Literature Review

Researchers have identified a form of B12 deficiency caused by autoantibodies that specifically affects the central nervous system.

Discovered while studying a puzzling case of one patient with inexplicable neurological systems, the same autoantibody was detected in a small percentage of healthy individuals and was nearly four times as prevalent in patients with neuropsychiatric systemic lupus erythematosus (SLE).

“I didn’t think this single investigation was going to yield a broader phenomenon with other patients,” lead author John V. Pluvinage, MD, PhD, a neurology resident at the University of California San Francisco, said in an interview. “It started as an N-of-one study just based on scientific curiosity.”

“It’s a beautifully done study,” added Betty Diamond, MD, director of the Institute of Molecular Medicine at the Feinstein Institutes for Medical Research in Manhasset, New York, commenting on the research. It uncovers “yet another example of a disease where antibodies getting into the brain are the problem.”

The research was published in Science Translational Medicine.
 

The Patient

The investigation began in 2014 with a 67-year-old woman presenting with difficulty speaking, ataxia, and tremor. Her blood tests showed no signs of B12 deficiency, and testing for known autoantibodies came back negative.

Solving this mystery required a more exhaustive approach. The patient enrolled in a research study focused on identifying novel autoantibodies in suspected neuroinflammatory disease, using a screening technology called phage immunoprecipitation sequencing.

“We adapted this technology to screen for autoantibodies in an unbiased manner by displaying every peptide across the human proteome and then mixing those peptides with patient antibodies in order to figure out what the antibodies are binding to,” explained Dr. Pluvinage.

Using this method, he and colleagues discovered that this woman had autoantibodies that target CD320 — a receptor important in the cellular uptake of B12. While her blood tests were normal, B12 in the patient’s cerebral spinal fluid (CSF) was “nearly undetectable,” Dr. Pluvinage said. Using an in vitro model of the blood-brain barrier (BBB), the researchers determined that anti-CD320 impaired the transport of B12 across the BBB by targeting receptors on the cell surface.

Treating the patient with a combination of immunosuppressant medication and high-dose B12 supplementation increased B12 levels in the patient’s CSF and improved clinical symptoms.
 

Identifying More Cases

Dr. Pluvinage and colleagues tested the 254 other individuals enrolled in the neuroinflammatory disease study and identified seven participants with CSF anti-CD320 autoantibodies — four of whom had low B12 in the CSF.

In a group of healthy controls, anti-CD320 seropositivity was 6%, similar to the positivity rate in 132 paired serum and CSF samples from a cohort of patients with multiple sclerosis (5.7%). In this group of patients with multiple sclerosis, anti-CD320 presence in the blood was highly predictive of high levels of CSF methylmalonic acid, a metabolic marker of B12 deficiency.

Researchers also screened for anti-CD320 seropositivity in 408 patients with non-neurologic SLE and 28 patients with neuropsychiatric SLE and found that the autoantibody was nearly four times as prevalent in patients with neurologic symptoms (21.4%) compared with in those with non-neurologic SLE (5.6%).

“The clinical relevance of anti-CD320 in healthy controls remains uncertain,” the authors wrote. However, it is not uncommon to have healthy patients with known autoantibodies.

“There are always people who have autoantibodies who don’t get disease, and why that is we don’t know,” said Dr. Diamond. Some individuals may develop clinical symptoms later, or there may be other reasons why they are protected against disease.

Pluvinage is eager to follow some seropositive healthy individuals to track their neurologic health overtime, to see if the presence of anti-CD320 “alters their neurologic trajectories.”
 

Alternative Pathways

Lastly, Dr. Pluvinage and colleagues set out to explain why patients with anti-CD320 in their blood did not show any signs of B12 deficiency. They hypothesized that another receptor may be compensating and still allowing blood cells to take up B12. Using CRISPR screening, the team identified the low-density lipoprotein receptor as an alternative pathway to B12 uptake.

“These findings suggest a model in which anti-CD320 impairs transport of B12 across the BBB, leading to autoimmune B12 central deficiency (ABCD) with varied neurologic manifestations but sparing peripheral manifestations of B12 deficiency,” the authors wrote.

The work was supported by the National Institute of Mental Health, National Center for Chronic Disease Prevention and Health Promotion, Department of Defense, UCSF Helen Diller Family Comprehensive Cancer Center Laboratory for Cell Analysis Shared Resource Facility, National Multiple Sclerosis Society, Valhalla Foundation, and the Westridge Foundation. Dr. Pluvinage is a co-inventor on a patent application related to this work. Dr. Diamond had no relevant disclosures.

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

Researchers have identified a form of B12 deficiency caused by autoantibodies that specifically affects the central nervous system.

Discovered while studying a puzzling case of one patient with inexplicable neurological systems, the same autoantibody was detected in a small percentage of healthy individuals and was nearly four times as prevalent in patients with neuropsychiatric systemic lupus erythematosus (SLE).

“I didn’t think this single investigation was going to yield a broader phenomenon with other patients,” lead author John V. Pluvinage, MD, PhD, a neurology resident at the University of California San Francisco, said in an interview. “It started as an N-of-one study just based on scientific curiosity.”

“It’s a beautifully done study,” added Betty Diamond, MD, director of the Institute of Molecular Medicine at the Feinstein Institutes for Medical Research in Manhasset, New York, commenting on the research. It uncovers “yet another example of a disease where antibodies getting into the brain are the problem.”

The research was published in Science Translational Medicine.
 

The Patient

The investigation began in 2014 with a 67-year-old woman presenting with difficulty speaking, ataxia, and tremor. Her blood tests showed no signs of B12 deficiency, and testing for known autoantibodies came back negative.

Solving this mystery required a more exhaustive approach. The patient enrolled in a research study focused on identifying novel autoantibodies in suspected neuroinflammatory disease, using a screening technology called phage immunoprecipitation sequencing.

“We adapted this technology to screen for autoantibodies in an unbiased manner by displaying every peptide across the human proteome and then mixing those peptides with patient antibodies in order to figure out what the antibodies are binding to,” explained Dr. Pluvinage.

Using this method, he and colleagues discovered that this woman had autoantibodies that target CD320 — a receptor important in the cellular uptake of B12. While her blood tests were normal, B12 in the patient’s cerebral spinal fluid (CSF) was “nearly undetectable,” Dr. Pluvinage said. Using an in vitro model of the blood-brain barrier (BBB), the researchers determined that anti-CD320 impaired the transport of B12 across the BBB by targeting receptors on the cell surface.

Treating the patient with a combination of immunosuppressant medication and high-dose B12 supplementation increased B12 levels in the patient’s CSF and improved clinical symptoms.
 

Identifying More Cases

Dr. Pluvinage and colleagues tested the 254 other individuals enrolled in the neuroinflammatory disease study and identified seven participants with CSF anti-CD320 autoantibodies — four of whom had low B12 in the CSF.

In a group of healthy controls, anti-CD320 seropositivity was 6%, similar to the positivity rate in 132 paired serum and CSF samples from a cohort of patients with multiple sclerosis (5.7%). In this group of patients with multiple sclerosis, anti-CD320 presence in the blood was highly predictive of high levels of CSF methylmalonic acid, a metabolic marker of B12 deficiency.

Researchers also screened for anti-CD320 seropositivity in 408 patients with non-neurologic SLE and 28 patients with neuropsychiatric SLE and found that the autoantibody was nearly four times as prevalent in patients with neurologic symptoms (21.4%) compared with in those with non-neurologic SLE (5.6%).

“The clinical relevance of anti-CD320 in healthy controls remains uncertain,” the authors wrote. However, it is not uncommon to have healthy patients with known autoantibodies.

“There are always people who have autoantibodies who don’t get disease, and why that is we don’t know,” said Dr. Diamond. Some individuals may develop clinical symptoms later, or there may be other reasons why they are protected against disease.

Pluvinage is eager to follow some seropositive healthy individuals to track their neurologic health overtime, to see if the presence of anti-CD320 “alters their neurologic trajectories.”
 

Alternative Pathways

Lastly, Dr. Pluvinage and colleagues set out to explain why patients with anti-CD320 in their blood did not show any signs of B12 deficiency. They hypothesized that another receptor may be compensating and still allowing blood cells to take up B12. Using CRISPR screening, the team identified the low-density lipoprotein receptor as an alternative pathway to B12 uptake.

