Neurology

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) have overlapping neurologic symptoms — particularly profound fatigue. The similarity between these two conditions has led to the question of whether they are indeed distinct central nervous system (CNS) entities, or whether they exist along a spectrum and are actually two different manifestations of the same disease process.

A new study utilized a novel methodology — unbiased quantitative mass spectrometry-based proteomics — to investigate this question by analyzing cerebrospinal fluid (CSF) in a group of patients with ME/CFS and another group of patients diagnosed with both ME/CFS and FM.

Close to 2,100 proteins were identified, of which nearly 1,800 were common to both conditions.

“ME/CFS and fibromyalgia do not appear to be distinct entities, with respect to their cerebrospinal fluid proteins,” lead author Steven Schutzer, MD, professor of medicine, Rutgers New Jersey School of Medicine, told this news organization.

“Work is underway to solve the multiple mysteries of ME/CFS, fibromyalgia, and other neurologic-associated diseases,” he continued. “We have further affirmed that we have a precise objective discovery tool in our hands. Collectively studying multiple diseases brings clarity to each individual disease.”

The study was published in the December 2023 issue of Annals of Medicine.
 

Cutting-Edge Technology

“ME/CFS is characterized by disabling fatigue, and FM is an illness characterized by body-wide pain,” Dr. Schutzer said. These “medically unexplained” illnesses often coexist by current definitions, and the overlap between them has suggested that they may be part of the “same illness spectrum.”

But co-investigator Benjamin Natelson, MD, professor of neurology and director of the Pain and Fatigue Study Center, Mount Sinai, New York, and others found in previous research that there are distinct differences between the conditions, raising the possibility that there may be different pathophysiological processes.

“The physicians and scientists on our team have had longstanding interest in studying neurologic diseases with cutting-edge tools such as mass spectrometry applied to CSF,” Dr. Schutzer said. “We have had success using this message to distinguish diseases such as ME/CFS from post-treatment Lyme disease, multiple sclerosis, and healthy normal people.”

Dr. Schutzer explained that Dr. Natelson had acquired CSF samples from “well-characterized [ME/CFS] patients and controls.”

Since the cause of ME/CFS is “unknown,” it seemed “ripe to investigate it further with the discovery tool of mass spectrometry” by harnessing the “most advanced equipment in the country at the pacific Northwest National Laboratory, which is part of the US Department of Energy.”

Dr. Schutzer noted that it was the “merger of different clinical and laboratory expertise” that enabled them to address whether ME/CFS and FM are two distinct disease processes.

The choice of analyzing CSF is that it’s the fluid closest to the brain, he added. “A lot of people have studied ME/CFS peripherally because they don’t have access to spinal fluid or it’s easier to look peripherally in the blood, but that doesn’t mean that the blood is where the real ‘action’ is occurring.”

The researchers compared the CSF of 15 patients with ME/CFS only to 15 patients with ME/CFS+FM using mass spectrometry-based proteomics, which they had employed in previous research to see whether ME/CFS was distinct from persistent neurologic Lyme disease syndrome.

This technology has become the “method of choice and discovery tool to rapidly uncover protein biomarkers that can distinguish one disease from another,” the authors stated.

In particular, in unbiased quantitative mass spectrometry-based proteomics, the researchers do not have to know in advance what’s in a sample before studying it, Dr. Schutzer explained.
 

Shared Pathophysiology?

Both groups of patients were of similar age (41.3 ± 9.4 years and 40.1 ± 11.0 years, respectively), with no differences in gender or rates of current comorbid psychiatric diagnoses between the groups.

The researchers quantified a total of 2,083 proteins, including 1,789 that were specifically quantified in all of the CSF samples, regardless of the presence or absence of FM.

Several analyses (including an ANOVA analysis with adjusted P values, a Random Forest machine learning approach that looked at relative protein abundance changes between those with ME/CFS and ME/CFS+FM, and unsupervised hierarchical clustering analyses) did not find distinguishing differences between the groups.

“The sum of these results does not support the hypothesis that ME/CFS and ME/CFS+FM are distinct entities, as currently defined,” the authors stated.

They noted that both conditions are “medically unexplained,” with core symptoms of pain, fatigue, sleep problems, and cognitive difficulty. The fact that these two syndromes coexist so often has led to the assumption that the “similarities between them outweigh the differences,” they wrote.

They pointed to some differences between the conditions, including an increase in substance P in the CSF of FM patients, but not in ME/CFS patients reported by others. There are also some immunological, physiological and genetic differences.

But if the conclusion that the two illnesses may share a similar pathophysiological basis is supported by other research that includes FM-only patients as comparators to those with ME/CFS, “this would support the notion that the two illnesses fall along a common illness spectrum and may be approached as a single entity — with implications for both diagnosis and the development of new treatment approaches,” they concluded.
 

‘Noncontributory’ Findings

Commenting on the research, Robert G. Lahita, MD, PhD, director of the Institute for Autoimmune and Rheumatic Diseases, St. Joseph Health, Wayne, New Jersey, stated that he does not regard these diseases as neurologic but rather as rheumatologic.

“Most neurologists don’t see these diseases, but as a rheumatologist, I see them every day,” said Dr. Lahita, professor of medicine at Hackensack (New Jersey) Meridian School of Medicine and a clinical professor of medicine at Rutgers New Jersey Medical School, New Brunswick. “ME/CFS isn’t as common in my practice, but we do deal with many post-COVID patients who are afflicted mostly with ME/CFS.”

He noted that an important reason for fatigue in FM is that patients generally don’t sleep, or their sleep is disrupted. This is different from the cause of fatigue in ME/CFS.

In addition, the small sample size and the lack of difference between males and females were both limitations of the current study, said Dr. Lahita, who was not involved in this research. “We know that FM disproportionately affects women — in my practice, for example, over 95% of the patients with FM are female — while ME/CFS affects both genders similarly.”

Using proteomics as a biomarker was also problematic, according to Dr. Lahita. “It would have been more valuable to investigate differences in cytokines, for example,” he suggested.

Ultimately, Dr. Lahita thinks that the study is “non-contributory to the field and, as complex as the analysis was, it does nothing to shed differentiate the two conditions or explain the syndromes themselves.”

He added that it would have been more valuable to compare ME/CFS not only to ME/CFS plus FM but also with FM without ME/CFS and to healthy controls, and perhaps to a group with an autoimmune condition, such as lupus or Hashimoto’s thyroiditis.

Dr. Schutzer acknowledged that a limitation of the current study is that his team was unable analyze the CSF of patients with only FM. He and his colleagues “combed the world’s labs” for existing CSF samples of patients with FM alone but were unable to obtain any. “We see this study as a ‘stepping stone’ and hope that future studies will include patients with FM who are willing to donate CSF samples that we can use for comparison,” he said.

The authors received support from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and National Institute of Neurological Disorders and Stroke. Dr. Schutzer, coauthors, and Dr. Lahita reported no relevant financial relationships.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) have overlapping neurologic symptoms — particularly profound fatigue. The similarity between these two conditions has led to the question of whether they are indeed distinct central nervous system (CNS) entities, or whether they exist along a spectrum and are actually two different manifestations of the same disease process.

A new study utilized a novel methodology — unbiased quantitative mass spectrometry-based proteomics — to investigate this question by analyzing cerebrospinal fluid (CSF) in a group of patients with ME/CFS and another group of patients diagnosed with both ME/CFS and FM.

Close to 2,100 proteins were identified, of which nearly 1,800 were common to both conditions.

“ME/CFS and fibromyalgia do not appear to be distinct entities, with respect to their cerebrospinal fluid proteins,” lead author Steven Schutzer, MD, professor of medicine, Rutgers New Jersey School of Medicine, told this news organization.

“Work is underway to solve the multiple mysteries of ME/CFS, fibromyalgia, and other neurologic-associated diseases,” he continued. “We have further affirmed that we have a precise objective discovery tool in our hands. Collectively studying multiple diseases brings clarity to each individual disease.”

The study was published in the December 2023 issue of Annals of Medicine.
 

Cutting-Edge Technology

“ME/CFS is characterized by disabling fatigue, and FM is an illness characterized by body-wide pain,” Dr. Schutzer said. These “medically unexplained” illnesses often coexist by current definitions, and the overlap between them has suggested that they may be part of the “same illness spectrum.”

But co-investigator Benjamin Natelson, MD, professor of neurology and director of the Pain and Fatigue Study Center, Mount Sinai, New York, and others found in previous research that there are distinct differences between the conditions, raising the possibility that there may be different pathophysiological processes.

“The physicians and scientists on our team have had longstanding interest in studying neurologic diseases with cutting-edge tools such as mass spectrometry applied to CSF,” Dr. Schutzer said. “We have had success using this message to distinguish diseases such as ME/CFS from post-treatment Lyme disease, multiple sclerosis, and healthy normal people.”

Dr. Schutzer explained that Dr. Natelson had acquired CSF samples from “well-characterized [ME/CFS] patients and controls.”

Since the cause of ME/CFS is “unknown,” it seemed “ripe to investigate it further with the discovery tool of mass spectrometry” by harnessing the “most advanced equipment in the country at the pacific Northwest National Laboratory, which is part of the US Department of Energy.”

Dr. Schutzer noted that it was the “merger of different clinical and laboratory expertise” that enabled them to address whether ME/CFS and FM are two distinct disease processes.

The choice of analyzing CSF is that it’s the fluid closest to the brain, he added. “A lot of people have studied ME/CFS peripherally because they don’t have access to spinal fluid or it’s easier to look peripherally in the blood, but that doesn’t mean that the blood is where the real ‘action’ is occurring.”

The researchers compared the CSF of 15 patients with ME/CFS only to 15 patients with ME/CFS+FM using mass spectrometry-based proteomics, which they had employed in previous research to see whether ME/CFS was distinct from persistent neurologic Lyme disease syndrome.

This technology has become the “method of choice and discovery tool to rapidly uncover protein biomarkers that can distinguish one disease from another,” the authors stated.

In particular, in unbiased quantitative mass spectrometry-based proteomics, the researchers do not have to know in advance what’s in a sample before studying it, Dr. Schutzer explained.
 

Shared Pathophysiology?

Both groups of patients were of similar age (41.3 ± 9.4 years and 40.1 ± 11.0 years, respectively), with no differences in gender or rates of current comorbid psychiatric diagnoses between the groups.

The researchers quantified a total of 2,083 proteins, including 1,789 that were specifically quantified in all of the CSF samples, regardless of the presence or absence of FM.

Several analyses (including an ANOVA analysis with adjusted P values, a Random Forest machine learning approach that looked at relative protein abundance changes between those with ME/CFS and ME/CFS+FM, and unsupervised hierarchical clustering analyses) did not find distinguishing differences between the groups.

“The sum of these results does not support the hypothesis that ME/CFS and ME/CFS+FM are distinct entities, as currently defined,” the authors stated.

They noted that both conditions are “medically unexplained,” with core symptoms of pain, fatigue, sleep problems, and cognitive difficulty. The fact that these two syndromes coexist so often has led to the assumption that the “similarities between them outweigh the differences,” they wrote.

They pointed to some differences between the conditions, including an increase in substance P in the CSF of FM patients, but not in ME/CFS patients reported by others. There are also some immunological, physiological and genetic differences.

But if the conclusion that the two illnesses may share a similar pathophysiological basis is supported by other research that includes FM-only patients as comparators to those with ME/CFS, “this would support the notion that the two illnesses fall along a common illness spectrum and may be approached as a single entity — with implications for both diagnosis and the development of new treatment approaches,” they concluded.
 

‘Noncontributory’ Findings

Commenting on the research, Robert G. Lahita, MD, PhD, director of the Institute for Autoimmune and Rheumatic Diseases, St. Joseph Health, Wayne, New Jersey, stated that he does not regard these diseases as neurologic but rather as rheumatologic.

“Most neurologists don’t see these diseases, but as a rheumatologist, I see them every day,” said Dr. Lahita, professor of medicine at Hackensack (New Jersey) Meridian School of Medicine and a clinical professor of medicine at Rutgers New Jersey Medical School, New Brunswick. “ME/CFS isn’t as common in my practice, but we do deal with many post-COVID patients who are afflicted mostly with ME/CFS.”

He noted that an important reason for fatigue in FM is that patients generally don’t sleep, or their sleep is disrupted. This is different from the cause of fatigue in ME/CFS.

In addition, the small sample size and the lack of difference between males and females were both limitations of the current study, said Dr. Lahita, who was not involved in this research. “We know that FM disproportionately affects women — in my practice, for example, over 95% of the patients with FM are female — while ME/CFS affects both genders similarly.”

Using proteomics as a biomarker was also problematic, according to Dr. Lahita. “It would have been more valuable to investigate differences in cytokines, for example,” he suggested.

Ultimately, Dr. Lahita thinks that the study is “non-contributory to the field and, as complex as the analysis was, it does nothing to shed differentiate the two conditions or explain the syndromes themselves.”

He added that it would have been more valuable to compare ME/CFS not only to ME/CFS plus FM but also with FM without ME/CFS and to healthy controls, and perhaps to a group with an autoimmune condition, such as lupus or Hashimoto’s thyroiditis.

Dr. Schutzer acknowledged that a limitation of the current study is that his team was unable analyze the CSF of patients with only FM. He and his colleagues “combed the world’s labs” for existing CSF samples of patients with FM alone but were unable to obtain any. “We see this study as a ‘stepping stone’ and hope that future studies will include patients with FM who are willing to donate CSF samples that we can use for comparison,” he said.

The authors received support from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and National Institute of Neurological Disorders and Stroke. Dr. Schutzer, coauthors, and Dr. Lahita reported no relevant financial relationships.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) have overlapping neurologic symptoms — particularly profound fatigue. The similarity between these two conditions has led to the question of whether they are indeed distinct central nervous system (CNS) entities, or whether they exist along a spectrum and are actually two different manifestations of the same disease process.

A new study utilized a novel methodology — unbiased quantitative mass spectrometry-based proteomics — to investigate this question by analyzing cerebrospinal fluid (CSF) in a group of patients with ME/CFS and another group of patients diagnosed with both ME/CFS and FM.

Close to 2,100 proteins were identified, of which nearly 1,800 were common to both conditions.

“ME/CFS and fibromyalgia do not appear to be distinct entities, with respect to their cerebrospinal fluid proteins,” lead author Steven Schutzer, MD, professor of medicine, Rutgers New Jersey School of Medicine, told this news organization.

“Work is underway to solve the multiple mysteries of ME/CFS, fibromyalgia, and other neurologic-associated diseases,” he continued. “We have further affirmed that we have a precise objective discovery tool in our hands. Collectively studying multiple diseases brings clarity to each individual disease.”

The study was published in the December 2023 issue of Annals of Medicine.
 

Cutting-Edge Technology

“ME/CFS is characterized by disabling fatigue, and FM is an illness characterized by body-wide pain,” Dr. Schutzer said. These “medically unexplained” illnesses often coexist by current definitions, and the overlap between them has suggested that they may be part of the “same illness spectrum.”

But co-investigator Benjamin Natelson, MD, professor of neurology and director of the Pain and Fatigue Study Center, Mount Sinai, New York, and others found in previous research that there are distinct differences between the conditions, raising the possibility that there may be different pathophysiological processes.

“The physicians and scientists on our team have had longstanding interest in studying neurologic diseases with cutting-edge tools such as mass spectrometry applied to CSF,” Dr. Schutzer said. “We have had success using this message to distinguish diseases such as ME/CFS from post-treatment Lyme disease, multiple sclerosis, and healthy normal people.”

Dr. Schutzer explained that Dr. Natelson had acquired CSF samples from “well-characterized [ME/CFS] patients and controls.”

Since the cause of ME/CFS is “unknown,” it seemed “ripe to investigate it further with the discovery tool of mass spectrometry” by harnessing the “most advanced equipment in the country at the pacific Northwest National Laboratory, which is part of the US Department of Energy.”

Dr. Schutzer noted that it was the “merger of different clinical and laboratory expertise” that enabled them to address whether ME/CFS and FM are two distinct disease processes.

The choice of analyzing CSF is that it’s the fluid closest to the brain, he added. “A lot of people have studied ME/CFS peripherally because they don’t have access to spinal fluid or it’s easier to look peripherally in the blood, but that doesn’t mean that the blood is where the real ‘action’ is occurring.”

The researchers compared the CSF of 15 patients with ME/CFS only to 15 patients with ME/CFS+FM using mass spectrometry-based proteomics, which they had employed in previous research to see whether ME/CFS was distinct from persistent neurologic Lyme disease syndrome.

This technology has become the “method of choice and discovery tool to rapidly uncover protein biomarkers that can distinguish one disease from another,” the authors stated.

In particular, in unbiased quantitative mass spectrometry-based proteomics, the researchers do not have to know in advance what’s in a sample before studying it, Dr. Schutzer explained.
 

Shared Pathophysiology?

Both groups of patients were of similar age (41.3 ± 9.4 years and 40.1 ± 11.0 years, respectively), with no differences in gender or rates of current comorbid psychiatric diagnoses between the groups.

The researchers quantified a total of 2,083 proteins, including 1,789 that were specifically quantified in all of the CSF samples, regardless of the presence or absence of FM.

Several analyses (including an ANOVA analysis with adjusted P values, a Random Forest machine learning approach that looked at relative protein abundance changes between those with ME/CFS and ME/CFS+FM, and unsupervised hierarchical clustering analyses) did not find distinguishing differences between the groups.

“The sum of these results does not support the hypothesis that ME/CFS and ME/CFS+FM are distinct entities, as currently defined,” the authors stated.

They noted that both conditions are “medically unexplained,” with core symptoms of pain, fatigue, sleep problems, and cognitive difficulty. The fact that these two syndromes coexist so often has led to the assumption that the “similarities between them outweigh the differences,” they wrote.

They pointed to some differences between the conditions, including an increase in substance P in the CSF of FM patients, but not in ME/CFS patients reported by others. There are also some immunological, physiological and genetic differences.

But if the conclusion that the two illnesses may share a similar pathophysiological basis is supported by other research that includes FM-only patients as comparators to those with ME/CFS, “this would support the notion that the two illnesses fall along a common illness spectrum and may be approached as a single entity — with implications for both diagnosis and the development of new treatment approaches,” they concluded.
 

‘Noncontributory’ Findings

Commenting on the research, Robert G. Lahita, MD, PhD, director of the Institute for Autoimmune and Rheumatic Diseases, St. Joseph Health, Wayne, New Jersey, stated that he does not regard these diseases as neurologic but rather as rheumatologic.

“Most neurologists don’t see these diseases, but as a rheumatologist, I see them every day,” said Dr. Lahita, professor of medicine at Hackensack (New Jersey) Meridian School of Medicine and a clinical professor of medicine at Rutgers New Jersey Medical School, New Brunswick. “ME/CFS isn’t as common in my practice, but we do deal with many post-COVID patients who are afflicted mostly with ME/CFS.”

He noted that an important reason for fatigue in FM is that patients generally don’t sleep, or their sleep is disrupted. This is different from the cause of fatigue in ME/CFS.

In addition, the small sample size and the lack of difference between males and females were both limitations of the current study, said Dr. Lahita, who was not involved in this research. “We know that FM disproportionately affects women — in my practice, for example, over 95% of the patients with FM are female — while ME/CFS affects both genders similarly.”

Using proteomics as a biomarker was also problematic, according to Dr. Lahita. “It would have been more valuable to investigate differences in cytokines, for example,” he suggested.

Ultimately, Dr. Lahita thinks that the study is “non-contributory to the field and, as complex as the analysis was, it does nothing to shed differentiate the two conditions or explain the syndromes themselves.”

He added that it would have been more valuable to compare ME/CFS not only to ME/CFS plus FM but also with FM without ME/CFS and to healthy controls, and perhaps to a group with an autoimmune condition, such as lupus or Hashimoto’s thyroiditis.

Dr. Schutzer acknowledged that a limitation of the current study is that his team was unable analyze the CSF of patients with only FM. He and his colleagues “combed the world’s labs” for existing CSF samples of patients with FM alone but were unable to obtain any. “We see this study as a ‘stepping stone’ and hope that future studies will include patients with FM who are willing to donate CSF samples that we can use for comparison,” he said.

The authors received support from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and National Institute of Neurological Disorders and Stroke. Dr. Schutzer, coauthors, and Dr. Lahita reported no relevant financial relationships.

Women with autoimmune disease are more likely to have perinatal depression (PND), according to findings from a new study that also suggested the reverse relationship is true: Women with a history of PND have a higher risk of developing autoimmune disease.

The research, published online on January 9, 2024, in Molecular Psychiatry, was led by Emma Bränn, PhD, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.

The researchers used data from the Swedish Medical Birth Register and identified all women who had given birth in Sweden between 2001 and 2013. Out of the group of approximately 815,000 women and 1.3 million pregnancies, just more than 55,000 women had been diagnosed with depression during their pregnancy or within a year after delivery.

The researchers then compared the incidence of 41 autoimmune diseases in women who had and did not have PND. They controlled for factors including genetic makeup and childhood environment.

Results indicated that women with autoimmune disease were 30% more likely to have PND (odds ratio, 1.30; 95% CI, 1.25-1.35). Conversely, women with PND were 30% more likely than women with no PND to develop an autoimmune disease (hazard ratio, 1.30; 95% CI, 1.25-1.36).

A sibling comparison helped confirm the results by controlling for some shared genetic and early life environmental factors related to the household in which sisters grew up.
 

Potential Shared Biological Mechanisms

The association was independent of psychiatric comorbidities, suggesting there may be shared biological mechanisms.

Dr. Bränn told this news organization that the research team wanted to do the study because previous research has shown involvement of the immune system in depression, with similarities in both the symptoms of immune system–activated diseases and depression and the molecular pathways activated by the immune system.

“Adding on top of the tremendous changes in the immune system that we see in the body of the woman during the perinatal period, we hypothesized that autoimmune diseases could be associated to perinatal depression,” she said. “This had also been shown in some previous literature but not to the extent as what we have investigated in this paper.”

She said their results help make a case for counseling women at several points in healthcare interactions — before and after conception and childbirth — and in rheumatology visits to inform women with autoimmune diseases who are contemplating motherhood of the association with developing PND. The results may also demonstrate a need for monitoring women in these groups for depression or autoimmune disease.

