a study of her own published last year, which showed later onset of Parkinson’s disease among individuals with a Mediterranean-style diet.

“We are accumulating evidence for a role of diet (or more broadly, the food exposome) for the risk to develop Parkinson’s disease,” Dr. Appel-Cresswell said, noting that “key pieces are still missing, including mechanisms underlying associations, clinical trials in individuals with established Parkinson’s disease and – eventually – preventive interventions. This research is urgently needed and analyses will need to take sex differences and a large range of potential other factors into account.”
 

A ‘modest’ contributing factor?

Vikas Kotagal, MD, associate professor of neurology at the University of Michigan, Ann Arbor, offered a perspective on the study methodology, and suggested that a causal link between dairy intake and Parkinson’s disease, if present, is likely minimal.

“Limitations to the study include the fact that participants weren’t actually asked or tested for how much dairy they truly consumed,” Dr. Kotagal said*. “Their dairy intake was estimated based on their genetic background – there are certainly many assumptions baked into this analytic approach which may or may not be true. It is also worth noting the fact that this causal association was seen in men and not women, suggesting that even if dairy intake was truly causal, it is likely to be a modest contributing factor and not a significant cause of Parkinson’s disease in the broader population in general.”

Still, Dr. Kotagal agreed with Dr. Appel-Cresswell that underlying mechanisms need further investigation.

“The biggest takeaway here is to heighten the urgency for researchers and funders to explore whether factors that might cluster with dairy intake – including pesticide exposure in milk or even the make-up of bacterial populations in different peoples’ intestines – might deserve closer scrutiny as a missing link connecting dairy consumption to increased Parkinson’s disease risk,” Dr. Kotagal said.
 

Dietary advice

Considering all available evidence, Dr. Appel-Cresswell offered some dietary advice with benefits that may extend beyond prevention of Parkinson’s disease.

“From a clinical point of view, I suggest to limit dairy intake to a moderate amount,” she said. “Mediterranean diets so far have the best supporting evidence for a lower Parkinson’s disease risk, although data is lacking for benefits in established Parkinson’s disease. Given the low risk of the Mediterranean diet and the established benefits for a host of other medical conditions, this is generally a safe and delicious recommendation whether one is living with Parkinson’s or not.”

The study was supported by the European Union Joint Program for Neurodegenerative Disease Research, the National Centre of Excellence in Research on Parkinson’s Disease, the National Institutes of Health, and others. The investigators disclosed additional relationships with Astellas Pharma, Sanofi, Pfizer, and others. Dr. Kotagal and Dr. Appel-Cresswell reported no relevant conflicts of interest.

*Correction, 2/10/22: An earlier version of this article misstated Dr. Kotagal's name in certain instances, including a photo caption.

Dairy intake may increase risk of Parkinson’s disease in men, according to investigators. Men of European ancestry with a genetic marker predicting dairy consumption had significantly greater risk of Parkinson’s disease than individuals without the marker, suggesting a causal relationship between dairy intake and Parkinson’s disease, lead author Cloé Domenighetti, MSc, a PhD student at UVSQ, Université Paris Sud, and colleagues reported.

“Previous studies highlighted dairy intake as a risk factor of Parkinson’s disease,” the investigators wrote in Movement Disorders. “A meta-analysis of prospective studies reported a 40% increased Parkinson’s disease risk in participants with the highest intake. It is unclear whether the association is causal or explained by confounding or reverse causation, given the long prodromal phase of Parkinson’s disease.”
 

A Mendelian randomization study

The investigators evaluated this link by comparing 9,823 cases of Parkinson’s disease with 8,376 controls, all individuals of European ancestry from the Courage-Parkinson’s disease consortium, comprising 23 studies. Data were analyzed by two-sample Mendelian randomization, a technique that uses genotype to predict behavior, thereby replacing conventional methods of capturing behavior, such as questionnaires. In this case, the investigators screened all participants for rs4988235, a single-nucleotide polymorphism (SNP) upstream of the lactase gene that is well documented to predict dairy intake among individuals of European ancestry.

“Mendelian randomization uses genetic variants associated with exposures as instrumental variables to estimate causal relationships between exposures and outcomes,” the investigators wrote. “Mendelian randomization analyses are less likely to be biased by confounding or reverse causation than observational studies if a set of assumptions are met.”

