First Cases of Medically Acquired Alzheimer’s Disease Reported

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Changed
Mon, 01/29/2024 - 14:02

Five people in the United Kingdom have been diagnosed with Alzheimer’s disease resulting from a medical treatment they received decades earlier, new research shows. 

Investigators say they are the first known cases of medically acquired AD in living people, but outside experts say the findings should be interpreted cautiously.

The individuals received treatment as children with human growth hormone extracted from pituitary glands of cadavers (c-hGH). Between 1958-1985, an estimated 30,000 people worldwide, mostly children, were treated with c-hGH for genetic disorders and growth hormone deficiencies. 

The therapy was halted in 1985 after three patients in the US who received the treatment later died of Creutzfeldt-Jakob disease (CJD) transmitted through batches of c-hGH that were contaminated with disease-causing prions. 

The new study builds on the investigators’ earlier work that showed the batches of c-hGH also contained amyloid-beta protein and that the protein could be transmitted decades later. These five cases were referred to or reviewed by researchers and clinicians at a prion clinic led by one of the lead researchers.

There are no reports of amyloid-beta transmission through any other medical or surgical procedures, researchers stress, and there is no evidence that amyloid-beta can be passed on during routine patient care or in daily activities. 

“However, the recognition of transmission of amyloid-beta pathology in these rare situations should lead us to review measures to prevent accidental transmission via other medical or surgical procedures, in order to prevent such cases occurring in future,” lead author John Collinge, MD, director of the University of College London Institute of Prion Diseases, London, England, and leader of the UK’s National Prion Clinic, said in a press release. 

“Importantly, our findings also suggest that Alzheimer’s and some other neurological conditions share similar disease processes to CJD, and this may have important implications for understanding and treating Alzheimer’s disease in the future,” Dr. Collinge continued.

The findings were published online January 29 in Nature Medicine. 
 

Building on Earlier Work

The research builds on investigators’ previous 2015 work that found archived samples of c-hGH were also contaminated with amyloid-beta protein. In 2018, mouse studies showed that c-hGH samples stored for decades could still transmit amyloid-beta via injection. 

Researchers said the findings suggested that individuals exposed to contaminated c-hGH who did not die from CJD might eventually develop AD.

Patients in the new study developed neurological symptoms consistent with AD between the ages of 38 and 55 years. The individual cases were either referred to or reviewed by experts in the National Prion Clinic in the UK between 2017 and 2022. The clinic coordinates the National Prion Monitoring Cohort, a longitudinal study of individuals with confirmed prion diseases. 

Of the eight cases, three were diagnosed with AD before referral to the clinic; two others met criteria for an AD diagnosis; and three did not meet the criteria. Three of the patients — two of whom had AD — are now deceased. 

All patients in the study received c-hGH prepared using a method called Wilhelmi or Hartree-modified Wilhelmi preparation (HWP).

Biomarker analyses confirmed the AD diagnosis in two patients. Other cases showed either progressive brain volume loss on brain imaging or elevated cerebrospinal fluid total tau and phosphorylated tau, or evidence of amyloid-beta deposits on autopsy. 
 

 

 

‘Potentially Transmissible’

The cases offered diverse presentations. Some were not symptomatic and some failed to meet current diagnostic criteria for sporadic Alzheimer’s disease. Treatment duration and frequency differed among those in the study, as did their age at treatment onset and completion. That and other factors could contribute to the diverse phenotype recorded in individuals, investigators note. 

Investigators examined and ruled out other factors that might explain the individuals’ cognitive symptoms, including childhood intellectual disability, which has been linked to dementia risk, the underlying condition that prompted their treatment with c-hGH, growth hormone deficiency, and cranial radiotherapy, which four of the individuals had received. They also ruled out inherited disease in all five of the cases with samples available for testing. 

“Taken together, the only factor common to all of the patients whom we describe is treatment with the HWP subtype of c-hGH,” the authors write. “Given the strong experimental evidence for A-beta transmission from relevant archived HWP c-hGH batches, we conclude that this is the most plausible explanation for the findings observed.”

Investigators say the findings show that, like other prion diseases, AD has three etiologies: sporadic, inherited, and rare acquired forms, or iatrogenic AD. 

“The clinical syndrome developed by these individuals can, therefore, be termed iatrogenic Alzheimer’s disease, and Alzheimer’s disease should now be recognized as a potentially transmissible disorder,” the authors write. 

“Our cases suggest that, similarly to what is observed in human prion diseases, iatrogenic forms of Alzheimer’s disease differ phenotypically from sporadic and inherited forms, with some individuals remaining asymptomatic despite exposure to A-beta seeds due to protective factors that, at present, are unknown,” they continue
 

‘Measure of Skepticism’

In an accompanying editorial, Mathias Jucker, PhD, of the Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany, and Lary C. Walker, PhD, in the Department of Neurology at Emory University, Atlanta, write that the findings should be considered “with a measure of skepticism.”

“The cases presented are diverse and complicated; the individuals had undergone a variety of medical interventions for various disorders earlier in life, and it is difficult to exclude a contribution of these circumstances to the complex disease phenotypes that appeared many years later,” they write. 

However, they continue, “there is good reason to take the findings seriously.”

“From a practical standpoint, this report reinforces the potential of amyloid-beta seeds as targets for early prevention, and it underscores the importance of informed caution in the preparation of surgical instruments, handling of tissues, and implementation of therapeutic biologics, particularly those derived from human sources,” Dr. Jucker and Dr. Walker write. 

Commenting on the findings for this news organization, Christopher Weber, PhD, director of global science initiatives for the Alzheimer’s Association, says the idea that amyloid-beta is transmissible between individuals has been shown before. 

“We’ve known for a long time that it is possible to create abnormal amyloid buildup — similar to that seen in Alzheimer’s – in the brain of an animal by injecting it with amyloid-beta. We also transfer human Alzheimer’s genes into animals to initiate abnormal, Alzheimer’s-like processes in their brains,” he said. “Thus, the idea that amyloid is transferable between individuals is not so novel as implied in the new paper.”

However, the study does highlight the importance of safety measures to prevent the accidental transmission of amyloid-beta, Weber added. 

“It is a reasonable and actionable caution that the scientific and clinical communities must understand the possible risks and ensure that all methods of transmission are eliminated — for example, with complete and conscientious sterilization of surgical instruments,” he said. “Bottom line: We shouldn’t put amyloid-beta into people’s brains, either accidentally or on purpose, and appropriate measures should be in place to ensure that doesn’t happen.”

The study was supported by the Medical Research Council, the National Institute for Health and Care Research (NIHR), the NIHR University College of London Hospital Biomedical Research Centre, Alzheimer’s Research UK, and the Stroke Association. Dr. Collinge is a shareholder and director of D-Gen, Ltd., an academic spin-out company working in the field of prion disease diagnosis, decontamination and therapeutics. Dr. Jucker and Dr. Walker report no conflicts of interest. 

A version of this article appeared on Medscape.com.

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Five people in the United Kingdom have been diagnosed with Alzheimer’s disease resulting from a medical treatment they received decades earlier, new research shows. 

Investigators say they are the first known cases of medically acquired AD in living people, but outside experts say the findings should be interpreted cautiously.

The individuals received treatment as children with human growth hormone extracted from pituitary glands of cadavers (c-hGH). Between 1958-1985, an estimated 30,000 people worldwide, mostly children, were treated with c-hGH for genetic disorders and growth hormone deficiencies. 

The therapy was halted in 1985 after three patients in the US who received the treatment later died of Creutzfeldt-Jakob disease (CJD) transmitted through batches of c-hGH that were contaminated with disease-causing prions. 

The new study builds on the investigators’ earlier work that showed the batches of c-hGH also contained amyloid-beta protein and that the protein could be transmitted decades later. These five cases were referred to or reviewed by researchers and clinicians at a prion clinic led by one of the lead researchers.

There are no reports of amyloid-beta transmission through any other medical or surgical procedures, researchers stress, and there is no evidence that amyloid-beta can be passed on during routine patient care or in daily activities. 

“However, the recognition of transmission of amyloid-beta pathology in these rare situations should lead us to review measures to prevent accidental transmission via other medical or surgical procedures, in order to prevent such cases occurring in future,” lead author John Collinge, MD, director of the University of College London Institute of Prion Diseases, London, England, and leader of the UK’s National Prion Clinic, said in a press release. 

“Importantly, our findings also suggest that Alzheimer’s and some other neurological conditions share similar disease processes to CJD, and this may have important implications for understanding and treating Alzheimer’s disease in the future,” Dr. Collinge continued.

The findings were published online January 29 in Nature Medicine. 
 

Building on Earlier Work

The research builds on investigators’ previous 2015 work that found archived samples of c-hGH were also contaminated with amyloid-beta protein. In 2018, mouse studies showed that c-hGH samples stored for decades could still transmit amyloid-beta via injection. 

Researchers said the findings suggested that individuals exposed to contaminated c-hGH who did not die from CJD might eventually develop AD.

Patients in the new study developed neurological symptoms consistent with AD between the ages of 38 and 55 years. The individual cases were either referred to or reviewed by experts in the National Prion Clinic in the UK between 2017 and 2022. The clinic coordinates the National Prion Monitoring Cohort, a longitudinal study of individuals with confirmed prion diseases. 

Of the eight cases, three were diagnosed with AD before referral to the clinic; two others met criteria for an AD diagnosis; and three did not meet the criteria. Three of the patients — two of whom had AD — are now deceased. 

All patients in the study received c-hGH prepared using a method called Wilhelmi or Hartree-modified Wilhelmi preparation (HWP).

Biomarker analyses confirmed the AD diagnosis in two patients. Other cases showed either progressive brain volume loss on brain imaging or elevated cerebrospinal fluid total tau and phosphorylated tau, or evidence of amyloid-beta deposits on autopsy. 
 

 

 

‘Potentially Transmissible’

The cases offered diverse presentations. Some were not symptomatic and some failed to meet current diagnostic criteria for sporadic Alzheimer’s disease. Treatment duration and frequency differed among those in the study, as did their age at treatment onset and completion. That and other factors could contribute to the diverse phenotype recorded in individuals, investigators note. 

Investigators examined and ruled out other factors that might explain the individuals’ cognitive symptoms, including childhood intellectual disability, which has been linked to dementia risk, the underlying condition that prompted their treatment with c-hGH, growth hormone deficiency, and cranial radiotherapy, which four of the individuals had received. They also ruled out inherited disease in all five of the cases with samples available for testing. 

“Taken together, the only factor common to all of the patients whom we describe is treatment with the HWP subtype of c-hGH,” the authors write. “Given the strong experimental evidence for A-beta transmission from relevant archived HWP c-hGH batches, we conclude that this is the most plausible explanation for the findings observed.”

Investigators say the findings show that, like other prion diseases, AD has three etiologies: sporadic, inherited, and rare acquired forms, or iatrogenic AD. 

“The clinical syndrome developed by these individuals can, therefore, be termed iatrogenic Alzheimer’s disease, and Alzheimer’s disease should now be recognized as a potentially transmissible disorder,” the authors write. 

“Our cases suggest that, similarly to what is observed in human prion diseases, iatrogenic forms of Alzheimer’s disease differ phenotypically from sporadic and inherited forms, with some individuals remaining asymptomatic despite exposure to A-beta seeds due to protective factors that, at present, are unknown,” they continue
 

‘Measure of Skepticism’

In an accompanying editorial, Mathias Jucker, PhD, of the Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany, and Lary C. Walker, PhD, in the Department of Neurology at Emory University, Atlanta, write that the findings should be considered “with a measure of skepticism.”

“The cases presented are diverse and complicated; the individuals had undergone a variety of medical interventions for various disorders earlier in life, and it is difficult to exclude a contribution of these circumstances to the complex disease phenotypes that appeared many years later,” they write. 