Fred Miller, MD, PhD, retired Scientist Emeritus of the Environmental Autoimmunity Group at the National Institute of Environmental Health Sciences, who was not part of the study, said the results seem plausible as they build on early work that demonstrated selected associations between autoimmune conditions and mental illness.

“These associations may be the result of shared genetic and environmental risk factors, including stress, hormonal changes, medications, and the proinflammatory states that can lead to both,” he said.

The novelty, he said, is in the relatively strong associations of PND with autoimmune disease overall and with specific autoimmune diseases.
 

Strong Link Found With Multiple Sclerosis (MS)

According to the paper, a significant positive bidirectional link was found for autoimmune thyroid disease, psoriasis, MS, ulcerative colitis, and celiac disease.

Researchers found a particularly strong association — double the risk in both directions — between PND and MS.

Dr. Miller said though it is unclear from this study why the association of PND with MS was stronger than with other autoimmune diseases, people with MS are known to be at a high risk for depression in general. That may come from greater shared genetic and environmental risk factors, he added.

Additionally, MS is one of the more common autoimmune diseases, he noted, so the population is larger for study.

He said he was surprised the researchers didn’t investigate medication use because medications used in depression have immunologic effects and medications used in autoimmune diseases could have effects on mental conditions.

The study has implications for clinicians in a wide variety of specialties, Dr. Miller noted.

“It suggests that caregivers be more alert to the signs of developing autoimmune disease in women with perinatal depression and to the signs of developing perinatal depression in those with autoimmune disease,” Dr. Miller said, “so that appropriate screening, diagnostics, and interventions may be undertaken.”

The researchers say they will continue to examine the long-term effects of depression during pregnancy and in the year after childbirth.

“Depression during this sensitive period can have serious consequences for both the mother and the baby,” Dr. Bränn said. “We hope that our results will help decision-makers to steer funding toward maternal healthcare so that more women can get help and support in time.”

The study was financed by Karolinska Institute, Forte (the Swedish Research Council for Health, Working Life and Welfare), the Swedish Research Council, and the Icelandic Research Fund.

The researchers and Dr. Miller reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Women with autoimmune disease are more likely to have perinatal depression (PND), according to findings from a new study that also suggested the reverse relationship is true: Women with a history of PND have a higher risk of developing autoimmune disease.

The research, published online on January 9, 2024, in Molecular Psychiatry, was led by Emma Bränn, PhD, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.

The researchers used data from the Swedish Medical Birth Register and identified all women who had given birth in Sweden between 2001 and 2013. Out of the group of approximately 815,000 women and 1.3 million pregnancies, just more than 55,000 women had been diagnosed with depression during their pregnancy or within a year after delivery.

The researchers then compared the incidence of 41 autoimmune diseases in women who had and did not have PND. They controlled for factors including genetic makeup and childhood environment.

Results indicated that women with autoimmune disease were 30% more likely to have PND (odds ratio, 1.30; 95% CI, 1.25-1.35). Conversely, women with PND were 30% more likely than women with no PND to develop an autoimmune disease (hazard ratio, 1.30; 95% CI, 1.25-1.36).

A sibling comparison helped confirm the results by controlling for some shared genetic and early life environmental factors related to the household in which sisters grew up.
 

Potential Shared Biological Mechanisms

The association was independent of psychiatric comorbidities, suggesting there may be shared biological mechanisms.

Dr. Bränn told this news organization that the research team wanted to do the study because previous research has shown involvement of the immune system in depression, with similarities in both the symptoms of immune system–activated diseases and depression and the molecular pathways activated by the immune system.

“Adding on top of the tremendous changes in the immune system that we see in the body of the woman during the perinatal period, we hypothesized that autoimmune diseases could be associated to perinatal depression,” she said. “This had also been shown in some previous literature but not to the extent as what we have investigated in this paper.”

She said their results help make a case for counseling women at several points in healthcare interactions — before and after conception and childbirth — and in rheumatology visits to inform women with autoimmune diseases who are contemplating motherhood of the association with developing PND. The results may also demonstrate a need for monitoring women in these groups for depression or autoimmune disease.

Fred Miller, MD, PhD, retired Scientist Emeritus of the Environmental Autoimmunity Group at the National Institute of Environmental Health Sciences, who was not part of the study, said the results seem plausible as they build on early work that demonstrated selected associations between autoimmune conditions and mental illness.

“These associations may be the result of shared genetic and environmental risk factors, including stress, hormonal changes, medications, and the proinflammatory states that can lead to both,” he said.

The novelty, he said, is in the relatively strong associations of PND with autoimmune disease overall and with specific autoimmune diseases.
 

Strong Link Found With Multiple Sclerosis (MS)

According to the paper, a significant positive bidirectional link was found for autoimmune thyroid disease, psoriasis, MS, ulcerative colitis, and celiac disease.

Researchers found a particularly strong association — double the risk in both directions — between PND and MS.

Dr. Miller said though it is unclear from this study why the association of PND with MS was stronger than with other autoimmune diseases, people with MS are known to be at a high risk for depression in general. That may come from greater shared genetic and environmental risk factors, he added.

Additionally, MS is one of the more common autoimmune diseases, he noted, so the population is larger for study.

He said he was surprised the researchers didn’t investigate medication use because medications used in depression have immunologic effects and medications used in autoimmune diseases could have effects on mental conditions.

The study has implications for clinicians in a wide variety of specialties, Dr. Miller noted.

“It suggests that caregivers be more alert to the signs of developing autoimmune disease in women with perinatal depression and to the signs of developing perinatal depression in those with autoimmune disease,” Dr. Miller said, “so that appropriate screening, diagnostics, and interventions may be undertaken.”

The researchers say they will continue to examine the long-term effects of depression during pregnancy and in the year after childbirth.

“Depression during this sensitive period can have serious consequences for both the mother and the baby,” Dr. Bränn said. “We hope that our results will help decision-makers to steer funding toward maternal healthcare so that more women can get help and support in time.”

The study was financed by Karolinska Institute, Forte (the Swedish Research Council for Health, Working Life and Welfare), the Swedish Research Council, and the Icelandic Research Fund.

The researchers and Dr. Miller reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Women with autoimmune disease are more likely to have perinatal depression (PND), according to findings from a new study that also suggested the reverse relationship is true: Women with a history of PND have a higher risk of developing autoimmune disease.

The research, published online on January 9, 2024, in Molecular Psychiatry, was led by Emma Bränn, PhD, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.

The researchers used data from the Swedish Medical Birth Register and identified all women who had given birth in Sweden between 2001 and 2013. Out of the group of approximately 815,000 women and 1.3 million pregnancies, just more than 55,000 women had been diagnosed with depression during their pregnancy or within a year after delivery.

The researchers then compared the incidence of 41 autoimmune diseases in women who had and did not have PND. They controlled for factors including genetic makeup and childhood environment.

Results indicated that women with autoimmune disease were 30% more likely to have PND (odds ratio, 1.30; 95% CI, 1.25-1.35). Conversely, women with PND were 30% more likely than women with no PND to develop an autoimmune disease (hazard ratio, 1.30; 95% CI, 1.25-1.36).

A sibling comparison helped confirm the results by controlling for some shared genetic and early life environmental factors related to the household in which sisters grew up.
 

Potential Shared Biological Mechanisms

The association was independent of psychiatric comorbidities, suggesting there may be shared biological mechanisms.

Dr. Bränn told this news organization that the research team wanted to do the study because previous research has shown involvement of the immune system in depression, with similarities in both the symptoms of immune system–activated diseases and depression and the molecular pathways activated by the immune system.

“Adding on top of the tremendous changes in the immune system that we see in the body of the woman during the perinatal period, we hypothesized that autoimmune diseases could be associated to perinatal depression,” she said. “This had also been shown in some previous literature but not to the extent as what we have investigated in this paper.”

She said their results help make a case for counseling women at several points in healthcare interactions — before and after conception and childbirth — and in rheumatology visits to inform women with autoimmune diseases who are contemplating motherhood of the association with developing PND. The results may also demonstrate a need for monitoring women in these groups for depression or autoimmune disease.

Fred Miller, MD, PhD, retired Scientist Emeritus of the Environmental Autoimmunity Group at the National Institute of Environmental Health Sciences, who was not part of the study, said the results seem plausible as they build on early work that demonstrated selected associations between autoimmune conditions and mental illness.

“These associations may be the result of shared genetic and environmental risk factors, including stress, hormonal changes, medications, and the proinflammatory states that can lead to both,” he said.

The novelty, he said, is in the relatively strong associations of PND with autoimmune disease overall and with specific autoimmune diseases.
 

Strong Link Found With Multiple Sclerosis (MS)

According to the paper, a significant positive bidirectional link was found for autoimmune thyroid disease, psoriasis, MS, ulcerative colitis, and celiac disease.

Researchers found a particularly strong association — double the risk in both directions — between PND and MS.

Dr. Miller said though it is unclear from this study why the association of PND with MS was stronger than with other autoimmune diseases, people with MS are known to be at a high risk for depression in general. That may come from greater shared genetic and environmental risk factors, he added.

Additionally, MS is one of the more common autoimmune diseases, he noted, so the population is larger for study.

He said he was surprised the researchers didn’t investigate medication use because medications used in depression have immunologic effects and medications used in autoimmune diseases could have effects on mental conditions.

The study has implications for clinicians in a wide variety of specialties, Dr. Miller noted.

“It suggests that caregivers be more alert to the signs of developing autoimmune disease in women with perinatal depression and to the signs of developing perinatal depression in those with autoimmune disease,” Dr. Miller said, “so that appropriate screening, diagnostics, and interventions may be undertaken.”

The researchers say they will continue to examine the long-term effects of depression during pregnancy and in the year after childbirth.

“Depression during this sensitive period can have serious consequences for both the mother and the baby,” Dr. Bränn said. “We hope that our results will help decision-makers to steer funding toward maternal healthcare so that more women can get help and support in time.”

The study was financed by Karolinska Institute, Forte (the Swedish Research Council for Health, Working Life and Welfare), the Swedish Research Council, and the Icelandic Research Fund.

The researchers and Dr. Miller reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

The relationship between lipid levels and the development of dementia is an evolving but confusing landscape.

“This is an incredibly complex area, and there really isn’t a clear consensus on this subject because different lipid classes reflect different things,” according to Betsy Mills, PhD, assistant director of aging and Alzheimer’s prevention at the Alzheimer’s Drug Discovery Foundation.

Some studies suggest that excessive lipid levels may increase the risk of developing dementia and Alzheimer’s disease (AD). Others imply that elevated low-density lipoprotein (LDL) cholesterol or even triglycerides may offer some protection against subsequent dementia whereas higher levels of high-density lipoprotein (HDL) cholesterol, hitherto thought to be protective, may have a deleterious effect.

“It depends on what lipids you’re measuring, what you’re using to measure those lipids, what age the person is, and multiple other factors,” Dr. Mills told this news organization.

Teasing out the variables and potential mechanisms for the association between lipids and dementia risk necessitates understanding the role that lipids play in the healthy brain, the negative impact of brain lipid dysregulation, and the interplay between cholesterol in the central nervous system (CNS) and the cholesterol in the rest of the body.

 

Beyond Amyloid

The role of lipids in AD risk has historically been “overlooked,” says Scott Hansen, PhD, associate professor, Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Florida.

“The common narrative is that amyloid is the culprit in AD and certainly that’s the case in familial AD,” he told this news organization. “It’s been assumed that because amyloid deposits are also found in the brains of people with late-onset AD — which is the vast majority of cases — amyloid is the cause, but that’s not clear at all.”

The “limited clinical success” of aducanumab, its “extremely small efficacy” — despite its obvious success in eradicating the amyloid plaques — suggests there’s “much more to the story than amyloid.”

He and a growing community of scientists recognize the role of inflammation and lipids. “The major finding of my lab is that cholesterol actually drives the synthesis of amyloid via inflammation. In other words, amyloid is downstream of cholesterol. Cholesterol drives the inflammation, and the inflammation drives amyloid,” he said.
 

‘Lipid Invasion Model’

Because the brain is an incredibly lipid-rich organ, Dr. Mills said that “any dysregulation in lipid homeostasis will impact the brain because cholesterol is needed for the myelin sheaths, cell membranes, and other functions.”

A healthy brain relies upon healthy lipid regulation, and “since the first description of AD over 100 years ago, the disease has been associated with altered lipids in the brain,” Dr. Hansen noted.

He cited the “ lipid invasion model” as a way of understanding brain lipid dysregulation. This hypothesis posits that AD is driven by external lipids that enter the brain as a result of damage to the blood-brain barrier (BBB).

“Cholesterol in the brain and cholesterol in the periphery — meaning, in the rest of the body, outside the brain — are separate,” Dr. Hansen explained. “The brain produces its own cholesterol and keeps tight control of it.”

Under normal circumstances, cholesterol from the diet doesn’t enter the brain. “Each pool of cholesterol — in the brain and in the periphery — has its own distinct regulatory mechanisms, target cells, and transport mechanisms.”

When the BBB has been compromised, it becomes permeable, allowing LDL cholesterol to enter the brain, said Dr. Hansen. Then the brain’s own lipoproteins transport the invading cholesterol, allowing it to be taken up by neurons. In turn, this causes neuronal amyloid levels to rise, ultimately leading to the creation of amyloid-b plaques. It also plays a role in tau phosphorylation. Both are key features of AD pathology.

Elevated levels of cholesterol and other lipids have been found in amyloid plaques, Dr. Hansen noted. Moreover, studies of brains of patients with AD have pointed to BBB damage.

And the risk factors for AD overlap with the risk factors for damage to the BBB (such as, aging, brain trauma, hypertension, stress, sleep deprivation, smoking, excess alcohol, obesity, diabetes, and APOE4 genotype), according to the lipid invasion model paper cited by Dr. Hansen.
 

‘Chicken and Egg’

“There is a strong link between the brain and the heart, and we know that cardiovascular risk factors have an overlap with dementia risk factors — especially vascular dementia,” said Dr. Mills. 

She explained that an atherogenic lipid profile results in narrowing of the arteries, with less blood reaching the brain. “This can lead to stress in the brain, which drives inflammation and pathology.”

But cholesterol itself plays an important role in inflammation, Dr. Hansen said. In the periphery, it is “part of an integral response to tissue damage and infection.”

In the brain, once cholesterol is synthesized by the astrocytes, it is transported to neurons via the apolipoprotein E (APOE) protein, which plays a role in brain cholesterol homeostasis, Dr. Mills explained. Those with the ε4 allele of APOE (APOE4) tend to have faultier transport and storage of lipids in the brain, relative to the other APOE variants.

It’s known that individuals with APOE4 are particularly vulnerable to late-onset AD, Dr. Hansen observed. By contrast, APOE2 has a more protective effect. “Most people have APOE3, which is ‘in between,’ ” he said.

When there is neuronal uptake of “invading cholesterol,” not only is amyloid produced but also neuroinflammatory cytokines, further driving inflammation. A vicious cycle ensues: Cholesterol induces cytokine release; and cytokine release, in turn, induces cholesterol synthesis — which “suggests an autocatalytic function of cholesterol in the escalation of inflammation,” Dr. Hansen suggested. He noted that permeability of the BBB also allows inflammatory cytokines from elsewhere in the body to invade the brain, further driving inflammation.

Dr. Mills elaborated: “We know that generally, in dementia, there appear to be some changes in cholesterol metabolism in the brain, but it’s a chicken-and-egg question. We know that as the disease progresses, neurons are dying and getting remodeled. Do these changes have to do with the degenerative process, or are the changes in the cholesterol metabolism actually driving the degenerative disease process? It’s probably a combination, but it’s unclear at this point.”
 

Lipids in Plasma vs CSF

Dr. Mills explained that HDL particles in the brain differ from those in the periphery. “In the CNS, you have ‘HDL-like particles,’ which are similar in size and composition [to HDL in the periphery] but aren’t the same particles.” The brain itself generates HDL-like lipoproteins, which are produced by astrocytes and other glial cells and found in cerebrospinal fluid (CSF).

Dyslipidemia in the periphery can be a marker for cardiovascular pathology. In the brain, “it can be an indication that there is active damage going on, depending on which compartment you’re looking at.”

She noted that plasma lipid levels and brain CSF lipid levels are “very different.” Research suggests that HDL in the CSF exhibits similar heterogeneity to plasma HDL, but these CSF lipoproteins present at 100-fold lower concentrations, compared to plasma HDL and have unique combinations of protein subpopulations. Lipidomics analysis studies show that these compartments “get very different readings, in terms of the predominant lipid disease state, and they are regulated differently from the way lipids in the periphery are regulated.” 

In the brain, the cholesterol “needs to get shuttled from glial cells to neurons,” so defects in the transport process can disrupt overall brain homeostasis, said Dr. Mills. But since the brain system is separate from the peripheral system, measuring plasma lipids is more likely to point to cardiovascular risks, while changes reflected in CSF lipids are “more indicative of alteration in lipid homeostasis in the brain.”
 

HDL and Triglycerides: A Complicated Story

Dr. Mills noted that HDL in the periphery is “very complicated,” and the idea that HDL, as a measure on its own, is “necessarily ‘good’ isn’t particularly informative.” Rather, HDL is “extremely heterogeneous, very diverse, has different lipid compositions, different classes, and different modifications.” For example, like oxidized LDL, oxidized HDL is also “bad,” preventing the HDL from having protective functions.

Similarly, the apolipoproteins associated with HDL can affect the function of the HDL. “Our understanding of the HDL-like particles in the CNS is limited, but we do understand the APOE4 link,” Dr. Mills said. “It seems that the HDL-like particles containing APOE2 or APOE3 are larger and are more effective at transferring the lipids and cholesterol linked to them relative to APOE4-containing particles.” 

Because HDL is more complex than simply being “good,” measuring HDL doesn’t “give you the full story,” said Dr. Mills. She speculates that this may be why there are studies suggesting that high levels of HDL might not have protective benefits and might even be detrimental. This makes it difficult to look at population studies, where the different subclasses of HDL are not necessarily captured in depth. 

Dr. Mills pointed to another confounding factor, which is that much of the risk for the development of AD appears to be related to the interaction of HDL, LDL, and triglycerides. “When you look at each of these individually, you get a lot of heterogeneity, and it’s unclear what’s driving what,” she said.

An advantage of observational studies is that they give information about which of these markers are associated with trends and disease risks in specific groups vs others. 

“For example, higher levels of triglycerides are associated with cardiovascular risk more in women, relative to men,” she said. And the triglyceride-to-HDL ratio seems “particularly robust” as a measure of cardiovascular health and risk. 

The interpretation of associations with triglycerides can be “tricky” and “confusing” because results differ so much between studies, she said. “There are differences between middle age and older age, which have to do with age-related changes in metabolism and lipid metabolism and not necessarily that the markers are indicating something different,” she said.

Some research has suggested that triglycerides may have a protective effect against dementia, noted Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and director of nutritional psychiatry at MGH Academy.

This may be because the brain “runs mostly on energy from burning triglycerides,” suggested Dr. Naidoo, author of the books Calm Your Mind With Food and This Is Your Brain on Food.

In addition, having higher levels of triglycerides may be linked with having overall healthier behaviors, Dr. Naidoo told this news organization.

Dr. Mills said that in middle-aged individuals, high levels of LDL-C and triglycerides are “often indicative of more atherogenic particles and risk to cardiovascular health, which is a generally negative trajectory. But in older individuals, things become more complicated because there are differences in terms of clearance of some of these particles, tissue clearance and distribution, and nutrient status. So for older individuals, it seems that fluctuations in either direction—either too high or too low—tend to be more informative that some overall dysregulation is going on the system.” 

She emphasized that, in this “emerging area, looking at only one or two studies is confusing. But if you look at the spectrum of studies, you can see a pattern, which is that the regulation gets ‘off,’ as people age.”

 

The Potential Role of Statins

Dr. Mills speculated that there may be “neuroprotective benefits for some of the statins which appear to be related to cardiovascular benefits. But at this point, we don’t have any clear data whether statins actually directly impact brain cholesterol, since it’s a separate pool.”

They could help “by increasing blood flow and reducing narrowing of the arteries, but any direct impact on the brain is still under investigation.”

Dr. Hansen pointed to research suggesting statins taken at midlife appear to be cardioprotective and may be protective of brain health as well, whereas statins initiated in older age do not appear to have these benefits.

He speculated that one reason statins seem less helpful when initiated later in life is that the BBB has already been damaged by systemic inflammation in the periphery, and the neuroinflammatory process resulting in neuronal destruction is already underway. “I think statins aren’t going to fix that problem, so although lowering cholesterol can be helpful in some respects, it might be too late to affect cognition because the nerves have already died and won’t grow back.”
 

Can Dietary Approaches Help?

Dr. Naidoo said that when looking at neurologic and psychiatric disease, “it’s important to think about the ‘long game’ — how can we improve our blood and cardiovascular health earlier in life to help potentiate healthy aging?”

From a nutritional psychiatry standpoint, Dr. Naidoo focuses on nourishing the gut microbiome and decreasing inflammation. “A healthy and balanced microbiome supports cognition, while the composition of gut bacteria is actually drastically different in patients with neurological diseases, such as AD.” 

She recommends a nutrient-dense, anti-inflammatory diet including probiotic-rich foods (such as kimchi, sauerkraut, plain yogurt, and miso). Moreover, “the quality and structure of our fatty acids may be relevant as well: Increasing our intake of polyunsaturated fatty acids and avoiding processed fats like trans fats and hydrogenated oils may benefit our overall brain health.”

Dr. Naidoo recommends extra-virgin olive oil as a source of healthy fat. Its consumption is linked to lower incidence of AD by way of encouraging autophagy, which she calls “our own process of “cellular cleanup.’”

Dr. Naidoo believes that clinicians’ guidance to patients should “focus on healthy nutrition and other lifestyle practices, such as exercise, outdoor time, good sleep, and stress reduction.” 