The approach uncovered a significant association between rs4988235 and Parkinson’s disease, with a 70% increase in disease risk per one serving of dairy per day (odds ratio, 1.70; 95% confidence interval, 1.12-2.60; P = .013). Further analysis revealed that this finding was driven by men, who had a 2.5-fold increased risk of Parkinson’s disease per one serving per day (OR, 2.50; 95% CI, 1.37-4.56; P = .003) versus women, among whom there was no significant association (OR, 1.04; 95% CI, 0.56-1.92; P = .91). No significant associations were observed among individuals grouped by age or Parkinson’s disease duration.

“Our findings suggest that dairy intake increases Parkinson’s disease risk,” the investigators concluded. “Therefore, diets with limited milk intake (e.g., Mediterranean diet) may be beneficial with respect to Parkinson’s disease.”
 

Further evidence supporting a link between diet and Parkinson’s disease

According to Silke Appel-Cresswell, MD, Marg Meikle Professor for Parkinson’s Research at the University of British Columbia, Vancouver, the findings align with previous prospective cohort studies demonstrating an increased risk of Parkinson’s disease with greater consumption of dairy.

“What the current study adds,” Dr. Appel-Cresswell said, “is a complementary approach to assess the association where the risk of reverse causation and of confounding are minimized. Like in some of the previous studies, the authors find sex differences with an increased risk for men but not women.”

Dr. Appel-Cresswell noted that an increasing body of evidence supports a link between diet and Parkinson’s disease, including a study of her own published last year, which showed later onset of Parkinson’s disease among individuals with a Mediterranean-style diet.

“We are accumulating evidence for a role of diet (or more broadly, the food exposome) for the risk to develop Parkinson’s disease,” Dr. Appel-Cresswell said, noting that “key pieces are still missing, including mechanisms underlying associations, clinical trials in individuals with established Parkinson’s disease and – eventually – preventive interventions. This research is urgently needed and analyses will need to take sex differences and a large range of potential other factors into account.”
 

A ‘modest’ contributing factor?

Vikas Kotagal, MD, associate professor of neurology at the University of Michigan, Ann Arbor, offered a perspective on the study methodology, and suggested that a causal link between dairy intake and Parkinson’s disease, if present, is likely minimal.

“Limitations to the study include the fact that participants weren’t actually asked or tested for how much dairy they truly consumed,” Dr. Kotagal said*. “Their dairy intake was estimated based on their genetic background – there are certainly many assumptions baked into this analytic approach which may or may not be true. It is also worth noting the fact that this causal association was seen in men and not women, suggesting that even if dairy intake was truly causal, it is likely to be a modest contributing factor and not a significant cause of Parkinson’s disease in the broader population in general.”

Still, Dr. Kotagal agreed with Dr. Appel-Cresswell that underlying mechanisms need further investigation.

“The biggest takeaway here is to heighten the urgency for researchers and funders to explore whether factors that might cluster with dairy intake – including pesticide exposure in milk or even the make-up of bacterial populations in different peoples’ intestines – might deserve closer scrutiny as a missing link connecting dairy consumption to increased Parkinson’s disease risk,” Dr. Kotagal said.
 

Dietary advice

Considering all available evidence, Dr. Appel-Cresswell offered some dietary advice with benefits that may extend beyond prevention of Parkinson’s disease.

“From a clinical point of view, I suggest to limit dairy intake to a moderate amount,” she said. “Mediterranean diets so far have the best supporting evidence for a lower Parkinson’s disease risk, although data is lacking for benefits in established Parkinson’s disease. Given the low risk of the Mediterranean diet and the established benefits for a host of other medical conditions, this is generally a safe and delicious recommendation whether one is living with Parkinson’s or not.”

The study was supported by the European Union Joint Program for Neurodegenerative Disease Research, the National Centre of Excellence in Research on Parkinson’s Disease, the National Institutes of Health, and others. The investigators disclosed additional relationships with Astellas Pharma, Sanofi, Pfizer, and others. Dr. Kotagal and Dr. Appel-Cresswell reported no relevant conflicts of interest.

*Correction, 2/10/22: An earlier version of this article misstated Dr. Kotagal's name in certain instances, including a photo caption.

Impaired cognition associated with COVID-19 appears to have a biological versus psychological basis, early research suggests. Investigators found abnormalities in cerebrospinal fluid (CSF) and other risk factors, including diabetes and hypertension, present in individuals with mild COVID-19 experiencing persistent cognitive problems, often referred to as “brain fog.”