“These findings suggest a model in which anti-CD320 impairs transport of B12 across the BBB, leading to autoimmune B12 central deficiency (ABCD) with varied neurologic manifestations but sparing peripheral manifestations of B12 deficiency,” the authors wrote.

The work was supported by the National Institute of Mental Health, National Center for Chronic Disease Prevention and Health Promotion, Department of Defense, UCSF Helen Diller Family Comprehensive Cancer Center Laboratory for Cell Analysis Shared Resource Facility, National Multiple Sclerosis Society, Valhalla Foundation, and the Westridge Foundation. Dr. Pluvinage is a co-inventor on a patent application related to this work. Dr. Diamond had no relevant disclosures.

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

Researchers have identified a form of B12 deficiency caused by autoantibodies that specifically affects the central nervous system.

Discovered while studying a puzzling case of one patient with inexplicable neurological systems, the same autoantibody was detected in a small percentage of healthy individuals and was nearly four times as prevalent in patients with neuropsychiatric systemic lupus erythematosus (SLE).

“I didn’t think this single investigation was going to yield a broader phenomenon with other patients,” lead author John V. Pluvinage, MD, PhD, a neurology resident at the University of California San Francisco, said in an interview. “It started as an N-of-one study just based on scientific curiosity.”

“It’s a beautifully done study,” added Betty Diamond, MD, director of the Institute of Molecular Medicine at the Feinstein Institutes for Medical Research in Manhasset, New York, commenting on the research. It uncovers “yet another example of a disease where antibodies getting into the brain are the problem.”

The research was published in Science Translational Medicine.
 

The Patient

The investigation began in 2014 with a 67-year-old woman presenting with difficulty speaking, ataxia, and tremor. Her blood tests showed no signs of B12 deficiency, and testing for known autoantibodies came back negative.

Solving this mystery required a more exhaustive approach. The patient enrolled in a research study focused on identifying novel autoantibodies in suspected neuroinflammatory disease, using a screening technology called phage immunoprecipitation sequencing.

“We adapted this technology to screen for autoantibodies in an unbiased manner by displaying every peptide across the human proteome and then mixing those peptides with patient antibodies in order to figure out what the antibodies are binding to,” explained Dr. Pluvinage.

Using this method, he and colleagues discovered that this woman had autoantibodies that target CD320 — a receptor important in the cellular uptake of B12. While her blood tests were normal, B12 in the patient’s cerebral spinal fluid (CSF) was “nearly undetectable,” Dr. Pluvinage said. Using an in vitro model of the blood-brain barrier (BBB), the researchers determined that anti-CD320 impaired the transport of B12 across the BBB by targeting receptors on the cell surface.

Treating the patient with a combination of immunosuppressant medication and high-dose B12 supplementation increased B12 levels in the patient’s CSF and improved clinical symptoms.
 

Identifying More Cases

Dr. Pluvinage and colleagues tested the 254 other individuals enrolled in the neuroinflammatory disease study and identified seven participants with CSF anti-CD320 autoantibodies — four of whom had low B12 in the CSF.

In a group of healthy controls, anti-CD320 seropositivity was 6%, similar to the positivity rate in 132 paired serum and CSF samples from a cohort of patients with multiple sclerosis (5.7%). In this group of patients with multiple sclerosis, anti-CD320 presence in the blood was highly predictive of high levels of CSF methylmalonic acid, a metabolic marker of B12 deficiency.

Researchers also screened for anti-CD320 seropositivity in 408 patients with non-neurologic SLE and 28 patients with neuropsychiatric SLE and found that the autoantibody was nearly four times as prevalent in patients with neurologic symptoms (21.4%) compared with in those with non-neurologic SLE (5.6%).

“The clinical relevance of anti-CD320 in healthy controls remains uncertain,” the authors wrote. However, it is not uncommon to have healthy patients with known autoantibodies.

“There are always people who have autoantibodies who don’t get disease, and why that is we don’t know,” said Dr. Diamond. Some individuals may develop clinical symptoms later, or there may be other reasons why they are protected against disease.

Pluvinage is eager to follow some seropositive healthy individuals to track their neurologic health overtime, to see if the presence of anti-CD320 “alters their neurologic trajectories.”
 

Alternative Pathways

Lastly, Dr. Pluvinage and colleagues set out to explain why patients with anti-CD320 in their blood did not show any signs of B12 deficiency. They hypothesized that another receptor may be compensating and still allowing blood cells to take up B12. Using CRISPR screening, the team identified the low-density lipoprotein receptor as an alternative pathway to B12 uptake.

“These findings suggest a model in which anti-CD320 impairs transport of B12 across the BBB, leading to autoimmune B12 central deficiency (ABCD) with varied neurologic manifestations but sparing peripheral manifestations of B12 deficiency,” the authors wrote.

The work was supported by the National Institute of Mental Health, National Center for Chronic Disease Prevention and Health Promotion, Department of Defense, UCSF Helen Diller Family Comprehensive Cancer Center Laboratory for Cell Analysis Shared Resource Facility, National Multiple Sclerosis Society, Valhalla Foundation, and the Westridge Foundation. Dr. Pluvinage is a co-inventor on a patent application related to this work. Dr. Diamond had no relevant disclosures.

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

In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As reported by The New York Times, his family said that he had become increasingly erratic and violent during the months before the rampage.

A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a press release. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”

Members of the military, such as Mr. Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.

New data suggest that repeated blast exposure may impair the brain’s waste clearance system, leading to biomarker changes indicative of preclinical Alzheimer’s disease 20 years earlier than typical. A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues, according to experts interviewed.

In 2022, the US Department of Defense (DOD) launched its Warfighter Brain Health Initiative with the aim of “optimizing service member brain health and countering traumatic brain injuries.”

In April 2024, the Blast Overpressure Safety Act was introduced in the Senate to require the DOD to enact better blast screening, tracking, prevention, and treatment. The DOD initiated 26 blast overpressure studies.

Heather Snyder, PhD, Alzheimer’s Association vice president of Medical and Scientific Relations, said that an important component of that research involves “the need to study the difference between TBI-caused dementia and dementia caused independently” and “the need to study biomarkers to better understand the long-term consequences of TBI.”
 

What Is the Underlying Biology?

Dr. Snyder was the lead author of a white paper produced by the Alzheimer’s Association in 2018 on military-related risk factors for Alzheimer’s disease and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she said.

The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.

“We are also trying to understand the underlying biology around brain changes, such as accumulation of tau and amyloid and other specific markers related to brain changes in Alzheimer’s disease,” said Dr. Snyder, chair of the Peer Reviewed Alzheimer’s Research Program Programmatic Panel for Alzheimer’s Disease/Alzheimer’s Disease and Related Dementias and TBI.
 

Common Biomarker Signatures

A recent study in Neurology comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.

“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” said coauthor Elaine R. Peskind, MD, professor of psychiatry and behavioral sciences, University of Washington, Seattle.

The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.

The researchers found that the mTBI group “had biomarker signatures in common with the earliest stages of Alzheimer’s disease,” said Dr. Peskind.

For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Abeta42), the earliest marker of brain parenchymal Abeta deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).

High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for Alzheimer’s disease. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.

The mTBI group also showed worse cognitive performance at older ages (P < .08). Poorer verbal memory and verbal fluency performance were associated with lower CSF Abeta42 in older participants (P ≤ .05).

In Alzheimer’s disease, a reduction in CSF Abeta42 may occur up to 20 years before the onset of clinical symptoms, according to Dr. Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Abeta42.
 

Is Impaired Clearance the Culprit?

Coauthor Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.

“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Abeta42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he said. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”

Dr. Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”

A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.

The evidence base corroborating that hypothesis is in its infancy; however, new research conducted by Dr. Iliff and his colleagues sheds light on this potential mechanism.

In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as gray and white matter — to accelerate at different rates,” according to Dr. Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”

It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for Alzheimer’s disease and related dementing disorders, as well as CTE.

The missing link may be the glymphatic system — a “brain-wide network of perivascular pathways, along which CSF and interstitial fluid (ISF) exchange, supporting the clearance of interstitial solutes, including amyloid-beta.”

Dr. Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.

In their new study, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.

And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.

The earlier Neurology study “showed impairment of biomarkers in the CSF, but the new study showed ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Dr. Iliff explained.
 