Dr. Mills notes the importance of omega-3 fatty acids, such as docosahexaenoic acid (DHA) , for brain health. “DHA is a major lipid component of neuronal membranes,” she said. “Because of inefficiencies in metabolism with APOE4, people tend to metabolize more of the lipids on the membranes themselves, so they have higher lipid membrane turnover and a greater need to supplement. Supplementing particularly through diet, with foods such as fatty fish rich in omega-3, can help boost the levels to help keep neuronal membranes intact.”
 

What This Means for the Clinician

“At this point, we see all of these associations between lipids and dementia, but we haven’t worked out exactly what it means on the individual level for an individual patient,” said Dr. Mills. Certainly, the picture is complex, and the understanding is growing and shifting. “The clinical applications remain unclear.”

One potential clinical take-home is that clinicians might consider tracking lipid levels over time. “If you follow a patient and see an increase or decrease [in lipid levels], that can be informative.” Looking at ratios of lipids might be more useful than looking only at a change in a single measure. “If you see trends in a variety of measures that track with one another, it might be more of a sign that something is potentially wrong.” 

Whether the patient should first try a lifestyle intervention or might need medication is a “personalized clinical decision, depending on the individual, their risk factors, and how their levels are going,” said Dr. Mills. 

Dr. Mills, Dr. Hansen, and Dr. Naidoo declared no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

The relationship between lipid levels and the development of dementia is an evolving but confusing landscape.

“This is an incredibly complex area, and there really isn’t a clear consensus on this subject because different lipid classes reflect different things,” according to Betsy Mills, PhD, assistant director of aging and Alzheimer’s prevention at the Alzheimer’s Drug Discovery Foundation.

Some studies suggest that excessive lipid levels may increase the risk of developing dementia and Alzheimer’s disease (AD). Others imply that elevated low-density lipoprotein (LDL) cholesterol or even triglycerides may offer some protection against subsequent dementia whereas higher levels of high-density lipoprotein (HDL) cholesterol, hitherto thought to be protective, may have a deleterious effect.

“It depends on what lipids you’re measuring, what you’re using to measure those lipids, what age the person is, and multiple other factors,” Dr. Mills told this news organization.

Teasing out the variables and potential mechanisms for the association between lipids and dementia risk necessitates understanding the role that lipids play in the healthy brain, the negative impact of brain lipid dysregulation, and the interplay between cholesterol in the central nervous system (CNS) and the cholesterol in the rest of the body.

 

Beyond Amyloid

The role of lipids in AD risk has historically been “overlooked,” says Scott Hansen, PhD, associate professor, Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Florida.

“The common narrative is that amyloid is the culprit in AD and certainly that’s the case in familial AD,” he told this news organization. “It’s been assumed that because amyloid deposits are also found in the brains of people with late-onset AD — which is the vast majority of cases — amyloid is the cause, but that’s not clear at all.”

The “limited clinical success” of aducanumab, its “extremely small efficacy” — despite its obvious success in eradicating the amyloid plaques — suggests there’s “much more to the story than amyloid.”

He and a growing community of scientists recognize the role of inflammation and lipids. “The major finding of my lab is that cholesterol actually drives the synthesis of amyloid via inflammation. In other words, amyloid is downstream of cholesterol. Cholesterol drives the inflammation, and the inflammation drives amyloid,” he said.
 

‘Lipid Invasion Model’

Because the brain is an incredibly lipid-rich organ, Dr. Mills said that “any dysregulation in lipid homeostasis will impact the brain because cholesterol is needed for the myelin sheaths, cell membranes, and other functions.”

A healthy brain relies upon healthy lipid regulation, and “since the first description of AD over 100 years ago, the disease has been associated with altered lipids in the brain,” Dr. Hansen noted.

He cited the “ lipid invasion model” as a way of understanding brain lipid dysregulation. This hypothesis posits that AD is driven by external lipids that enter the brain as a result of damage to the blood-brain barrier (BBB).

“Cholesterol in the brain and cholesterol in the periphery — meaning, in the rest of the body, outside the brain — are separate,” Dr. Hansen explained. “The brain produces its own cholesterol and keeps tight control of it.”

Under normal circumstances, cholesterol from the diet doesn’t enter the brain. “Each pool of cholesterol — in the brain and in the periphery — has its own distinct regulatory mechanisms, target cells, and transport mechanisms.”

When the BBB has been compromised, it becomes permeable, allowing LDL cholesterol to enter the brain, said Dr. Hansen. Then the brain’s own lipoproteins transport the invading cholesterol, allowing it to be taken up by neurons. In turn, this causes neuronal amyloid levels to rise, ultimately leading to the creation of amyloid-b plaques. It also plays a role in tau phosphorylation. Both are key features of AD pathology.

Elevated levels of cholesterol and other lipids have been found in amyloid plaques, Dr. Hansen noted. Moreover, studies of brains of patients with AD have pointed to BBB damage.

And the risk factors for AD overlap with the risk factors for damage to the BBB (such as, aging, brain trauma, hypertension, stress, sleep deprivation, smoking, excess alcohol, obesity, diabetes, and APOE4 genotype), according to the lipid invasion model paper cited by Dr. Hansen.
 

‘Chicken and Egg’

“There is a strong link between the brain and the heart, and we know that cardiovascular risk factors have an overlap with dementia risk factors — especially vascular dementia,” said Dr. Mills. 

She explained that an atherogenic lipid profile results in narrowing of the arteries, with less blood reaching the brain. “This can lead to stress in the brain, which drives inflammation and pathology.”

But cholesterol itself plays an important role in inflammation, Dr. Hansen said. In the periphery, it is “part of an integral response to tissue damage and infection.”

In the brain, once cholesterol is synthesized by the astrocytes, it is transported to neurons via the apolipoprotein E (APOE) protein, which plays a role in brain cholesterol homeostasis, Dr. Mills explained. Those with the ε4 allele of APOE (APOE4) tend to have faultier transport and storage of lipids in the brain, relative to the other APOE variants.

It’s known that individuals with APOE4 are particularly vulnerable to late-onset AD, Dr. Hansen observed. By contrast, APOE2 has a more protective effect. “Most people have APOE3, which is ‘in between,’ ” he said.

When there is neuronal uptake of “invading cholesterol,” not only is amyloid produced but also neuroinflammatory cytokines, further driving inflammation. A vicious cycle ensues: Cholesterol induces cytokine release; and cytokine release, in turn, induces cholesterol synthesis — which “suggests an autocatalytic function of cholesterol in the escalation of inflammation,” Dr. Hansen suggested. He noted that permeability of the BBB also allows inflammatory cytokines from elsewhere in the body to invade the brain, further driving inflammation.

Dr. Mills elaborated: “We know that generally, in dementia, there appear to be some changes in cholesterol metabolism in the brain, but it’s a chicken-and-egg question. We know that as the disease progresses, neurons are dying and getting remodeled. Do these changes have to do with the degenerative process, or are the changes in the cholesterol metabolism actually driving the degenerative disease process? It’s probably a combination, but it’s unclear at this point.”
 

Lipids in Plasma vs CSF

Dr. Mills explained that HDL particles in the brain differ from those in the periphery. “In the CNS, you have ‘HDL-like particles,’ which are similar in size and composition [to HDL in the periphery] but aren’t the same particles.” The brain itself generates HDL-like lipoproteins, which are produced by astrocytes and other glial cells and found in cerebrospinal fluid (CSF).

Dyslipidemia in the periphery can be a marker for cardiovascular pathology. In the brain, “it can be an indication that there is active damage going on, depending on which compartment you’re looking at.”

She noted that plasma lipid levels and brain CSF lipid levels are “very different.” Research suggests that HDL in the CSF exhibits similar heterogeneity to plasma HDL, but these CSF lipoproteins present at 100-fold lower concentrations, compared to plasma HDL and have unique combinations of protein subpopulations. Lipidomics analysis studies show that these compartments “get very different readings, in terms of the predominant lipid disease state, and they are regulated differently from the way lipids in the periphery are regulated.” 

In the brain, the cholesterol “needs to get shuttled from glial cells to neurons,” so defects in the transport process can disrupt overall brain homeostasis, said Dr. Mills. But since the brain system is separate from the peripheral system, measuring plasma lipids is more likely to point to cardiovascular risks, while changes reflected in CSF lipids are “more indicative of alteration in lipid homeostasis in the brain.”
 

HDL and Triglycerides: A Complicated Story

Dr. Mills noted that HDL in the periphery is “very complicated,” and the idea that HDL, as a measure on its own, is “necessarily ‘good’ isn’t particularly informative.” Rather, HDL is “extremely heterogeneous, very diverse, has different lipid compositions, different classes, and different modifications.” For example, like oxidized LDL, oxidized HDL is also “bad,” preventing the HDL from having protective functions.

Similarly, the apolipoproteins associated with HDL can affect the function of the HDL. “Our understanding of the HDL-like particles in the CNS is limited, but we do understand the APOE4 link,” Dr. Mills said. “It seems that the HDL-like particles containing APOE2 or APOE3 are larger and are more effective at transferring the lipids and cholesterol linked to them relative to APOE4-containing particles.” 

Because HDL is more complex than simply being “good,” measuring HDL doesn’t “give you the full story,” said Dr. Mills. She speculates that this may be why there are studies suggesting that high levels of HDL might not have protective benefits and might even be detrimental. This makes it difficult to look at population studies, where the different subclasses of HDL are not necessarily captured in depth. 

Dr. Mills pointed to another confounding factor, which is that much of the risk for the development of AD appears to be related to the interaction of HDL, LDL, and triglycerides. “When you look at each of these individually, you get a lot of heterogeneity, and it’s unclear what’s driving what,” she said.

An advantage of observational studies is that they give information about which of these markers are associated with trends and disease risks in specific groups vs others. 

“For example, higher levels of triglycerides are associated with cardiovascular risk more in women, relative to men,” she said. And the triglyceride-to-HDL ratio seems “particularly robust” as a measure of cardiovascular health and risk. 

The interpretation of associations with triglycerides can be “tricky” and “confusing” because results differ so much between studies, she said. “There are differences between middle age and older age, which have to do with age-related changes in metabolism and lipid metabolism and not necessarily that the markers are indicating something different,” she said.

Some research has suggested that triglycerides may have a protective effect against dementia, noted Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and director of nutritional psychiatry at MGH Academy.

This may be because the brain “runs mostly on energy from burning triglycerides,” suggested Dr. Naidoo, author of the books Calm Your Mind With Food and This Is Your Brain on Food.

In addition, having higher levels of triglycerides may be linked with having overall healthier behaviors, Dr. Naidoo told this news organization.

Dr. Mills said that in middle-aged individuals, high levels of LDL-C and triglycerides are “often indicative of more atherogenic particles and risk to cardiovascular health, which is a generally negative trajectory. But in older individuals, things become more complicated because there are differences in terms of clearance of some of these particles, tissue clearance and distribution, and nutrient status. So for older individuals, it seems that fluctuations in either direction—either too high or too low—tend to be more informative that some overall dysregulation is going on the system.” 

She emphasized that, in this “emerging area, looking at only one or two studies is confusing. But if you look at the spectrum of studies, you can see a pattern, which is that the regulation gets ‘off,’ as people age.”

 

The Potential Role of Statins

Dr. Mills speculated that there may be “neuroprotective benefits for some of the statins which appear to be related to cardiovascular benefits. But at this point, we don’t have any clear data whether statins actually directly impact brain cholesterol, since it’s a separate pool.”

They could help “by increasing blood flow and reducing narrowing of the arteries, but any direct impact on the brain is still under investigation.”

Dr. Hansen pointed to research suggesting statins taken at midlife appear to be cardioprotective and may be protective of brain health as well, whereas statins initiated in older age do not appear to have these benefits.

He speculated that one reason statins seem less helpful when initiated later in life is that the BBB has already been damaged by systemic inflammation in the periphery, and the neuroinflammatory process resulting in neuronal destruction is already underway. “I think statins aren’t going to fix that problem, so although lowering cholesterol can be helpful in some respects, it might be too late to affect cognition because the nerves have already died and won’t grow back.”
 

Can Dietary Approaches Help?

Dr. Naidoo said that when looking at neurologic and psychiatric disease, “it’s important to think about the ‘long game’ — how can we improve our blood and cardiovascular health earlier in life to help potentiate healthy aging?”

From a nutritional psychiatry standpoint, Dr. Naidoo focuses on nourishing the gut microbiome and decreasing inflammation. “A healthy and balanced microbiome supports cognition, while the composition of gut bacteria is actually drastically different in patients with neurological diseases, such as AD.” 

She recommends a nutrient-dense, anti-inflammatory diet including probiotic-rich foods (such as kimchi, sauerkraut, plain yogurt, and miso). Moreover, “the quality and structure of our fatty acids may be relevant as well: Increasing our intake of polyunsaturated fatty acids and avoiding processed fats like trans fats and hydrogenated oils may benefit our overall brain health.”

Dr. Naidoo recommends extra-virgin olive oil as a source of healthy fat. Its consumption is linked to lower incidence of AD by way of encouraging autophagy, which she calls “our own process of “cellular cleanup.’”

Dr. Naidoo believes that clinicians’ guidance to patients should “focus on healthy nutrition and other lifestyle practices, such as exercise, outdoor time, good sleep, and stress reduction.” 

Dr. Mills notes the importance of omega-3 fatty acids, such as docosahexaenoic acid (DHA) , for brain health. “DHA is a major lipid component of neuronal membranes,” she said. “Because of inefficiencies in metabolism with APOE4, people tend to metabolize more of the lipids on the membranes themselves, so they have higher lipid membrane turnover and a greater need to supplement. Supplementing particularly through diet, with foods such as fatty fish rich in omega-3, can help boost the levels to help keep neuronal membranes intact.”
 

What This Means for the Clinician

“At this point, we see all of these associations between lipids and dementia, but we haven’t worked out exactly what it means on the individual level for an individual patient,” said Dr. Mills. Certainly, the picture is complex, and the understanding is growing and shifting. “The clinical applications remain unclear.”

One potential clinical take-home is that clinicians might consider tracking lipid levels over time. “If you follow a patient and see an increase or decrease [in lipid levels], that can be informative.” Looking at ratios of lipids might be more useful than looking only at a change in a single measure. “If you see trends in a variety of measures that track with one another, it might be more of a sign that something is potentially wrong.” 

Whether the patient should first try a lifestyle intervention or might need medication is a “personalized clinical decision, depending on the individual, their risk factors, and how their levels are going,” said Dr. Mills. 

Dr. Mills, Dr. Hansen, and Dr. Naidoo declared no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

The relationship between lipid levels and the development of dementia is an evolving but confusing landscape.

“This is an incredibly complex area, and there really isn’t a clear consensus on this subject because different lipid classes reflect different things,” according to Betsy Mills, PhD, assistant director of aging and Alzheimer’s prevention at the Alzheimer’s Drug Discovery Foundation.

Some studies suggest that excessive lipid levels may increase the risk of developing dementia and Alzheimer’s disease (AD). Others imply that elevated low-density lipoprotein (LDL) cholesterol or even triglycerides may offer some protection against subsequent dementia whereas higher levels of high-density lipoprotein (HDL) cholesterol, hitherto thought to be protective, may have a deleterious effect.

“It depends on what lipids you’re measuring, what you’re using to measure those lipids, what age the person is, and multiple other factors,” Dr. Mills told this news organization.

Teasing out the variables and potential mechanisms for the association between lipids and dementia risk necessitates understanding the role that lipids play in the healthy brain, the negative impact of brain lipid dysregulation, and the interplay between cholesterol in the central nervous system (CNS) and the cholesterol in the rest of the body.

 

Beyond Amyloid

The role of lipids in AD risk has historically been “overlooked,” says Scott Hansen, PhD, associate professor, Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Florida.

“The common narrative is that amyloid is the culprit in AD and certainly that’s the case in familial AD,” he told this news organization. “It’s been assumed that because amyloid deposits are also found in the brains of people with late-onset AD — which is the vast majority of cases — amyloid is the cause, but that’s not clear at all.”

The “limited clinical success” of aducanumab, its “extremely small efficacy” — despite its obvious success in eradicating the amyloid plaques — suggests there’s “much more to the story than amyloid.”

He and a growing community of scientists recognize the role of inflammation and lipids. “The major finding of my lab is that cholesterol actually drives the synthesis of amyloid via inflammation. In other words, amyloid is downstream of cholesterol. Cholesterol drives the inflammation, and the inflammation drives amyloid,” he said.
 

‘Lipid Invasion Model’

Because the brain is an incredibly lipid-rich organ, Dr. Mills said that “any dysregulation in lipid homeostasis will impact the brain because cholesterol is needed for the myelin sheaths, cell membranes, and other functions.”

A healthy brain relies upon healthy lipid regulation, and “since the first description of AD over 100 years ago, the disease has been associated with altered lipids in the brain,” Dr. Hansen noted.

He cited the “ lipid invasion model” as a way of understanding brain lipid dysregulation. This hypothesis posits that AD is driven by external lipids that enter the brain as a result of damage to the blood-brain barrier (BBB).

“Cholesterol in the brain and cholesterol in the periphery — meaning, in the rest of the body, outside the brain — are separate,” Dr. Hansen explained. “The brain produces its own cholesterol and keeps tight control of it.”

Under normal circumstances, cholesterol from the diet doesn’t enter the brain. “Each pool of cholesterol — in the brain and in the periphery — has its own distinct regulatory mechanisms, target cells, and transport mechanisms.”

When the BBB has been compromised, it becomes permeable, allowing LDL cholesterol to enter the brain, said Dr. Hansen. Then the brain’s own lipoproteins transport the invading cholesterol, allowing it to be taken up by neurons. In turn, this causes neuronal amyloid levels to rise, ultimately leading to the creation of amyloid-b plaques. It also plays a role in tau phosphorylation. Both are key features of AD pathology.

Elevated levels of cholesterol and other lipids have been found in amyloid plaques, Dr. Hansen noted. Moreover, studies of brains of patients with AD have pointed to BBB damage.

And the risk factors for AD overlap with the risk factors for damage to the BBB (such as, aging, brain trauma, hypertension, stress, sleep deprivation, smoking, excess alcohol, obesity, diabetes, and APOE4 genotype), according to the lipid invasion model paper cited by Dr. Hansen.
 

‘Chicken and Egg’

“There is a strong link between the brain and the heart, and we know that cardiovascular risk factors have an overlap with dementia risk factors — especially vascular dementia,” said Dr. Mills. 

She explained that an atherogenic lipid profile results in narrowing of the arteries, with less blood reaching the brain. “This can lead to stress in the brain, which drives inflammation and pathology.”

But cholesterol itself plays an important role in inflammation, Dr. Hansen said. In the periphery, it is “part of an integral response to tissue damage and infection.”

In the brain, once cholesterol is synthesized by the astrocytes, it is transported to neurons via the apolipoprotein E (APOE) protein, which plays a role in brain cholesterol homeostasis, Dr. Mills explained. Those with the ε4 allele of APOE (APOE4) tend to have faultier transport and storage of lipids in the brain, relative to the other APOE variants.

It’s known that individuals with APOE4 are particularly vulnerable to late-onset AD, Dr. Hansen observed. By contrast, APOE2 has a more protective effect. “Most people have APOE3, which is ‘in between,’ ” he said.

When there is neuronal uptake of “invading cholesterol,” not only is amyloid produced but also neuroinflammatory cytokines, further driving inflammation. A vicious cycle ensues: Cholesterol induces cytokine release; and cytokine release, in turn, induces cholesterol synthesis — which “suggests an autocatalytic function of cholesterol in the escalation of inflammation,” Dr. Hansen suggested. He noted that permeability of the BBB also allows inflammatory cytokines from elsewhere in the body to invade the brain, further driving inflammation.

Dr. Mills elaborated: “We know that generally, in dementia, there appear to be some changes in cholesterol metabolism in the brain, but it’s a chicken-and-egg question. We know that as the disease progresses, neurons are dying and getting remodeled. Do these changes have to do with the degenerative process, or are the changes in the cholesterol metabolism actually driving the degenerative disease process? It’s probably a combination, but it’s unclear at this point.”
 

Lipids in Plasma vs CSF

Dr. Mills explained that HDL particles in the brain differ from those in the periphery. “In the CNS, you have ‘HDL-like particles,’ which are similar in size and composition [to HDL in the periphery] but aren’t the same particles.” The brain itself generates HDL-like lipoproteins, which are produced by astrocytes and other glial cells and found in cerebrospinal fluid (CSF).

Dyslipidemia in the periphery can be a marker for cardiovascular pathology. In the brain, “it can be an indication that there is active damage going on, depending on which compartment you’re looking at.”

She noted that plasma lipid levels and brain CSF lipid levels are “very different.” Research suggests that HDL in the CSF exhibits similar heterogeneity to plasma HDL, but these CSF lipoproteins present at 100-fold lower concentrations, compared to plasma HDL and have unique combinations of protein subpopulations. Lipidomics analysis studies show that these compartments “get very different readings, in terms of the predominant lipid disease state, and they are regulated differently from the way lipids in the periphery are regulated.” 

In the brain, the cholesterol “needs to get shuttled from glial cells to neurons,” so defects in the transport process can disrupt overall brain homeostasis, said Dr. Mills. But since the brain system is separate from the peripheral system, measuring plasma lipids is more likely to point to cardiovascular risks, while changes reflected in CSF lipids are “more indicative of alteration in lipid homeostasis in the brain.”
 

HDL and Triglycerides: A Complicated Story

Dr. Mills noted that HDL in the periphery is “very complicated,” and the idea that HDL, as a measure on its own, is “necessarily ‘good’ isn’t particularly informative.” Rather, HDL is “extremely heterogeneous, very diverse, has different lipid compositions, different classes, and different modifications.” For example, like oxidized LDL, oxidized HDL is also “bad,” preventing the HDL from having protective functions.

Similarly, the apolipoproteins associated with HDL can affect the function of the HDL. “Our understanding of the HDL-like particles in the CNS is limited, but we do understand the APOE4 link,” Dr. Mills said. “It seems that the HDL-like particles containing APOE2 or APOE3 are larger and are more effective at transferring the lipids and cholesterol linked to them relative to APOE4-containing particles.” 

Because HDL is more complex than simply being “good,” measuring HDL doesn’t “give you the full story,” said Dr. Mills. She speculates that this may be why there are studies suggesting that high levels of HDL might not have protective benefits and might even be detrimental. This makes it difficult to look at population studies, where the different subclasses of HDL are not necessarily captured in depth. 