However, they continue, “there is good reason to take the findings seriously.”

“From a practical standpoint, this report reinforces the potential of amyloid-beta seeds as targets for early prevention, and it underscores the importance of informed caution in the preparation of surgical instruments, handling of tissues, and implementation of therapeutic biologics, particularly those derived from human sources,” Dr. Jucker and Dr. Walker write. 

Commenting on the findings for this news organization, Christopher Weber, PhD, director of global science initiatives for the Alzheimer’s Association, says the idea that amyloid-beta is transmissible between individuals has been shown before. 

“We’ve known for a long time that it is possible to create abnormal amyloid buildup — similar to that seen in Alzheimer’s – in the brain of an animal by injecting it with amyloid-beta. We also transfer human Alzheimer’s genes into animals to initiate abnormal, Alzheimer’s-like processes in their brains,” he said. “Thus, the idea that amyloid is transferable between individuals is not so novel as implied in the new paper.”

However, the study does highlight the importance of safety measures to prevent the accidental transmission of amyloid-beta, Weber added. 

“It is a reasonable and actionable caution that the scientific and clinical communities must understand the possible risks and ensure that all methods of transmission are eliminated — for example, with complete and conscientious sterilization of surgical instruments,” he said. “Bottom line: We shouldn’t put amyloid-beta into people’s brains, either accidentally or on purpose, and appropriate measures should be in place to ensure that doesn’t happen.”

The study was supported by the Medical Research Council, the National Institute for Health and Care Research (NIHR), the NIHR University College of London Hospital Biomedical Research Centre, Alzheimer’s Research UK, and the Stroke Association. Dr. Collinge is a shareholder and director of D-Gen, Ltd., an academic spin-out company working in the field of prion disease diagnosis, decontamination and therapeutics. Dr. Jucker and Dr. Walker report no conflicts of interest. 

A version of this article appeared on Medscape.com.

Five people in the United Kingdom have been diagnosed with Alzheimer’s disease resulting from a medical treatment they received decades earlier, new research shows. 

Investigators say they are the first known cases of medically acquired AD in living people, but outside experts say the findings should be interpreted cautiously.

The individuals received treatment as children with human growth hormone extracted from pituitary glands of cadavers (c-hGH). Between 1958-1985, an estimated 30,000 people worldwide, mostly children, were treated with c-hGH for genetic disorders and growth hormone deficiencies. 

The therapy was halted in 1985 after three patients in the US who received the treatment later died of Creutzfeldt-Jakob disease (CJD) transmitted through batches of c-hGH that were contaminated with disease-causing prions. 

The new study builds on the investigators’ earlier work that showed the batches of c-hGH also contained amyloid-beta protein and that the protein could be transmitted decades later. These five cases were referred to or reviewed by researchers and clinicians at a prion clinic led by one of the lead researchers.

There are no reports of amyloid-beta transmission through any other medical or surgical procedures, researchers stress, and there is no evidence that amyloid-beta can be passed on during routine patient care or in daily activities. 

“However, the recognition of transmission of amyloid-beta pathology in these rare situations should lead us to review measures to prevent accidental transmission via other medical or surgical procedures, in order to prevent such cases occurring in future,” lead author John Collinge, MD, director of the University of College London Institute of Prion Diseases, London, England, and leader of the UK’s National Prion Clinic, said in a press release. 

“Importantly, our findings also suggest that Alzheimer’s and some other neurological conditions share similar disease processes to CJD, and this may have important implications for understanding and treating Alzheimer’s disease in the future,” Dr. Collinge continued.

The findings were published online January 29 in Nature Medicine. 
 

Building on Earlier Work

The research builds on investigators’ previous 2015 work that found archived samples of c-hGH were also contaminated with amyloid-beta protein. In 2018, mouse studies showed that c-hGH samples stored for decades could still transmit amyloid-beta via injection. 

Researchers said the findings suggested that individuals exposed to contaminated c-hGH who did not die from CJD might eventually develop AD.

Patients in the new study developed neurological symptoms consistent with AD between the ages of 38 and 55 years. The individual cases were either referred to or reviewed by experts in the National Prion Clinic in the UK between 2017 and 2022. The clinic coordinates the National Prion Monitoring Cohort, a longitudinal study of individuals with confirmed prion diseases. 

Of the eight cases, three were diagnosed with AD before referral to the clinic; two others met criteria for an AD diagnosis; and three did not meet the criteria. Three of the patients — two of whom had AD — are now deceased. 

All patients in the study received c-hGH prepared using a method called Wilhelmi or Hartree-modified Wilhelmi preparation (HWP).

Biomarker analyses confirmed the AD diagnosis in two patients. Other cases showed either progressive brain volume loss on brain imaging or elevated cerebrospinal fluid total tau and phosphorylated tau, or evidence of amyloid-beta deposits on autopsy. 
 

 

 

‘Potentially Transmissible’

The cases offered diverse presentations. Some were not symptomatic and some failed to meet current diagnostic criteria for sporadic Alzheimer’s disease. Treatment duration and frequency differed among those in the study, as did their age at treatment onset and completion. That and other factors could contribute to the diverse phenotype recorded in individuals, investigators note. 

Investigators examined and ruled out other factors that might explain the individuals’ cognitive symptoms, including childhood intellectual disability, which has been linked to dementia risk, the underlying condition that prompted their treatment with c-hGH, growth hormone deficiency, and cranial radiotherapy, which four of the individuals had received. They also ruled out inherited disease in all five of the cases with samples available for testing. 

“Taken together, the only factor common to all of the patients whom we describe is treatment with the HWP subtype of c-hGH,” the authors write. “Given the strong experimental evidence for A-beta transmission from relevant archived HWP c-hGH batches, we conclude that this is the most plausible explanation for the findings observed.”

Investigators say the findings show that, like other prion diseases, AD has three etiologies: sporadic, inherited, and rare acquired forms, or iatrogenic AD. 

“The clinical syndrome developed by these individuals can, therefore, be termed iatrogenic Alzheimer’s disease, and Alzheimer’s disease should now be recognized as a potentially transmissible disorder,” the authors write. 

“Our cases suggest that, similarly to what is observed in human prion diseases, iatrogenic forms of Alzheimer’s disease differ phenotypically from sporadic and inherited forms, with some individuals remaining asymptomatic despite exposure to A-beta seeds due to protective factors that, at present, are unknown,” they continue
 

‘Measure of Skepticism’

In an accompanying editorial, Mathias Jucker, PhD, of the Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany, and Lary C. Walker, PhD, in the Department of Neurology at Emory University, Atlanta, write that the findings should be considered “with a measure of skepticism.”

“The cases presented are diverse and complicated; the individuals had undergone a variety of medical interventions for various disorders earlier in life, and it is difficult to exclude a contribution of these circumstances to the complex disease phenotypes that appeared many years later,” they write. 

However, they continue, “there is good reason to take the findings seriously.”

“From a practical standpoint, this report reinforces the potential of amyloid-beta seeds as targets for early prevention, and it underscores the importance of informed caution in the preparation of surgical instruments, handling of tissues, and implementation of therapeutic biologics, particularly those derived from human sources,” Dr. Jucker and Dr. Walker write. 

Commenting on the findings for this news organization, Christopher Weber, PhD, director of global science initiatives for the Alzheimer’s Association, says the idea that amyloid-beta is transmissible between individuals has been shown before. 

“We’ve known for a long time that it is possible to create abnormal amyloid buildup — similar to that seen in Alzheimer’s – in the brain of an animal by injecting it with amyloid-beta. We also transfer human Alzheimer’s genes into animals to initiate abnormal, Alzheimer’s-like processes in their brains,” he said. “Thus, the idea that amyloid is transferable between individuals is not so novel as implied in the new paper.”

However, the study does highlight the importance of safety measures to prevent the accidental transmission of amyloid-beta, Weber added. 

“It is a reasonable and actionable caution that the scientific and clinical communities must understand the possible risks and ensure that all methods of transmission are eliminated — for example, with complete and conscientious sterilization of surgical instruments,” he said. “Bottom line: We shouldn’t put amyloid-beta into people’s brains, either accidentally or on purpose, and appropriate measures should be in place to ensure that doesn’t happen.”

The study was supported by the Medical Research Council, the National Institute for Health and Care Research (NIHR), the NIHR University College of London Hospital Biomedical Research Centre, Alzheimer’s Research UK, and the Stroke Association. Dr. Collinge is a shareholder and director of D-Gen, Ltd., an academic spin-out company working in the field of prion disease diagnosis, decontamination and therapeutics. Dr. Jucker and Dr. Walker report no conflicts of interest. 

A version of this article appeared on Medscape.com.

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Robotic Garment Improves Stride in Patient With Parkinson’s Disease

Article Type
Changed
Tue, 01/23/2024 - 09:22

A wearable, soft, robotic device could help patients with Parkinson’s disease (PD) walk without experiencing freezing of gait (FoG), early research suggested.

The robotic apparel, worn around the hips and thighs, gently pushes the hips as the leg swings, facilitating a longer stride and preventing FoG, a common disorder in PD that affects nearly all patients over the disease course.

The small, proof-of-concept study included one person with PD. But investigators noted the reduction in freezing and falls and improvement in walking distance and speed was dramatic. Incidence of FoG decreased from 63% to just 6% when the patient wore the robotic garment outdoors. Wearing the device indoors eliminated freezing altogether.

“We demonstrate proof-of-concept that FoG can be averted using a soft robotic device — a machine that aims to apply physical assistance to movement with minimal restriction, a fundamentally different approach to rigid exoskeletons,” lead investigators Conor Walsh, PhD, and Terry Ellis, PhD, PT, told this news organization.

Walsh is a professor at Harvard John A. Paulson School of Engineering and Applied Sciences in Boston, and Ellis is a professor and chair of the physical therapy department and director of the Center for Neurorehabilitation, Boston University, Boston, Massachusetts.

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

Disabling Disturbance

From a biomechanical perspective, FoG is manifested by an overt breakdown in spatial and temporal mechanics of walking. The impaired limb coordination occurs during the “swing phase” of the gait cycle.

There are currently no interventions that prevent FoG. Available treatment interventions include pharmacotherapy, such as dopamine replacement; deep brain stimulation (DBS) of the subthalamic nucleus; and behavioral interventions, such as cueing strategies. All have shown only modest effects in reducing FoG and, in some cases, might even worsen it, the investigators noted.

“This challenge led us to become interested in leveraging soft wearable robots to deliver mechanical cues to disrupt aberrant gait mechanics and prevent FOG in people with PD,” Dr. Walsh and Dr. Ellis said.

“Wearable robots” have been used to augment kinematics in neurologic conditions, such as stroke, cerebral palsy, and spinal cord injury. Harnessing this technology to address FoG required “a collaboration between engineers, rehabilitation scientists, physical therapists, biomechanists, and apparel designers,” the researchers said.

The wearable robotic device uses cable-driven actuators, which enable physical movement by converting electrical energy into mechanical force, and sensors worn around the waist and thighs. Using motion data collected by the sensors, algorithms estimate the phase of the walking cycle and generate assistive forces in concert with biological muscles.

Real-World Testing

The researchers tested the robotic garment on a 73-year-old man with idiopathic PD of 10-year duration. The man’s ongoing pharmacologic treatment included 1.5 tablets of 25- to 100-mg carbidopa/levodopa taken four times per day, one tablet of 100-mg amantadine twice per day, and one tablet of 200-mg entacapone taken four times per day.

He had also undergone DBS to the globus pallidus internus and utilized behavioral strategies. Despite these interventions, he continued to endure more than 10 episodes of FoG per day and numerous falls.

The patient tended to use walls to stabilize himself when walking. Freezing episodes were observed mostly when he walked in open hallways, turned, walked outdoors, and when he tried to walk and talk simultaneously.