Veterans Especially Vulnerable

Dr. Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.

“These were highly exposed combat vets,” she said. “And that number doesn’t even account for subconcussive exposure to blasts, which now appear to cause detectable brain damage, even in the absence of a diagnosable TBI.”

The Maine shooter, Mr. Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to The New York Times.

Dr. Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”

Dr. Snyder added that the majority of blast TBIs have been studied in military personnel, and she is not aware of studies that have looked at blast injuries in other industries, such as demolition or mining, to see if they have the same type of biologic consequences.

Dr. Snyder hopes that the researchers will follow the participants in the Neurology study and continue looking at specific markers related to Alzheimer’s disease brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”

Michael Alosco, PhD, associate professor and vice chair of research, department of neurology, Boston University Chobanian & Avedisian School of Medicine, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”

He coauthored an editorial on the earlier Neurology study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”
 

Clinical Implications

For Dr. Peskind, the “inflection point” was seeing lower CSF Abeta42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.

But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”

The clinical take-home messages are not unique to service members or veterans or people with a history of head injuries or a genetic predisposition to Alzheimer’s disease, she emphasized. “If anyone of any age or occupation comes in with cognitive issues, such as [impaired] memory or executive function, they deserve a workup for dementing disorders.” Frontotemporal dementia, for example, can present earlier than Alzheimer’s disease typically does.

Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.

Dr. Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”

Of all of these factors, the only truly directly modifiable one is sleep disruption, including that caused by OSA or sleep disorders related to PTSD, he added. “Epidemiologic data suggest a connection particularly between midlife sleep disruption and the risk of dementia and Alzheimer’s disease, and so it’s worth thinking about sleep as a modifiable risk factor even as early as the 40s and 50s, whether the patient is or isn’t a veteran.”

Dr. Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”

Dr. Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.

The study by Li and colleagues was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun and colleagues was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the DOD. Dr. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to Gryphon Biosciences. Dr. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Dr. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation Inc., and Life Molecular Imaging Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he received royalties from Oxford University Press Inc. The other authors’ disclosures are listed in the original papers.
 

A version of this article appeared on Medscape.com.

In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As reported by The New York Times, his family said that he had become increasingly erratic and violent during the months before the rampage.

A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a press release. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”

Members of the military, such as Mr. Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.

New data suggest that repeated blast exposure may impair the brain’s waste clearance system, leading to biomarker changes indicative of preclinical Alzheimer’s disease 20 years earlier than typical. A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues, according to experts interviewed.

In 2022, the US Department of Defense (DOD) launched its Warfighter Brain Health Initiative with the aim of “optimizing service member brain health and countering traumatic brain injuries.”

In April 2024, the Blast Overpressure Safety Act was introduced in the Senate to require the DOD to enact better blast screening, tracking, prevention, and treatment. The DOD initiated 26 blast overpressure studies.

Heather Snyder, PhD, Alzheimer’s Association vice president of Medical and Scientific Relations, said that an important component of that research involves “the need to study the difference between TBI-caused dementia and dementia caused independently” and “the need to study biomarkers to better understand the long-term consequences of TBI.”
 

What Is the Underlying Biology?

Dr. Snyder was the lead author of a white paper produced by the Alzheimer’s Association in 2018 on military-related risk factors for Alzheimer’s disease and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she said.

The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.

“We are also trying to understand the underlying biology around brain changes, such as accumulation of tau and amyloid and other specific markers related to brain changes in Alzheimer’s disease,” said Dr. Snyder, chair of the Peer Reviewed Alzheimer’s Research Program Programmatic Panel for Alzheimer’s Disease/Alzheimer’s Disease and Related Dementias and TBI.
 

Common Biomarker Signatures

A recent study in Neurology comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.

“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” said coauthor Elaine R. Peskind, MD, professor of psychiatry and behavioral sciences, University of Washington, Seattle.

The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.

The researchers found that the mTBI group “had biomarker signatures in common with the earliest stages of Alzheimer’s disease,” said Dr. Peskind.

For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Abeta42), the earliest marker of brain parenchymal Abeta deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).

High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for Alzheimer’s disease. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.

The mTBI group also showed worse cognitive performance at older ages (P < .08). Poorer verbal memory and verbal fluency performance were associated with lower CSF Abeta42 in older participants (P ≤ .05).

In Alzheimer’s disease, a reduction in CSF Abeta42 may occur up to 20 years before the onset of clinical symptoms, according to Dr. Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Abeta42.
 

Is Impaired Clearance the Culprit?

Coauthor Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.

“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Abeta42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he said. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”

Dr. Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”

A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.

The evidence base corroborating that hypothesis is in its infancy; however, new research conducted by Dr. Iliff and his colleagues sheds light on this potential mechanism.

In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as gray and white matter — to accelerate at different rates,” according to Dr. Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”

It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for Alzheimer’s disease and related dementing disorders, as well as CTE.

The missing link may be the glymphatic system — a “brain-wide network of perivascular pathways, along which CSF and interstitial fluid (ISF) exchange, supporting the clearance of interstitial solutes, including amyloid-beta.”

Dr. Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.

In their new study, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.

And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.

The earlier Neurology study “showed impairment of biomarkers in the CSF, but the new study showed ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Dr. Iliff explained.
 

Veterans Especially Vulnerable

Dr. Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.

“These were highly exposed combat vets,” she said. “And that number doesn’t even account for subconcussive exposure to blasts, which now appear to cause detectable brain damage, even in the absence of a diagnosable TBI.”

The Maine shooter, Mr. Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to The New York Times.

Dr. Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”

Dr. Snyder added that the majority of blast TBIs have been studied in military personnel, and she is not aware of studies that have looked at blast injuries in other industries, such as demolition or mining, to see if they have the same type of biologic consequences.

Dr. Snyder hopes that the researchers will follow the participants in the Neurology study and continue looking at specific markers related to Alzheimer’s disease brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”

Michael Alosco, PhD, associate professor and vice chair of research, department of neurology, Boston University Chobanian & Avedisian School of Medicine, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”

He coauthored an editorial on the earlier Neurology study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”
 

Clinical Implications

For Dr. Peskind, the “inflection point” was seeing lower CSF Abeta42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.

But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”

The clinical take-home messages are not unique to service members or veterans or people with a history of head injuries or a genetic predisposition to Alzheimer’s disease, she emphasized. “If anyone of any age or occupation comes in with cognitive issues, such as [impaired] memory or executive function, they deserve a workup for dementing disorders.” Frontotemporal dementia, for example, can present earlier than Alzheimer’s disease typically does.

Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.

Dr. Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”

Of all of these factors, the only truly directly modifiable one is sleep disruption, including that caused by OSA or sleep disorders related to PTSD, he added. “Epidemiologic data suggest a connection particularly between midlife sleep disruption and the risk of dementia and Alzheimer’s disease, and so it’s worth thinking about sleep as a modifiable risk factor even as early as the 40s and 50s, whether the patient is or isn’t a veteran.”

Dr. Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”

Dr. Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.

The study by Li and colleagues was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun and colleagues was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the DOD. Dr. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to Gryphon Biosciences. Dr. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Dr. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation Inc., and Life Molecular Imaging Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he received royalties from Oxford University Press Inc. The other authors’ disclosures are listed in the original papers.
 

A version of this article appeared on Medscape.com.

In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As reported by The New York Times, his family said that he had become increasingly erratic and violent during the months before the rampage.

A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a press release. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”

Members of the military, such as Mr. Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.

New data suggest that repeated blast exposure may impair the brain’s waste clearance system, leading to biomarker changes indicative of preclinical Alzheimer’s disease 20 years earlier than typical. A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues, according to experts interviewed.

In 2022, the US Department of Defense (DOD) launched its Warfighter Brain Health Initiative with the aim of “optimizing service member brain health and countering traumatic brain injuries.”

In April 2024, the Blast Overpressure Safety Act was introduced in the Senate to require the DOD to enact better blast screening, tracking, prevention, and treatment. The DOD initiated 26 blast overpressure studies.

Heather Snyder, PhD, Alzheimer’s Association vice president of Medical and Scientific Relations, said that an important component of that research involves “the need to study the difference between TBI-caused dementia and dementia caused independently” and “the need to study biomarkers to better understand the long-term consequences of TBI.”
 

What Is the Underlying Biology?

Dr. Snyder was the lead author of a white paper produced by the Alzheimer’s Association in 2018 on military-related risk factors for Alzheimer’s disease and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she said.