Dr. Mills pointed to another confounding factor, which is that much of the risk for the development of AD appears to be related to the interaction of HDL, LDL, and triglycerides. “When you look at each of these individually, you get a lot of heterogeneity, and it’s unclear what’s driving what,” she said.

An advantage of observational studies is that they give information about which of these markers are associated with trends and disease risks in specific groups vs others. 

“For example, higher levels of triglycerides are associated with cardiovascular risk more in women, relative to men,” she said. And the triglyceride-to-HDL ratio seems “particularly robust” as a measure of cardiovascular health and risk. 

The interpretation of associations with triglycerides can be “tricky” and “confusing” because results differ so much between studies, she said. “There are differences between middle age and older age, which have to do with age-related changes in metabolism and lipid metabolism and not necessarily that the markers are indicating something different,” she said.

Some research has suggested that triglycerides may have a protective effect against dementia, noted Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and director of nutritional psychiatry at MGH Academy.

This may be because the brain “runs mostly on energy from burning triglycerides,” suggested Dr. Naidoo, author of the books Calm Your Mind With Food and This Is Your Brain on Food.

In addition, having higher levels of triglycerides may be linked with having overall healthier behaviors, Dr. Naidoo told this news organization.

Dr. Mills said that in middle-aged individuals, high levels of LDL-C and triglycerides are “often indicative of more atherogenic particles and risk to cardiovascular health, which is a generally negative trajectory. But in older individuals, things become more complicated because there are differences in terms of clearance of some of these particles, tissue clearance and distribution, and nutrient status. So for older individuals, it seems that fluctuations in either direction—either too high or too low—tend to be more informative that some overall dysregulation is going on the system.” 

She emphasized that, in this “emerging area, looking at only one or two studies is confusing. But if you look at the spectrum of studies, you can see a pattern, which is that the regulation gets ‘off,’ as people age.”

 

The Potential Role of Statins

Dr. Mills speculated that there may be “neuroprotective benefits for some of the statins which appear to be related to cardiovascular benefits. But at this point, we don’t have any clear data whether statins actually directly impact brain cholesterol, since it’s a separate pool.”

They could help “by increasing blood flow and reducing narrowing of the arteries, but any direct impact on the brain is still under investigation.”

Dr. Hansen pointed to research suggesting statins taken at midlife appear to be cardioprotective and may be protective of brain health as well, whereas statins initiated in older age do not appear to have these benefits.

He speculated that one reason statins seem less helpful when initiated later in life is that the BBB has already been damaged by systemic inflammation in the periphery, and the neuroinflammatory process resulting in neuronal destruction is already underway. “I think statins aren’t going to fix that problem, so although lowering cholesterol can be helpful in some respects, it might be too late to affect cognition because the nerves have already died and won’t grow back.”
 

Can Dietary Approaches Help?

Dr. Naidoo said that when looking at neurologic and psychiatric disease, “it’s important to think about the ‘long game’ — how can we improve our blood and cardiovascular health earlier in life to help potentiate healthy aging?”

From a nutritional psychiatry standpoint, Dr. Naidoo focuses on nourishing the gut microbiome and decreasing inflammation. “A healthy and balanced microbiome supports cognition, while the composition of gut bacteria is actually drastically different in patients with neurological diseases, such as AD.” 

She recommends a nutrient-dense, anti-inflammatory diet including probiotic-rich foods (such as kimchi, sauerkraut, plain yogurt, and miso). Moreover, “the quality and structure of our fatty acids may be relevant as well: Increasing our intake of polyunsaturated fatty acids and avoiding processed fats like trans fats and hydrogenated oils may benefit our overall brain health.”

Dr. Naidoo recommends extra-virgin olive oil as a source of healthy fat. Its consumption is linked to lower incidence of AD by way of encouraging autophagy, which she calls “our own process of “cellular cleanup.’”

Dr. Naidoo believes that clinicians’ guidance to patients should “focus on healthy nutrition and other lifestyle practices, such as exercise, outdoor time, good sleep, and stress reduction.” 

Dr. Mills notes the importance of omega-3 fatty acids, such as docosahexaenoic acid (DHA) , for brain health. “DHA is a major lipid component of neuronal membranes,” she said. “Because of inefficiencies in metabolism with APOE4, people tend to metabolize more of the lipids on the membranes themselves, so they have higher lipid membrane turnover and a greater need to supplement. Supplementing particularly through diet, with foods such as fatty fish rich in omega-3, can help boost the levels to help keep neuronal membranes intact.”
 

What This Means for the Clinician

“At this point, we see all of these associations between lipids and dementia, but we haven’t worked out exactly what it means on the individual level for an individual patient,” said Dr. Mills. Certainly, the picture is complex, and the understanding is growing and shifting. “The clinical applications remain unclear.”

One potential clinical take-home is that clinicians might consider tracking lipid levels over time. “If you follow a patient and see an increase or decrease [in lipid levels], that can be informative.” Looking at ratios of lipids might be more useful than looking only at a change in a single measure. “If you see trends in a variety of measures that track with one another, it might be more of a sign that something is potentially wrong.” 

Whether the patient should first try a lifestyle intervention or might need medication is a “personalized clinical decision, depending on the individual, their risk factors, and how their levels are going,” said Dr. Mills. 

Dr. Mills, Dr. Hansen, and Dr. Naidoo declared no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

TOPLINE:

In addition to better known risk factors such as diabetes, stroke, heart disease, and depression, findings of a large study suggested vitamin D deficiency, elevated C-reactive protein (CRP) levels, and social isolation increase the risk for young-onset dementia (YOD).

METHODOLOGY:

• The study included 356,052 participants younger than 65 years (mean baseline age, 54.6 years) without dementia from the UK Biobank, an ongoing prospective cohort study.
• Participants underwent a comprehensive baseline assessment, provided biological samples, completed touch screen questionnaires, and underwent a physical examination.
• Researchers identified incident all-cause YOD cases from hospital inpatient registers or death register linkage.
• The researchers detected 39 potential risk factors and grouped them into domains of sociodemographic, genetic, lifestyle, environmental, vitamin D and CRP levels, cardiometabolic, psychiatric, and other factors.
• Researchers analyzed incidence rates of YOD for 5-year age bands starting at age 40 years and separately for men and women.

TAKEAWAY:

• During a mean follow-up of 8.12 years, there were 485 incident YOD cases (incidence rate of 16.8 per 100,000 person-years; 95% CI 15.4-18.3).
• The final analysis identified 15 risk factors associated with significantly higher incidence of YOD, including traditional factors like stroke (hazard ratio [HR], 2.07), heart disease (HR, 1.61), diabetes (HR, 1.65), and depression (HR, 3.25) but also less-recognized risk factors like vitamin D deficiency (< 10 ng/mL; HR, 1.59), high CRP levels (> 1 mg/dL; HR, 1.54), and social isolation (infrequent visits to friends or family; HR, 1.53), with lower socioeconomic status (HR, 1.82), having two apolipoprotein E epsilon-4 alleles (HR, 1.87), orthostatic hypotension, which the authors said may be an early sign of Parkinson dementia or Lewy body dementia (HR, 4.20), and hearing impairment (HR, 1.56) also increasing risk.
• Interestingly, some alcohol use seemed to be protective (moderate or heavy alcohol use had a lower association with YOD than alcohol abstinence, possibly due to the “healthy drinker effect” where people who drink are healthier than abstainers who may have illnesses preventing them from drinking, said the authors), as was higher education level and higher than normative handgrip strength (less strength is a proxy for physical frailty).
• Men with diabetes had higher YOD risk than those without diabetes, while there was no association with diabetes in women; on the other hand, women with high CRP levels had greater YOD risk than those with low levels, while there was no association with CRP in men.

IN PRACTICE:

“While further exploration of these risk factors is necessary to identify potential underlying mechanisms, addressing these modifiable factors may prove effective in mitigating the risk of developing YOD and can be readily integrated in current dementia prevention initiatives,” the investigators wrote.

SOURCE:

The study was led by Stevie Hendriks, PhD, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands. It was published online in JAMA Neurology.

LIMITATIONS:

The study was observational and so can’t infer causality. Several factors were based on self-reported data, which might be a source of response bias. Factors not considered in the study, for example, family history of dementia and drug (other than alcohol) use disorder, may have confounded associations. Some factors including orthostatic hypotension had few exposed cases, leading to decreased power to detect associations. Hospital and death records may not have captured all YOD cases. The UK Biobank is overrepresented by healthy and White participants, so results may not be generalizable to other racial and ethnic groups. The analyses only focused on all-cause dementia.

DISCLOSURES:

The study was supported by Alzheimer Netherlands. Hendriks has no relevant conflicts of interest; see paper for disclosures of other authors.

A version of this article appeared on Medscape.com.

TOPLINE:

In addition to better known risk factors such as diabetes, stroke, heart disease, and depression, findings of a large study suggested vitamin D deficiency, elevated C-reactive protein (CRP) levels, and social isolation increase the risk for young-onset dementia (YOD).

METHODOLOGY:

• The study included 356,052 participants younger than 65 years (mean baseline age, 54.6 years) without dementia from the UK Biobank, an ongoing prospective cohort study.
• Participants underwent a comprehensive baseline assessment, provided biological samples, completed touch screen questionnaires, and underwent a physical examination.
• Researchers identified incident all-cause YOD cases from hospital inpatient registers or death register linkage.
• The researchers detected 39 potential risk factors and grouped them into domains of sociodemographic, genetic, lifestyle, environmental, vitamin D and CRP levels, cardiometabolic, psychiatric, and other factors.
• Researchers analyzed incidence rates of YOD for 5-year age bands starting at age 40 years and separately for men and women.

TAKEAWAY:

• During a mean follow-up of 8.12 years, there were 485 incident YOD cases (incidence rate of 16.8 per 100,000 person-years; 95% CI 15.4-18.3).
• The final analysis identified 15 risk factors associated with significantly higher incidence of YOD, including traditional factors like stroke (hazard ratio [HR], 2.07), heart disease (HR, 1.61), diabetes (HR, 1.65), and depression (HR, 3.25) but also less-recognized risk factors like vitamin D deficiency (< 10 ng/mL; HR, 1.59), high CRP levels (> 1 mg/dL; HR, 1.54), and social isolation (infrequent visits to friends or family; HR, 1.53), with lower socioeconomic status (HR, 1.82), having two apolipoprotein E epsilon-4 alleles (HR, 1.87), orthostatic hypotension, which the authors said may be an early sign of Parkinson dementia or Lewy body dementia (HR, 4.20), and hearing impairment (HR, 1.56) also increasing risk.
• Interestingly, some alcohol use seemed to be protective (moderate or heavy alcohol use had a lower association with YOD than alcohol abstinence, possibly due to the “healthy drinker effect” where people who drink are healthier than abstainers who may have illnesses preventing them from drinking, said the authors), as was higher education level and higher than normative handgrip strength (less strength is a proxy for physical frailty).
• Men with diabetes had higher YOD risk than those without diabetes, while there was no association with diabetes in women; on the other hand, women with high CRP levels had greater YOD risk than those with low levels, while there was no association with CRP in men.

IN PRACTICE:

“While further exploration of these risk factors is necessary to identify potential underlying mechanisms, addressing these modifiable factors may prove effective in mitigating the risk of developing YOD and can be readily integrated in current dementia prevention initiatives,” the investigators wrote.

SOURCE:

The study was led by Stevie Hendriks, PhD, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands. It was published online in JAMA Neurology.

LIMITATIONS:

The study was observational and so can’t infer causality. Several factors were based on self-reported data, which might be a source of response bias. Factors not considered in the study, for example, family history of dementia and drug (other than alcohol) use disorder, may have confounded associations. Some factors including orthostatic hypotension had few exposed cases, leading to decreased power to detect associations. Hospital and death records may not have captured all YOD cases. The UK Biobank is overrepresented by healthy and White participants, so results may not be generalizable to other racial and ethnic groups. The analyses only focused on all-cause dementia.

DISCLOSURES:

The study was supported by Alzheimer Netherlands. Hendriks has no relevant conflicts of interest; see paper for disclosures of other authors.

A version of this article appeared on Medscape.com.

TOPLINE:

In addition to better known risk factors such as diabetes, stroke, heart disease, and depression, findings of a large study suggested vitamin D deficiency, elevated C-reactive protein (CRP) levels, and social isolation increase the risk for young-onset dementia (YOD).

METHODOLOGY:

• The study included 356,052 participants younger than 65 years (mean baseline age, 54.6 years) without dementia from the UK Biobank, an ongoing prospective cohort study.
• Participants underwent a comprehensive baseline assessment, provided biological samples, completed touch screen questionnaires, and underwent a physical examination.
• Researchers identified incident all-cause YOD cases from hospital inpatient registers or death register linkage.
• The researchers detected 39 potential risk factors and grouped them into domains of sociodemographic, genetic, lifestyle, environmental, vitamin D and CRP levels, cardiometabolic, psychiatric, and other factors.
• Researchers analyzed incidence rates of YOD for 5-year age bands starting at age 40 years and separately for men and women.

TAKEAWAY:

• During a mean follow-up of 8.12 years, there were 485 incident YOD cases (incidence rate of 16.8 per 100,000 person-years; 95% CI 15.4-18.3).
• The final analysis identified 15 risk factors associated with significantly higher incidence of YOD, including traditional factors like stroke (hazard ratio [HR], 2.07), heart disease (HR, 1.61), diabetes (HR, 1.65), and depression (HR, 3.25) but also less-recognized risk factors like vitamin D deficiency (< 10 ng/mL; HR, 1.59), high CRP levels (> 1 mg/dL; HR, 1.54), and social isolation (infrequent visits to friends or family; HR, 1.53), with lower socioeconomic status (HR, 1.82), having two apolipoprotein E epsilon-4 alleles (HR, 1.87), orthostatic hypotension, which the authors said may be an early sign of Parkinson dementia or Lewy body dementia (HR, 4.20), and hearing impairment (HR, 1.56) also increasing risk.
• Interestingly, some alcohol use seemed to be protective (moderate or heavy alcohol use had a lower association with YOD than alcohol abstinence, possibly due to the “healthy drinker effect” where people who drink are healthier than abstainers who may have illnesses preventing them from drinking, said the authors), as was higher education level and higher than normative handgrip strength (less strength is a proxy for physical frailty).
• Men with diabetes had higher YOD risk than those without diabetes, while there was no association with diabetes in women; on the other hand, women with high CRP levels had greater YOD risk than those with low levels, while there was no association with CRP in men.

IN PRACTICE:

“While further exploration of these risk factors is necessary to identify potential underlying mechanisms, addressing these modifiable factors may prove effective in mitigating the risk of developing YOD and can be readily integrated in current dementia prevention initiatives,” the investigators wrote.

SOURCE:

The study was led by Stevie Hendriks, PhD, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands. It was published online in JAMA Neurology.

LIMITATIONS:

The study was observational and so can’t infer causality. Several factors were based on self-reported data, which might be a source of response bias. Factors not considered in the study, for example, family history of dementia and drug (other than alcohol) use disorder, may have confounded associations. Some factors including orthostatic hypotension had few exposed cases, leading to decreased power to detect associations. Hospital and death records may not have captured all YOD cases. The UK Biobank is overrepresented by healthy and White participants, so results may not be generalizable to other racial and ethnic groups. The analyses only focused on all-cause dementia.

DISCLOSURES:

The study was supported by Alzheimer Netherlands. Hendriks has no relevant conflicts of interest; see paper for disclosures of other authors.

A version of this article appeared on Medscape.com.

The plant-based psychoactive compound ibogaine, combined with magnesium to protect the heart, is linked to improvement in severe psychiatric symptoms including depression, anxiety, and functioning in veterans with traumatic brain injury (TBI), early results from a small study showed.

“The most unique findings we observed are the improvements in disability and cognition. At the start of the study, participants had mild to moderate levels of disability. However, a month after treatment, their average disability rating indicated no disability and cognitive testing indicated improvements in concentration and memory,” study investigator Nolan Williams, MD, Stanford University, Stanford, California, told this news organization.

Also noteworthy were improvements across all participants in posttraumatic stress disorder (PTSD), depression, and anxiety — effects that lasted for at least 1 month after treatment, he said.

“These results are remarkable and exceeded our expectations. There is no drug today that can broadly relieve functional and neuropsychiatric symptoms of TBI as we observed with ibogaine,” Dr. Williams added.

The study was published online on January 5, 2024, in Nature Medicine.
 

‘The Storm Lifted’

Ibogaine is derived from the root bark of the Tabernanthe iboga shrub and related plants and is traditionally used in African spiritual and healing ceremonies.

It is known to interact with multiple neurotransmitter systems and has been studied primarily as a treatment of substance use disorders (SUDs). Some studies of ibogaine for SUDs have also noted improvements in self-reported measures of mood.

In the United States, ibogaine is classified as a Schedule I substance, but legal ibogaine treatments are offered in clinics in Canada and Mexico.

Dr. Williams noted that a handful of US veterans who went to Mexico for ibogaine treatment anecdotally reported improvements a variety of aspects of their lives.

The goal of the current study was to characterize those improvements with structured clinical and neurobiological assessments.

Participants included 30 US Special Operations Forces veterans (SOVs) with predominantly mild TBI from combat/blast exposures and psychiatric symptoms and functional limitations. All of them had independently scheduled themselves for treatment with magnesium and ibogaine at a clinic in Mexico.

Before treatment, the veterans had an average disability rating of 30.2 on the World Health Organization Disability Assessment Scale 2.0, equivalent to mild to moderate disability. One month after ibogaine treatment, that rating improved to 5.1, indicating no disability, the researchers reported.

One month after treatment, participants also experienced average reductions of 88% in PTSD symptoms, 87% in depression symptoms, and 81% in anxiety symptoms relative to before treatment.

Neuropsychological testing revealed improved concentration, information processing, memory, and impulsivity. There was also a substantial reduction in suicidal ideation.

“Before the treatment, I was living life in a blizzard with zero visibility and a cold, hopeless, listless feeling. After ibogaine, the storm lifted,” Sean, a 51-year-old veteran from Arizona with six combat deployments who participated in the study, said in a Stanford news release.

There were no serious side effects of ibogaine, and no instances of heart problems associated with the treatment.

Although the study findings are promising, additional research is needed to address some clear limitations, the researchers noted.

“Most importantly, the study was not controlled and so the relative contribution of any therapeutic benefits from non-ibogaine elements of the experience, such as complementary treatments, group activities, coaching, international travel, expectancy, or other nonspecific effects, cannot be determined,” they wrote.

In addition, follow-up was limited to 1 month, and longer-term data are needed to determine durability of the effects.

“We plan to study this compound further, as well as launch future studies to continue to understand how this drug can be used to treat TBI and possibly as a broader neuro-rehab drug. We will work towards a US-based set of trials to confirm efficacy with a multisite design,” said Dr. Williams.
 

Promising, but Very Preliminary

Commenting on the study for this news organization, Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the Clinical TBI Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, said the results are “promising, but very preliminary.”

Dr. Diaz-Arrastia noted that this was an open-label, nonrandomized study, early phase 2a study with “highly subjective outcome measures and the likelihood of it being a placebo effect is very high.”

Nonetheless, “there is a lot of interest in these ‘psychedelic’ alkaloids, and ibogaine is a good candidate for further study,” Dr. Diaz-Arrastia said.

Also providing perspective, Alan K. Davis, PhD, director of the Center for Psychedelic Drug Research and Education, Ohio State University, Columbus, said “mounting evidence supports the importance of studying this treatment in rigorous clinical trials in the US.”

Dr. Davis and colleagues recently observed that treatment with two naturally occurring psychedelics — ibogaine and 5-MeO-DMT — was associated with reduced depressive and anxiety symptoms in trauma-exposed SOVs, as previously reported by this news organization.

This new study “basically is a replication of what we’ve already published on this topic, and we published data from much larger samples and longer follow up,” said Dr. Davis.

Dr. Davis said it’s “important for the public to know that there are important and serious risks associated with ibogaine therapy, including the possibility of cardiac problems and death. These risks are compounded when people are in clinics or settings where proper screening and medical oversight are not completed.”

“Furthermore, the long-term effectiveness of this treatment is not well established. It may only help in the short term for most people. For many, ongoing clinical aftercare therapy and other forms of treatment may be needed,” Dr. Davis noted.

The study was independently funded by philanthropic gifts from Steve and Genevieve Jurvetson and another anonymous donor. Williams is an inventor on a patent application related to the safety of MISTIC administration as described in the paper and a separate patent related to the use of ibogaine to treat disorders associated with brain aging. Dr. Davis is a board member at Source Resource Foundation and a lead trainer at Fluence. Dr. Diaz-Arrastia has no relevant disclosures.

A version of this article appeared on Medscape.com.

The plant-based psychoactive compound ibogaine, combined with magnesium to protect the heart, is linked to improvement in severe psychiatric symptoms including depression, anxiety, and functioning in veterans with traumatic brain injury (TBI), early results from a small study showed.

“The most unique findings we observed are the improvements in disability and cognition. At the start of the study, participants had mild to moderate levels of disability. However, a month after treatment, their average disability rating indicated no disability and cognitive testing indicated improvements in concentration and memory,” study investigator Nolan Williams, MD, Stanford University, Stanford, California, told this news organization.

Also noteworthy were improvements across all participants in posttraumatic stress disorder (PTSD), depression, and anxiety — effects that lasted for at least 1 month after treatment, he said.

“These results are remarkable and exceeded our expectations. There is no drug today that can broadly relieve functional and neuropsychiatric symptoms of TBI as we observed with ibogaine,” Dr. Williams added.

The study was published online on January 5, 2024, in Nature Medicine.
 

‘The Storm Lifted’

Ibogaine is derived from the root bark of the Tabernanthe iboga shrub and related plants and is traditionally used in African spiritual and healing ceremonies.

It is known to interact with multiple neurotransmitter systems and has been studied primarily as a treatment of substance use disorders (SUDs). Some studies of ibogaine for SUDs have also noted improvements in self-reported measures of mood.

In the United States, ibogaine is classified as a Schedule I substance, but legal ibogaine treatments are offered in clinics in Canada and Mexico.