“We’re seeing changes to the [CSF] in the brain of most people who report cognitive changes,” said Joanna Hellmuth, MD, assistant professor of neurology, Memory and Aging Center, University of California, San Francisco. “We’re just in the beginning stages, but I hope this study will provide some legitimacy to this being a true neurologic condition.”

The study was published online Jan. 18, 2022, in Annals of Clinical and Translational Neurology.
 

No guidance

There is currently no guidance on how to identify patients with COVID-related cognitive changes, said Dr. Hellmuth. “The term ‘brain fog’ is not based in science or medicine, but that’s the most common term we use to describe this.”

The analysis included adults with confirmed SARS-CoV-2 infection not requiring hospitalization who were enrolled in the Long-term Impact of Infection with Novel Coronavirus study.

Participants underwent a structured interview that covered COVID-19 illness, past medical history, preexisting cognitive risk factors, medications, and cognitive symptoms following onset of COVID-19. They also completed an in-person battery of cognitive tests.

The analysis included 22 participants with at least one new cognitive symptom who had cognitive post-acute sequelae of SARS-CoV-2 infection (PASC). Ten cognitive controls reported no new cognitive symptoms after acute infection.

Participants were a median age of 41 years, had a median of 16 years of education, and were assessed a median of 10.1 months from their first COVID-19 symptom. There were no group differences in terms of age, gender, years of education, or distribution of race/ethnicity (all P > .05).

Among those with cognitive PASC, 43% reported cognitive symptoms starting 1 or more months after the first COVID symptom. About 29% reported cognitive changes started 2 or more months after their first COVID symptom.

“The immune system could be altered in some way after the infection, and perhaps that’s what’s contributing to these delayed onset cognitive changes,” said Dr. Hellmuth.

Compared with controls, participants with cognitive PASC had more preexisting cognitive risk factors (a median of 2.5 vs. 0; P = .03). These included hypertension and diabetes, which increase the risk of stroke, mild cognitive impairment, vascular dementia, traumatic brain injury, (TBI), learning disabilities, anxiety, depression, stimulant use, and ADHD, which may make the brain more vulnerable to executive functioning problems.

Dr. Hellmuth noted that the study wasn’t powered to determine whether any individual risk factor was associated with risk of cognitive changes.

As there are no published neuropsychological testing criteria for cognitive PASC, the researchers applied the equivalent criteria for HIV-associated neurocognitive disorder (HAND), a similar, virally associated cognitive disorder. Only 59% of those with cognitive PASC met equivalent HAND criteria for objective cognitive impairment versus 70% of cognitive controls. This, the investigators noted, highlights “the challenges and incongruities of using subjective, versus objective cognitive assessments for diagnosis.”
 

Is self-report enough?

While there is currently “nothing objective doctors can hang their hats on to say ‘you do’ or ‘you don’t’ have cognitive changes related to COVID,” using the HAND criteria is “not particularly helpful,” said Dr. Hellmuth. “Comparing an individual to a population-based norm in this case is really nuanced, and we shouldn’t rely on this solely to determine whether they do, or don’t, have cognitive changes.”

Perhaps self-reports in this case are “enough” said Dr. Hellmuth. “People know their brains better than anyone else, better than any doctor will.”

A total of 13 in the cognitive PASC group and 4 in the control group consented to a lumbar puncture. Cognitive PASC participants were older than controls (median of 47 vs. 28 years; P = .03) with no other between-group differences.

Overall, 77% of participants with cognitive PASC had a CSF abnormality, compared with 0% of cognitive controls (P = .01). CSF abnormalities included elevated protein levels with no other explainable cause in 2 of the 13 subjects with PASC, which Dr. Hellmuth said is typically a marker of inflammation.

Researchers also noted abnormal oligoclonal banding, a collection of antibodies, in the blood or brain fluid. These were identified in 69% of participants with cognitive PASC, compared with 0% of cognitive controls (P = .03).

“When we find this pattern in both blood and brain, it suggests a systemic inflammatory disorder,” although “we have no idea what these antibodies are targeting,” said Dr. Hellmuth.

The study represents “the very beginning stages” of PASC becoming a medical diagnosis “where doctors know what to call it, how to treat it, and how to do blood and cerebrospinal fluid tests to diagnose it,” said Dr. Hellmuth.