The research was conducted over a 6-month period, with a total of five study sessions that consisted of walking trials. Four were administered in the laboratory. The fifth was conducted in a real-world outdoor community setting.

During the first visit, a biomechanical analysis of walking was performed under single-task conditions during the medication-on phase.

Testing was usually conducted during medication-on phase and under single-task conditions. But testing conditions also included attention-demanding dual tasks and single-task walking during the medication-off phase.

The researchers compared the effects of the assistance of the robotic apparel to no apparel and with the apparel turned off. They measured the percentage of time spent freezing and the total distance walked.

 

 

Robust Response

The participant demonstrated a “robust response” to the robotic apparel. With the garment’s assistance, FoG was eliminated when worn indoors, and walking distance increased by 55%. The participant walked faster and had a 25% reduction in gait variability.

These beneficial effects were repeated across multiple days as well as different types of provoking conditions and environmental contexts. When the device was tried outdoors, FoG decreased from 63% to 6% of the time. The patient was also able to simultaneously walk and talk without freezing.

“When the device assisted with hip flexion during the terminal stance phase of walking (when lifting the toe), FoG was instantaneously eliminated during inner walking, accompanied by clinically significant improvement in walking speeds and distance,” Dr. Walsh and Dr. Ellis reported.

The approach “suggests the potential benefits of a ‘bottom-up’ rather than a ‘top-down’ solution to treating gait freezing,” they commented. “We see that restoring almost-normal biomechanics alters the peripheral dynamics of gait and may influence the central processing of gait control.”

Bringing Hope

Rebecca Gilbert MD, PhD, chief mission officer, American Parkinson Disease Association, said this new approach is “exciting.”

Whether the benefits will be as robust in other people with PD “remains to be seen,” said Dr. Gilbert, who was not involved with the study.

“The paper states that multiple experimental variables utilizing the device could potentially be adjusted to serve different people with PD, and these will need to be tested in clinical trials as well,” Dr. Gilbert said.

Additionally, “the device itself is complex and may be challenging to get on and off without help, which may limit its usability in the community,” Dr. Gilbert noted.

Although more work is needed, the study “represents a remarkable proof of concept that brings hope to those with FoG,” she added.

These “promising findings prompt further investigation to validate the effects of the robotic apparel on a broader range of individuals with PD experiencing FoG and across various FoG phenotypes and environments and task contexts, complemented with FoG metrics that include quantification of the severity of the freezing episodes,” Walsh and Ellis added.

This study was based on work supported by the National Science Foundation, the National Institutes of Health, and the Massachusetts Technology Collaborative, Collaborative Research and Development Matching Grant. This work was also partially funded by the John A. Paulson School of Engineering and Applied Sciences at Harvard University as well as received financial support from the Samsung Scholarship.
 

A version of this article appeared on Medscape.com.

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A wearable, soft, robotic device could help patients with Parkinson’s disease (PD) walk without experiencing freezing of gait (FoG), early research suggested.

The robotic apparel, worn around the hips and thighs, gently pushes the hips as the leg swings, facilitating a longer stride and preventing FoG, a common disorder in PD that affects nearly all patients over the disease course.

The small, proof-of-concept study included one person with PD. But investigators noted the reduction in freezing and falls and improvement in walking distance and speed was dramatic. Incidence of FoG decreased from 63% to just 6% when the patient wore the robotic garment outdoors. Wearing the device indoors eliminated freezing altogether.

“We demonstrate proof-of-concept that FoG can be averted using a soft robotic device — a machine that aims to apply physical assistance to movement with minimal restriction, a fundamentally different approach to rigid exoskeletons,” lead investigators Conor Walsh, PhD, and Terry Ellis, PhD, PT, told this news organization.

Walsh is a professor at Harvard John A. Paulson School of Engineering and Applied Sciences in Boston, and Ellis is a professor and chair of the physical therapy department and director of the Center for Neurorehabilitation, Boston University, Boston, Massachusetts.

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

Disabling Disturbance

From a biomechanical perspective, FoG is manifested by an overt breakdown in spatial and temporal mechanics of walking. The impaired limb coordination occurs during the “swing phase” of the gait cycle.

There are currently no interventions that prevent FoG. Available treatment interventions include pharmacotherapy, such as dopamine replacement; deep brain stimulation (DBS) of the subthalamic nucleus; and behavioral interventions, such as cueing strategies. All have shown only modest effects in reducing FoG and, in some cases, might even worsen it, the investigators noted.

“This challenge led us to become interested in leveraging soft wearable robots to deliver mechanical cues to disrupt aberrant gait mechanics and prevent FOG in people with PD,” Dr. Walsh and Dr. Ellis said.

“Wearable robots” have been used to augment kinematics in neurologic conditions, such as stroke, cerebral palsy, and spinal cord injury. Harnessing this technology to address FoG required “a collaboration between engineers, rehabilitation scientists, physical therapists, biomechanists, and apparel designers,” the researchers said.

The wearable robotic device uses cable-driven actuators, which enable physical movement by converting electrical energy into mechanical force, and sensors worn around the waist and thighs. Using motion data collected by the sensors, algorithms estimate the phase of the walking cycle and generate assistive forces in concert with biological muscles.

Real-World Testing

The researchers tested the robotic garment on a 73-year-old man with idiopathic PD of 10-year duration. The man’s ongoing pharmacologic treatment included 1.5 tablets of 25- to 100-mg carbidopa/levodopa taken four times per day, one tablet of 100-mg amantadine twice per day, and one tablet of 200-mg entacapone taken four times per day.

He had also undergone DBS to the globus pallidus internus and utilized behavioral strategies. Despite these interventions, he continued to endure more than 10 episodes of FoG per day and numerous falls.

The patient tended to use walls to stabilize himself when walking. Freezing episodes were observed mostly when he walked in open hallways, turned, walked outdoors, and when he tried to walk and talk simultaneously.

The research was conducted over a 6-month period, with a total of five study sessions that consisted of walking trials. Four were administered in the laboratory. The fifth was conducted in a real-world outdoor community setting.

During the first visit, a biomechanical analysis of walking was performed under single-task conditions during the medication-on phase.

Testing was usually conducted during medication-on phase and under single-task conditions. But testing conditions also included attention-demanding dual tasks and single-task walking during the medication-off phase.

The researchers compared the effects of the assistance of the robotic apparel to no apparel and with the apparel turned off. They measured the percentage of time spent freezing and the total distance walked.

 

 

Robust Response

The participant demonstrated a “robust response” to the robotic apparel. With the garment’s assistance, FoG was eliminated when worn indoors, and walking distance increased by 55%. The participant walked faster and had a 25% reduction in gait variability.

These beneficial effects were repeated across multiple days as well as different types of provoking conditions and environmental contexts. When the device was tried outdoors, FoG decreased from 63% to 6% of the time. The patient was also able to simultaneously walk and talk without freezing.

“When the device assisted with hip flexion during the terminal stance phase of walking (when lifting the toe), FoG was instantaneously eliminated during inner walking, accompanied by clinically significant improvement in walking speeds and distance,” Dr. Walsh and Dr. Ellis reported.

The approach “suggests the potential benefits of a ‘bottom-up’ rather than a ‘top-down’ solution to treating gait freezing,” they commented. “We see that restoring almost-normal biomechanics alters the peripheral dynamics of gait and may influence the central processing of gait control.”

Bringing Hope

Rebecca Gilbert MD, PhD, chief mission officer, American Parkinson Disease Association, said this new approach is “exciting.”

Whether the benefits will be as robust in other people with PD “remains to be seen,” said Dr. Gilbert, who was not involved with the study.

“The paper states that multiple experimental variables utilizing the device could potentially be adjusted to serve different people with PD, and these will need to be tested in clinical trials as well,” Dr. Gilbert said.

Additionally, “the device itself is complex and may be challenging to get on and off without help, which may limit its usability in the community,” Dr. Gilbert noted.

Although more work is needed, the study “represents a remarkable proof of concept that brings hope to those with FoG,” she added.

These “promising findings prompt further investigation to validate the effects of the robotic apparel on a broader range of individuals with PD experiencing FoG and across various FoG phenotypes and environments and task contexts, complemented with FoG metrics that include quantification of the severity of the freezing episodes,” Walsh and Ellis added.

This study was based on work supported by the National Science Foundation, the National Institutes of Health, and the Massachusetts Technology Collaborative, Collaborative Research and Development Matching Grant. This work was also partially funded by the John A. Paulson School of Engineering and Applied Sciences at Harvard University as well as received financial support from the Samsung Scholarship.
 

A version of this article appeared on Medscape.com.

A wearable, soft, robotic device could help patients with Parkinson’s disease (PD) walk without experiencing freezing of gait (FoG), early research suggested.

The robotic apparel, worn around the hips and thighs, gently pushes the hips as the leg swings, facilitating a longer stride and preventing FoG, a common disorder in PD that affects nearly all patients over the disease course.

The small, proof-of-concept study included one person with PD. But investigators noted the reduction in freezing and falls and improvement in walking distance and speed was dramatic. Incidence of FoG decreased from 63% to just 6% when the patient wore the robotic garment outdoors. Wearing the device indoors eliminated freezing altogether.

“We demonstrate proof-of-concept that FoG can be averted using a soft robotic device — a machine that aims to apply physical assistance to movement with minimal restriction, a fundamentally different approach to rigid exoskeletons,” lead investigators Conor Walsh, PhD, and Terry Ellis, PhD, PT, told this news organization.

Walsh is a professor at Harvard John A. Paulson School of Engineering and Applied Sciences in Boston, and Ellis is a professor and chair of the physical therapy department and director of the Center for Neurorehabilitation, Boston University, Boston, Massachusetts.

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

Disabling Disturbance

From a biomechanical perspective, FoG is manifested by an overt breakdown in spatial and temporal mechanics of walking. The impaired limb coordination occurs during the “swing phase” of the gait cycle.

There are currently no interventions that prevent FoG. Available treatment interventions include pharmacotherapy, such as dopamine replacement; deep brain stimulation (DBS) of the subthalamic nucleus; and behavioral interventions, such as cueing strategies. All have shown only modest effects in reducing FoG and, in some cases, might even worsen it, the investigators noted.

“This challenge led us to become interested in leveraging soft wearable robots to deliver mechanical cues to disrupt aberrant gait mechanics and prevent FOG in people with PD,” Dr. Walsh and Dr. Ellis said.

“Wearable robots” have been used to augment kinematics in neurologic conditions, such as stroke, cerebral palsy, and spinal cord injury. Harnessing this technology to address FoG required “a collaboration between engineers, rehabilitation scientists, physical therapists, biomechanists, and apparel designers,” the researchers said.

The wearable robotic device uses cable-driven actuators, which enable physical movement by converting electrical energy into mechanical force, and sensors worn around the waist and thighs. Using motion data collected by the sensors, algorithms estimate the phase of the walking cycle and generate assistive forces in concert with biological muscles.

Real-World Testing

The researchers tested the robotic garment on a 73-year-old man with idiopathic PD of 10-year duration. The man’s ongoing pharmacologic treatment included 1.5 tablets of 25- to 100-mg carbidopa/levodopa taken four times per day, one tablet of 100-mg amantadine twice per day, and one tablet of 200-mg entacapone taken four times per day.

He had also undergone DBS to the globus pallidus internus and utilized behavioral strategies. Despite these interventions, he continued to endure more than 10 episodes of FoG per day and numerous falls.

The patient tended to use walls to stabilize himself when walking. Freezing episodes were observed mostly when he walked in open hallways, turned, walked outdoors, and when he tried to walk and talk simultaneously.

The research was conducted over a 6-month period, with a total of five study sessions that consisted of walking trials. Four were administered in the laboratory. The fifth was conducted in a real-world outdoor community setting.

During the first visit, a biomechanical analysis of walking was performed under single-task conditions during the medication-on phase.