Dr. Williams noted that a handful of US veterans who went to Mexico for ibogaine treatment anecdotally reported improvements a variety of aspects of their lives.

The goal of the current study was to characterize those improvements with structured clinical and neurobiological assessments.

Participants included 30 US Special Operations Forces veterans (SOVs) with predominantly mild TBI from combat/blast exposures and psychiatric symptoms and functional limitations. All of them had independently scheduled themselves for treatment with magnesium and ibogaine at a clinic in Mexico.

Before treatment, the veterans had an average disability rating of 30.2 on the World Health Organization Disability Assessment Scale 2.0, equivalent to mild to moderate disability. One month after ibogaine treatment, that rating improved to 5.1, indicating no disability, the researchers reported.

One month after treatment, participants also experienced average reductions of 88% in PTSD symptoms, 87% in depression symptoms, and 81% in anxiety symptoms relative to before treatment.

Neuropsychological testing revealed improved concentration, information processing, memory, and impulsivity. There was also a substantial reduction in suicidal ideation.

“Before the treatment, I was living life in a blizzard with zero visibility and a cold, hopeless, listless feeling. After ibogaine, the storm lifted,” Sean, a 51-year-old veteran from Arizona with six combat deployments who participated in the study, said in a Stanford news release.

There were no serious side effects of ibogaine, and no instances of heart problems associated with the treatment.

Although the study findings are promising, additional research is needed to address some clear limitations, the researchers noted.

“Most importantly, the study was not controlled and so the relative contribution of any therapeutic benefits from non-ibogaine elements of the experience, such as complementary treatments, group activities, coaching, international travel, expectancy, or other nonspecific effects, cannot be determined,” they wrote.

In addition, follow-up was limited to 1 month, and longer-term data are needed to determine durability of the effects.

“We plan to study this compound further, as well as launch future studies to continue to understand how this drug can be used to treat TBI and possibly as a broader neuro-rehab drug. We will work towards a US-based set of trials to confirm efficacy with a multisite design,” said Dr. Williams.
 

Promising, but Very Preliminary

Commenting on the study for this news organization, Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the Clinical TBI Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, said the results are “promising, but very preliminary.”

Dr. Diaz-Arrastia noted that this was an open-label, nonrandomized study, early phase 2a study with “highly subjective outcome measures and the likelihood of it being a placebo effect is very high.”

Nonetheless, “there is a lot of interest in these ‘psychedelic’ alkaloids, and ibogaine is a good candidate for further study,” Dr. Diaz-Arrastia said.

Also providing perspective, Alan K. Davis, PhD, director of the Center for Psychedelic Drug Research and Education, Ohio State University, Columbus, said “mounting evidence supports the importance of studying this treatment in rigorous clinical trials in the US.”

Dr. Davis and colleagues recently observed that treatment with two naturally occurring psychedelics — ibogaine and 5-MeO-DMT — was associated with reduced depressive and anxiety symptoms in trauma-exposed SOVs, as previously reported by this news organization.

This new study “basically is a replication of what we’ve already published on this topic, and we published data from much larger samples and longer follow up,” said Dr. Davis.

Dr. Davis said it’s “important for the public to know that there are important and serious risks associated with ibogaine therapy, including the possibility of cardiac problems and death. These risks are compounded when people are in clinics or settings where proper screening and medical oversight are not completed.”

“Furthermore, the long-term effectiveness of this treatment is not well established. It may only help in the short term for most people. For many, ongoing clinical aftercare therapy and other forms of treatment may be needed,” Dr. Davis noted.

The study was independently funded by philanthropic gifts from Steve and Genevieve Jurvetson and another anonymous donor. Williams is an inventor on a patent application related to the safety of MISTIC administration as described in the paper and a separate patent related to the use of ibogaine to treat disorders associated with brain aging. Dr. Davis is a board member at Source Resource Foundation and a lead trainer at Fluence. Dr. Diaz-Arrastia has no relevant disclosures.

A version of this article appeared on Medscape.com.

The plant-based psychoactive compound ibogaine, combined with magnesium to protect the heart, is linked to improvement in severe psychiatric symptoms including depression, anxiety, and functioning in veterans with traumatic brain injury (TBI), early results from a small study showed.

“The most unique findings we observed are the improvements in disability and cognition. At the start of the study, participants had mild to moderate levels of disability. However, a month after treatment, their average disability rating indicated no disability and cognitive testing indicated improvements in concentration and memory,” study investigator Nolan Williams, MD, Stanford University, Stanford, California, told this news organization.

Also noteworthy were improvements across all participants in posttraumatic stress disorder (PTSD), depression, and anxiety — effects that lasted for at least 1 month after treatment, he said.

“These results are remarkable and exceeded our expectations. There is no drug today that can broadly relieve functional and neuropsychiatric symptoms of TBI as we observed with ibogaine,” Dr. Williams added.

The study was published online on January 5, 2024, in Nature Medicine.
 

‘The Storm Lifted’

Ibogaine is derived from the root bark of the Tabernanthe iboga shrub and related plants and is traditionally used in African spiritual and healing ceremonies.

It is known to interact with multiple neurotransmitter systems and has been studied primarily as a treatment of substance use disorders (SUDs). Some studies of ibogaine for SUDs have also noted improvements in self-reported measures of mood.

In the United States, ibogaine is classified as a Schedule I substance, but legal ibogaine treatments are offered in clinics in Canada and Mexico.

Dr. Williams noted that a handful of US veterans who went to Mexico for ibogaine treatment anecdotally reported improvements a variety of aspects of their lives.

The goal of the current study was to characterize those improvements with structured clinical and neurobiological assessments.

Participants included 30 US Special Operations Forces veterans (SOVs) with predominantly mild TBI from combat/blast exposures and psychiatric symptoms and functional limitations. All of them had independently scheduled themselves for treatment with magnesium and ibogaine at a clinic in Mexico.

Before treatment, the veterans had an average disability rating of 30.2 on the World Health Organization Disability Assessment Scale 2.0, equivalent to mild to moderate disability. One month after ibogaine treatment, that rating improved to 5.1, indicating no disability, the researchers reported.

One month after treatment, participants also experienced average reductions of 88% in PTSD symptoms, 87% in depression symptoms, and 81% in anxiety symptoms relative to before treatment.

Neuropsychological testing revealed improved concentration, information processing, memory, and impulsivity. There was also a substantial reduction in suicidal ideation.

“Before the treatment, I was living life in a blizzard with zero visibility and a cold, hopeless, listless feeling. After ibogaine, the storm lifted,” Sean, a 51-year-old veteran from Arizona with six combat deployments who participated in the study, said in a Stanford news release.

There were no serious side effects of ibogaine, and no instances of heart problems associated with the treatment.

Although the study findings are promising, additional research is needed to address some clear limitations, the researchers noted.

“Most importantly, the study was not controlled and so the relative contribution of any therapeutic benefits from non-ibogaine elements of the experience, such as complementary treatments, group activities, coaching, international travel, expectancy, or other nonspecific effects, cannot be determined,” they wrote.

In addition, follow-up was limited to 1 month, and longer-term data are needed to determine durability of the effects.

“We plan to study this compound further, as well as launch future studies to continue to understand how this drug can be used to treat TBI and possibly as a broader neuro-rehab drug. We will work towards a US-based set of trials to confirm efficacy with a multisite design,” said Dr. Williams.
 

Promising, but Very Preliminary

Commenting on the study for this news organization, Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the Clinical TBI Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, said the results are “promising, but very preliminary.”

Dr. Diaz-Arrastia noted that this was an open-label, nonrandomized study, early phase 2a study with “highly subjective outcome measures and the likelihood of it being a placebo effect is very high.”

Nonetheless, “there is a lot of interest in these ‘psychedelic’ alkaloids, and ibogaine is a good candidate for further study,” Dr. Diaz-Arrastia said.

Also providing perspective, Alan K. Davis, PhD, director of the Center for Psychedelic Drug Research and Education, Ohio State University, Columbus, said “mounting evidence supports the importance of studying this treatment in rigorous clinical trials in the US.”

Dr. Davis and colleagues recently observed that treatment with two naturally occurring psychedelics — ibogaine and 5-MeO-DMT — was associated with reduced depressive and anxiety symptoms in trauma-exposed SOVs, as previously reported by this news organization.

This new study “basically is a replication of what we’ve already published on this topic, and we published data from much larger samples and longer follow up,” said Dr. Davis.

Dr. Davis said it’s “important for the public to know that there are important and serious risks associated with ibogaine therapy, including the possibility of cardiac problems and death. These risks are compounded when people are in clinics or settings where proper screening and medical oversight are not completed.”

“Furthermore, the long-term effectiveness of this treatment is not well established. It may only help in the short term for most people. For many, ongoing clinical aftercare therapy and other forms of treatment may be needed,” Dr. Davis noted.

The study was independently funded by philanthropic gifts from Steve and Genevieve Jurvetson and another anonymous donor. Williams is an inventor on a patent application related to the safety of MISTIC administration as described in the paper and a separate patent related to the use of ibogaine to treat disorders associated with brain aging. Dr. Davis is a board member at Source Resource Foundation and a lead trainer at Fluence. Dr. Diaz-Arrastia has no relevant disclosures.

A version of this article appeared on Medscape.com.

Proper care of teeth and gums may offer benefits beyond oral health, including improving brain health, new research suggests.

In a large observational study of middle-aged adults without stroke or dementia, poor oral health was strongly associated with multiple neuroimaging markers of white matter injury.

“Because the neuroimaging markers evaluated in this study precede and are established risk factors of stroke and dementia, our results suggest that oral health, an easily modifiable process, may be a promising target for very early interventions focused on improving brain health,” wrote the authors, led by Cyprien A. Rivier, MD, MS, with the Department of Neurology, Yale University School of Medicine, New Haven, Connecticut.

The study was published online on December 20, 2023, in Neurology.

Research data came from 40,175 adults (mean age, 55 years; 53% women) with no history of stroke or dementia who enrolled in the UK Biobank from 2006 to 2010 and had brain MRI between 2014 and 2016.

Altogether, 5470 (14%) participants had poor oral health, defined as the presence of dentures or loose teeth. Those with poor (vs optimal) oral health were older, more likely to be male, and had higher prevalence of hypertension, hypercholesterolemia, diabetes, overweight/obesity, and current or past smoking history.

In a multivariable model, poor oral health was associated with a 9% increase in white matter hyperintensity (WMH) volume (P < .001), a well-established marker of clinically silent cerebrovascular disease.

Poor oral health was also associated with a 10% change in aggregate fractional anisotropy (FA) score (P < .001) and a 5% change in aggregate mean diffusivity (MD) score (P < .001), two diffusion tensor imaging metrics that accurately represent white matter disintegrity.

Genetic analyses using Mendelian randomization confirmed these associations. Individuals who were genetically prone to poor oral health had a 30% increase in WMH volume (P < .001), 43% change in aggregate FA score (P < .001), and 10% change in aggregate MD score (P < .01), the researchers reported.

These findings, they noted, add to prior epidemiologic evidence for an association between poor oral health and a higher risk for clinical outcomes related to brain health, including cognitive decline.

‘Huge Dividends’

The authors of an accompanying editorial praised the authors for looking at the consequences of poor oral health in a “new and powerful way by using as their outcome MRI-defined white matter injury, which is associated with, but antedates by many years, cognitive decline and stroke.”

“The fact that these imaging changes are seen in asymptomatic persons offers the hope that if the association is causal, interventions to improve oral health could pay huge dividends in subsequent brain health,” wrote Steven J. Kittner, MD, MPH, and Breana L. Taylor, MD, with the Department of Neurology, University of Maryland School of Medicine in Baltimore.

“The mechanisms mediating the relationship between the oral health genetic risk score and white matter injury are likely to be complex, but the authors have taken an important step forward in addressing a hypothesis of immense public health importance,” they added.

Data from the World Health Organization suggested that oral diseases, which are largely preventable, affect nearly 3.5 billion people globally, with three out of four people affected in middle-income countries.

Funding for the study was provided in part by grants from the National Institutes of Health, the American Heart Association, and the Neurocritical Care Society Research Fellowship. The authors and editorialists disclosed no relevant conflicts of interest.

Megan Brooks has disclosed no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

Proper care of teeth and gums may offer benefits beyond oral health, including improving brain health, new research suggests.

In a large observational study of middle-aged adults without stroke or dementia, poor oral health was strongly associated with multiple neuroimaging markers of white matter injury.

“Because the neuroimaging markers evaluated in this study precede and are established risk factors of stroke and dementia, our results suggest that oral health, an easily modifiable process, may be a promising target for very early interventions focused on improving brain health,” wrote the authors, led by Cyprien A. Rivier, MD, MS, with the Department of Neurology, Yale University School of Medicine, New Haven, Connecticut.

The study was published online on December 20, 2023, in Neurology.

Research data came from 40,175 adults (mean age, 55 years; 53% women) with no history of stroke or dementia who enrolled in the UK Biobank from 2006 to 2010 and had brain MRI between 2014 and 2016.

Altogether, 5470 (14%) participants had poor oral health, defined as the presence of dentures or loose teeth. Those with poor (vs optimal) oral health were older, more likely to be male, and had higher prevalence of hypertension, hypercholesterolemia, diabetes, overweight/obesity, and current or past smoking history.

In a multivariable model, poor oral health was associated with a 9% increase in white matter hyperintensity (WMH) volume (P < .001), a well-established marker of clinically silent cerebrovascular disease.

Poor oral health was also associated with a 10% change in aggregate fractional anisotropy (FA) score (P < .001) and a 5% change in aggregate mean diffusivity (MD) score (P < .001), two diffusion tensor imaging metrics that accurately represent white matter disintegrity.

Genetic analyses using Mendelian randomization confirmed these associations. Individuals who were genetically prone to poor oral health had a 30% increase in WMH volume (P < .001), 43% change in aggregate FA score (P < .001), and 10% change in aggregate MD score (P < .01), the researchers reported.

These findings, they noted, add to prior epidemiologic evidence for an association between poor oral health and a higher risk for clinical outcomes related to brain health, including cognitive decline.

‘Huge Dividends’

The authors of an accompanying editorial praised the authors for looking at the consequences of poor oral health in a “new and powerful way by using as their outcome MRI-defined white matter injury, which is associated with, but antedates by many years, cognitive decline and stroke.”

“The fact that these imaging changes are seen in asymptomatic persons offers the hope that if the association is causal, interventions to improve oral health could pay huge dividends in subsequent brain health,” wrote Steven J. Kittner, MD, MPH, and Breana L. Taylor, MD, with the Department of Neurology, University of Maryland School of Medicine in Baltimore.

“The mechanisms mediating the relationship between the oral health genetic risk score and white matter injury are likely to be complex, but the authors have taken an important step forward in addressing a hypothesis of immense public health importance,” they added.

Data from the World Health Organization suggested that oral diseases, which are largely preventable, affect nearly 3.5 billion people globally, with three out of four people affected in middle-income countries.

Funding for the study was provided in part by grants from the National Institutes of Health, the American Heart Association, and the Neurocritical Care Society Research Fellowship. The authors and editorialists disclosed no relevant conflicts of interest.

Megan Brooks has disclosed no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

Proper care of teeth and gums may offer benefits beyond oral health, including improving brain health, new research suggests.

In a large observational study of middle-aged adults without stroke or dementia, poor oral health was strongly associated with multiple neuroimaging markers of white matter injury.

“Because the neuroimaging markers evaluated in this study precede and are established risk factors of stroke and dementia, our results suggest that oral health, an easily modifiable process, may be a promising target for very early interventions focused on improving brain health,” wrote the authors, led by Cyprien A. Rivier, MD, MS, with the Department of Neurology, Yale University School of Medicine, New Haven, Connecticut.

The study was published online on December 20, 2023, in Neurology.

Research data came from 40,175 adults (mean age, 55 years; 53% women) with no history of stroke or dementia who enrolled in the UK Biobank from 2006 to 2010 and had brain MRI between 2014 and 2016.

Altogether, 5470 (14%) participants had poor oral health, defined as the presence of dentures or loose teeth. Those with poor (vs optimal) oral health were older, more likely to be male, and had higher prevalence of hypertension, hypercholesterolemia, diabetes, overweight/obesity, and current or past smoking history.

In a multivariable model, poor oral health was associated with a 9% increase in white matter hyperintensity (WMH) volume (P < .001), a well-established marker of clinically silent cerebrovascular disease.

Poor oral health was also associated with a 10% change in aggregate fractional anisotropy (FA) score (P < .001) and a 5% change in aggregate mean diffusivity (MD) score (P < .001), two diffusion tensor imaging metrics that accurately represent white matter disintegrity.

Genetic analyses using Mendelian randomization confirmed these associations. Individuals who were genetically prone to poor oral health had a 30% increase in WMH volume (P < .001), 43% change in aggregate FA score (P < .001), and 10% change in aggregate MD score (P < .01), the researchers reported.

These findings, they noted, add to prior epidemiologic evidence for an association between poor oral health and a higher risk for clinical outcomes related to brain health, including cognitive decline.

‘Huge Dividends’

The authors of an accompanying editorial praised the authors for looking at the consequences of poor oral health in a “new and powerful way by using as their outcome MRI-defined white matter injury, which is associated with, but antedates by many years, cognitive decline and stroke.”

“The fact that these imaging changes are seen in asymptomatic persons offers the hope that if the association is causal, interventions to improve oral health could pay huge dividends in subsequent brain health,” wrote Steven J. Kittner, MD, MPH, and Breana L. Taylor, MD, with the Department of Neurology, University of Maryland School of Medicine in Baltimore.

“The mechanisms mediating the relationship between the oral health genetic risk score and white matter injury are likely to be complex, but the authors have taken an important step forward in addressing a hypothesis of immense public health importance,” they added.

Data from the World Health Organization suggested that oral diseases, which are largely preventable, affect nearly 3.5 billion people globally, with three out of four people affected in middle-income countries.

Funding for the study was provided in part by grants from the National Institutes of Health, the American Heart Association, and the Neurocritical Care Society Research Fellowship. The authors and editorialists disclosed no relevant conflicts of interest.

Megan Brooks has disclosed no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

Less than 2 minutes of transcranial magnetic stimulation (TMS) targeting specific areas of the brain can boost an individual’s ability to be hypnotized, in new findings that could increase the efficacy of therapeutic hypnosis and expand the pool of patients who can benefit from it.

“We were able to increase hypnotizability, a neuropsychological trait previously shown to be as stable as IQ in adulthood,” said co-senior author David Spiegel, MD, professor of psychiatry and behavioral sciences, Stanford University, Palo Alto, California.

“Our findings would allow us to combine neurostimulation with hypnosis to expand the number of people able to benefit from hypnosis and enhance their responsiveness to treatment,” Dr. Spiegel added.

The study was published online on January 4, 2024, in Nature Mental Health.

A Breakthrough for Hypnotherapy?

Hypnosis has long been used to treat and manage a host of psychiatric and neurologic symptoms. However, not all patients respond equally to this therapy type.

About two thirds of the general adult population are estimated to be at least somewhat hypnotizable, and 15% are highly hypnotizable.

Through brain imaging, the Stanford team found that high hypnotizability is associated with greater functional connectivity between the left dorsolateral prefrontal cortex (DLPFC) and the dorsal anterior cingulate cortex.

In the double-blind study, they randomly assigned 80 patients (mean age, 48 years; 94% women) with fibromyalgia syndrome to active, or sham, continuous theta-burst stimulation over a personalized neuroimaging-derived left DLPFC target — a technique known as Stanford Hypnosis Integrated with Functional Connectivity-targeted Transcranial Stimulation (SHIFT). Individuals who were naturally highly hypnotizable were excluded.

“A novel aspect of this trial is that we used the person’s own brain networks, based on brain imaging, to target the right spot,” Co-senior author Nolan Williams, MD, with Stanford University, California, said in a news release.

The team chose patients with chronic pain because hypnosis has been shown to be a “highly effective analgesic that has a far better risk/benefit ratio than widely overutilized opioids that have serious fatal overdose potential,” Spiegel told this news organization.

The pre-to-post SHIFT change in hypnotic induction profile scores, a standardized measure of hypnotizability, was significantly greater in the active vs sham group after just 92 seconds of stimulation (P = .046).

Only the active SHIFT group showed a significant increase in hypnotizability following stimulation, an effect that lasted for about 1 hour.

“Increasing hypnotizability in people who are low-to-medium hypnotizable individuals could improve both the efficacy and effectiveness of therapeutic hypnosis as a clinical intervention,” the researchers wrote.

They note that because this was a “mechanistic study,” it did not explore the impact of increased hypnotizability on disease symptoms. They also note that further studies are needed to assess the dose-response relationships of SHIFT.

Transformative Research

“This line of research is fascinating,” Shaheen Lakhan, MD, PhD, neurologist, and researcher in Boston, told this news organization.

“We are nearing an era of personalized, noninvasive brain modulation. The ability to individually modulate the DLPFC opens new possibilities for brain health beyond hypnotizability for fibromyalgia,” said Dr. Lakhan, who wasn’t involved in the study.

“The DLPFC is involved in executive functions (and disorders) like attention (ADHD), emotional regulation (depression), motivation (schizophrenia), and impulse control (addiction),” he noted.

“Soon we may no longer need large expensive devices like transcranial magnetic stimulators as in this research study. Smartphones could deliver tailored digital therapeutics by engaging specific brain circuits,” Dr. Lakhan predicted.

“Imagine using an app to receive treatment customized to your unique brain and needs — all without anything implanted and delivered anywhere. The potential to precisely modulate the brain’s wiring to enhance cognition and mental health, without surgery or physical constraints, is incredibly promising. The possibilities are intriguing and could truly transform how we address brain diseases,” he added.

The study was supported by a grant from the National Center for Complementary and Integrative Health (NCCIH), part of the National Institutes of Health (NIH). Dr. Williams is a named inventor on Stanford-owned intellectual property relating to accelerated TMS pulse pattern sequences and neuroimaging-based TMS targeting; has served on scientific advisory boards for Otsuka, NeuraWell, Magnus Medical, and Nooma as a paid advisor; and holds equity/stock options in Magnus Medical, NeuraWell, and Nooma. Dr. Spiegel is a cofounder of Reveri Health, Inc., an interactive hypnosis app (not utilized in the current study).
 