She hopes PASC will receive medical legitimacy just as TBI has. In years past, a player was hit on the head or had their “bell rung,” simply returned to the field. “Now that we understand the science, we call it a mild TBI or concussion, and we have a very different medical approach to it.”

A limitation of the study was the small sample size, which may hinder the results’ validity. In addition, the study demographics may not reflect the broader population of those impacted by PASC.
 

‘A first substantial step’

Commenting on the research, William Schaffner, MD, professor, division of infectious diseases, Vanderbilt University Medical Center, Nashville, Tenn., said the new results represent “a first substantial step on the road to trying to find out what’s going on” with COVID patients dealing with cognitive issues.

Dr. Schaffner noted that elevated protein levels, identified in some study subjects, “is usually a consequence of previous inflammation” and is “a very interesting” finding. “In people who are otherwise normal, if you do a lumbar puncture, you don’t find elevated proteins.”

However, he noted the “diversity of results” from CSF examinations. “A single pattern does not leap out.”

What the researchers are observing “is not just a phenomenon of the mind or just something psychological,” said Dr. Schaffner. “Something physical is going on here.”

The study was funded by grants from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke. Dr. Hellmuth received grant support from the National Institutes of Health/NIMH supporting this work and personal fees for medical-legal consultation outside of the submitted work. Dr. Schaffner has disclosed not relevant financial relationships.

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

Impaired cognition associated with COVID-19 appears to have a biological versus psychological basis, early research suggests. Investigators found abnormalities in cerebrospinal fluid (CSF) and other risk factors, including diabetes and hypertension, present in individuals with mild COVID-19 experiencing persistent cognitive problems, often referred to as “brain fog.”

“We’re seeing changes to the [CSF] in the brain of most people who report cognitive changes,” said Joanna Hellmuth, MD, assistant professor of neurology, Memory and Aging Center, University of California, San Francisco. “We’re just in the beginning stages, but I hope this study will provide some legitimacy to this being a true neurologic condition.”

The study was published online Jan. 18, 2022, in Annals of Clinical and Translational Neurology.
 

No guidance

There is currently no guidance on how to identify patients with COVID-related cognitive changes, said Dr. Hellmuth. “The term ‘brain fog’ is not based in science or medicine, but that’s the most common term we use to describe this.”

The analysis included adults with confirmed SARS-CoV-2 infection not requiring hospitalization who were enrolled in the Long-term Impact of Infection with Novel Coronavirus study.

Participants underwent a structured interview that covered COVID-19 illness, past medical history, preexisting cognitive risk factors, medications, and cognitive symptoms following onset of COVID-19. They also completed an in-person battery of cognitive tests.

The analysis included 22 participants with at least one new cognitive symptom who had cognitive post-acute sequelae of SARS-CoV-2 infection (PASC). Ten cognitive controls reported no new cognitive symptoms after acute infection.

Participants were a median age of 41 years, had a median of 16 years of education, and were assessed a median of 10.1 months from their first COVID-19 symptom. There were no group differences in terms of age, gender, years of education, or distribution of race/ethnicity (all P > .05).

Among those with cognitive PASC, 43% reported cognitive symptoms starting 1 or more months after the first COVID symptom. About 29% reported cognitive changes started 2 or more months after their first COVID symptom.

“The immune system could be altered in some way after the infection, and perhaps that’s what’s contributing to these delayed onset cognitive changes,” said Dr. Hellmuth.

Compared with controls, participants with cognitive PASC had more preexisting cognitive risk factors (a median of 2.5 vs. 0; P = .03). These included hypertension and diabetes, which increase the risk of stroke, mild cognitive impairment, vascular dementia, traumatic brain injury, (TBI), learning disabilities, anxiety, depression, stimulant use, and ADHD, which may make the brain more vulnerable to executive functioning problems.

Dr. Hellmuth noted that the study wasn’t powered to determine whether any individual risk factor was associated with risk of cognitive changes.

As there are no published neuropsychological testing criteria for cognitive PASC, the researchers applied the equivalent criteria for HIV-associated neurocognitive disorder (HAND), a similar, virally associated cognitive disorder. Only 59% of those with cognitive PASC met equivalent HAND criteria for objective cognitive impairment versus 70% of cognitive controls. This, the investigators noted, highlights “the challenges and incongruities of using subjective, versus objective cognitive assessments for diagnosis.”
 

Is self-report enough?