Testing was usually conducted during medication-on phase and under single-task conditions. But testing conditions also included attention-demanding dual tasks and single-task walking during the medication-off phase.

The researchers compared the effects of the assistance of the robotic apparel to no apparel and with the apparel turned off. They measured the percentage of time spent freezing and the total distance walked.

 

 

Robust Response

The participant demonstrated a “robust response” to the robotic apparel. With the garment’s assistance, FoG was eliminated when worn indoors, and walking distance increased by 55%. The participant walked faster and had a 25% reduction in gait variability.

These beneficial effects were repeated across multiple days as well as different types of provoking conditions and environmental contexts. When the device was tried outdoors, FoG decreased from 63% to 6% of the time. The patient was also able to simultaneously walk and talk without freezing.

“When the device assisted with hip flexion during the terminal stance phase of walking (when lifting the toe), FoG was instantaneously eliminated during inner walking, accompanied by clinically significant improvement in walking speeds and distance,” Dr. Walsh and Dr. Ellis reported.

The approach “suggests the potential benefits of a ‘bottom-up’ rather than a ‘top-down’ solution to treating gait freezing,” they commented. “We see that restoring almost-normal biomechanics alters the peripheral dynamics of gait and may influence the central processing of gait control.”

Bringing Hope

Rebecca Gilbert MD, PhD, chief mission officer, American Parkinson Disease Association, said this new approach is “exciting.”

Whether the benefits will be as robust in other people with PD “remains to be seen,” said Dr. Gilbert, who was not involved with the study.

“The paper states that multiple experimental variables utilizing the device could potentially be adjusted to serve different people with PD, and these will need to be tested in clinical trials as well,” Dr. Gilbert said.

Additionally, “the device itself is complex and may be challenging to get on and off without help, which may limit its usability in the community,” Dr. Gilbert noted.

Although more work is needed, the study “represents a remarkable proof of concept that brings hope to those with FoG,” she added.

These “promising findings prompt further investigation to validate the effects of the robotic apparel on a broader range of individuals with PD experiencing FoG and across various FoG phenotypes and environments and task contexts, complemented with FoG metrics that include quantification of the severity of the freezing episodes,” Walsh and Ellis added.

This study was based on work supported by the National Science Foundation, the National Institutes of Health, and the Massachusetts Technology Collaborative, Collaborative Research and Development Matching Grant. This work was also partially funded by the John A. Paulson School of Engineering and Applied Sciences at Harvard University as well as received financial support from the Samsung Scholarship.
 

A version of this article appeared on Medscape.com.

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Certain Gut Microbes Tied to Cognitive Function in Children

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TOPLINE:

Cognitive function in children aged 18 months to 10 years is associated with the enrichment or depletion of specific species of gut microbes, new research reveals.

METHODOLOGY: 

  • Researchers analyzed the relationship between the microbiome, neuroanatomy, and cognition (ie, the microbiome-gut-brain axis) in stool samples from 381 neurotypically developing children aged 40 days to 10 years (mean age, 2 years and 2 months).
  • Stool samples were taken within a week of age-appropriate cognitive and behavioral assessments.
  • Shotgun metagenomic sequencing was used to analyze the DNA of the organisms present in each sample.
  • MRI data were obtained, with machine models then used to predict whether participants’ brain region volume was influenced by microbial profiles.

TAKEAWAY: 

  • Researchers found increasing variation in microbial species and microbial gene functions in children older than 18 months, and the overall variation was significantly associated with variation in cognitive function scores.
  • Several microbial species were significantly enriched in children with higher cognitive function scores (eg, Alistipes obesiAsaccharobacter celatusEubacterium eligens, and Faecalibacterium prausnitzii), with Sutterella wadsworthensis being the only species significantly negatively associated with these scores.
  • Machine models indicated that taxa key in predicting cognitive function were similarly important for predicting individual brain regions and subscales of cognitive function.

IN PRACTICE:

“Understanding the gut-brain-microbiome axis in early life is particularly important since differences or interventions in early life can have outsized and longer-term consequences than those at later ages,” the authors wrote.

SOURCE:

The study, led by Kevin S. Bonham, PhD, Wellesley College, Wellesley, Massachusetts, was published online on December 22, 2023, in Science Advances.

LIMITATIONS:

Use of multiple age-appropriate cognitive assessments enabled analysis across multiple developmental periods, but test-retest reliability and differences between test administrators may have introduced noise into these observations, particularly in the youngest children. The study period overlapped with the beginning of the pandemic, and score reductions due to the lockdowns were more pronounced in some age groups than during the recruitment period. 

DISCLOSURES:

The study was funded by the US National Institutes of Health and Wellcome: LEAP 1kD. The authors declared no competing interests.

A version of this article appeared on Medscape.com.

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TOPLINE:

Cognitive function in children aged 18 months to 10 years is associated with the enrichment or depletion of specific species of gut microbes, new research reveals.

METHODOLOGY: 

  • Researchers analyzed the relationship between the microbiome, neuroanatomy, and cognition (ie, the microbiome-gut-brain axis) in stool samples from 381 neurotypically developing children aged 40 days to 10 years (mean age, 2 years and 2 months).
  • Stool samples were taken within a week of age-appropriate cognitive and behavioral assessments.
  • Shotgun metagenomic sequencing was used to analyze the DNA of the organisms present in each sample.
  • MRI data were obtained, with machine models then used to predict whether participants’ brain region volume was influenced by microbial profiles.

TAKEAWAY: 

  • Researchers found increasing variation in microbial species and microbial gene functions in children older than 18 months, and the overall variation was significantly associated with variation in cognitive function scores.
  • Several microbial species were significantly enriched in children with higher cognitive function scores (eg, Alistipes obesiAsaccharobacter celatusEubacterium eligens, and Faecalibacterium prausnitzii), with Sutterella wadsworthensis being the only species significantly negatively associated with these scores.
  • Machine models indicated that taxa key in predicting cognitive function were similarly important for predicting individual brain regions and subscales of cognitive function.

IN PRACTICE:

“Understanding the gut-brain-microbiome axis in early life is particularly important since differences or interventions in early life can have outsized and longer-term consequences than those at later ages,” the authors wrote.

SOURCE:

The study, led by Kevin S. Bonham, PhD, Wellesley College, Wellesley, Massachusetts, was published online on December 22, 2023, in Science Advances.

LIMITATIONS:

Use of multiple age-appropriate cognitive assessments enabled analysis across multiple developmental periods, but test-retest reliability and differences between test administrators may have introduced noise into these observations, particularly in the youngest children. The study period overlapped with the beginning of the pandemic, and score reductions due to the lockdowns were more pronounced in some age groups than during the recruitment period. 

DISCLOSURES:

The study was funded by the US National Institutes of Health and Wellcome: LEAP 1kD. The authors declared no competing interests.

A version of this article appeared on Medscape.com.

 

TOPLINE:

Cognitive function in children aged 18 months to 10 years is associated with the enrichment or depletion of specific species of gut microbes, new research reveals.

METHODOLOGY: 

  • Researchers analyzed the relationship between the microbiome, neuroanatomy, and cognition (ie, the microbiome-gut-brain axis) in stool samples from 381 neurotypically developing children aged 40 days to 10 years (mean age, 2 years and 2 months).
  • Stool samples were taken within a week of age-appropriate cognitive and behavioral assessments.
  • Shotgun metagenomic sequencing was used to analyze the DNA of the organisms present in each sample.
  • MRI data were obtained, with machine models then used to predict whether participants’ brain region volume was influenced by microbial profiles.

TAKEAWAY: 

  • Researchers found increasing variation in microbial species and microbial gene functions in children older than 18 months, and the overall variation was significantly associated with variation in cognitive function scores.
  • Several microbial species were significantly enriched in children with higher cognitive function scores (eg, Alistipes obesiAsaccharobacter celatusEubacterium eligens, and Faecalibacterium prausnitzii), with Sutterella wadsworthensis being the only species significantly negatively associated with these scores.
  • Machine models indicated that taxa key in predicting cognitive function were similarly important for predicting individual brain regions and subscales of cognitive function.

IN PRACTICE:

“Understanding the gut-brain-microbiome axis in early life is particularly important since differences or interventions in early life can have outsized and longer-term consequences than those at later ages,” the authors wrote.

SOURCE:

The study, led by Kevin S. Bonham, PhD, Wellesley College, Wellesley, Massachusetts, was published online on December 22, 2023, in Science Advances.

LIMITATIONS:

Use of multiple age-appropriate cognitive assessments enabled analysis across multiple developmental periods, but test-retest reliability and differences between test administrators may have introduced noise into these observations, particularly in the youngest children. The study period overlapped with the beginning of the pandemic, and score reductions due to the lockdowns were more pronounced in some age groups than during the recruitment period. 

DISCLOSURES:

The study was funded by the US National Institutes of Health and Wellcome: LEAP 1kD. The authors declared no competing interests.

A version of this article appeared on Medscape.com.

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Traumatic Brain Injury and CVD: What’s the Link?

Article Type
Changed
Fri, 01/19/2024 - 13:27

The long-term impact of traumatic brain injury (TBI) on neurologic and psychiatric function is well-established, but a growing body of research is pointing to unexpected medical sequalae, including cardiovascular disease (CVD).

recent review looked at the investigation to date into this surprising connection, not only summarizing study findings but also suggesting potential mechanisms that might account for the association.

This work offers further evidence that individuals with TBI are at an elevated risk of unfavorable cardiovascular outcomes for an extended period following the initial incident; consequently, they should undergo regular monitoring,” senior author Ross Zafonte, DO, president of Spaulding Rehabilitation Network, Boston, and lead author Saef Izzy, MD, MBChB, a neurologist at the Stroke and Cerebrovascular Center of Brigham and Women’s Hospital, Boston, Massachusetts, told this news organization.

“This holds significant importance for healthcare practitioners, as there exist several strategies to mitigate cardiovascular disease risk — including weight management, adopting a healthy diet, engaging in regular physical activity, and quitting smoking,” they stated.

Leslie Croll, MD, American Heart Association volunteer and assistant professor of clinical neurology at the Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, told this news organization that it’s “extremely important to learn more about the interplay between TBI, neurologic disease, psychiatric complications, and the cardiovascular system.”

Hopefully, she added, “future research will help us understand what kind of cardiovascular disease monitoring and prevention measures stand to give TBI patients the most benefit.”
 

Chronic Condition

TBI is “a major cause of long-term disability and premature death,” and is “highly prevalent among contact sports players, military personnel (eg, due to injuries sustained during conflict), and the general population (eg, due to falls and road traffic incidents),” the authors wrote.

Most studies pertaining to TBI have “primarily focused on establishing connections between single TBI, repetitive TBI, and their acute and chronic neurological and psychiatric consequences, such as Parkinson’s diseaseAlzheimer’s disease, and chronic traumatic encephalopathy (CTE),” Drs. Zafonte and Izzy noted. By contrast, there has been a “notable lack of research attention given to non-neurological conditions associated with TBI.”

They pointed out that recent insights into TBI — particularly the acknowledgment of TBI as an “emerging chronic condition rather than merely an acute aftermath of brain injury” — have come to light through epidemiologic and pathologic investigations involving military veterans, professional American-style football players, and the civilian population. “This recognition opens up an opportunity to broaden our perspective and delve into the medical aspects of health that may be influenced by TBI.”

To broaden the investigation, the researchers reviewed literature published between January 1, 2001, and June 18, 2023. Of 26,335 articles, they narrowed their review down to 15 studies that investigated CVD, CVD risk factors, and cerebrovascular disease in the chronic phase of TBI, including community, military, or sport-related brain trauma, regardless of the timing of disease occurrence with respect to brain injury via TBI or repetitive head impact.
 