A version of this article appeared on Medscape.com.

Less than 2 minutes of transcranial magnetic stimulation (TMS) targeting specific areas of the brain can boost an individual’s ability to be hypnotized, in new findings that could increase the efficacy of therapeutic hypnosis and expand the pool of patients who can benefit from it.

“We were able to increase hypnotizability, a neuropsychological trait previously shown to be as stable as IQ in adulthood,” said co-senior author David Spiegel, MD, professor of psychiatry and behavioral sciences, Stanford University, Palo Alto, California.

“Our findings would allow us to combine neurostimulation with hypnosis to expand the number of people able to benefit from hypnosis and enhance their responsiveness to treatment,” Dr. Spiegel added.

The study was published online on January 4, 2024, in Nature Mental Health.

A Breakthrough for Hypnotherapy?

Hypnosis has long been used to treat and manage a host of psychiatric and neurologic symptoms. However, not all patients respond equally to this therapy type.

About two thirds of the general adult population are estimated to be at least somewhat hypnotizable, and 15% are highly hypnotizable.

Through brain imaging, the Stanford team found that high hypnotizability is associated with greater functional connectivity between the left dorsolateral prefrontal cortex (DLPFC) and the dorsal anterior cingulate cortex.

In the double-blind study, they randomly assigned 80 patients (mean age, 48 years; 94% women) with fibromyalgia syndrome to active, or sham, continuous theta-burst stimulation over a personalized neuroimaging-derived left DLPFC target — a technique known as Stanford Hypnosis Integrated with Functional Connectivity-targeted Transcranial Stimulation (SHIFT). Individuals who were naturally highly hypnotizable were excluded.

“A novel aspect of this trial is that we used the person’s own brain networks, based on brain imaging, to target the right spot,” Co-senior author Nolan Williams, MD, with Stanford University, California, said in a news release.

The team chose patients with chronic pain because hypnosis has been shown to be a “highly effective analgesic that has a far better risk/benefit ratio than widely overutilized opioids that have serious fatal overdose potential,” Spiegel told this news organization.

The pre-to-post SHIFT change in hypnotic induction profile scores, a standardized measure of hypnotizability, was significantly greater in the active vs sham group after just 92 seconds of stimulation (P = .046).

Only the active SHIFT group showed a significant increase in hypnotizability following stimulation, an effect that lasted for about 1 hour.

“Increasing hypnotizability in people who are low-to-medium hypnotizable individuals could improve both the efficacy and effectiveness of therapeutic hypnosis as a clinical intervention,” the researchers wrote.

They note that because this was a “mechanistic study,” it did not explore the impact of increased hypnotizability on disease symptoms. They also note that further studies are needed to assess the dose-response relationships of SHIFT.

Transformative Research

“This line of research is fascinating,” Shaheen Lakhan, MD, PhD, neurologist, and researcher in Boston, told this news organization.

“We are nearing an era of personalized, noninvasive brain modulation. The ability to individually modulate the DLPFC opens new possibilities for brain health beyond hypnotizability for fibromyalgia,” said Dr. Lakhan, who wasn’t involved in the study.

“The DLPFC is involved in executive functions (and disorders) like attention (ADHD), emotional regulation (depression), motivation (schizophrenia), and impulse control (addiction),” he noted.

“Soon we may no longer need large expensive devices like transcranial magnetic stimulators as in this research study. Smartphones could deliver tailored digital therapeutics by engaging specific brain circuits,” Dr. Lakhan predicted.

“Imagine using an app to receive treatment customized to your unique brain and needs — all without anything implanted and delivered anywhere. The potential to precisely modulate the brain’s wiring to enhance cognition and mental health, without surgery or physical constraints, is incredibly promising. The possibilities are intriguing and could truly transform how we address brain diseases,” he added.

The study was supported by a grant from the National Center for Complementary and Integrative Health (NCCIH), part of the National Institutes of Health (NIH). Dr. Williams is a named inventor on Stanford-owned intellectual property relating to accelerated TMS pulse pattern sequences and neuroimaging-based TMS targeting; has served on scientific advisory boards for Otsuka, NeuraWell, Magnus Medical, and Nooma as a paid advisor; and holds equity/stock options in Magnus Medical, NeuraWell, and Nooma. Dr. Spiegel is a cofounder of Reveri Health, Inc., an interactive hypnosis app (not utilized in the current study).
 

A version of this article appeared on Medscape.com.

Less than 2 minutes of transcranial magnetic stimulation (TMS) targeting specific areas of the brain can boost an individual’s ability to be hypnotized, in new findings that could increase the efficacy of therapeutic hypnosis and expand the pool of patients who can benefit from it.

“We were able to increase hypnotizability, a neuropsychological trait previously shown to be as stable as IQ in adulthood,” said co-senior author David Spiegel, MD, professor of psychiatry and behavioral sciences, Stanford University, Palo Alto, California.

“Our findings would allow us to combine neurostimulation with hypnosis to expand the number of people able to benefit from hypnosis and enhance their responsiveness to treatment,” Dr. Spiegel added.

The study was published online on January 4, 2024, in Nature Mental Health.

A Breakthrough for Hypnotherapy?

Hypnosis has long been used to treat and manage a host of psychiatric and neurologic symptoms. However, not all patients respond equally to this therapy type.

About two thirds of the general adult population are estimated to be at least somewhat hypnotizable, and 15% are highly hypnotizable.

Through brain imaging, the Stanford team found that high hypnotizability is associated with greater functional connectivity between the left dorsolateral prefrontal cortex (DLPFC) and the dorsal anterior cingulate cortex.

In the double-blind study, they randomly assigned 80 patients (mean age, 48 years; 94% women) with fibromyalgia syndrome to active, or sham, continuous theta-burst stimulation over a personalized neuroimaging-derived left DLPFC target — a technique known as Stanford Hypnosis Integrated with Functional Connectivity-targeted Transcranial Stimulation (SHIFT). Individuals who were naturally highly hypnotizable were excluded.

“A novel aspect of this trial is that we used the person’s own brain networks, based on brain imaging, to target the right spot,” Co-senior author Nolan Williams, MD, with Stanford University, California, said in a news release.

The team chose patients with chronic pain because hypnosis has been shown to be a “highly effective analgesic that has a far better risk/benefit ratio than widely overutilized opioids that have serious fatal overdose potential,” Spiegel told this news organization.

The pre-to-post SHIFT change in hypnotic induction profile scores, a standardized measure of hypnotizability, was significantly greater in the active vs sham group after just 92 seconds of stimulation (P = .046).

Only the active SHIFT group showed a significant increase in hypnotizability following stimulation, an effect that lasted for about 1 hour.

“Increasing hypnotizability in people who are low-to-medium hypnotizable individuals could improve both the efficacy and effectiveness of therapeutic hypnosis as a clinical intervention,” the researchers wrote.

They note that because this was a “mechanistic study,” it did not explore the impact of increased hypnotizability on disease symptoms. They also note that further studies are needed to assess the dose-response relationships of SHIFT.

Transformative Research

“This line of research is fascinating,” Shaheen Lakhan, MD, PhD, neurologist, and researcher in Boston, told this news organization.

“We are nearing an era of personalized, noninvasive brain modulation. The ability to individually modulate the DLPFC opens new possibilities for brain health beyond hypnotizability for fibromyalgia,” said Dr. Lakhan, who wasn’t involved in the study.

“The DLPFC is involved in executive functions (and disorders) like attention (ADHD), emotional regulation (depression), motivation (schizophrenia), and impulse control (addiction),” he noted.

“Soon we may no longer need large expensive devices like transcranial magnetic stimulators as in this research study. Smartphones could deliver tailored digital therapeutics by engaging specific brain circuits,” Dr. Lakhan predicted.

“Imagine using an app to receive treatment customized to your unique brain and needs — all without anything implanted and delivered anywhere. The potential to precisely modulate the brain’s wiring to enhance cognition and mental health, without surgery or physical constraints, is incredibly promising. The possibilities are intriguing and could truly transform how we address brain diseases,” he added.

The study was supported by a grant from the National Center for Complementary and Integrative Health (NCCIH), part of the National Institutes of Health (NIH). Dr. Williams is a named inventor on Stanford-owned intellectual property relating to accelerated TMS pulse pattern sequences and neuroimaging-based TMS targeting; has served on scientific advisory boards for Otsuka, NeuraWell, Magnus Medical, and Nooma as a paid advisor; and holds equity/stock options in Magnus Medical, NeuraWell, and Nooma. Dr. Spiegel is a cofounder of Reveri Health, Inc., an interactive hypnosis app (not utilized in the current study).
 

A version of this article appeared on Medscape.com.

ORLANDO — People with epilepsy are more likely to decline cognitively compared with those without epilepsy, new research suggests.

Results of the large, longitudinal study show that seizures predicted earlier conversion time from normal cognition to mild cognitive impairment (MCI) but were not associated with conversion from MCI to dementia.

“Modifiable cardiovascular risk factors such as hypertension and diabetes need to be treated more aggressively because they can impact cognition, but epilepsy is another risk factor that needs to be treated in a timely fashion because it appears to be also associated with cognitive impairment,” said study investigator Ifrah Zawar MD, assistant professor, Department of Neurology, University of Virginia in Charlottesville.

The study (abstract #2.172) was presented on December 2 at the American Epilepsy Society annual meeting.
 

An Understudied Issue

Comorbid seizures occur in up to 64% of those with dementia, and patients with dementia and epilepsy have a more aggressive disease course, faster cognitive decline, and more severe neuronal loss, Dr. Zawar told Medscape Medical News.

But the impact of seizures on the conversion of cognitively healthy to MCI and from MCI to dementia, after accounting for cardiovascular risk factors, has not been well studied.

Researchers analyzed longitudinal data of 13,726 patients, mean age about 70 years, who were cognitively healthy or had mild cognitive impairment (MCI). Participants were recruited from 39 Alzheimer’s Disease (AD) centers in the United States from 2005 to 2021. 

Investigators categorized participants into three groups: active (having had seizures in the past year and/or requiring active treatment; N = 118), resolved (not on any treatment for the past year and not having seizures; N = 226), and no seizures (never having had seizures; N = 13,382).

The primary outcome was conversion from cognitively healthy to MCI/dementia and from MCI to dementia in those with and without active epilepsy and resolved epilepsy.

Factors associated with conversion from cognitively healthy to MCI among those with current or active epilepsy included older age (P <.001 for ages 60-80 years and P =.002 for age 80 years or older vs younger than 60 years), male sex (P <.001), lower education (P <.001), hypertension (P <.001), and diabetes (P <.001).

The hazard ratio (HR) for earlier conversion from healthy to worse cognition among those with active epilepsy was 1.76 (95% CI, 1.38-2.24; P <.001), even after accounting for risk factors.

Kaplan-Meier curves showed that the median time to convert from healthy cognition to MCI among people with active epilepsy was about 5 years compared with about 9 years for those with resolved epilepsy and 10.5 years for those without epilepsy.

The story was similar for faster conversion from MCI to dementia. Compared with having no epilepsy, the HR for faster conversion for active epilepsy was 1.44 (95% CI, 1.20-1.73; P <.001).

In addition, the median time to conversion from MCI to dementia was about 3 years for those with active epilepsy compared with about 5 years for those with resolved epilepsy and about 5 years for those without epilepsy.

“It’s important for physicians to understand that uncontrolled epilepsy or active epilepsy is going to impact patients’ cognition adversely, which in itself is associated with increased comorbidity and mortality,” said Dr. Zawar.

The mechanism driving the acceleration to worse cognition in people with epilepsy is “complicated and involves a multitude of factors,” she said.

The researchers did not specifically investigate how use of antiseizure medications correlated with cognitive outcomes, but Dr. Zawar believes that “epilepsy in itself impacts cognition.”

The researchers also didn’t have EEG data for study participants who were recruited from Alzheimer’s disease centers where EEGs aren’t routinely carried out, so such data for many patients may not necessarily exist, said Dr. Zawar.
 

Important Research

Commenting for this news organization, Bruce Hermann, PhD, professor emeritus, Department of Neurology, University of Wisconsin School of Medicine and Public Health,  said that the study is important because of the, “tremendous interest and concern about aging with epilepsy.”

“We want to know how people with chronic epilepsy age cognitively and what’s the cognitive course of those who have late onset epilepsy, particularly those with unknown etiology,” he added. 

Dr. Hermann noted that much of the research in this area has been relatively small and single-center investigations. 

“These larger-scale investigations from outside the epilepsy community are so important because they have data on large numbers of subjects, they have cognitive data, and follow-ups over long periods of time, and they’re providing some really novel information,” Dr. Hermann said. 

He added that terms used in the dementia world such as MCI and frank dementia are somewhat foreign to epileptologists. In addition, interventions to delay, treat, or prevent cognitive decline such as exercise, diet, social activity, and mental stimulation that are regularly discussed by dementia experts are underrepresented in the epilepsy world.

“The things they talk about in memory clinics in the aging world almost routinely have not penetrated to the epilepsy clinics for aging individuals and for the epilepsy community in general.”

The study used the Montreal Cognitive Assessment to identify cognitive decline. “It would be nice to see how these people look with traditional neuropsychological tests,” said Dr. Hermann.

He added that information on the impact of epilepsy on different MCI phenotypes, for example, pure memory impairment subtype; pure nonmemory subtype; and multiple domain subtype, would also be useful.

The study was supported by the AES and the Alzheimer’s Association. 

Dr. Zawar and Dr. Hermann report no relevant disclosures.

A version of this article appeared on Medscape.com.

ORLANDO — People with epilepsy are more likely to decline cognitively compared with those without epilepsy, new research suggests.

Results of the large, longitudinal study show that seizures predicted earlier conversion time from normal cognition to mild cognitive impairment (MCI) but were not associated with conversion from MCI to dementia.

“Modifiable cardiovascular risk factors such as hypertension and diabetes need to be treated more aggressively because they can impact cognition, but epilepsy is another risk factor that needs to be treated in a timely fashion because it appears to be also associated with cognitive impairment,” said study investigator Ifrah Zawar MD, assistant professor, Department of Neurology, University of Virginia in Charlottesville.

The study (abstract #2.172) was presented on December 2 at the American Epilepsy Society annual meeting.
 

An Understudied Issue

Comorbid seizures occur in up to 64% of those with dementia, and patients with dementia and epilepsy have a more aggressive disease course, faster cognitive decline, and more severe neuronal loss, Dr. Zawar told Medscape Medical News.

But the impact of seizures on the conversion of cognitively healthy to MCI and from MCI to dementia, after accounting for cardiovascular risk factors, has not been well studied.

Researchers analyzed longitudinal data of 13,726 patients, mean age about 70 years, who were cognitively healthy or had mild cognitive impairment (MCI). Participants were recruited from 39 Alzheimer’s Disease (AD) centers in the United States from 2005 to 2021. 

Investigators categorized participants into three groups: active (having had seizures in the past year and/or requiring active treatment; N = 118), resolved (not on any treatment for the past year and not having seizures; N = 226), and no seizures (never having had seizures; N = 13,382).

The primary outcome was conversion from cognitively healthy to MCI/dementia and from MCI to dementia in those with and without active epilepsy and resolved epilepsy.

Factors associated with conversion from cognitively healthy to MCI among those with current or active epilepsy included older age (P <.001 for ages 60-80 years and P =.002 for age 80 years or older vs younger than 60 years), male sex (P <.001), lower education (P <.001), hypertension (P <.001), and diabetes (P <.001).

The hazard ratio (HR) for earlier conversion from healthy to worse cognition among those with active epilepsy was 1.76 (95% CI, 1.38-2.24; P <.001), even after accounting for risk factors.

Kaplan-Meier curves showed that the median time to convert from healthy cognition to MCI among people with active epilepsy was about 5 years compared with about 9 years for those with resolved epilepsy and 10.5 years for those without epilepsy.

The story was similar for faster conversion from MCI to dementia. Compared with having no epilepsy, the HR for faster conversion for active epilepsy was 1.44 (95% CI, 1.20-1.73; P <.001).

In addition, the median time to conversion from MCI to dementia was about 3 years for those with active epilepsy compared with about 5 years for those with resolved epilepsy and about 5 years for those without epilepsy.

“It’s important for physicians to understand that uncontrolled epilepsy or active epilepsy is going to impact patients’ cognition adversely, which in itself is associated with increased comorbidity and mortality,” said Dr. Zawar.

The mechanism driving the acceleration to worse cognition in people with epilepsy is “complicated and involves a multitude of factors,” she said.

The researchers did not specifically investigate how use of antiseizure medications correlated with cognitive outcomes, but Dr. Zawar believes that “epilepsy in itself impacts cognition.”

The researchers also didn’t have EEG data for study participants who were recruited from Alzheimer’s disease centers where EEGs aren’t routinely carried out, so such data for many patients may not necessarily exist, said Dr. Zawar.
 

Important Research

Commenting for this news organization, Bruce Hermann, PhD, professor emeritus, Department of Neurology, University of Wisconsin School of Medicine and Public Health,  said that the study is important because of the, “tremendous interest and concern about aging with epilepsy.”

“We want to know how people with chronic epilepsy age cognitively and what’s the cognitive course of those who have late onset epilepsy, particularly those with unknown etiology,” he added. 

Dr. Hermann noted that much of the research in this area has been relatively small and single-center investigations. 

“These larger-scale investigations from outside the epilepsy community are so important because they have data on large numbers of subjects, they have cognitive data, and follow-ups over long periods of time, and they’re providing some really novel information,” Dr. Hermann said. 

He added that terms used in the dementia world such as MCI and frank dementia are somewhat foreign to epileptologists. In addition, interventions to delay, treat, or prevent cognitive decline such as exercise, diet, social activity, and mental stimulation that are regularly discussed by dementia experts are underrepresented in the epilepsy world.

“The things they talk about in memory clinics in the aging world almost routinely have not penetrated to the epilepsy clinics for aging individuals and for the epilepsy community in general.”

The study used the Montreal Cognitive Assessment to identify cognitive decline. “It would be nice to see how these people look with traditional neuropsychological tests,” said Dr. Hermann.

He added that information on the impact of epilepsy on different MCI phenotypes, for example, pure memory impairment subtype; pure nonmemory subtype; and multiple domain subtype, would also be useful.

The study was supported by the AES and the Alzheimer’s Association. 

Dr. Zawar and Dr. Hermann report no relevant disclosures.

A version of this article appeared on Medscape.com.

ORLANDO — People with epilepsy are more likely to decline cognitively compared with those without epilepsy, new research suggests.

Results of the large, longitudinal study show that seizures predicted earlier conversion time from normal cognition to mild cognitive impairment (MCI) but were not associated with conversion from MCI to dementia.

“Modifiable cardiovascular risk factors such as hypertension and diabetes need to be treated more aggressively because they can impact cognition, but epilepsy is another risk factor that needs to be treated in a timely fashion because it appears to be also associated with cognitive impairment,” said study investigator Ifrah Zawar MD, assistant professor, Department of Neurology, University of Virginia in Charlottesville.

The study (abstract #2.172) was presented on December 2 at the American Epilepsy Society annual meeting.
 

An Understudied Issue

Comorbid seizures occur in up to 64% of those with dementia, and patients with dementia and epilepsy have a more aggressive disease course, faster cognitive decline, and more severe neuronal loss, Dr. Zawar told Medscape Medical News.

But the impact of seizures on the conversion of cognitively healthy to MCI and from MCI to dementia, after accounting for cardiovascular risk factors, has not been well studied.

Researchers analyzed longitudinal data of 13,726 patients, mean age about 70 years, who were cognitively healthy or had mild cognitive impairment (MCI). Participants were recruited from 39 Alzheimer’s Disease (AD) centers in the United States from 2005 to 2021. 

Investigators categorized participants into three groups: active (having had seizures in the past year and/or requiring active treatment; N = 118), resolved (not on any treatment for the past year and not having seizures; N = 226), and no seizures (never having had seizures; N = 13,382).

The primary outcome was conversion from cognitively healthy to MCI/dementia and from MCI to dementia in those with and without active epilepsy and resolved epilepsy.

Factors associated with conversion from cognitively healthy to MCI among those with current or active epilepsy included older age (P <.001 for ages 60-80 years and P =.002 for age 80 years or older vs younger than 60 years), male sex (P <.001), lower education (P <.001), hypertension (P <.001), and diabetes (P <.001).

The hazard ratio (HR) for earlier conversion from healthy to worse cognition among those with active epilepsy was 1.76 (95% CI, 1.38-2.24; P <.001), even after accounting for risk factors.

Kaplan-Meier curves showed that the median time to convert from healthy cognition to MCI among people with active epilepsy was about 5 years compared with about 9 years for those with resolved epilepsy and 10.5 years for those without epilepsy.

The story was similar for faster conversion from MCI to dementia. Compared with having no epilepsy, the HR for faster conversion for active epilepsy was 1.44 (95% CI, 1.20-1.73; P <.001).

In addition, the median time to conversion from MCI to dementia was about 3 years for those with active epilepsy compared with about 5 years for those with resolved epilepsy and about 5 years for those without epilepsy.

“It’s important for physicians to understand that uncontrolled epilepsy or active epilepsy is going to impact patients’ cognition adversely, which in itself is associated with increased comorbidity and mortality,” said Dr. Zawar.

The mechanism driving the acceleration to worse cognition in people with epilepsy is “complicated and involves a multitude of factors,” she said.

The researchers did not specifically investigate how use of antiseizure medications correlated with cognitive outcomes, but Dr. Zawar believes that “epilepsy in itself impacts cognition.”

The researchers also didn’t have EEG data for study participants who were recruited from Alzheimer’s disease centers where EEGs aren’t routinely carried out, so such data for many patients may not necessarily exist, said Dr. Zawar.
 

Important Research

Commenting for this news organization, Bruce Hermann, PhD, professor emeritus, Department of Neurology, University of Wisconsin School of Medicine and Public Health,  said that the study is important because of the, “tremendous interest and concern about aging with epilepsy.”

“We want to know how people with chronic epilepsy age cognitively and what’s the cognitive course of those who have late onset epilepsy, particularly those with unknown etiology,” he added. 