The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.

“We are also trying to understand the underlying biology around brain changes, such as accumulation of tau and amyloid and other specific markers related to brain changes in Alzheimer’s disease,” said Dr. Snyder, chair of the Peer Reviewed Alzheimer’s Research Program Programmatic Panel for Alzheimer’s Disease/Alzheimer’s Disease and Related Dementias and TBI.
 

Common Biomarker Signatures

A recent study in Neurology comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.

“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” said coauthor Elaine R. Peskind, MD, professor of psychiatry and behavioral sciences, University of Washington, Seattle.

The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.

The researchers found that the mTBI group “had biomarker signatures in common with the earliest stages of Alzheimer’s disease,” said Dr. Peskind.

For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Abeta42), the earliest marker of brain parenchymal Abeta deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).

High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for Alzheimer’s disease. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.

The mTBI group also showed worse cognitive performance at older ages (P < .08). Poorer verbal memory and verbal fluency performance were associated with lower CSF Abeta42 in older participants (P ≤ .05).

In Alzheimer’s disease, a reduction in CSF Abeta42 may occur up to 20 years before the onset of clinical symptoms, according to Dr. Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Abeta42.
 

Is Impaired Clearance the Culprit?

Coauthor Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.

“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Abeta42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he said. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”

Dr. Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”

A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.

The evidence base corroborating that hypothesis is in its infancy; however, new research conducted by Dr. Iliff and his colleagues sheds light on this potential mechanism.

In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as gray and white matter — to accelerate at different rates,” according to Dr. Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”

It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for Alzheimer’s disease and related dementing disorders, as well as CTE.

The missing link may be the glymphatic system — a “brain-wide network of perivascular pathways, along which CSF and interstitial fluid (ISF) exchange, supporting the clearance of interstitial solutes, including amyloid-beta.”

Dr. Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.

In their new study, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.

And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.

The earlier Neurology study “showed impairment of biomarkers in the CSF, but the new study showed ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Dr. Iliff explained.
 

Veterans Especially Vulnerable

Dr. Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.

“These were highly exposed combat vets,” she said. “And that number doesn’t even account for subconcussive exposure to blasts, which now appear to cause detectable brain damage, even in the absence of a diagnosable TBI.”

The Maine shooter, Mr. Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to The New York Times.

Dr. Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”

Dr. Snyder added that the majority of blast TBIs have been studied in military personnel, and she is not aware of studies that have looked at blast injuries in other industries, such as demolition or mining, to see if they have the same type of biologic consequences.

Dr. Snyder hopes that the researchers will follow the participants in the Neurology study and continue looking at specific markers related to Alzheimer’s disease brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”

Michael Alosco, PhD, associate professor and vice chair of research, department of neurology, Boston University Chobanian & Avedisian School of Medicine, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”

He coauthored an editorial on the earlier Neurology study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”
 

Clinical Implications

For Dr. Peskind, the “inflection point” was seeing lower CSF Abeta42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.

But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”

The clinical take-home messages are not unique to service members or veterans or people with a history of head injuries or a genetic predisposition to Alzheimer’s disease, she emphasized. “If anyone of any age or occupation comes in with cognitive issues, such as [impaired] memory or executive function, they deserve a workup for dementing disorders.” Frontotemporal dementia, for example, can present earlier than Alzheimer’s disease typically does.

Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.

Dr. Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”

Of all of these factors, the only truly directly modifiable one is sleep disruption, including that caused by OSA or sleep disorders related to PTSD, he added. “Epidemiologic data suggest a connection particularly between midlife sleep disruption and the risk of dementia and Alzheimer’s disease, and so it’s worth thinking about sleep as a modifiable risk factor even as early as the 40s and 50s, whether the patient is or isn’t a veteran.”

Dr. Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”

Dr. Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.

The study by Li and colleagues was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun and colleagues was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the DOD. Dr. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to Gryphon Biosciences. Dr. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Dr. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation Inc., and Life Molecular Imaging Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he received royalties from Oxford University Press Inc. The other authors’ disclosures are listed in the original papers.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Poor vision and contrast sensitivity at baseline increase the likelihood of incident dementia in older adults; a decline in contrast sensitivity over time also correlates with the risk of developing dementia.

METHODOLOGY:

• Researchers conducted a longitudinal study to analyze the association of visual function with the risk for dementia in 2159 men and women (mean age, 77.9 years; 54% women) included from the National Health and Aging Trends Study between 2021 and 2022.
• All participants were free from dementia at baseline and underwent visual assessment while wearing their usual glasses or contact lenses.
• Distance and near visual acuity were measured as the log minimum angle of resolution (logMAR) units where higher values indicated worse visual acuity; contrast sensitivity was measured as the log contrast sensitivity (logCS) units where lower values represented worse outcomes.
• Dementia status was determined by a medical diagnosis, a dementia score of 2 or more, or poor performance on cognitive testing.

TAKEAWAY:

• Over the 1-year follow-up period, 192 adults (6.6%) developed dementia.
• Worsening of distant and near vision by 0.1 logMAR increased the risk for dementia by 8% (P = .01) and 7% (P = .02), respectively.
• Each 0.1 logCS decline in baseline contrast sensitivity increased the risk for dementia by 9% (P = .003).
• A yearly decline in contrast sensitivity by 0.1 logCS increased the likelihood of dementia by 14% (P = .007).
• Changes in distant and near vision over time did not show a significant association with risk for dementia (P = .58 and P = .79, respectively).

IN PRACTICE:

“Visual function, especially contrast sensitivity, might be a risk factor for developing dementia,” the authors wrote. “Early vision screening may help identify adults at higher risk of dementia, allowing for timely interventions.”

SOURCE:

The study was led by Louay Almidani, MD, MSc, of the Wilmer Eye Institute at the Johns Hopkins University School of Medicine, in Baltimore, and was published online in the American Journal of Ophthalmology.

LIMITATIONS:

The study had a limited follow-up period of 1 year and may not have captured the long-term association between visual impairment and the risk for dementia. Moreover, the researchers did not consider other visual function measures such as depth perception and visual field, which might have affected the results.

DISCLOSURES:

The study did not have any funding source. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Poor vision and contrast sensitivity at baseline increase the likelihood of incident dementia in older adults; a decline in contrast sensitivity over time also correlates with the risk of developing dementia.

METHODOLOGY:

• Researchers conducted a longitudinal study to analyze the association of visual function with the risk for dementia in 2159 men and women (mean age, 77.9 years; 54% women) included from the National Health and Aging Trends Study between 2021 and 2022.
• All participants were free from dementia at baseline and underwent visual assessment while wearing their usual glasses or contact lenses.
• Distance and near visual acuity were measured as the log minimum angle of resolution (logMAR) units where higher values indicated worse visual acuity; contrast sensitivity was measured as the log contrast sensitivity (logCS) units where lower values represented worse outcomes.
• Dementia status was determined by a medical diagnosis, a dementia score of 2 or more, or poor performance on cognitive testing.

TAKEAWAY:

• Over the 1-year follow-up period, 192 adults (6.6%) developed dementia.
• Worsening of distant and near vision by 0.1 logMAR increased the risk for dementia by 8% (P = .01) and 7% (P = .02), respectively.
• Each 0.1 logCS decline in baseline contrast sensitivity increased the risk for dementia by 9% (P = .003).
• A yearly decline in contrast sensitivity by 0.1 logCS increased the likelihood of dementia by 14% (P = .007).
• Changes in distant and near vision over time did not show a significant association with risk for dementia (P = .58 and P = .79, respectively).

IN PRACTICE:

“Visual function, especially contrast sensitivity, might be a risk factor for developing dementia,” the authors wrote. “Early vision screening may help identify adults at higher risk of dementia, allowing for timely interventions.”

SOURCE:

The study was led by Louay Almidani, MD, MSc, of the Wilmer Eye Institute at the Johns Hopkins University School of Medicine, in Baltimore, and was published online in the American Journal of Ophthalmology.

LIMITATIONS:

The study had a limited follow-up period of 1 year and may not have captured the long-term association between visual impairment and the risk for dementia. Moreover, the researchers did not consider other visual function measures such as depth perception and visual field, which might have affected the results.