While there is currently “nothing objective doctors can hang their hats on to say ‘you do’ or ‘you don’t’ have cognitive changes related to COVID,” using the HAND criteria is “not particularly helpful,” said Dr. Hellmuth. “Comparing an individual to a population-based norm in this case is really nuanced, and we shouldn’t rely on this solely to determine whether they do, or don’t, have cognitive changes.”

Perhaps self-reports in this case are “enough” said Dr. Hellmuth. “People know their brains better than anyone else, better than any doctor will.”

A total of 13 in the cognitive PASC group and 4 in the control group consented to a lumbar puncture. Cognitive PASC participants were older than controls (median of 47 vs. 28 years; P = .03) with no other between-group differences.

Overall, 77% of participants with cognitive PASC had a CSF abnormality, compared with 0% of cognitive controls (P = .01). CSF abnormalities included elevated protein levels with no other explainable cause in 2 of the 13 subjects with PASC, which Dr. Hellmuth said is typically a marker of inflammation.

Researchers also noted abnormal oligoclonal banding, a collection of antibodies, in the blood or brain fluid. These were identified in 69% of participants with cognitive PASC, compared with 0% of cognitive controls (P = .03).

“When we find this pattern in both blood and brain, it suggests a systemic inflammatory disorder,” although “we have no idea what these antibodies are targeting,” said Dr. Hellmuth.

The study represents “the very beginning stages” of PASC becoming a medical diagnosis “where doctors know what to call it, how to treat it, and how to do blood and cerebrospinal fluid tests to diagnose it,” said Dr. Hellmuth.

She hopes PASC will receive medical legitimacy just as TBI has. In years past, a player was hit on the head or had their “bell rung,” simply returned to the field. “Now that we understand the science, we call it a mild TBI or concussion, and we have a very different medical approach to it.”

A limitation of the study was the small sample size, which may hinder the results’ validity. In addition, the study demographics may not reflect the broader population of those impacted by PASC.
 

‘A first substantial step’

Commenting on the research, William Schaffner, MD, professor, division of infectious diseases, Vanderbilt University Medical Center, Nashville, Tenn., said the new results represent “a first substantial step on the road to trying to find out what’s going on” with COVID patients dealing with cognitive issues.

Dr. Schaffner noted that elevated protein levels, identified in some study subjects, “is usually a consequence of previous inflammation” and is “a very interesting” finding. “In people who are otherwise normal, if you do a lumbar puncture, you don’t find elevated proteins.”

However, he noted the “diversity of results” from CSF examinations. “A single pattern does not leap out.”

What the researchers are observing “is not just a phenomenon of the mind or just something psychological,” said Dr. Schaffner. “Something physical is going on here.”

The study was funded by grants from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke. Dr. Hellmuth received grant support from the National Institutes of Health/NIMH supporting this work and personal fees for medical-legal consultation outside of the submitted work. Dr. Schaffner has disclosed not relevant financial relationships.

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

Impaired cognition associated with COVID-19 appears to have a biological versus psychological basis, early research suggests. Investigators found abnormalities in cerebrospinal fluid (CSF) and other risk factors, including diabetes and hypertension, present in individuals with mild COVID-19 experiencing persistent cognitive problems, often referred to as “brain fog.”

“We’re seeing changes to the [CSF] in the brain of most people who report cognitive changes,” said Joanna Hellmuth, MD, assistant professor of neurology, Memory and Aging Center, University of California, San Francisco. “We’re just in the beginning stages, but I hope this study will provide some legitimacy to this being a true neurologic condition.”

The study was published online Jan. 18, 2022, in Annals of Clinical and Translational Neurology.
 

No guidance

There is currently no guidance on how to identify patients with COVID-related cognitive changes, said Dr. Hellmuth. “The term ‘brain fog’ is not based in science or medicine, but that’s the most common term we use to describe this.”

The analysis included adults with confirmed SARS-CoV-2 infection not requiring hospitalization who were enrolled in the Long-term Impact of Infection with Novel Coronavirus study.

Participants underwent a structured interview that covered COVID-19 illness, past medical history, preexisting cognitive risk factors, medications, and cognitive symptoms following onset of COVID-19. They also completed an in-person battery of cognitive tests.

The analysis included 22 participants with at least one new cognitive symptom who had cognitive post-acute sequelae of SARS-CoV-2 infection (PASC). Ten cognitive controls reported no new cognitive symptoms after acute infection.