New Cardiovascular Risk

Studies that used national or local registries tended to be retrospective and predominantly conducted in people with preexisting cardiovascular conditions. In these studies, TBI was found to be an independent risk factor for myocardial dysfunction. However, although these studies do provide evidence of elevated cardiovascular risk subsequent to a single TBI, including individuals with preexisting medical comorbidities “makes it difficult to determine the timing of incident cardiovascular disease and cardiovascular risk factors subsequent to brain injury,” they wrote.

However, some studies showed that even individuals with TBI but without preexisting myocardial dysfunction at baseline had a significantly higher risk for CVD than those without a history of TBI.

In fact, several studies included populations without preexisting medical and cardiovascular comorbidities to “better refine the order and timing of CVD and other risk factors in individuals with TBI.”

For example, one study of concussion survivors without preexisting diagnoses showed that cardiovascular, endocrinological, and neuropsychiatric comorbidities occurred at a “significantly higher incidence within 5 years after concussive TBI compared with healthy individuals who were matched in terms of age, race, and sex and didn’t have a TBI exposure.” Other studies yielded similar findings.

Because cardiovascular risk factors and events become more common with age, it’s important to account for age in evaluating the effects of TBI. Although many studies of TBI and subsequent CVD didn’t stratify individuals by age, one 10-year study of people without any known cardiovascular or neuropsychiatric conditions who sustained TBI found that people as young as 18-40 years were more likely to develop hypertension, hyperlipidemia, obesity, and diabetes within 3-5 years following brain injury than matched individuals in the control group.

“Individuals who have encountered TBI, surprisingly even those who are young and in good health with no prior comorbid conditions, face an increased risk of adverse cardiovascular outcomes for an extended duration after the initial event,” Drs. Zafonte and Izzy summarized. “Therefore, it’s imperative that they receive regular and long-term screenings for CVD and associated risk factors.”
 

 

 

Bidirectional Relationship

Brain injury has been associated with acute cardiovascular dysfunction, including autonomic heart-brain axis dysregulation, imbalances between the sympathetic and parasympathetic nervous systems, and excessive catecholamine release, the authors noted.

Drs. Zafonte and Izzy suggested several plausible links between TBI and cardiovascular dysfunction, noting that they are “likely multifaceted, potentially encompassing risk factors that span the pre-injury, injury, and post-injury phases of the condition.”

TBI may induce alterations in neurobiological processes, which have been reported to be associated with an increased risk for CVD (eg, chronic dysfunction of the autonomic system, systemic inflammation, and modifications in the brain-gut connection).

Patients with TBI might develop additional risk factors following the injury, including conditions like posttraumatic stress disorderdepression, and other psychiatric illnesses, which are “known to augment the risk of CVD.”

TBI can lead to subsequent behavioral and lifestyle changes that place patients at an elevated risk for both cardiovascular and cognitive dysfunction when compared to the general population of TBI survivors.

There may be additional as yet undefined risks.

They believe there’s a bidirectional relationship between TBI and CVD. “On one hand, TBI has been associated with an elevated risk of CVD,” they said. “Conversely, cardiovascular risk factors such as diabetes, hypertension, hyperlipidemia, and sleep disturbances that have been demonstrated to negatively influence cognitive function and heighten the risk of dementia. Consequently, this interplay can further compound the long-term consequences of the injury.”

Their work aims to try and disentangle this “complex series of relationships.”

They recommend screening to identify diseases in their earliest and “most manageable phases” because TBI has been “unveiled as an underappreciated risk factor for CVD within contact sports, military, and community setting.”

An effective screening program “should rely on quantifiable and dependable biomarkers such as blood pressure, BMI, waist circumference, blood lipid levels, and glucose. Additionally, it should take into account other factors like smoking habits, physical activity, and dietary choices,” they recommended.
 

Heart-Brain Connection

Dr. Croll noted that TBI is “associated with many poorly understood physiologic changes and complications, so it’s exciting to see research aimed at clarifying this chronic disease process.”

In recent years, “we have seen a greater appreciation and understanding of the heart-brain connection,” she said. “Moving forward, more research, including TBI research, will target that connection.”

She added that there are probably “multiple mechanisms” at play underlying the connection between TBI and CVD.

Most importantly, “we are increasingly learning that TBI is not only a discrete event that requires immediate treatment but also a chronic disease process,” and when we “think about the substantial long-term morbidity associated with TBI, we should keep increased risk for CVD on top of mind,” said Dr. Croll.

The review received no funding. Izzy reported receiving grants from the US National Institutes of Health (NIH) and 2023 Stepping Strong Innovator Award. Dr. Zafonte reported receiving grants from the NIH and royalties from Springer and Demos publishing for serving as a coeditor of Brain Injury Medicine. Dr. Zafonte has also served as an adviser to Myomo, Oncare.ai, Nanodiagnostics, and Kisbee. He reported evaluating patients in the Massachusetts General Hospital Brain and Body–TRUST Program, which is funded by the NFL Players Association. The other authors’ disclosures are listed on the original paper. Dr. Croll declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

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The long-term impact of traumatic brain injury (TBI) on neurologic and psychiatric function is well-established, but a growing body of research is pointing to unexpected medical sequalae, including cardiovascular disease (CVD).

recent review looked at the investigation to date into this surprising connection, not only summarizing study findings but also suggesting potential mechanisms that might account for the association.

This work offers further evidence that individuals with TBI are at an elevated risk of unfavorable cardiovascular outcomes for an extended period following the initial incident; consequently, they should undergo regular monitoring,” senior author Ross Zafonte, DO, president of Spaulding Rehabilitation Network, Boston, and lead author Saef Izzy, MD, MBChB, a neurologist at the Stroke and Cerebrovascular Center of Brigham and Women’s Hospital, Boston, Massachusetts, told this news organization.

“This holds significant importance for healthcare practitioners, as there exist several strategies to mitigate cardiovascular disease risk — including weight management, adopting a healthy diet, engaging in regular physical activity, and quitting smoking,” they stated.

Leslie Croll, MD, American Heart Association volunteer and assistant professor of clinical neurology at the Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, told this news organization that it’s “extremely important to learn more about the interplay between TBI, neurologic disease, psychiatric complications, and the cardiovascular system.”

Hopefully, she added, “future research will help us understand what kind of cardiovascular disease monitoring and prevention measures stand to give TBI patients the most benefit.”
 

Chronic Condition

TBI is “a major cause of long-term disability and premature death,” and is “highly prevalent among contact sports players, military personnel (eg, due to injuries sustained during conflict), and the general population (eg, due to falls and road traffic incidents),” the authors wrote.

Most studies pertaining to TBI have “primarily focused on establishing connections between single TBI, repetitive TBI, and their acute and chronic neurological and psychiatric consequences, such as Parkinson’s diseaseAlzheimer’s disease, and chronic traumatic encephalopathy (CTE),” Drs. Zafonte and Izzy noted. By contrast, there has been a “notable lack of research attention given to non-neurological conditions associated with TBI.”

They pointed out that recent insights into TBI — particularly the acknowledgment of TBI as an “emerging chronic condition rather than merely an acute aftermath of brain injury” — have come to light through epidemiologic and pathologic investigations involving military veterans, professional American-style football players, and the civilian population. “This recognition opens up an opportunity to broaden our perspective and delve into the medical aspects of health that may be influenced by TBI.”

To broaden the investigation, the researchers reviewed literature published between January 1, 2001, and June 18, 2023. Of 26,335 articles, they narrowed their review down to 15 studies that investigated CVD, CVD risk factors, and cerebrovascular disease in the chronic phase of TBI, including community, military, or sport-related brain trauma, regardless of the timing of disease occurrence with respect to brain injury via TBI or repetitive head impact.
 

New Cardiovascular Risk

Studies that used national or local registries tended to be retrospective and predominantly conducted in people with preexisting cardiovascular conditions. In these studies, TBI was found to be an independent risk factor for myocardial dysfunction. However, although these studies do provide evidence of elevated cardiovascular risk subsequent to a single TBI, including individuals with preexisting medical comorbidities “makes it difficult to determine the timing of incident cardiovascular disease and cardiovascular risk factors subsequent to brain injury,” they wrote.

However, some studies showed that even individuals with TBI but without preexisting myocardial dysfunction at baseline had a significantly higher risk for CVD than those without a history of TBI.

In fact, several studies included populations without preexisting medical and cardiovascular comorbidities to “better refine the order and timing of CVD and other risk factors in individuals with TBI.”

For example, one study of concussion survivors without preexisting diagnoses showed that cardiovascular, endocrinological, and neuropsychiatric comorbidities occurred at a “significantly higher incidence within 5 years after concussive TBI compared with healthy individuals who were matched in terms of age, race, and sex and didn’t have a TBI exposure.” Other studies yielded similar findings.

Because cardiovascular risk factors and events become more common with age, it’s important to account for age in evaluating the effects of TBI. Although many studies of TBI and subsequent CVD didn’t stratify individuals by age, one 10-year study of people without any known cardiovascular or neuropsychiatric conditions who sustained TBI found that people as young as 18-40 years were more likely to develop hypertension, hyperlipidemia, obesity, and diabetes within 3-5 years following brain injury than matched individuals in the control group.

“Individuals who have encountered TBI, surprisingly even those who are young and in good health with no prior comorbid conditions, face an increased risk of adverse cardiovascular outcomes for an extended duration after the initial event,” Drs. Zafonte and Izzy summarized. “Therefore, it’s imperative that they receive regular and long-term screenings for CVD and associated risk factors.”
 

 

 

Bidirectional Relationship

Brain injury has been associated with acute cardiovascular dysfunction, including autonomic heart-brain axis dysregulation, imbalances between the sympathetic and parasympathetic nervous systems, and excessive catecholamine release, the authors noted.

Drs. Zafonte and Izzy suggested several plausible links between TBI and cardiovascular dysfunction, noting that they are “likely multifaceted, potentially encompassing risk factors that span the pre-injury, injury, and post-injury phases of the condition.”

TBI may induce alterations in neurobiological processes, which have been reported to be associated with an increased risk for CVD (eg, chronic dysfunction of the autonomic system, systemic inflammation, and modifications in the brain-gut connection).

Patients with TBI might develop additional risk factors following the injury, including conditions like posttraumatic stress disorderdepression, and other psychiatric illnesses, which are “known to augment the risk of CVD.”

TBI can lead to subsequent behavioral and lifestyle changes that place patients at an elevated risk for both cardiovascular and cognitive dysfunction when compared to the general population of TBI survivors.

There may be additional as yet undefined risks.

They believe there’s a bidirectional relationship between TBI and CVD. “On one hand, TBI has been associated with an elevated risk of CVD,” they said. “Conversely, cardiovascular risk factors such as diabetes, hypertension, hyperlipidemia, and sleep disturbances that have been demonstrated to negatively influence cognitive function and heighten the risk of dementia. Consequently, this interplay can further compound the long-term consequences of the injury.”

Their work aims to try and disentangle this “complex series of relationships.”

They recommend screening to identify diseases in their earliest and “most manageable phases” because TBI has been “unveiled as an underappreciated risk factor for CVD within contact sports, military, and community setting.”

An effective screening program “should rely on quantifiable and dependable biomarkers such as blood pressure, BMI, waist circumference, blood lipid levels, and glucose. Additionally, it should take into account other factors like smoking habits, physical activity, and dietary choices,” they recommended.
 

Heart-Brain Connection

Dr. Croll noted that TBI is “associated with many poorly understood physiologic changes and complications, so it’s exciting to see research aimed at clarifying this chronic disease process.”

In recent years, “we have seen a greater appreciation and understanding of the heart-brain connection,” she said. “Moving forward, more research, including TBI research, will target that connection.”

She added that there are probably “multiple mechanisms” at play underlying the connection between TBI and CVD.

Most importantly, “we are increasingly learning that TBI is not only a discrete event that requires immediate treatment but also a chronic disease process,” and when we “think about the substantial long-term morbidity associated with TBI, we should keep increased risk for CVD on top of mind,” said Dr. Croll.