DISCLOSURES:

The study did not have any funding source. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Poor vision and contrast sensitivity at baseline increase the likelihood of incident dementia in older adults; a decline in contrast sensitivity over time also correlates with the risk of developing dementia.

METHODOLOGY:

• Researchers conducted a longitudinal study to analyze the association of visual function with the risk for dementia in 2159 men and women (mean age, 77.9 years; 54% women) included from the National Health and Aging Trends Study between 2021 and 2022.
• All participants were free from dementia at baseline and underwent visual assessment while wearing their usual glasses or contact lenses.
• Distance and near visual acuity were measured as the log minimum angle of resolution (logMAR) units where higher values indicated worse visual acuity; contrast sensitivity was measured as the log contrast sensitivity (logCS) units where lower values represented worse outcomes.
• Dementia status was determined by a medical diagnosis, a dementia score of 2 or more, or poor performance on cognitive testing.

TAKEAWAY:

• Over the 1-year follow-up period, 192 adults (6.6%) developed dementia.
• Worsening of distant and near vision by 0.1 logMAR increased the risk for dementia by 8% (P = .01) and 7% (P = .02), respectively.
• Each 0.1 logCS decline in baseline contrast sensitivity increased the risk for dementia by 9% (P = .003).
• A yearly decline in contrast sensitivity by 0.1 logCS increased the likelihood of dementia by 14% (P = .007).
• Changes in distant and near vision over time did not show a significant association with risk for dementia (P = .58 and P = .79, respectively).

IN PRACTICE:

“Visual function, especially contrast sensitivity, might be a risk factor for developing dementia,” the authors wrote. “Early vision screening may help identify adults at higher risk of dementia, allowing for timely interventions.”

SOURCE:

The study was led by Louay Almidani, MD, MSc, of the Wilmer Eye Institute at the Johns Hopkins University School of Medicine, in Baltimore, and was published online in the American Journal of Ophthalmology.

LIMITATIONS:

The study had a limited follow-up period of 1 year and may not have captured the long-term association between visual impairment and the risk for dementia. Moreover, the researchers did not consider other visual function measures such as depth perception and visual field, which might have affected the results.

DISCLOSURES:

The study did not have any funding source. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

A single course of treatment with emotional awareness and expression therapy (EAET) was associated with a significantly greater reduction in chronic pain severity than cognitive-behavioral therapy (CBT), the current psychotherapeutic gold standard, a new study suggested.

Two thirds of the patients who received EAET reported at least a 30% reduction in pain compared with 17% of those who received CBT. The randomized clinical trial also showed that individuals with depression and anxiety responded more favorably to EAET, a novel finding.

The study is one of only a few to directly compare EAET with CBT.

“Most people with chronic pain don’t consider psychotherapy at all,” said study investigator Brandon C. Yarns, MD, a staff psychiatrist at the VA Greater Los Angeles Healthcare System, and clinical professor of health sciences at the Department of Psychiatry and Biobehavioral Sciences, UCLA Health.

Although patients were allowed to continue medication for pain and other comorbidities during the study, those who received EAET “had larger improvements in pain, depression, and anxiety,” Dr. Yarns said. “That suggests that the effect was due to the EAET.”

The findings were published online in JAMA Network Open.
 

‘Gold Standard’

EAET was first used in the early 2010s. In the therapy, patients are asked to recall a difficult or traumatic memory, engage in experiencing how the related emotions feel in the body, express those feelings in words, and release or let them go. They are taught that the brain’s perception of pain is strongly influenced by the evasion of grief, fear, rage, or guilt, Dr. Yarns said.

This contrasts with CBT — considered the current gold standard for chronic pain — which teaches patients to improve the ability to tolerate pain though guided imagery, muscle relaxation, and other exercises and to adapt their thinking to change how they think about pain.

Although prior studies suggested EAET is effective in reducing pain in fibromyalgia and chronic musculoskeletal, pelvic, and head pain, most included primarily younger, female patients.

The research is the “first full-scale evaluation of EAET, to our knowledge, in a medically or psychiatrically complex, racially and ethnically diverse, older sample comprising predominantly men,” investigators wrote.

The trial enrolled 126 veterans (92% men; 55% Black or African American) aged 60-95 years with at least 3 months of musculoskeletal pain. More than two thirds of patients had a psychiatric diagnosis, with about one third having posttraumatic stress disorder (PTSD). Almost all had back pain, and many had pain in multiple locations.

All services were delivered in-person at the US Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles. Half underwent CBT, while the other half received EAET.

Each patient had one 90-minute individual session and eight additional 90-minute group sessions.

Patients were asked to rate their pain using a 0-10 scale in the Brief Pain Inventory (BPI) before starting treatment, at the end of the nine sessions (at week 10), and 6 months after the sessions ended. Baseline BPI score for both groups was a mean of around 6.

Post treatment, people in the EAET versus CBT group had a mean two-point reduction versus 0.60 reduction, respectively, on the BPI scale. A clinically significant reduction in pain — defined as ≥ 30% decrease — was reported in 63% of EAET patients versus 17% of CBT patients (odds ratio [OR], 21.54; P < .001).

At 6 months, the mean reduction was 1.2 for the EAET group compared with 0.25 for the CBT group, and 40% of the EAET group reported a clinically significant reduction in pain.

A little more than a third (35%) of veterans receiving EAET reported at least a 50% reduction in pain at 10 weeks compared with 7% of those receiving CBT. At 6 months, 16% of the EAET arm reported a halving of their pain.

EAET was also superior to CBT in reducing anxiety, depression, and PTSD symptoms at the 10-week mark.
 

More Work Needed

In an accompanying editorial, Matthias Karst, MD, PhD, a clinician with the Pain Clinic, Hannover Medical School, in Hannover, Germany, noted that EAET’s effects “are significantly superior to those of CBT in almost all dimensions, even after 6 months.”

EAET “assigns a special place to the integration of the body into the emotional experience,” he wrote.

The study demonstrated that “the evocation and expression of emotions is superior to the mere cognitive discussion of these emotions in therapy of patients with chronic pain.”

Commenting on the findings, Traci J. Speed, MD, PhD, assistant professor of psychiatry and behavioral sciences and an attending psychiatrist of the Johns Hopkins Pain Treatment Program at Johns Hopkins University, Baltimore, called the study “ground-breaking” because it showed effectiveness in people with high rates of PTSD, anxiety, and depression.

“It is a little bit surprising how impressive the study outcomes are in terms of maintaining the effects at the end of the treatment and sustaining some of the effects on pain sensitivity even at the 6-month follow-up,” said Dr. Speed, who was not part of the study.

However, she continued, “I don’t think it changes the current standard of practice yet. CBT has decades of research and evidence that it is effective for chronic pain and that will I think continue to be the standard of care.”

Although EAET is in its infancy, chronic pain experts are interested in learning more about the therapy, Dr. Speed added.

“It blends well with the current techniques and extends the current gold standard treatment approaches,” she said. “We are starting to really appreciate the role that emotions play in pain sensitivity.”

Both Dr. Karst and Dr. Speed noted that more study is needed to determine the sustainability of treatment effects.

Dr. Yarns agreed. “We need more research on what the appropriate dose is and perhaps how one might go about personalizing that for the patient,” he said.

The study was funded by a career development award to Dr. Yarns from the VA Clinical Science Research and Development Service. Dr. Yarns reported receiving grants from the US Department of Veterans Affairs during the study. Other authors’ disclosures are in the original article. Dr. Speed reported no conflicts.
 

A version of this article appeared on Medscape.com.

A single course of treatment with emotional awareness and expression therapy (EAET) was associated with a significantly greater reduction in chronic pain severity than cognitive-behavioral therapy (CBT), the current psychotherapeutic gold standard, a new study suggested.

Two thirds of the patients who received EAET reported at least a 30% reduction in pain compared with 17% of those who received CBT. The randomized clinical trial also showed that individuals with depression and anxiety responded more favorably to EAET, a novel finding.

The study is one of only a few to directly compare EAET with CBT.

“Most people with chronic pain don’t consider psychotherapy at all,” said study investigator Brandon C. Yarns, MD, a staff psychiatrist at the VA Greater Los Angeles Healthcare System, and clinical professor of health sciences at the Department of Psychiatry and Biobehavioral Sciences, UCLA Health.

Although patients were allowed to continue medication for pain and other comorbidities during the study, those who received EAET “had larger improvements in pain, depression, and anxiety,” Dr. Yarns said. “That suggests that the effect was due to the EAET.”