Dr. Hermann noted that much of the research in this area has been relatively small and single-center investigations. 

“These larger-scale investigations from outside the epilepsy community are so important because they have data on large numbers of subjects, they have cognitive data, and follow-ups over long periods of time, and they’re providing some really novel information,” Dr. Hermann said. 

He added that terms used in the dementia world such as MCI and frank dementia are somewhat foreign to epileptologists. In addition, interventions to delay, treat, or prevent cognitive decline such as exercise, diet, social activity, and mental stimulation that are regularly discussed by dementia experts are underrepresented in the epilepsy world.

“The things they talk about in memory clinics in the aging world almost routinely have not penetrated to the epilepsy clinics for aging individuals and for the epilepsy community in general.”

The study used the Montreal Cognitive Assessment to identify cognitive decline. “It would be nice to see how these people look with traditional neuropsychological tests,” said Dr. Hermann.

He added that information on the impact of epilepsy on different MCI phenotypes, for example, pure memory impairment subtype; pure nonmemory subtype; and multiple domain subtype, would also be useful.

The study was supported by the AES and the Alzheimer’s Association. 

Dr. Zawar and Dr. Hermann report no relevant disclosures.

A version of this article appeared on Medscape.com.

ORLANDO — Combining an enzyme-inducing antiseizure medication with a direct-acting oral anticoagulant (DOAC) does not significantly increase the risk of thromboembolic events in patients with epilepsy, preliminary results of a new study show.

These new data are important, “particularly when we’re talking about a more global perspective, given the vital role of enzyme-inducing antiseizure medications in epilepsy care across many middle- and low-income countries where they may be the only readily available treatment options,” said study investigator Emily K. Acton, PhD candidate in epidemiology and a medical student, University of Pennsylvania Perelman School of Medicine, Philadelphia, and University of Illinois College of Medicine, Chicago. 

The findings also suggest that use of enzyme-inducing antiseizure medication with DOACs may be associated with a reduction in major bleeding events, although Ms. Acton stressed this requires more research.

The findings were presented at the American Epilepsy Society annual meeting.
 

Important Implications

Enzyme-inducing antiseizure medications may induce key drug metabolizing enzymes that result in wide-ranging interactions, Ms. Acton told this news organization. “But, in many cases, the clinical significance of these pharmacokinetic interactions is not completely understood.”

This has important implications for managing anticoagulation, said Ms. Acton. “The ease of DOAC use, and growing evidence of the drugs’ safety and efficacy compared to vitamin K antagonists, has led to widespread shifts in clinical practice towards DOACs.”

Due to the relative novelty of DOACs, their interaction profiles have been less than complete, she explained. Evidence that enzyme-inducing antiseizure medications may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk, comes mainly from in vitro and animal studies.

“Research in humans is lacking and complicated in interpretation by inconsistent findings and methodological limitations,” she said.

The investigators wanted to address the “clinical uncertainty” surrounding the real-world relevance of enzyme-inducing antiseizure medications and DOAC interactions but conducting a randomized trial “would be neither feasible nor ethical,” said Ms. Acton. 

Using healthcare claims data from October 2010 to September 2021, the researchers conducted an active comparator, new-user cohort study among a nationally representative sample of adults with epilepsy who had been co-prescribed these drugs. 

They compared thromboembolic and major bleeding event rates between exposure to DOACs with enzyme-inducing antiseizure medications vs exposure to DOACs with non-enzyme inducing antiseizure medications.

Enzyme-inducing antiseizure medications included in the study were carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, and topiramate. Non-enzyme-inducing antiseizure medications included gabapentin, lacosamide, lamotrigine, levetiracetam, and pregabalin.

The researchers used data-adaptive high-dimensional propensity score matching to control for “hundreds and hundreds” of observed confounders, and proxies for unobserved confounders, said Ms. Acton. They identified outcomes based on validated diagnostic coding algorithms for thromboembolic and major bleeding events and estimated adjusted hazard ratios (aHRs) using Cox proportional hazard models with robust variance estimators to account for clustering within matched pairs.
 

Reduced Risk of Major Bleeding 

Outcomes were analyzed in three separate cohorts. These included patients on DOACs for any indication (indication-agnostic); those on DOACs for atrial fibrillation (AF); and those taking DOACs for deep vein thrombus/pulmonary embolism (DVT/PE).

In the indication-agnostic analysis, the investigators examined thromboembolic events among 5989 episodes in patients taking both DOACs and enzyme-inducing antiseizure medications, compared witha reference group of 14,671 episodes in patients taking DOACs and non-enzyme-inducing antiseizure medications.

The reference group was generally older and had a greater prevalence of a number of major comorbidities compared with the exposed group, noted Ms. Acton.

For the indication-agnostic analysis, the aHR was 1.11 (95% CI 0.89-1.39). Results were similar for the AF indication (aHR 1.10; 95% CI 0.82-1.46) and for the DVT/PE indication (aHR 1.11; 95% CI 0.81-1.51).

“This research provides large-scale, real-world evidence enzyme-inducing antiseizure medication use alongside DOACs does not significantly elevate risk of thromboembolic events among a nationally representative epilepsy population,” said Ms. Acton.

However, “it’s always important to consider risk factors for thromboembolic and bleeding events at the level of the individual patient,” she added.

With respect to major bleeding events, there was a slightly reduced risk in the exposed group, specifically in the analysis of subjects with atrial fibrillation, where the aHR was 0.63 (95% CI 0.44-0.89).

“A potential explanation may be pharmacokinetic interaction with enzyme-inducing antiseizure medications occurring to a degree that lowers DOAC levels without necessarily negating therapeutic effects,” said Ms. Acton.

However, she cautioned that more research is needed.

As for the differential potency among the various enzyme-inducing antiseizure medications studied, Ms. Acton said results from a secondary analysis in the atrial fibrillation assessment that removed the potentially less potent enzyme inducers, oxcarbazepine and topiramate, didn’t significantly change the study results.
 

‘Really Great News’

Commenting on the findings for this news organization, epilepsy expert Daniel M. Goldenholz, MD, PhD, assistant professor of Neurology, Harvard Beth Israel Deaconess Medical Center, Boston, Massachusetts, said the finding of no meaningful difference between DOAC plus enzyme-inducing medications vs DOACs plus non-enzyme-inducing medications is encouraging.

“This study asks a very important question at the population level and appropriately tries to control for present and hidden factors using a propensity matching approach,” he said.

The fact that the data support no difference in terms of thromboembolic events “is really great news” for patients taking an enzyme-inducing antiseizure medication who need to use a DOAC, he said.

While some patients or clinicians might consider transitioning off an enzyme-inducing antiseizure medication, this can lead to new side effects and potentially higher drug costs. “Knowing that a transition may be unnecessary is exciting,” said Dr. Goldenholz.

However, he’s concerned the 1.5-year observation period may not be long enough to see a true effect of these drug combinations.

He also noted that due to the “theoretical higher risk,” patients combining DOACs with enzyme-inducing drugs typically need extra monitoring, which may be less practical outside the US. This suggests “the result may not necessarily generalize outside high-income countries,” he said.

Dr. Goldenholz emphasized that the data are preliminary. “As always, I look forward to a full peer-reviewed study before forming final conclusions.”

The study was supported by the US Department of Health and Human Services’ National Institute of Neurological Disorders and Stroke.

Ms. Acton and Dr. Goldenholz report no relevant financial relationships.

A version of this article appeared on Medscape.com.

ORLANDO — Combining an enzyme-inducing antiseizure medication with a direct-acting oral anticoagulant (DOAC) does not significantly increase the risk of thromboembolic events in patients with epilepsy, preliminary results of a new study show.

These new data are important, “particularly when we’re talking about a more global perspective, given the vital role of enzyme-inducing antiseizure medications in epilepsy care across many middle- and low-income countries where they may be the only readily available treatment options,” said study investigator Emily K. Acton, PhD candidate in epidemiology and a medical student, University of Pennsylvania Perelman School of Medicine, Philadelphia, and University of Illinois College of Medicine, Chicago. 

The findings also suggest that use of enzyme-inducing antiseizure medication with DOACs may be associated with a reduction in major bleeding events, although Ms. Acton stressed this requires more research.

The findings were presented at the American Epilepsy Society annual meeting.
 

Important Implications

Enzyme-inducing antiseizure medications may induce key drug metabolizing enzymes that result in wide-ranging interactions, Ms. Acton told this news organization. “But, in many cases, the clinical significance of these pharmacokinetic interactions is not completely understood.”

This has important implications for managing anticoagulation, said Ms. Acton. “The ease of DOAC use, and growing evidence of the drugs’ safety and efficacy compared to vitamin K antagonists, has led to widespread shifts in clinical practice towards DOACs.”

Due to the relative novelty of DOACs, their interaction profiles have been less than complete, she explained. Evidence that enzyme-inducing antiseizure medications may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk, comes mainly from in vitro and animal studies.

“Research in humans is lacking and complicated in interpretation by inconsistent findings and methodological limitations,” she said.

The investigators wanted to address the “clinical uncertainty” surrounding the real-world relevance of enzyme-inducing antiseizure medications and DOAC interactions but conducting a randomized trial “would be neither feasible nor ethical,” said Ms. Acton. 

Using healthcare claims data from October 2010 to September 2021, the researchers conducted an active comparator, new-user cohort study among a nationally representative sample of adults with epilepsy who had been co-prescribed these drugs. 

They compared thromboembolic and major bleeding event rates between exposure to DOACs with enzyme-inducing antiseizure medications vs exposure to DOACs with non-enzyme inducing antiseizure medications.

Enzyme-inducing antiseizure medications included in the study were carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, and topiramate. Non-enzyme-inducing antiseizure medications included gabapentin, lacosamide, lamotrigine, levetiracetam, and pregabalin.

The researchers used data-adaptive high-dimensional propensity score matching to control for “hundreds and hundreds” of observed confounders, and proxies for unobserved confounders, said Ms. Acton. They identified outcomes based on validated diagnostic coding algorithms for thromboembolic and major bleeding events and estimated adjusted hazard ratios (aHRs) using Cox proportional hazard models with robust variance estimators to account for clustering within matched pairs.
 

Reduced Risk of Major Bleeding 

Outcomes were analyzed in three separate cohorts. These included patients on DOACs for any indication (indication-agnostic); those on DOACs for atrial fibrillation (AF); and those taking DOACs for deep vein thrombus/pulmonary embolism (DVT/PE).

In the indication-agnostic analysis, the investigators examined thromboembolic events among 5989 episodes in patients taking both DOACs and enzyme-inducing antiseizure medications, compared witha reference group of 14,671 episodes in patients taking DOACs and non-enzyme-inducing antiseizure medications.

The reference group was generally older and had a greater prevalence of a number of major comorbidities compared with the exposed group, noted Ms. Acton.

For the indication-agnostic analysis, the aHR was 1.11 (95% CI 0.89-1.39). Results were similar for the AF indication (aHR 1.10; 95% CI 0.82-1.46) and for the DVT/PE indication (aHR 1.11; 95% CI 0.81-1.51).

“This research provides large-scale, real-world evidence enzyme-inducing antiseizure medication use alongside DOACs does not significantly elevate risk of thromboembolic events among a nationally representative epilepsy population,” said Ms. Acton.

However, “it’s always important to consider risk factors for thromboembolic and bleeding events at the level of the individual patient,” she added.

With respect to major bleeding events, there was a slightly reduced risk in the exposed group, specifically in the analysis of subjects with atrial fibrillation, where the aHR was 0.63 (95% CI 0.44-0.89).

“A potential explanation may be pharmacokinetic interaction with enzyme-inducing antiseizure medications occurring to a degree that lowers DOAC levels without necessarily negating therapeutic effects,” said Ms. Acton.

However, she cautioned that more research is needed.

As for the differential potency among the various enzyme-inducing antiseizure medications studied, Ms. Acton said results from a secondary analysis in the atrial fibrillation assessment that removed the potentially less potent enzyme inducers, oxcarbazepine and topiramate, didn’t significantly change the study results.
 

‘Really Great News’

Commenting on the findings for this news organization, epilepsy expert Daniel M. Goldenholz, MD, PhD, assistant professor of Neurology, Harvard Beth Israel Deaconess Medical Center, Boston, Massachusetts, said the finding of no meaningful difference between DOAC plus enzyme-inducing medications vs DOACs plus non-enzyme-inducing medications is encouraging.

“This study asks a very important question at the population level and appropriately tries to control for present and hidden factors using a propensity matching approach,” he said.

The fact that the data support no difference in terms of thromboembolic events “is really great news” for patients taking an enzyme-inducing antiseizure medication who need to use a DOAC, he said.

While some patients or clinicians might consider transitioning off an enzyme-inducing antiseizure medication, this can lead to new side effects and potentially higher drug costs. “Knowing that a transition may be unnecessary is exciting,” said Dr. Goldenholz.

However, he’s concerned the 1.5-year observation period may not be long enough to see a true effect of these drug combinations.

He also noted that due to the “theoretical higher risk,” patients combining DOACs with enzyme-inducing drugs typically need extra monitoring, which may be less practical outside the US. This suggests “the result may not necessarily generalize outside high-income countries,” he said.

Dr. Goldenholz emphasized that the data are preliminary. “As always, I look forward to a full peer-reviewed study before forming final conclusions.”

The study was supported by the US Department of Health and Human Services’ National Institute of Neurological Disorders and Stroke.

Ms. Acton and Dr. Goldenholz report no relevant financial relationships.

A version of this article appeared on Medscape.com.

ORLANDO — Combining an enzyme-inducing antiseizure medication with a direct-acting oral anticoagulant (DOAC) does not significantly increase the risk of thromboembolic events in patients with epilepsy, preliminary results of a new study show.

These new data are important, “particularly when we’re talking about a more global perspective, given the vital role of enzyme-inducing antiseizure medications in epilepsy care across many middle- and low-income countries where they may be the only readily available treatment options,” said study investigator Emily K. Acton, PhD candidate in epidemiology and a medical student, University of Pennsylvania Perelman School of Medicine, Philadelphia, and University of Illinois College of Medicine, Chicago. 

The findings also suggest that use of enzyme-inducing antiseizure medication with DOACs may be associated with a reduction in major bleeding events, although Ms. Acton stressed this requires more research.

The findings were presented at the American Epilepsy Society annual meeting.
 

Important Implications

Enzyme-inducing antiseizure medications may induce key drug metabolizing enzymes that result in wide-ranging interactions, Ms. Acton told this news organization. “But, in many cases, the clinical significance of these pharmacokinetic interactions is not completely understood.”

This has important implications for managing anticoagulation, said Ms. Acton. “The ease of DOAC use, and growing evidence of the drugs’ safety and efficacy compared to vitamin K antagonists, has led to widespread shifts in clinical practice towards DOACs.”

Due to the relative novelty of DOACs, their interaction profiles have been less than complete, she explained. Evidence that enzyme-inducing antiseizure medications may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk, comes mainly from in vitro and animal studies.

“Research in humans is lacking and complicated in interpretation by inconsistent findings and methodological limitations,” she said.

The investigators wanted to address the “clinical uncertainty” surrounding the real-world relevance of enzyme-inducing antiseizure medications and DOAC interactions but conducting a randomized trial “would be neither feasible nor ethical,” said Ms. Acton. 

Using healthcare claims data from October 2010 to September 2021, the researchers conducted an active comparator, new-user cohort study among a nationally representative sample of adults with epilepsy who had been co-prescribed these drugs. 

They compared thromboembolic and major bleeding event rates between exposure to DOACs with enzyme-inducing antiseizure medications vs exposure to DOACs with non-enzyme inducing antiseizure medications.

Enzyme-inducing antiseizure medications included in the study were carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, and topiramate. Non-enzyme-inducing antiseizure medications included gabapentin, lacosamide, lamotrigine, levetiracetam, and pregabalin.

The researchers used data-adaptive high-dimensional propensity score matching to control for “hundreds and hundreds” of observed confounders, and proxies for unobserved confounders, said Ms. Acton. They identified outcomes based on validated diagnostic coding algorithms for thromboembolic and major bleeding events and estimated adjusted hazard ratios (aHRs) using Cox proportional hazard models with robust variance estimators to account for clustering within matched pairs.
 

Reduced Risk of Major Bleeding 

Outcomes were analyzed in three separate cohorts. These included patients on DOACs for any indication (indication-agnostic); those on DOACs for atrial fibrillation (AF); and those taking DOACs for deep vein thrombus/pulmonary embolism (DVT/PE).

In the indication-agnostic analysis, the investigators examined thromboembolic events among 5989 episodes in patients taking both DOACs and enzyme-inducing antiseizure medications, compared witha reference group of 14,671 episodes in patients taking DOACs and non-enzyme-inducing antiseizure medications.

The reference group was generally older and had a greater prevalence of a number of major comorbidities compared with the exposed group, noted Ms. Acton.

For the indication-agnostic analysis, the aHR was 1.11 (95% CI 0.89-1.39). Results were similar for the AF indication (aHR 1.10; 95% CI 0.82-1.46) and for the DVT/PE indication (aHR 1.11; 95% CI 0.81-1.51).

“This research provides large-scale, real-world evidence enzyme-inducing antiseizure medication use alongside DOACs does not significantly elevate risk of thromboembolic events among a nationally representative epilepsy population,” said Ms. Acton.

However, “it’s always important to consider risk factors for thromboembolic and bleeding events at the level of the individual patient,” she added.

With respect to major bleeding events, there was a slightly reduced risk in the exposed group, specifically in the analysis of subjects with atrial fibrillation, where the aHR was 0.63 (95% CI 0.44-0.89).

“A potential explanation may be pharmacokinetic interaction with enzyme-inducing antiseizure medications occurring to a degree that lowers DOAC levels without necessarily negating therapeutic effects,” said Ms. Acton.

However, she cautioned that more research is needed.

As for the differential potency among the various enzyme-inducing antiseizure medications studied, Ms. Acton said results from a secondary analysis in the atrial fibrillation assessment that removed the potentially less potent enzyme inducers, oxcarbazepine and topiramate, didn’t significantly change the study results.
 

‘Really Great News’

Commenting on the findings for this news organization, epilepsy expert Daniel M. Goldenholz, MD, PhD, assistant professor of Neurology, Harvard Beth Israel Deaconess Medical Center, Boston, Massachusetts, said the finding of no meaningful difference between DOAC plus enzyme-inducing medications vs DOACs plus non-enzyme-inducing medications is encouraging.

“This study asks a very important question at the population level and appropriately tries to control for present and hidden factors using a propensity matching approach,” he said.

The fact that the data support no difference in terms of thromboembolic events “is really great news” for patients taking an enzyme-inducing antiseizure medication who need to use a DOAC, he said.

While some patients or clinicians might consider transitioning off an enzyme-inducing antiseizure medication, this can lead to new side effects and potentially higher drug costs. “Knowing that a transition may be unnecessary is exciting,” said Dr. Goldenholz.

However, he’s concerned the 1.5-year observation period may not be long enough to see a true effect of these drug combinations.

He also noted that due to the “theoretical higher risk,” patients combining DOACs with enzyme-inducing drugs typically need extra monitoring, which may be less practical outside the US. This suggests “the result may not necessarily generalize outside high-income countries,” he said.

Dr. Goldenholz emphasized that the data are preliminary. “As always, I look forward to a full peer-reviewed study before forming final conclusions.”

The study was supported by the US Department of Health and Human Services’ National Institute of Neurological Disorders and Stroke.

Ms. Acton and Dr. Goldenholz report no relevant financial relationships.

A version of this article appeared on Medscape.com.

The mechanisms underlying poststroke depression (PSD), a common and debilitating complication of stroke, are unclear. Is it neurobiological, psychosocial, or both?

Two studies offer new insight into this question. In the first, investigators systematically reviewed studies comparing stroke and non-stroke participants with depression and found the groups were similar in most dimensions of depressive symptoms. But surprisingly, anhedonia was less severe in patients with PSD compared with non-stroke controls, and those with PSD also showed greater emotional dysregulation.

“Our findings support previous recommendations that clinicians should adapt the provision of psychological support to the specific needs and difficulties of stroke survivors,” said lead author Joshua Blake, DClinPsy, lecturer in clinical psychology, University of East Anglia, Norwich, United Kingdom.

The study was published online in Neuropsychology Review

A second study used a machine learning algorithm to analyze blood samples from adults who had suffered a stroke, determining whether plasma protein data could predict mood and identifying potential proteins associated with mood in these patients.

“We can now look at a stroke survivor’s blood and predict their mood,” senior author Marion Buckwalter, MD, PhD, professor of neurology and neurosurgery at Stanford Medicine, California, said in a news release. “This means there is a genuine association between what’s happening in the blood and what’s happening with a person’s mood. It also means that, down the road, we may be able to develop new treatments for PSD.”

The study was published in November 2023 in Brain, Behavior, and Immunity.
 

‘Surprising’ Findings

“There has long been uncertainty over whether PSD might differ in its causes, phenomenology, and treatability, due to the presence of brain injury, related biological changes, and the psychosocial context unique to this population,” Dr. Blake said. “We felt that understanding symptomatologic similarities and differences would constructively contribute to this debate.”

The researchers reviewed 12 papers that sampled both stroke and non-stroke participants. “We compared profiles of depression symptoms, correlation strengths of individual depression symptoms with general depression, and latent item severity,” Dr. Blake reported.

They extracted 38 symptoms from five standardized depression tools and then organized the symptoms into nine dimensions.

They found mostly nonsignificant differences between patients with PSD and non-stroke controls in most dimensions, including negative affect, negative cognitions, somatic features, anxiety/worry, and suicidal ideation. Those with PSD more frequently had cognitive impairment, and “work inhibition” was more common in PSD.

But the most striking finding was greater severity/prevalence of emotional dysregulation in PSD vs non-stroke depression and also less anhedonia.

Dr. Blake acknowledged being “surprised.”

One possible explanation is that stroke recovery “appears to be a highly emotional journey, with extreme findings of both positive and negative emotions reported by survivors as they psychologically adjust,” which might be protective against anhedonia, he suggested.

Moreover, neurologically driven emotional dysregulation “may similarly reduce experiences of anhedonia.”