The review received no funding. Izzy reported receiving grants from the US National Institutes of Health (NIH) and 2023 Stepping Strong Innovator Award. Dr. Zafonte reported receiving grants from the NIH and royalties from Springer and Demos publishing for serving as a coeditor of Brain Injury Medicine. Dr. Zafonte has also served as an adviser to Myomo, Oncare.ai, Nanodiagnostics, and Kisbee. He reported evaluating patients in the Massachusetts General Hospital Brain and Body–TRUST Program, which is funded by the NFL Players Association. The other authors’ disclosures are listed on the original paper. Dr. Croll declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

The long-term impact of traumatic brain injury (TBI) on neurologic and psychiatric function is well-established, but a growing body of research is pointing to unexpected medical sequalae, including cardiovascular disease (CVD).

recent review looked at the investigation to date into this surprising connection, not only summarizing study findings but also suggesting potential mechanisms that might account for the association.

This work offers further evidence that individuals with TBI are at an elevated risk of unfavorable cardiovascular outcomes for an extended period following the initial incident; consequently, they should undergo regular monitoring,” senior author Ross Zafonte, DO, president of Spaulding Rehabilitation Network, Boston, and lead author Saef Izzy, MD, MBChB, a neurologist at the Stroke and Cerebrovascular Center of Brigham and Women’s Hospital, Boston, Massachusetts, told this news organization.

“This holds significant importance for healthcare practitioners, as there exist several strategies to mitigate cardiovascular disease risk — including weight management, adopting a healthy diet, engaging in regular physical activity, and quitting smoking,” they stated.

Leslie Croll, MD, American Heart Association volunteer and assistant professor of clinical neurology at the Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, told this news organization that it’s “extremely important to learn more about the interplay between TBI, neurologic disease, psychiatric complications, and the cardiovascular system.”

Hopefully, she added, “future research will help us understand what kind of cardiovascular disease monitoring and prevention measures stand to give TBI patients the most benefit.”
 

Chronic Condition

TBI is “a major cause of long-term disability and premature death,” and is “highly prevalent among contact sports players, military personnel (eg, due to injuries sustained during conflict), and the general population (eg, due to falls and road traffic incidents),” the authors wrote.

Most studies pertaining to TBI have “primarily focused on establishing connections between single TBI, repetitive TBI, and their acute and chronic neurological and psychiatric consequences, such as Parkinson’s diseaseAlzheimer’s disease, and chronic traumatic encephalopathy (CTE),” Drs. Zafonte and Izzy noted. By contrast, there has been a “notable lack of research attention given to non-neurological conditions associated with TBI.”

They pointed out that recent insights into TBI — particularly the acknowledgment of TBI as an “emerging chronic condition rather than merely an acute aftermath of brain injury” — have come to light through epidemiologic and pathologic investigations involving military veterans, professional American-style football players, and the civilian population. “This recognition opens up an opportunity to broaden our perspective and delve into the medical aspects of health that may be influenced by TBI.”

To broaden the investigation, the researchers reviewed literature published between January 1, 2001, and June 18, 2023. Of 26,335 articles, they narrowed their review down to 15 studies that investigated CVD, CVD risk factors, and cerebrovascular disease in the chronic phase of TBI, including community, military, or sport-related brain trauma, regardless of the timing of disease occurrence with respect to brain injury via TBI or repetitive head impact.
 

New Cardiovascular Risk

Studies that used national or local registries tended to be retrospective and predominantly conducted in people with preexisting cardiovascular conditions. In these studies, TBI was found to be an independent risk factor for myocardial dysfunction. However, although these studies do provide evidence of elevated cardiovascular risk subsequent to a single TBI, including individuals with preexisting medical comorbidities “makes it difficult to determine the timing of incident cardiovascular disease and cardiovascular risk factors subsequent to brain injury,” they wrote.

However, some studies showed that even individuals with TBI but without preexisting myocardial dysfunction at baseline had a significantly higher risk for CVD than those without a history of TBI.

In fact, several studies included populations without preexisting medical and cardiovascular comorbidities to “better refine the order and timing of CVD and other risk factors in individuals with TBI.”

For example, one study of concussion survivors without preexisting diagnoses showed that cardiovascular, endocrinological, and neuropsychiatric comorbidities occurred at a “significantly higher incidence within 5 years after concussive TBI compared with healthy individuals who were matched in terms of age, race, and sex and didn’t have a TBI exposure.” Other studies yielded similar findings.

Because cardiovascular risk factors and events become more common with age, it’s important to account for age in evaluating the effects of TBI. Although many studies of TBI and subsequent CVD didn’t stratify individuals by age, one 10-year study of people without any known cardiovascular or neuropsychiatric conditions who sustained TBI found that people as young as 18-40 years were more likely to develop hypertension, hyperlipidemia, obesity, and diabetes within 3-5 years following brain injury than matched individuals in the control group.

“Individuals who have encountered TBI, surprisingly even those who are young and in good health with no prior comorbid conditions, face an increased risk of adverse cardiovascular outcomes for an extended duration after the initial event,” Drs. Zafonte and Izzy summarized. “Therefore, it’s imperative that they receive regular and long-term screenings for CVD and associated risk factors.”
 

 

 

Bidirectional Relationship

Brain injury has been associated with acute cardiovascular dysfunction, including autonomic heart-brain axis dysregulation, imbalances between the sympathetic and parasympathetic nervous systems, and excessive catecholamine release, the authors noted.

Drs. Zafonte and Izzy suggested several plausible links between TBI and cardiovascular dysfunction, noting that they are “likely multifaceted, potentially encompassing risk factors that span the pre-injury, injury, and post-injury phases of the condition.”

TBI may induce alterations in neurobiological processes, which have been reported to be associated with an increased risk for CVD (eg, chronic dysfunction of the autonomic system, systemic inflammation, and modifications in the brain-gut connection).

Patients with TBI might develop additional risk factors following the injury, including conditions like posttraumatic stress disorderdepression, and other psychiatric illnesses, which are “known to augment the risk of CVD.”

TBI can lead to subsequent behavioral and lifestyle changes that place patients at an elevated risk for both cardiovascular and cognitive dysfunction when compared to the general population of TBI survivors.

There may be additional as yet undefined risks.

They believe there’s a bidirectional relationship between TBI and CVD. “On one hand, TBI has been associated with an elevated risk of CVD,” they said. “Conversely, cardiovascular risk factors such as diabetes, hypertension, hyperlipidemia, and sleep disturbances that have been demonstrated to negatively influence cognitive function and heighten the risk of dementia. Consequently, this interplay can further compound the long-term consequences of the injury.”

Their work aims to try and disentangle this “complex series of relationships.”

They recommend screening to identify diseases in their earliest and “most manageable phases” because TBI has been “unveiled as an underappreciated risk factor for CVD within contact sports, military, and community setting.”

An effective screening program “should rely on quantifiable and dependable biomarkers such as blood pressure, BMI, waist circumference, blood lipid levels, and glucose. Additionally, it should take into account other factors like smoking habits, physical activity, and dietary choices,” they recommended.
 

Heart-Brain Connection

Dr. Croll noted that TBI is “associated with many poorly understood physiologic changes and complications, so it’s exciting to see research aimed at clarifying this chronic disease process.”

In recent years, “we have seen a greater appreciation and understanding of the heart-brain connection,” she said. “Moving forward, more research, including TBI research, will target that connection.”

She added that there are probably “multiple mechanisms” at play underlying the connection between TBI and CVD.

Most importantly, “we are increasingly learning that TBI is not only a discrete event that requires immediate treatment but also a chronic disease process,” and when we “think about the substantial long-term morbidity associated with TBI, we should keep increased risk for CVD on top of mind,” said Dr. Croll.

The review received no funding. Izzy reported receiving grants from the US National Institutes of Health (NIH) and 2023 Stepping Strong Innovator Award. Dr. Zafonte reported receiving grants from the NIH and royalties from Springer and Demos publishing for serving as a coeditor of Brain Injury Medicine. Dr. Zafonte has also served as an adviser to Myomo, Oncare.ai, Nanodiagnostics, and Kisbee. He reported evaluating patients in the Massachusetts General Hospital Brain and Body–TRUST Program, which is funded by the NFL Players Association. The other authors’ disclosures are listed on the original paper. Dr. Croll declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

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How Much Does Screen Time Really Affect Child Development?

Article Type
Changed
Thu, 01/18/2024 - 15:08

France did it 5 years ago and now, from January 1, the Dutch have followed suit, banning devices such as mobile phones and tablets in classrooms unless needed during lessons, for medical reasons, or by students with disabilities. The ban aims to limit distractions during the school day. 

We could all surely do with some device detox, but the question remains whether too much screen time has an impact on child development. Karen Mansfield, PhD, a postdoctoral researcher on adolescent well-being in the digital age at Oxford University, told this news organization, “The evidence is definitely not set in stone. There have been some recent reviews of screen time effects on children, demonstrating very mixed findings.”

The latest research, said Dr. Mansfield, is still young, lacking consistency in findings, and rife with misinterpretation.

Tiziana Metitieri, a cognitive neuropsychologist at the Meyer Hospital in Florence, Italy, echoed these sentiments, suggesting that the sheer quantity of screen time is an insufficient metric for understanding its impact on cognitive and psychological development. “There are two main reasons for this,” she explained to this news organization. “Firstly, because the current measurements of screen time rely on self-report data, which can be affected by an overestimation or underestimation of objective usage due to social desirability bias. Secondly, because digital experiences differ in terms of content, device used, context, location, and individuals involved.”
 

Are Politicians in Too Much of a Rush?

UNESCO’s most recent report on technology in education highlighted a correlation between excessive mobile phone use and reduced educational performance and emotional stability.

The OECD report “Empowering Young Children in the Digital Age,” rightly suggested there is a need to improve protection in digital environments, bridge the digital divide, and educate parents and teachers on safe digital practices.

But Dr. Mansfield said, “Currently, policy implementation is racing far ahead of the evidence, with similar suggestions to ban smartphones in schools in the United Kingdom and Canada. However, there is no available evidence on the long-term benefits of banning smartphones. Much of the research behind the OECD and UNESCO policies is observational in nature, which limits causal interpretation more than with interventions.”

While most governments are not pursuing restrictive practices, Dr. Metitieri said that “their approaches are based on their political ideology, often using moral panic as a means to rally support, showing their heartfelt commitment to defending against the invasions of digital technology ruining human civilizations.” 

Sakshi Ghai, PhD, Dr. Mansfield’s fellow postdoctoral researcher at Oxford University, reiterated Dr. Metitieri’s concerns, “Screen time as a concept has limitations, and policy guidance needs to be careful when drawing insights from such limited evidence. What do we mean by screen time? How can time spent on different activities be clearly delineated? An oversimplistic focus on screen time may overlook the nuances and complexity of digital media use.”
 

The Key Is the What and Where

Digital screens can be productive for children, such as when used for educational purposes, be it to join a class over Zoom or partake in extracurricular educational activities. However, Dr. Ghai emphasized the importance of identifying what constitutes reasonable consumption of digital media. “Screens can help disadvantaged children achieve positive educational outcomes, particularly those with learning difficulties,” said Dr. Ghai. “Using media to interact with other children can also bring positive social connections to racially diverse children or those from the LGBTQ community, which reiterates why finding the balance that allows children to reap the benefits of digital technology while safeguarding their mental, physical, and social health, is crucial.”

On the other hand, Dr. Metitieri explained that there is evidence that passive exposure to educational content does not necessarily lead to growth benefits. “The key is the relational environment in which these digital experiences occur,” she said. 

Dr. Mansfield said a lot of research describes excessive use of digital media as a form of addiction. “Some studies have attempted to validate and test ‘smartphone addiction’ scales for adolescent. Besides pathologizing an increasingly common activity, such self-report scales are highly subjective, implying serious limitations when attempting to define ‘cut offs’ or diagnostic thresholds.”