The findings were published online in JAMA Network Open.
 

‘Gold Standard’

EAET was first used in the early 2010s. In the therapy, patients are asked to recall a difficult or traumatic memory, engage in experiencing how the related emotions feel in the body, express those feelings in words, and release or let them go. They are taught that the brain’s perception of pain is strongly influenced by the evasion of grief, fear, rage, or guilt, Dr. Yarns said.

This contrasts with CBT — considered the current gold standard for chronic pain — which teaches patients to improve the ability to tolerate pain though guided imagery, muscle relaxation, and other exercises and to adapt their thinking to change how they think about pain.

Although prior studies suggested EAET is effective in reducing pain in fibromyalgia and chronic musculoskeletal, pelvic, and head pain, most included primarily younger, female patients.

The research is the “first full-scale evaluation of EAET, to our knowledge, in a medically or psychiatrically complex, racially and ethnically diverse, older sample comprising predominantly men,” investigators wrote.

The trial enrolled 126 veterans (92% men; 55% Black or African American) aged 60-95 years with at least 3 months of musculoskeletal pain. More than two thirds of patients had a psychiatric diagnosis, with about one third having posttraumatic stress disorder (PTSD). Almost all had back pain, and many had pain in multiple locations.

All services were delivered in-person at the US Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles. Half underwent CBT, while the other half received EAET.

Each patient had one 90-minute individual session and eight additional 90-minute group sessions.

Patients were asked to rate their pain using a 0-10 scale in the Brief Pain Inventory (BPI) before starting treatment, at the end of the nine sessions (at week 10), and 6 months after the sessions ended. Baseline BPI score for both groups was a mean of around 6.

Post treatment, people in the EAET versus CBT group had a mean two-point reduction versus 0.60 reduction, respectively, on the BPI scale. A clinically significant reduction in pain — defined as ≥ 30% decrease — was reported in 63% of EAET patients versus 17% of CBT patients (odds ratio [OR], 21.54; P < .001).

At 6 months, the mean reduction was 1.2 for the EAET group compared with 0.25 for the CBT group, and 40% of the EAET group reported a clinically significant reduction in pain.

A little more than a third (35%) of veterans receiving EAET reported at least a 50% reduction in pain at 10 weeks compared with 7% of those receiving CBT. At 6 months, 16% of the EAET arm reported a halving of their pain.

EAET was also superior to CBT in reducing anxiety, depression, and PTSD symptoms at the 10-week mark.
 

More Work Needed

In an accompanying editorial, Matthias Karst, MD, PhD, a clinician with the Pain Clinic, Hannover Medical School, in Hannover, Germany, noted that EAET’s effects “are significantly superior to those of CBT in almost all dimensions, even after 6 months.”

EAET “assigns a special place to the integration of the body into the emotional experience,” he wrote.

The study demonstrated that “the evocation and expression of emotions is superior to the mere cognitive discussion of these emotions in therapy of patients with chronic pain.”

Commenting on the findings, Traci J. Speed, MD, PhD, assistant professor of psychiatry and behavioral sciences and an attending psychiatrist of the Johns Hopkins Pain Treatment Program at Johns Hopkins University, Baltimore, called the study “ground-breaking” because it showed effectiveness in people with high rates of PTSD, anxiety, and depression.

“It is a little bit surprising how impressive the study outcomes are in terms of maintaining the effects at the end of the treatment and sustaining some of the effects on pain sensitivity even at the 6-month follow-up,” said Dr. Speed, who was not part of the study.

However, she continued, “I don’t think it changes the current standard of practice yet. CBT has decades of research and evidence that it is effective for chronic pain and that will I think continue to be the standard of care.”

Although EAET is in its infancy, chronic pain experts are interested in learning more about the therapy, Dr. Speed added.

“It blends well with the current techniques and extends the current gold standard treatment approaches,” she said. “We are starting to really appreciate the role that emotions play in pain sensitivity.”

Both Dr. Karst and Dr. Speed noted that more study is needed to determine the sustainability of treatment effects.

Dr. Yarns agreed. “We need more research on what the appropriate dose is and perhaps how one might go about personalizing that for the patient,” he said.

The study was funded by a career development award to Dr. Yarns from the VA Clinical Science Research and Development Service. Dr. Yarns reported receiving grants from the US Department of Veterans Affairs during the study. Other authors’ disclosures are in the original article. Dr. Speed reported no conflicts.
 

A version of this article appeared on Medscape.com.

A single course of treatment with emotional awareness and expression therapy (EAET) was associated with a significantly greater reduction in chronic pain severity than cognitive-behavioral therapy (CBT), the current psychotherapeutic gold standard, a new study suggested.

Two thirds of the patients who received EAET reported at least a 30% reduction in pain compared with 17% of those who received CBT. The randomized clinical trial also showed that individuals with depression and anxiety responded more favorably to EAET, a novel finding.

The study is one of only a few to directly compare EAET with CBT.

“Most people with chronic pain don’t consider psychotherapy at all,” said study investigator Brandon C. Yarns, MD, a staff psychiatrist at the VA Greater Los Angeles Healthcare System, and clinical professor of health sciences at the Department of Psychiatry and Biobehavioral Sciences, UCLA Health.

Although patients were allowed to continue medication for pain and other comorbidities during the study, those who received EAET “had larger improvements in pain, depression, and anxiety,” Dr. Yarns said. “That suggests that the effect was due to the EAET.”

The findings were published online in JAMA Network Open.
 

‘Gold Standard’

EAET was first used in the early 2010s. In the therapy, patients are asked to recall a difficult or traumatic memory, engage in experiencing how the related emotions feel in the body, express those feelings in words, and release or let them go. They are taught that the brain’s perception of pain is strongly influenced by the evasion of grief, fear, rage, or guilt, Dr. Yarns said.

This contrasts with CBT — considered the current gold standard for chronic pain — which teaches patients to improve the ability to tolerate pain though guided imagery, muscle relaxation, and other exercises and to adapt their thinking to change how they think about pain.

Although prior studies suggested EAET is effective in reducing pain in fibromyalgia and chronic musculoskeletal, pelvic, and head pain, most included primarily younger, female patients.

The research is the “first full-scale evaluation of EAET, to our knowledge, in a medically or psychiatrically complex, racially and ethnically diverse, older sample comprising predominantly men,” investigators wrote.

The trial enrolled 126 veterans (92% men; 55% Black or African American) aged 60-95 years with at least 3 months of musculoskeletal pain. More than two thirds of patients had a psychiatric diagnosis, with about one third having posttraumatic stress disorder (PTSD). Almost all had back pain, and many had pain in multiple locations.

All services were delivered in-person at the US Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles. Half underwent CBT, while the other half received EAET.

Each patient had one 90-minute individual session and eight additional 90-minute group sessions.

Patients were asked to rate their pain using a 0-10 scale in the Brief Pain Inventory (BPI) before starting treatment, at the end of the nine sessions (at week 10), and 6 months after the sessions ended. Baseline BPI score for both groups was a mean of around 6.

Post treatment, people in the EAET versus CBT group had a mean two-point reduction versus 0.60 reduction, respectively, on the BPI scale. A clinically significant reduction in pain — defined as ≥ 30% decrease — was reported in 63% of EAET patients versus 17% of CBT patients (odds ratio [OR], 21.54; P < .001).

At 6 months, the mean reduction was 1.2 for the EAET group compared with 0.25 for the CBT group, and 40% of the EAET group reported a clinically significant reduction in pain.

A little more than a third (35%) of veterans receiving EAET reported at least a 50% reduction in pain at 10 weeks compared with 7% of those receiving CBT. At 6 months, 16% of the EAET arm reported a halving of their pain.

EAET was also superior to CBT in reducing anxiety, depression, and PTSD symptoms at the 10-week mark.
 

More Work Needed

In an accompanying editorial, Matthias Karst, MD, PhD, a clinician with the Pain Clinic, Hannover Medical School, in Hannover, Germany, noted that EAET’s effects “are significantly superior to those of CBT in almost all dimensions, even after 6 months.”

EAET “assigns a special place to the integration of the body into the emotional experience,” he wrote.

The study demonstrated that “the evocation and expression of emotions is superior to the mere cognitive discussion of these emotions in therapy of patients with chronic pain.”