However, there was a “considerable risk of bias in many of the included studies, meaning it’s important that these findings are experimentally confirmed before stronger conclusions about phenomenological differences can be drawn,” he cautioned.
 

Common, Undertreated

Dr. Buckwalter said her team was motivated to conduct the research because PSD is among the top problems reported by chronic stroke patients, and for most, it is not adequately treated.

However, “despite the high prevalence of PSD, it is very poorly studied in the chronic time period.” In particular, PSD isn’t “well understood at a molecular level.”

She added that inflammation is a “promising candidate” as a mechanism, since neuroinflammation occurs in the stroke scar for decades, and chronic peripheral inflammation can produce neuroinflammation. Aberrant immune activation has also been implicated in major depression without stroke. But large studies with broad panels of plasma biomarkers are lacking in PSD.

To address this gap, the researchers used a proteomic approach. They recruited 85 chronic stroke patients (mean age, 65 years [interquartile range, 55-71], 41.2% female, 65.9% White, 17.6% Asian, and 0% Black) from the Stanford Stroke Recovery Program. Participants were between 5 months and 9 years after an ischemic stroke.

They analyzed a comprehensive panel of 1196 proteins in plasma samples, applying a machine learning algorithm to see whether the plasma protein levels “could be used to predict mood scores, using either the proteomics data alone or adding age and time since stroke.” The proteomics data were then incorporated into multivariable regression models, along with relevant clinical features, to ascertain the model’s predictive ability.

Mood was assessed using the Stroke Impact Scale mood questionnaire, with participants’ mood dichotomized into better mood (> 63) or worse mood (≤ 63).
 

‘Beautiful Mechanistic Model’

Machine learning verified a relationship between plasma proteomic data and mood, with the most accurate prediction occurring when the researchers added age and time since the stroke to the analysis.

Independent univariate analyses identified 202 proteins that were most highly correlated with mood in PSD. These were then organized into functional groups, including immune proteins, integrins, growth factors, synaptic function proteins, serotonin activity-related proteins, and cell death and stress-related functional groupings.

Although no single protein could predict depression, significant changes in levels of several proteins were found in PSD patients. A high proportion (45%) were proteins previously implicated in major depression, “likely providing a link to the underlying mechanisms of chronic PSD,” the authors stated.

Moreover, 80% of correlated immune proteins were higher in the plasma of people with worse mood, and several immune proteins known to have anti-inflammatory effects were reduced in those with worse mood.

And several pro-inflammatory cytokines were implicated. For example, interleukin 6, which has been extensively studied as a potential plasma marker of major depression in non-stroke cohorts, was significantly elevated in patients with worse mood after stroke (P = .0325), «implicating a broadly overactive immune system in PSD.»

“We demonstrated for the first time that we can use plasma protein measurements to predict mood in people with chronic stroke,” Dr. Buckwalter summarized. “This means there is a biological correlate of mood but [it] doesn’t tell us causality.”

To tease out causality, the researchers used their own data, as well as information from a literature review of previous studies, to assemble a model of how the immune response following a stroke could change both serotonin and brain plasticity.

“We used the most highly correlated proteins to construct a beautiful mechanistic model of how poststroke depression may work and how it may relate to mechanisms in major depression,” Dr. Buckwalter said.

The model “posits an increased inflammatory response that leads to decreased tryptophan, serotonin, and less synaptic function, all of which contribute to symptoms of depression.”

Currently, selective serotonin reuptake inhibitors represent the “best treatment” for people with PSD, but “unfortunately they don’t work for many patients,” Dr. Buckwalter noted. The findings “provide clues as to other molecular targets that are candidates novel therapies for poststroke depression.”

Dr. Blake commented that the proteomic study “complements the work by us and others interested in understanding PSD.”

Mood disorders “must be understood in terms of the dynamic relationships between structural neurological alterations, cellular and microbiological changes, psychological processes, and the person’s interactions with their social landscape,” Dr. Blake said.
 

New Treatments on the Horizon?

Gustavo C. Medeiros, MD, assistant professor, Department of Psychiatry, of the University of Maryland School of Medicine, Baltimore, said that knowing which individuals are more likely to develop PSD “allows treatment teams to implement earlier and more intensive interventions in those who are at higher risk.”

The findings [of the proteomic study] may also “help clarify the neurobiological correlates of PSD…[which] may help the development of new treatments that target these neurobiological changes,” said Dr. Medeiros, who wasn’t involved with either study.

However, he warned, “we should interpret their results with caution due to methodological reasons, including the relatively small sample size.”

Also commenting, Bruce Ovbiagele, MD, MSc, MAS, MBA, MLS, professor of neurology, UCSF Weill Institute for Neurosciences, California, said the proteomic study has some “clear limitations,” including the lack of Black or African American patients in the cohort, which limits generalizability, “since we know that Black and African American people are disproportionately affected by stroke and have very high rates of PSD and very severe presentation.”

The study by Dr. Blake et al. “was interesting because the phenotype of depressive symptoms after stroke differs from what’s seen in the general population, and the authors figured out a way to better understand the nuances of such differences,” said Dr. Ovbiagele, who wasn’t involved with either study.

He said he was also surprised by the finding regarding anhedonia and suggested that the findings be replicated in a study directly comparing patients with PSD and patients with depression from the general population.

The study by Bidoki et al. was funded by AHA/Paul Allen Foundation, the Leducq Stroke-IMPaCT Transatlantic Network of Excellence (MSB), the Wu Tsai Neurosciences Institute (MSB), the Alfred E. Mann Foundation (NA), and an Alzheimer’s Association Research Fellowship to one of the authors. No source of funding was listed for the study by Dr. Blake et al. The authors of both studies, Dr. Medeiros and Dr. Ovbiagele, declare no relevant financial relationships.

A version of this article appeared on Medscape.com.

The mechanisms underlying poststroke depression (PSD), a common and debilitating complication of stroke, are unclear. Is it neurobiological, psychosocial, or both?

Two studies offer new insight into this question. In the first, investigators systematically reviewed studies comparing stroke and non-stroke participants with depression and found the groups were similar in most dimensions of depressive symptoms. But surprisingly, anhedonia was less severe in patients with PSD compared with non-stroke controls, and those with PSD also showed greater emotional dysregulation.

“Our findings support previous recommendations that clinicians should adapt the provision of psychological support to the specific needs and difficulties of stroke survivors,” said lead author Joshua Blake, DClinPsy, lecturer in clinical psychology, University of East Anglia, Norwich, United Kingdom.

The study was published online in Neuropsychology Review

A second study used a machine learning algorithm to analyze blood samples from adults who had suffered a stroke, determining whether plasma protein data could predict mood and identifying potential proteins associated with mood in these patients.

“We can now look at a stroke survivor’s blood and predict their mood,” senior author Marion Buckwalter, MD, PhD, professor of neurology and neurosurgery at Stanford Medicine, California, said in a news release. “This means there is a genuine association between what’s happening in the blood and what’s happening with a person’s mood. It also means that, down the road, we may be able to develop new treatments for PSD.”

The study was published in November 2023 in Brain, Behavior, and Immunity.
 

‘Surprising’ Findings

“There has long been uncertainty over whether PSD might differ in its causes, phenomenology, and treatability, due to the presence of brain injury, related biological changes, and the psychosocial context unique to this population,” Dr. Blake said. “We felt that understanding symptomatologic similarities and differences would constructively contribute to this debate.”

The researchers reviewed 12 papers that sampled both stroke and non-stroke participants. “We compared profiles of depression symptoms, correlation strengths of individual depression symptoms with general depression, and latent item severity,” Dr. Blake reported.

They extracted 38 symptoms from five standardized depression tools and then organized the symptoms into nine dimensions.

They found mostly nonsignificant differences between patients with PSD and non-stroke controls in most dimensions, including negative affect, negative cognitions, somatic features, anxiety/worry, and suicidal ideation. Those with PSD more frequently had cognitive impairment, and “work inhibition” was more common in PSD.

But the most striking finding was greater severity/prevalence of emotional dysregulation in PSD vs non-stroke depression and also less anhedonia.

Dr. Blake acknowledged being “surprised.”

One possible explanation is that stroke recovery “appears to be a highly emotional journey, with extreme findings of both positive and negative emotions reported by survivors as they psychologically adjust,” which might be protective against anhedonia, he suggested.

Moreover, neurologically driven emotional dysregulation “may similarly reduce experiences of anhedonia.”

However, there was a “considerable risk of bias in many of the included studies, meaning it’s important that these findings are experimentally confirmed before stronger conclusions about phenomenological differences can be drawn,” he cautioned.
 

Common, Undertreated

Dr. Buckwalter said her team was motivated to conduct the research because PSD is among the top problems reported by chronic stroke patients, and for most, it is not adequately treated.

However, “despite the high prevalence of PSD, it is very poorly studied in the chronic time period.” In particular, PSD isn’t “well understood at a molecular level.”

She added that inflammation is a “promising candidate” as a mechanism, since neuroinflammation occurs in the stroke scar for decades, and chronic peripheral inflammation can produce neuroinflammation. Aberrant immune activation has also been implicated in major depression without stroke. But large studies with broad panels of plasma biomarkers are lacking in PSD.

To address this gap, the researchers used a proteomic approach. They recruited 85 chronic stroke patients (mean age, 65 years [interquartile range, 55-71], 41.2% female, 65.9% White, 17.6% Asian, and 0% Black) from the Stanford Stroke Recovery Program. Participants were between 5 months and 9 years after an ischemic stroke.

They analyzed a comprehensive panel of 1196 proteins in plasma samples, applying a machine learning algorithm to see whether the plasma protein levels “could be used to predict mood scores, using either the proteomics data alone or adding age and time since stroke.” The proteomics data were then incorporated into multivariable regression models, along with relevant clinical features, to ascertain the model’s predictive ability.

Mood was assessed using the Stroke Impact Scale mood questionnaire, with participants’ mood dichotomized into better mood (> 63) or worse mood (≤ 63).
 

‘Beautiful Mechanistic Model’

Machine learning verified a relationship between plasma proteomic data and mood, with the most accurate prediction occurring when the researchers added age and time since the stroke to the analysis.

Independent univariate analyses identified 202 proteins that were most highly correlated with mood in PSD. These were then organized into functional groups, including immune proteins, integrins, growth factors, synaptic function proteins, serotonin activity-related proteins, and cell death and stress-related functional groupings.

Although no single protein could predict depression, significant changes in levels of several proteins were found in PSD patients. A high proportion (45%) were proteins previously implicated in major depression, “likely providing a link to the underlying mechanisms of chronic PSD,” the authors stated.

Moreover, 80% of correlated immune proteins were higher in the plasma of people with worse mood, and several immune proteins known to have anti-inflammatory effects were reduced in those with worse mood.

And several pro-inflammatory cytokines were implicated. For example, interleukin 6, which has been extensively studied as a potential plasma marker of major depression in non-stroke cohorts, was significantly elevated in patients with worse mood after stroke (P = .0325), «implicating a broadly overactive immune system in PSD.»

“We demonstrated for the first time that we can use plasma protein measurements to predict mood in people with chronic stroke,” Dr. Buckwalter summarized. “This means there is a biological correlate of mood but [it] doesn’t tell us causality.”

To tease out causality, the researchers used their own data, as well as information from a literature review of previous studies, to assemble a model of how the immune response following a stroke could change both serotonin and brain plasticity.

“We used the most highly correlated proteins to construct a beautiful mechanistic model of how poststroke depression may work and how it may relate to mechanisms in major depression,” Dr. Buckwalter said.

The model “posits an increased inflammatory response that leads to decreased tryptophan, serotonin, and less synaptic function, all of which contribute to symptoms of depression.”

Currently, selective serotonin reuptake inhibitors represent the “best treatment” for people with PSD, but “unfortunately they don’t work for many patients,” Dr. Buckwalter noted. The findings “provide clues as to other molecular targets that are candidates novel therapies for poststroke depression.”

Dr. Blake commented that the proteomic study “complements the work by us and others interested in understanding PSD.”

Mood disorders “must be understood in terms of the dynamic relationships between structural neurological alterations, cellular and microbiological changes, psychological processes, and the person’s interactions with their social landscape,” Dr. Blake said.
 

New Treatments on the Horizon?

Gustavo C. Medeiros, MD, assistant professor, Department of Psychiatry, of the University of Maryland School of Medicine, Baltimore, said that knowing which individuals are more likely to develop PSD “allows treatment teams to implement earlier and more intensive interventions in those who are at higher risk.”

The findings [of the proteomic study] may also “help clarify the neurobiological correlates of PSD…[which] may help the development of new treatments that target these neurobiological changes,” said Dr. Medeiros, who wasn’t involved with either study.

However, he warned, “we should interpret their results with caution due to methodological reasons, including the relatively small sample size.”

Also commenting, Bruce Ovbiagele, MD, MSc, MAS, MBA, MLS, professor of neurology, UCSF Weill Institute for Neurosciences, California, said the proteomic study has some “clear limitations,” including the lack of Black or African American patients in the cohort, which limits generalizability, “since we know that Black and African American people are disproportionately affected by stroke and have very high rates of PSD and very severe presentation.”

The study by Dr. Blake et al. “was interesting because the phenotype of depressive symptoms after stroke differs from what’s seen in the general population, and the authors figured out a way to better understand the nuances of such differences,” said Dr. Ovbiagele, who wasn’t involved with either study.

He said he was also surprised by the finding regarding anhedonia and suggested that the findings be replicated in a study directly comparing patients with PSD and patients with depression from the general population.

The study by Bidoki et al. was funded by AHA/Paul Allen Foundation, the Leducq Stroke-IMPaCT Transatlantic Network of Excellence (MSB), the Wu Tsai Neurosciences Institute (MSB), the Alfred E. Mann Foundation (NA), and an Alzheimer’s Association Research Fellowship to one of the authors. No source of funding was listed for the study by Dr. Blake et al. The authors of both studies, Dr. Medeiros and Dr. Ovbiagele, declare no relevant financial relationships.

A version of this article appeared on Medscape.com.

The mechanisms underlying poststroke depression (PSD), a common and debilitating complication of stroke, are unclear. Is it neurobiological, psychosocial, or both?

Two studies offer new insight into this question. In the first, investigators systematically reviewed studies comparing stroke and non-stroke participants with depression and found the groups were similar in most dimensions of depressive symptoms. But surprisingly, anhedonia was less severe in patients with PSD compared with non-stroke controls, and those with PSD also showed greater emotional dysregulation.

“Our findings support previous recommendations that clinicians should adapt the provision of psychological support to the specific needs and difficulties of stroke survivors,” said lead author Joshua Blake, DClinPsy, lecturer in clinical psychology, University of East Anglia, Norwich, United Kingdom.

The study was published online in Neuropsychology Review

A second study used a machine learning algorithm to analyze blood samples from adults who had suffered a stroke, determining whether plasma protein data could predict mood and identifying potential proteins associated with mood in these patients.

“We can now look at a stroke survivor’s blood and predict their mood,” senior author Marion Buckwalter, MD, PhD, professor of neurology and neurosurgery at Stanford Medicine, California, said in a news release. “This means there is a genuine association between what’s happening in the blood and what’s happening with a person’s mood. It also means that, down the road, we may be able to develop new treatments for PSD.”

The study was published in November 2023 in Brain, Behavior, and Immunity.
 

‘Surprising’ Findings

“There has long been uncertainty over whether PSD might differ in its causes, phenomenology, and treatability, due to the presence of brain injury, related biological changes, and the psychosocial context unique to this population,” Dr. Blake said. “We felt that understanding symptomatologic similarities and differences would constructively contribute to this debate.”

The researchers reviewed 12 papers that sampled both stroke and non-stroke participants. “We compared profiles of depression symptoms, correlation strengths of individual depression symptoms with general depression, and latent item severity,” Dr. Blake reported.

They extracted 38 symptoms from five standardized depression tools and then organized the symptoms into nine dimensions.

They found mostly nonsignificant differences between patients with PSD and non-stroke controls in most dimensions, including negative affect, negative cognitions, somatic features, anxiety/worry, and suicidal ideation. Those with PSD more frequently had cognitive impairment, and “work inhibition” was more common in PSD.

But the most striking finding was greater severity/prevalence of emotional dysregulation in PSD vs non-stroke depression and also less anhedonia.

Dr. Blake acknowledged being “surprised.”

One possible explanation is that stroke recovery “appears to be a highly emotional journey, with extreme findings of both positive and negative emotions reported by survivors as they psychologically adjust,” which might be protective against anhedonia, he suggested.

Moreover, neurologically driven emotional dysregulation “may similarly reduce experiences of anhedonia.”

However, there was a “considerable risk of bias in many of the included studies, meaning it’s important that these findings are experimentally confirmed before stronger conclusions about phenomenological differences can be drawn,” he cautioned.
 

Common, Undertreated

Dr. Buckwalter said her team was motivated to conduct the research because PSD is among the top problems reported by chronic stroke patients, and for most, it is not adequately treated.

However, “despite the high prevalence of PSD, it is very poorly studied in the chronic time period.” In particular, PSD isn’t “well understood at a molecular level.”

She added that inflammation is a “promising candidate” as a mechanism, since neuroinflammation occurs in the stroke scar for decades, and chronic peripheral inflammation can produce neuroinflammation. Aberrant immune activation has also been implicated in major depression without stroke. But large studies with broad panels of plasma biomarkers are lacking in PSD.

To address this gap, the researchers used a proteomic approach. They recruited 85 chronic stroke patients (mean age, 65 years [interquartile range, 55-71], 41.2% female, 65.9% White, 17.6% Asian, and 0% Black) from the Stanford Stroke Recovery Program. Participants were between 5 months and 9 years after an ischemic stroke.

They analyzed a comprehensive panel of 1196 proteins in plasma samples, applying a machine learning algorithm to see whether the plasma protein levels “could be used to predict mood scores, using either the proteomics data alone or adding age and time since stroke.” The proteomics data were then incorporated into multivariable regression models, along with relevant clinical features, to ascertain the model’s predictive ability.

Mood was assessed using the Stroke Impact Scale mood questionnaire, with participants’ mood dichotomized into better mood (> 63) or worse mood (≤ 63).
 

‘Beautiful Mechanistic Model’

Machine learning verified a relationship between plasma proteomic data and mood, with the most accurate prediction occurring when the researchers added age and time since the stroke to the analysis.

Independent univariate analyses identified 202 proteins that were most highly correlated with mood in PSD. These were then organized into functional groups, including immune proteins, integrins, growth factors, synaptic function proteins, serotonin activity-related proteins, and cell death and stress-related functional groupings.

Although no single protein could predict depression, significant changes in levels of several proteins were found in PSD patients. A high proportion (45%) were proteins previously implicated in major depression, “likely providing a link to the underlying mechanisms of chronic PSD,” the authors stated.

Moreover, 80% of correlated immune proteins were higher in the plasma of people with worse mood, and several immune proteins known to have anti-inflammatory effects were reduced in those with worse mood.

And several pro-inflammatory cytokines were implicated. For example, interleukin 6, which has been extensively studied as a potential plasma marker of major depression in non-stroke cohorts, was significantly elevated in patients with worse mood after stroke (P = .0325), «implicating a broadly overactive immune system in PSD.»

“We demonstrated for the first time that we can use plasma protein measurements to predict mood in people with chronic stroke,” Dr. Buckwalter summarized. “This means there is a biological correlate of mood but [it] doesn’t tell us causality.”

To tease out causality, the researchers used their own data, as well as information from a literature review of previous studies, to assemble a model of how the immune response following a stroke could change both serotonin and brain plasticity.

“We used the most highly correlated proteins to construct a beautiful mechanistic model of how poststroke depression may work and how it may relate to mechanisms in major depression,” Dr. Buckwalter said.

The model “posits an increased inflammatory response that leads to decreased tryptophan, serotonin, and less synaptic function, all of which contribute to symptoms of depression.”

Currently, selective serotonin reuptake inhibitors represent the “best treatment” for people with PSD, but “unfortunately they don’t work for many patients,” Dr. Buckwalter noted. The findings “provide clues as to other molecular targets that are candidates novel therapies for poststroke depression.”

Dr. Blake commented that the proteomic study “complements the work by us and others interested in understanding PSD.”

Mood disorders “must be understood in terms of the dynamic relationships between structural neurological alterations, cellular and microbiological changes, psychological processes, and the person’s interactions with their social landscape,” Dr. Blake said.
 

New Treatments on the Horizon?

Gustavo C. Medeiros, MD, assistant professor, Department of Psychiatry, of the University of Maryland School of Medicine, Baltimore, said that knowing which individuals are more likely to develop PSD “allows treatment teams to implement earlier and more intensive interventions in those who are at higher risk.”

The findings [of the proteomic study] may also “help clarify the neurobiological correlates of PSD…[which] may help the development of new treatments that target these neurobiological changes,” said Dr. Medeiros, who wasn’t involved with either study.

However, he warned, “we should interpret their results with caution due to methodological reasons, including the relatively small sample size.”

Also commenting, Bruce Ovbiagele, MD, MSc, MAS, MBA, MLS, professor of neurology, UCSF Weill Institute for Neurosciences, California, said the proteomic study has some “clear limitations,” including the lack of Black or African American patients in the cohort, which limits generalizability, “since we know that Black and African American people are disproportionately affected by stroke and have very high rates of PSD and very severe presentation.”

The study by Dr. Blake et al. “was interesting because the phenotype of depressive symptoms after stroke differs from what’s seen in the general population, and the authors figured out a way to better understand the nuances of such differences,” said Dr. Ovbiagele, who wasn’t involved with either study.

He said he was also surprised by the finding regarding anhedonia and suggested that the findings be replicated in a study directly comparing patients with PSD and patients with depression from the general population.

The study by Bidoki et al. was funded by AHA/Paul Allen Foundation, the Leducq Stroke-IMPaCT Transatlantic Network of Excellence (MSB), the Wu Tsai Neurosciences Institute (MSB), the Alfred E. Mann Foundation (NA), and an Alzheimer’s Association Research Fellowship to one of the authors. No source of funding was listed for the study by Dr. Blake et al. The authors of both studies, Dr. Medeiros and Dr. Ovbiagele, declare no relevant financial relationships.

A version of this article appeared on Medscape.com.