Previous efforts to determine benchmarks for screen time usage, focusing on the relationship between historical screen usage and present mental well-being, have overlooked the nature of the digital interaction and the social and technological backdrop. “Effects of screen time on children is a continuously changing, rapidly developing research field, and other contextual factors have been shown to play a greater role on mental health,” explained Dr. Mansfield.
 

 

 

Are School Bans Too Restrictive?

Implementing nationwide policies that warrant a dramatic shift in how we approach activities that have become second nature, such as using a mobile phone, is profoundly difficult, particularly as evidence is inconclusive and inconsistent. “The long-term effects of different types of digital content on children’s learning are yet to be clear, and most education-related research so far has been carried out with college students,” said Dr. Mansfield.

For concerned parents and schools, Dr. Metitieri advised against overly restrictive approaches. “Children and adolescents can find ways around restrictions at home and school, meaning that an overly restrictive approach is limited in its effectiveness,” she said. “The best way to adapt to the changes happening in education, relationships, work, and leisure is through a combination of experiences offline and digital education.”

Mirroring Dr. Metitieri’s outlook, Dr. Mansfield suggested, “Restricting the use of smartphones and other personal devices is one method to reduce distraction, but ultimately, children will need to learn to optimize their use of digital devices.”

Recent Dutch media reports cited government ministers’ consultations with neuropsychiatrist Theo Compernolle, MD, PhD, who compared children’s current smartphone usage patterns to addiction and suggested that such habits may hinder the development of the prefrontal cortex. However, Dr. Mansfield said, “There is no evidence to back up this claim.” Although she acknowledged the potential short-term benefits of a screen time ban in enhancing classroom concentration, she said, “One study directly tested this hypothesis and found no association between social media use and brain development, meaning that any claims of long-term effects remain purely speculative.”

The issue of children’s screen time is complex. Understanding the content and context of screen time, educating parents and teachers, and integrating digital experiences with offline activities seem to be the way forward. While governments contend with the complexities of managing this rather modern challenge, the balance between digital engagement and cognitive development remains a critical topic for continued research and thoughtful policymaking. Dr. Metitieri summed it up, “As adult members of the digital society, it is important for us to educate ourselves on how to effectively use online platforms before sharing our experiences and concerns about the online world with children and adolescents.”

A version of this article appeared on Medscape.com.

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France did it 5 years ago and now, from January 1, the Dutch have followed suit, banning devices such as mobile phones and tablets in classrooms unless needed during lessons, for medical reasons, or by students with disabilities. The ban aims to limit distractions during the school day. 

We could all surely do with some device detox, but the question remains whether too much screen time has an impact on child development. Karen Mansfield, PhD, a postdoctoral researcher on adolescent well-being in the digital age at Oxford University, told this news organization, “The evidence is definitely not set in stone. There have been some recent reviews of screen time effects on children, demonstrating very mixed findings.”

The latest research, said Dr. Mansfield, is still young, lacking consistency in findings, and rife with misinterpretation.

Tiziana Metitieri, a cognitive neuropsychologist at the Meyer Hospital in Florence, Italy, echoed these sentiments, suggesting that the sheer quantity of screen time is an insufficient metric for understanding its impact on cognitive and psychological development. “There are two main reasons for this,” she explained to this news organization. “Firstly, because the current measurements of screen time rely on self-report data, which can be affected by an overestimation or underestimation of objective usage due to social desirability bias. Secondly, because digital experiences differ in terms of content, device used, context, location, and individuals involved.”
 

Are Politicians in Too Much of a Rush?

UNESCO’s most recent report on technology in education highlighted a correlation between excessive mobile phone use and reduced educational performance and emotional stability.

The OECD report “Empowering Young Children in the Digital Age,” rightly suggested there is a need to improve protection in digital environments, bridge the digital divide, and educate parents and teachers on safe digital practices.

But Dr. Mansfield said, “Currently, policy implementation is racing far ahead of the evidence, with similar suggestions to ban smartphones in schools in the United Kingdom and Canada. However, there is no available evidence on the long-term benefits of banning smartphones. Much of the research behind the OECD and UNESCO policies is observational in nature, which limits causal interpretation more than with interventions.”

While most governments are not pursuing restrictive practices, Dr. Metitieri said that “their approaches are based on their political ideology, often using moral panic as a means to rally support, showing their heartfelt commitment to defending against the invasions of digital technology ruining human civilizations.” 

Sakshi Ghai, PhD, Dr. Mansfield’s fellow postdoctoral researcher at Oxford University, reiterated Dr. Metitieri’s concerns, “Screen time as a concept has limitations, and policy guidance needs to be careful when drawing insights from such limited evidence. What do we mean by screen time? How can time spent on different activities be clearly delineated? An oversimplistic focus on screen time may overlook the nuances and complexity of digital media use.”
 

The Key Is the What and Where

Digital screens can be productive for children, such as when used for educational purposes, be it to join a class over Zoom or partake in extracurricular educational activities. However, Dr. Ghai emphasized the importance of identifying what constitutes reasonable consumption of digital media. “Screens can help disadvantaged children achieve positive educational outcomes, particularly those with learning difficulties,” said Dr. Ghai. “Using media to interact with other children can also bring positive social connections to racially diverse children or those from the LGBTQ community, which reiterates why finding the balance that allows children to reap the benefits of digital technology while safeguarding their mental, physical, and social health, is crucial.”

On the other hand, Dr. Metitieri explained that there is evidence that passive exposure to educational content does not necessarily lead to growth benefits. “The key is the relational environment in which these digital experiences occur,” she said. 

Dr. Mansfield said a lot of research describes excessive use of digital media as a form of addiction. “Some studies have attempted to validate and test ‘smartphone addiction’ scales for adolescent. Besides pathologizing an increasingly common activity, such self-report scales are highly subjective, implying serious limitations when attempting to define ‘cut offs’ or diagnostic thresholds.”

Previous efforts to determine benchmarks for screen time usage, focusing on the relationship between historical screen usage and present mental well-being, have overlooked the nature of the digital interaction and the social and technological backdrop. “Effects of screen time on children is a continuously changing, rapidly developing research field, and other contextual factors have been shown to play a greater role on mental health,” explained Dr. Mansfield.
 

 

 

Are School Bans Too Restrictive?

Implementing nationwide policies that warrant a dramatic shift in how we approach activities that have become second nature, such as using a mobile phone, is profoundly difficult, particularly as evidence is inconclusive and inconsistent. “The long-term effects of different types of digital content on children’s learning are yet to be clear, and most education-related research so far has been carried out with college students,” said Dr. Mansfield.

For concerned parents and schools, Dr. Metitieri advised against overly restrictive approaches. “Children and adolescents can find ways around restrictions at home and school, meaning that an overly restrictive approach is limited in its effectiveness,” she said. “The best way to adapt to the changes happening in education, relationships, work, and leisure is through a combination of experiences offline and digital education.”

Mirroring Dr. Metitieri’s outlook, Dr. Mansfield suggested, “Restricting the use of smartphones and other personal devices is one method to reduce distraction, but ultimately, children will need to learn to optimize their use of digital devices.”

Recent Dutch media reports cited government ministers’ consultations with neuropsychiatrist Theo Compernolle, MD, PhD, who compared children’s current smartphone usage patterns to addiction and suggested that such habits may hinder the development of the prefrontal cortex. However, Dr. Mansfield said, “There is no evidence to back up this claim.” Although she acknowledged the potential short-term benefits of a screen time ban in enhancing classroom concentration, she said, “One study directly tested this hypothesis and found no association between social media use and brain development, meaning that any claims of long-term effects remain purely speculative.”

The issue of children’s screen time is complex. Understanding the content and context of screen time, educating parents and teachers, and integrating digital experiences with offline activities seem to be the way forward. While governments contend with the complexities of managing this rather modern challenge, the balance between digital engagement and cognitive development remains a critical topic for continued research and thoughtful policymaking. Dr. Metitieri summed it up, “As adult members of the digital society, it is important for us to educate ourselves on how to effectively use online platforms before sharing our experiences and concerns about the online world with children and adolescents.”

A version of this article appeared on Medscape.com.

France did it 5 years ago and now, from January 1, the Dutch have followed suit, banning devices such as mobile phones and tablets in classrooms unless needed during lessons, for medical reasons, or by students with disabilities. The ban aims to limit distractions during the school day. 

We could all surely do with some device detox, but the question remains whether too much screen time has an impact on child development. Karen Mansfield, PhD, a postdoctoral researcher on adolescent well-being in the digital age at Oxford University, told this news organization, “The evidence is definitely not set in stone. There have been some recent reviews of screen time effects on children, demonstrating very mixed findings.”

The latest research, said Dr. Mansfield, is still young, lacking consistency in findings, and rife with misinterpretation.

Tiziana Metitieri, a cognitive neuropsychologist at the Meyer Hospital in Florence, Italy, echoed these sentiments, suggesting that the sheer quantity of screen time is an insufficient metric for understanding its impact on cognitive and psychological development. “There are two main reasons for this,” she explained to this news organization. “Firstly, because the current measurements of screen time rely on self-report data, which can be affected by an overestimation or underestimation of objective usage due to social desirability bias. Secondly, because digital experiences differ in terms of content, device used, context, location, and individuals involved.”
 

Are Politicians in Too Much of a Rush?

UNESCO’s most recent report on technology in education highlighted a correlation between excessive mobile phone use and reduced educational performance and emotional stability.

The OECD report “Empowering Young Children in the Digital Age,” rightly suggested there is a need to improve protection in digital environments, bridge the digital divide, and educate parents and teachers on safe digital practices.

But Dr. Mansfield said, “Currently, policy implementation is racing far ahead of the evidence, with similar suggestions to ban smartphones in schools in the United Kingdom and Canada. However, there is no available evidence on the long-term benefits of banning smartphones. Much of the research behind the OECD and UNESCO policies is observational in nature, which limits causal interpretation more than with interventions.”

While most governments are not pursuing restrictive practices, Dr. Metitieri said that “their approaches are based on their political ideology, often using moral panic as a means to rally support, showing their heartfelt commitment to defending against the invasions of digital technology ruining human civilizations.” 

Sakshi Ghai, PhD, Dr. Mansfield’s fellow postdoctoral researcher at Oxford University, reiterated Dr. Metitieri’s concerns, “Screen time as a concept has limitations, and policy guidance needs to be careful when drawing insights from such limited evidence. What do we mean by screen time? How can time spent on different activities be clearly delineated? An oversimplistic focus on screen time may overlook the nuances and complexity of digital media use.”
 

The Key Is the What and Where

Digital screens can be productive for children, such as when used for educational purposes, be it to join a class over Zoom or partake in extracurricular educational activities. However, Dr. Ghai emphasized the importance of identifying what constitutes reasonable consumption of digital media. “Screens can help disadvantaged children achieve positive educational outcomes, particularly those with learning difficulties,” said Dr. Ghai. “Using media to interact with other children can also bring positive social connections to racially diverse children or those from the LGBTQ community, which reiterates why finding the balance that allows children to reap the benefits of digital technology while safeguarding their mental, physical, and social health, is crucial.”

On the other hand, Dr. Metitieri explained that there is evidence that passive exposure to educational content does not necessarily lead to growth benefits. “The key is the relational environment in which these digital experiences occur,” she said. 

Dr. Mansfield said a lot of research describes excessive use of digital media as a form of addiction. “Some studies have attempted to validate and test ‘smartphone addiction’ scales for adolescent. Besides pathologizing an increasingly common activity, such self-report scales are highly subjective, implying serious limitations when attempting to define ‘cut offs’ or diagnostic thresholds.”