Commenting on the findings, Traci J. Speed, MD, PhD, assistant professor of psychiatry and behavioral sciences and an attending psychiatrist of the Johns Hopkins Pain Treatment Program at Johns Hopkins University, Baltimore, called the study “ground-breaking” because it showed effectiveness in people with high rates of PTSD, anxiety, and depression.

“It is a little bit surprising how impressive the study outcomes are in terms of maintaining the effects at the end of the treatment and sustaining some of the effects on pain sensitivity even at the 6-month follow-up,” said Dr. Speed, who was not part of the study.

However, she continued, “I don’t think it changes the current standard of practice yet. CBT has decades of research and evidence that it is effective for chronic pain and that will I think continue to be the standard of care.”

Although EAET is in its infancy, chronic pain experts are interested in learning more about the therapy, Dr. Speed added.

“It blends well with the current techniques and extends the current gold standard treatment approaches,” she said. “We are starting to really appreciate the role that emotions play in pain sensitivity.”

Both Dr. Karst and Dr. Speed noted that more study is needed to determine the sustainability of treatment effects.

Dr. Yarns agreed. “We need more research on what the appropriate dose is and perhaps how one might go about personalizing that for the patient,” he said.

The study was funded by a career development award to Dr. Yarns from the VA Clinical Science Research and Development Service. Dr. Yarns reported receiving grants from the US Department of Veterans Affairs during the study. Other authors’ disclosures are in the original article. Dr. Speed reported no conflicts.
 

A version of this article appeared on Medscape.com.

An intensive lifestyle intervention significantly improved cognition and function in many patients with mild cognitive impairment (MCI) or early dementia due to Alzheimer’s disease, in what authors said is the first randomized controlled trial of intensive lifestyle modification for patients diagnosed with Alzheimer’s disease. Results could help physicians address patients at risk of Alzheimer’s disease who reject relevant testing because they believe nothing can forestall development of the disease, the authors added. The study was published online in Alzheimer’s Research & Therapy.

Although technology allows probable Alzheimer’s disease diagnosis years before clinical symptoms appear, wrote investigators led by Dean Ornish, MD, of the Preventive Medicine Research Institute in Sausalito, California, “many people do not want to know if they are likely to get Alzheimer’s disease if they do not believe they can do anything about it. If intensive lifestyle changes may cause improvement in cognition and function in MCI or early dementia due to Alzheimer’s disease, then it is reasonable to think that these lifestyle changes may also help to prevent MCI or early dementia due to Alzheimer’s disease.” As with cardiovascular disease, the authors added, preventing Alzheimer’s disease might require less intensive lifestyle modifications than treating it.
 

Study Methodology

Investigators randomized 26 patients with Montréal Cognitive Assessment scores of 18 or higher to an intensive intervention involving nutrition, exercise, and stress management techniques. To improve adherence, the protocol included participants’ spouses or caregivers.

Two patients, both in the treatment group, withdrew over logistical concerns.

After 20 weeks, treated patients exhibited statistically significant differences in several key measures versus a 25-patient usual-care control group. Scores that improved in the intervention group and worsened among controls included the following:

• Clinical Global Impression of Change (CGIC, P = .001)
• Clinical Dementia Rating-Global (CDR-Global, -0.04, P = .037)
• Clinical Dementia Rating Sum of Boxes (CDR-SB, +0.08, P = .032)
• Alzheimer’s Disease Assessment Scale (ADAS-Cog, -1.01, P = .053)

The validity of these changes in cognition and function, and possible biological mechanisms of improvement, were supported by statistically significant improvements in several clinically relevant biomarkers versus controls, the investigators wrote. These biomarkers included Abeta42/40 ratio, HbA1c, insulin, and glycoprotein acetylation. “This information may also help in predicting which patients are more likely to show improvements in cognition and function by making these intensive lifestyle changes,” the authors added.

In primary analysis, the degree of lifestyle changes required to stop progression of MCI ranged from 71.4% (ADAS-Cog) to 120.6% (CDR-SB). “This helps to explain why other studies of less intensive lifestyle interventions may not have been sufficient to stop deterioration or improve cognition and function,” the authors wrote. Moreover, they added, variable adherence might explain why in the intervention group, 10 patients improved their CGIC scores, while the rest held static or worsened.
 

Caveats

Alzheimer’s Association Vice President of Medical and Scientific Relations Heather M. Snyder, PhD, said, “This is an interesting paper in an important area of research and adds to the growing body of literature on how behavior or lifestyle may be related to cognitive decline. However, because this is a small phase 2 study, it is important for this or similar work to be done in larger, more diverse populations and over a longer duration of the intervention.” She was not involved with the study but was asked to comment.

Investigators chose the 20-week duration, they explained, because control-group patients likely would not refrain from trying the lifestyle intervention beyond that timeframe. Perhaps more importantly, challenges created by the COVID-19 pandemic required researchers to cut planned enrollment in half, eliminate planned MRI and amyloid PET scans, and reduce the number of cognition and function tests.

Such shortcomings limit what neurologists can glean and generalize from the study, said Dr. Snyder. “That said,” she added, “it does demonstrate the potential of an intensive behavior/lifestyle intervention, and the importance of this sort of research in Alzheimer’s and dementia.” Although the complexity of the interventions makes these studies challenging, she added, “it is important that we continue to advance larger, longer studies in more representative study populations to develop specific recommendations.”
 

Further Study

The Alzheimer’s Association’s U.S. POINTER study is the first large-scale study in the United States to explore the impact of comprehensive lifestyle changes on cognitive health. About 2000 older adults at risk for cognitive decline are participating, from diverse locations across the country. More than 25% of participants come from groups typically underrepresented in dementia research, said Dr. Snyder. Initial results are expected in summer 2025.

Future research also should explore reasons (beyond adherence) why some patients respond to lifestyle interventions better than others, and the potential synergy of lifestyle changes with drug therapies, wrote Dr. Ornish and colleagues.

“For now,” said Dr. Snyder, “there is an opportunity for providers to incorporate or expand messaging with their patients and families about the habits that they can incorporate into their daily lives. The Alzheimer’s Association offers 10 Healthy Habits for Your Brain — everyday actions that can make a difference for your brain health.”

Investigators received study funding from more than two dozen charitable foundations and other organizations. Dr. Snyder is a full-time employee of the Alzheimer’s Association and in this role, serves on the leadership team of the U.S. POINTER study. Her partner works for Abbott in an unrelated field. 

An intensive lifestyle intervention significantly improved cognition and function in many patients with mild cognitive impairment (MCI) or early dementia due to Alzheimer’s disease, in what authors said is the first randomized controlled trial of intensive lifestyle modification for patients diagnosed with Alzheimer’s disease. Results could help physicians address patients at risk of Alzheimer’s disease who reject relevant testing because they believe nothing can forestall development of the disease, the authors added. The study was published online in Alzheimer’s Research & Therapy.

Although technology allows probable Alzheimer’s disease diagnosis years before clinical symptoms appear, wrote investigators led by Dean Ornish, MD, of the Preventive Medicine Research Institute in Sausalito, California, “many people do not want to know if they are likely to get Alzheimer’s disease if they do not believe they can do anything about it. If intensive lifestyle changes may cause improvement in cognition and function in MCI or early dementia due to Alzheimer’s disease, then it is reasonable to think that these lifestyle changes may also help to prevent MCI or early dementia due to Alzheimer’s disease.” As with cardiovascular disease, the authors added, preventing Alzheimer’s disease might require less intensive lifestyle modifications than treating it.
 

Study Methodology

Investigators randomized 26 patients with Montréal Cognitive Assessment scores of 18 or higher to an intensive intervention involving nutrition, exercise, and stress management techniques. To improve adherence, the protocol included participants’ spouses or caregivers.

Two patients, both in the treatment group, withdrew over logistical concerns.

After 20 weeks, treated patients exhibited statistically significant differences in several key measures versus a 25-patient usual-care control group. Scores that improved in the intervention group and worsened among controls included the following:

• Clinical Global Impression of Change (CGIC, P = .001)
• Clinical Dementia Rating-Global (CDR-Global, -0.04, P = .037)
• Clinical Dementia Rating Sum of Boxes (CDR-SB, +0.08, P = .032)
• Alzheimer’s Disease Assessment Scale (ADAS-Cog, -1.01, P = .053)

The validity of these changes in cognition and function, and possible biological mechanisms of improvement, were supported by statistically significant improvements in several clinically relevant biomarkers versus controls, the investigators wrote. These biomarkers included Abeta42/40 ratio, HbA1c, insulin, and glycoprotein acetylation. “This information may also help in predicting which patients are more likely to show improvements in cognition and function by making these intensive lifestyle changes,” the authors added.