Participants were a median age of 41 years, had a median of 16 years of education, and were assessed a median of 10.1 months from their first COVID-19 symptom. There were no group differences in terms of age, gender, years of education, or distribution of race/ethnicity (all P > .05).

Among those with cognitive PASC, 43% reported cognitive symptoms starting 1 or more months after the first COVID symptom. About 29% reported cognitive changes started 2 or more months after their first COVID symptom.

“The immune system could be altered in some way after the infection, and perhaps that’s what’s contributing to these delayed onset cognitive changes,” said Dr. Hellmuth.

Compared with controls, participants with cognitive PASC had more preexisting cognitive risk factors (a median of 2.5 vs. 0; P = .03). These included hypertension and diabetes, which increase the risk of stroke, mild cognitive impairment, vascular dementia, traumatic brain injury, (TBI), learning disabilities, anxiety, depression, stimulant use, and ADHD, which may make the brain more vulnerable to executive functioning problems.

Dr. Hellmuth noted that the study wasn’t powered to determine whether any individual risk factor was associated with risk of cognitive changes.

As there are no published neuropsychological testing criteria for cognitive PASC, the researchers applied the equivalent criteria for HIV-associated neurocognitive disorder (HAND), a similar, virally associated cognitive disorder. Only 59% of those with cognitive PASC met equivalent HAND criteria for objective cognitive impairment versus 70% of cognitive controls. This, the investigators noted, highlights “the challenges and incongruities of using subjective, versus objective cognitive assessments for diagnosis.”
 

Is self-report enough?

While there is currently “nothing objective doctors can hang their hats on to say ‘you do’ or ‘you don’t’ have cognitive changes related to COVID,” using the HAND criteria is “not particularly helpful,” said Dr. Hellmuth. “Comparing an individual to a population-based norm in this case is really nuanced, and we shouldn’t rely on this solely to determine whether they do, or don’t, have cognitive changes.”

Perhaps self-reports in this case are “enough” said Dr. Hellmuth. “People know their brains better than anyone else, better than any doctor will.”

A total of 13 in the cognitive PASC group and 4 in the control group consented to a lumbar puncture. Cognitive PASC participants were older than controls (median of 47 vs. 28 years; P = .03) with no other between-group differences.

Overall, 77% of participants with cognitive PASC had a CSF abnormality, compared with 0% of cognitive controls (P = .01). CSF abnormalities included elevated protein levels with no other explainable cause in 2 of the 13 subjects with PASC, which Dr. Hellmuth said is typically a marker of inflammation.

Researchers also noted abnormal oligoclonal banding, a collection of antibodies, in the blood or brain fluid. These were identified in 69% of participants with cognitive PASC, compared with 0% of cognitive controls (P = .03).

“When we find this pattern in both blood and brain, it suggests a systemic inflammatory disorder,” although “we have no idea what these antibodies are targeting,” said Dr. Hellmuth.

The study represents “the very beginning stages” of PASC becoming a medical diagnosis “where doctors know what to call it, how to treat it, and how to do blood and cerebrospinal fluid tests to diagnose it,” said Dr. Hellmuth.

She hopes PASC will receive medical legitimacy just as TBI has. In years past, a player was hit on the head or had their “bell rung,” simply returned to the field. “Now that we understand the science, we call it a mild TBI or concussion, and we have a very different medical approach to it.”

A limitation of the study was the small sample size, which may hinder the results’ validity. In addition, the study demographics may not reflect the broader population of those impacted by PASC.
 

‘A first substantial step’

Commenting on the research, William Schaffner, MD, professor, division of infectious diseases, Vanderbilt University Medical Center, Nashville, Tenn., said the new results represent “a first substantial step on the road to trying to find out what’s going on” with COVID patients dealing with cognitive issues.

Dr. Schaffner noted that elevated protein levels, identified in some study subjects, “is usually a consequence of previous inflammation” and is “a very interesting” finding. “In people who are otherwise normal, if you do a lumbar puncture, you don’t find elevated proteins.”

However, he noted the “diversity of results” from CSF examinations. “A single pattern does not leap out.”

What the researchers are observing “is not just a phenomenon of the mind or just something psychological,” said Dr. Schaffner. “Something physical is going on here.”

The study was funded by grants from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke. Dr. Hellmuth received grant support from the National Institutes of Health/NIMH supporting this work and personal fees for medical-legal consultation outside of the submitted work. Dr. Schaffner has disclosed not relevant financial relationships.

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