Previous efforts to determine benchmarks for screen time usage, focusing on the relationship between historical screen usage and present mental well-being, have overlooked the nature of the digital interaction and the social and technological backdrop. “Effects of screen time on children is a continuously changing, rapidly developing research field, and other contextual factors have been shown to play a greater role on mental health,” explained Dr. Mansfield.
 

 

 

Are School Bans Too Restrictive?

Implementing nationwide policies that warrant a dramatic shift in how we approach activities that have become second nature, such as using a mobile phone, is profoundly difficult, particularly as evidence is inconclusive and inconsistent. “The long-term effects of different types of digital content on children’s learning are yet to be clear, and most education-related research so far has been carried out with college students,” said Dr. Mansfield.

For concerned parents and schools, Dr. Metitieri advised against overly restrictive approaches. “Children and adolescents can find ways around restrictions at home and school, meaning that an overly restrictive approach is limited in its effectiveness,” she said. “The best way to adapt to the changes happening in education, relationships, work, and leisure is through a combination of experiences offline and digital education.”

Mirroring Dr. Metitieri’s outlook, Dr. Mansfield suggested, “Restricting the use of smartphones and other personal devices is one method to reduce distraction, but ultimately, children will need to learn to optimize their use of digital devices.”

Recent Dutch media reports cited government ministers’ consultations with neuropsychiatrist Theo Compernolle, MD, PhD, who compared children’s current smartphone usage patterns to addiction and suggested that such habits may hinder the development of the prefrontal cortex. However, Dr. Mansfield said, “There is no evidence to back up this claim.” Although she acknowledged the potential short-term benefits of a screen time ban in enhancing classroom concentration, she said, “One study directly tested this hypothesis and found no association between social media use and brain development, meaning that any claims of long-term effects remain purely speculative.”

The issue of children’s screen time is complex. Understanding the content and context of screen time, educating parents and teachers, and integrating digital experiences with offline activities seem to be the way forward. While governments contend with the complexities of managing this rather modern challenge, the balance between digital engagement and cognitive development remains a critical topic for continued research and thoughtful policymaking. Dr. Metitieri summed it up, “As adult members of the digital society, it is important for us to educate ourselves on how to effectively use online platforms before sharing our experiences and concerns about the online world with children and adolescents.”

A version of this article appeared on Medscape.com.

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ADHD Symptoms Linked With Physical Comorbidities

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Changed
Thu, 01/18/2024 - 09:36

Investigators from the French Health and Medical Research Institute (INSERM), University of Bordeaux, and Charles Perrens Hospital, alongside their Canadian, British, and Swedish counterparts, have shown that attention-deficit/hyperactivity disorder (ADHD) or attention-deficit disorder without hyperactivity is linked with physical health problems. Cédric Galéra, MD, PhD, child and adolescent psychiatrist and epidemiologist at the Bordeaux Population Health Research Center (INSERM/University of Bordeaux) and the Charles Perrens Hospital, explained these findings to this news organization.
 

A Bilateral Association 

ADHD is a neurodevelopmental condition that develops in childhood and is characterized by high levels of inattention or agitation and impulsiveness. Some studies have revealed a link between ADHD and medical comorbidities, but these studies were carried out on small patient samples and were cross-sectional.

A new longitudinal study published in Lancet Child and Adolescent Health has shown a reciprocal link between ADHD and physical health problems. The researchers conducted statistical analyses to measure the links between ADHD symptoms and subsequent development of certain physical conditions and, conversely, between physical problems during childhood and subsequent development of ADHD symptoms.
 

Children From Quebec

The study was conducted by a team headed by Dr. Galéra in collaboration with teams from Britain, Sweden, and Canada. “We studied a Quebec-based cohort of 2000 children aged between 5 months and 17 years,” said Dr. Galéra.

“The researchers in Quebec sent interviewers to question parents at home. And once the children were able to answer for themselves, from adolescence, they were asked to answer the questions directly,” he added.

The children were assessed on the severity of their ADHD symptoms as well as their physical condition (general well-being, any conditions diagnosed, etc.).
 

Dental Caries, Excess Weight

“We were able to show links between ADHD in childhood and physical health problems in adolescence. There is a greater risk for dental caries, infections, injuries, wounds, sleep disorders, and excess weight.

“Accounting for socioeconomic status and mental health problems such as anxiety and depression or medical treatments, we observed that dental caries, wounds, excess weight, and restless legs syndrome were the conditions that cropped up time and time again,” said Dr. Galéra.

On the other hand, the researchers noted that certain physical health issues in childhood were linked with the onset of ADHD at a later stage. “We discovered that asthma in early childhood, injuries, sleep disturbances, epilepsy, and excess weight were associated with ADHD. Taking all above-referenced features into account, we were left with just wounds and injuries as well as restless legs syndrome as being linked to ADHD,” Dr. Galéra concluded.

For Dr. Galéra, the study illustrates the direction and timing of the links between physical problems and ADHD. “This reflects the link between physical and mental health. It’s important that all healthcare professionals be alert to this. Psychiatrists and mental health professionals must be vigilant about the physical health risks, and pediatricians and family physicians must be aware of the fact that children can present with physical conditions that will later be linked with ADHD. Each of them must be able to refer their young patients to their medical colleagues to ensure that these people receive the best care,” he emphasized.

The team will continue to study this cohort to see which problems emerge in adulthood. They also wish to study the Elfe cohort, a French longitudinal study of children.

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

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Investigators from the French Health and Medical Research Institute (INSERM), University of Bordeaux, and Charles Perrens Hospital, alongside their Canadian, British, and Swedish counterparts, have shown that attention-deficit/hyperactivity disorder (ADHD) or attention-deficit disorder without hyperactivity is linked with physical health problems. Cédric Galéra, MD, PhD, child and adolescent psychiatrist and epidemiologist at the Bordeaux Population Health Research Center (INSERM/University of Bordeaux) and the Charles Perrens Hospital, explained these findings to this news organization.
 

A Bilateral Association 

ADHD is a neurodevelopmental condition that develops in childhood and is characterized by high levels of inattention or agitation and impulsiveness. Some studies have revealed a link between ADHD and medical comorbidities, but these studies were carried out on small patient samples and were cross-sectional.

A new longitudinal study published in Lancet Child and Adolescent Health has shown a reciprocal link between ADHD and physical health problems. The researchers conducted statistical analyses to measure the links between ADHD symptoms and subsequent development of certain physical conditions and, conversely, between physical problems during childhood and subsequent development of ADHD symptoms.
 

Children From Quebec

The study was conducted by a team headed by Dr. Galéra in collaboration with teams from Britain, Sweden, and Canada. “We studied a Quebec-based cohort of 2000 children aged between 5 months and 17 years,” said Dr. Galéra.

“The researchers in Quebec sent interviewers to question parents at home. And once the children were able to answer for themselves, from adolescence, they were asked to answer the questions directly,” he added.

The children were assessed on the severity of their ADHD symptoms as well as their physical condition (general well-being, any conditions diagnosed, etc.).
 

Dental Caries, Excess Weight

“We were able to show links between ADHD in childhood and physical health problems in adolescence. There is a greater risk for dental caries, infections, injuries, wounds, sleep disorders, and excess weight.

“Accounting for socioeconomic status and mental health problems such as anxiety and depression or medical treatments, we observed that dental caries, wounds, excess weight, and restless legs syndrome were the conditions that cropped up time and time again,” said Dr. Galéra.

On the other hand, the researchers noted that certain physical health issues in childhood were linked with the onset of ADHD at a later stage. “We discovered that asthma in early childhood, injuries, sleep disturbances, epilepsy, and excess weight were associated with ADHD. Taking all above-referenced features into account, we were left with just wounds and injuries as well as restless legs syndrome as being linked to ADHD,” Dr. Galéra concluded.

For Dr. Galéra, the study illustrates the direction and timing of the links between physical problems and ADHD. “This reflects the link between physical and mental health. It’s important that all healthcare professionals be alert to this. Psychiatrists and mental health professionals must be vigilant about the physical health risks, and pediatricians and family physicians must be aware of the fact that children can present with physical conditions that will later be linked with ADHD. Each of them must be able to refer their young patients to their medical colleagues to ensure that these people receive the best care,” he emphasized.

The team will continue to study this cohort to see which problems emerge in adulthood. They also wish to study the Elfe cohort, a French longitudinal study of children.

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

Investigators from the French Health and Medical Research Institute (INSERM), University of Bordeaux, and Charles Perrens Hospital, alongside their Canadian, British, and Swedish counterparts, have shown that attention-deficit/hyperactivity disorder (ADHD) or attention-deficit disorder without hyperactivity is linked with physical health problems. Cédric Galéra, MD, PhD, child and adolescent psychiatrist and epidemiologist at the Bordeaux Population Health Research Center (INSERM/University of Bordeaux) and the Charles Perrens Hospital, explained these findings to this news organization.
 

A Bilateral Association 

ADHD is a neurodevelopmental condition that develops in childhood and is characterized by high levels of inattention or agitation and impulsiveness. Some studies have revealed a link between ADHD and medical comorbidities, but these studies were carried out on small patient samples and were cross-sectional.

A new longitudinal study published in Lancet Child and Adolescent Health has shown a reciprocal link between ADHD and physical health problems. The researchers conducted statistical analyses to measure the links between ADHD symptoms and subsequent development of certain physical conditions and, conversely, between physical problems during childhood and subsequent development of ADHD symptoms.
 

Children From Quebec

The study was conducted by a team headed by Dr. Galéra in collaboration with teams from Britain, Sweden, and Canada. “We studied a Quebec-based cohort of 2000 children aged between 5 months and 17 years,” said Dr. Galéra.

“The researchers in Quebec sent interviewers to question parents at home. And once the children were able to answer for themselves, from adolescence, they were asked to answer the questions directly,” he added.

The children were assessed on the severity of their ADHD symptoms as well as their physical condition (general well-being, any conditions diagnosed, etc.).
 

Dental Caries, Excess Weight

“We were able to show links between ADHD in childhood and physical health problems in adolescence. There is a greater risk for dental caries, infections, injuries, wounds, sleep disorders, and excess weight.

“Accounting for socioeconomic status and mental health problems such as anxiety and depression or medical treatments, we observed that dental caries, wounds, excess weight, and restless legs syndrome were the conditions that cropped up time and time again,” said Dr. Galéra.

On the other hand, the researchers noted that certain physical health issues in childhood were linked with the onset of ADHD at a later stage. “We discovered that asthma in early childhood, injuries, sleep disturbances, epilepsy, and excess weight were associated with ADHD. Taking all above-referenced features into account, we were left with just wounds and injuries as well as restless legs syndrome as being linked to ADHD,” Dr. Galéra concluded.

For Dr. Galéra, the study illustrates the direction and timing of the links between physical problems and ADHD. “This reflects the link between physical and mental health. It’s important that all healthcare professionals be alert to this. Psychiatrists and mental health professionals must be vigilant about the physical health risks, and pediatricians and family physicians must be aware of the fact that children can present with physical conditions that will later be linked with ADHD. Each of them must be able to refer their young patients to their medical colleagues to ensure that these people receive the best care,” he emphasized.

The team will continue to study this cohort to see which problems emerge in adulthood. They also wish to study the Elfe cohort, a French longitudinal study of children.

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

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Chronic Fatigue Syndrome and Fibromyalgia: A Single Disease Entity?

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Changed
Wed, 01/17/2024 - 11:43

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.

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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.

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Autoimmune Diseases and Perinatal Depression May Share Two-Way Link

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Changed
Tue, 01/16/2024 - 17:04

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.

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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.

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Lipids and Dementia: A Complex and Evolving Story

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Fri, 01/12/2024 - 15:26

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.

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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.

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Modifiable Risk Factors for Young-Onset Dementia Flagged

Article Type
Changed
Tue, 01/09/2024 - 22:47

 

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.

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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.

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