In primary analysis, the degree of lifestyle changes required to stop progression of MCI ranged from 71.4% (ADAS-Cog) to 120.6% (CDR-SB). “This helps to explain why other studies of less intensive lifestyle interventions may not have been sufficient to stop deterioration or improve cognition and function,” the authors wrote. Moreover, they added, variable adherence might explain why in the intervention group, 10 patients improved their CGIC scores, while the rest held static or worsened.
 

Caveats

Alzheimer’s Association Vice President of Medical and Scientific Relations Heather M. Snyder, PhD, said, “This is an interesting paper in an important area of research and adds to the growing body of literature on how behavior or lifestyle may be related to cognitive decline. However, because this is a small phase 2 study, it is important for this or similar work to be done in larger, more diverse populations and over a longer duration of the intervention.” She was not involved with the study but was asked to comment.

Investigators chose the 20-week duration, they explained, because control-group patients likely would not refrain from trying the lifestyle intervention beyond that timeframe. Perhaps more importantly, challenges created by the COVID-19 pandemic required researchers to cut planned enrollment in half, eliminate planned MRI and amyloid PET scans, and reduce the number of cognition and function tests.

Such shortcomings limit what neurologists can glean and generalize from the study, said Dr. Snyder. “That said,” she added, “it does demonstrate the potential of an intensive behavior/lifestyle intervention, and the importance of this sort of research in Alzheimer’s and dementia.” Although the complexity of the interventions makes these studies challenging, she added, “it is important that we continue to advance larger, longer studies in more representative study populations to develop specific recommendations.”
 

Further Study

The Alzheimer’s Association’s U.S. POINTER study is the first large-scale study in the United States to explore the impact of comprehensive lifestyle changes on cognitive health. About 2000 older adults at risk for cognitive decline are participating, from diverse locations across the country. More than 25% of participants come from groups typically underrepresented in dementia research, said Dr. Snyder. Initial results are expected in summer 2025.

Future research also should explore reasons (beyond adherence) why some patients respond to lifestyle interventions better than others, and the potential synergy of lifestyle changes with drug therapies, wrote Dr. Ornish and colleagues.

“For now,” said Dr. Snyder, “there is an opportunity for providers to incorporate or expand messaging with their patients and families about the habits that they can incorporate into their daily lives. The Alzheimer’s Association offers 10 Healthy Habits for Your Brain — everyday actions that can make a difference for your brain health.”

Investigators received study funding from more than two dozen charitable foundations and other organizations. Dr. Snyder is a full-time employee of the Alzheimer’s Association and in this role, serves on the leadership team of the U.S. POINTER study. Her partner works for Abbott in an unrelated field. 

An intensive lifestyle intervention significantly improved cognition and function in many patients with mild cognitive impairment (MCI) or early dementia due to Alzheimer’s disease, in what authors said is the first randomized controlled trial of intensive lifestyle modification for patients diagnosed with Alzheimer’s disease. Results could help physicians address patients at risk of Alzheimer’s disease who reject relevant testing because they believe nothing can forestall development of the disease, the authors added. The study was published online in Alzheimer’s Research & Therapy.

Although technology allows probable Alzheimer’s disease diagnosis years before clinical symptoms appear, wrote investigators led by Dean Ornish, MD, of the Preventive Medicine Research Institute in Sausalito, California, “many people do not want to know if they are likely to get Alzheimer’s disease if they do not believe they can do anything about it. If intensive lifestyle changes may cause improvement in cognition and function in MCI or early dementia due to Alzheimer’s disease, then it is reasonable to think that these lifestyle changes may also help to prevent MCI or early dementia due to Alzheimer’s disease.” As with cardiovascular disease, the authors added, preventing Alzheimer’s disease might require less intensive lifestyle modifications than treating it.
 

Study Methodology

Investigators randomized 26 patients with Montréal Cognitive Assessment scores of 18 or higher to an intensive intervention involving nutrition, exercise, and stress management techniques. To improve adherence, the protocol included participants’ spouses or caregivers.

Two patients, both in the treatment group, withdrew over logistical concerns.

After 20 weeks, treated patients exhibited statistically significant differences in several key measures versus a 25-patient usual-care control group. Scores that improved in the intervention group and worsened among controls included the following:

• Clinical Global Impression of Change (CGIC, P = .001)
• Clinical Dementia Rating-Global (CDR-Global, -0.04, P = .037)
• Clinical Dementia Rating Sum of Boxes (CDR-SB, +0.08, P = .032)
• Alzheimer’s Disease Assessment Scale (ADAS-Cog, -1.01, P = .053)

The validity of these changes in cognition and function, and possible biological mechanisms of improvement, were supported by statistically significant improvements in several clinically relevant biomarkers versus controls, the investigators wrote. These biomarkers included Abeta42/40 ratio, HbA1c, insulin, and glycoprotein acetylation. “This information may also help in predicting which patients are more likely to show improvements in cognition and function by making these intensive lifestyle changes,” the authors added.

In primary analysis, the degree of lifestyle changes required to stop progression of MCI ranged from 71.4% (ADAS-Cog) to 120.6% (CDR-SB). “This helps to explain why other studies of less intensive lifestyle interventions may not have been sufficient to stop deterioration or improve cognition and function,” the authors wrote. Moreover, they added, variable adherence might explain why in the intervention group, 10 patients improved their CGIC scores, while the rest held static or worsened.
 

Caveats

Alzheimer’s Association Vice President of Medical and Scientific Relations Heather M. Snyder, PhD, said, “This is an interesting paper in an important area of research and adds to the growing body of literature on how behavior or lifestyle may be related to cognitive decline. However, because this is a small phase 2 study, it is important for this or similar work to be done in larger, more diverse populations and over a longer duration of the intervention.” She was not involved with the study but was asked to comment.

Investigators chose the 20-week duration, they explained, because control-group patients likely would not refrain from trying the lifestyle intervention beyond that timeframe. Perhaps more importantly, challenges created by the COVID-19 pandemic required researchers to cut planned enrollment in half, eliminate planned MRI and amyloid PET scans, and reduce the number of cognition and function tests.

Such shortcomings limit what neurologists can glean and generalize from the study, said Dr. Snyder. “That said,” she added, “it does demonstrate the potential of an intensive behavior/lifestyle intervention, and the importance of this sort of research in Alzheimer’s and dementia.” Although the complexity of the interventions makes these studies challenging, she added, “it is important that we continue to advance larger, longer studies in more representative study populations to develop specific recommendations.”
 

Further Study

The Alzheimer’s Association’s U.S. POINTER study is the first large-scale study in the United States to explore the impact of comprehensive lifestyle changes on cognitive health. About 2000 older adults at risk for cognitive decline are participating, from diverse locations across the country. More than 25% of participants come from groups typically underrepresented in dementia research, said Dr. Snyder. Initial results are expected in summer 2025.

Future research also should explore reasons (beyond adherence) why some patients respond to lifestyle interventions better than others, and the potential synergy of lifestyle changes with drug therapies, wrote Dr. Ornish and colleagues.

“For now,” said Dr. Snyder, “there is an opportunity for providers to incorporate or expand messaging with their patients and families about the habits that they can incorporate into their daily lives. The Alzheimer’s Association offers 10 Healthy Habits for Your Brain — everyday actions that can make a difference for your brain health.”

Investigators received study funding from more than two dozen charitable foundations and other organizations. Dr. Snyder is a full-time employee of the Alzheimer’s Association and in this role, serves on the leadership team of the U.S. POINTER study. Her partner works for Abbott in an unrelated field. 

Using combined genetic testing in early childhood may decrease the misdiagnosis rate for Global Development Delay (GDD) and may help identify intervention targets, a new study suggests.

Researchers, led by Jiamei Zhang, MS, Department of Rehabilitation Medicine, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China, in a multicenter, prospective cohort study enrolled patients ages 12 to 60 months with GDD from six centers in China from July 2020 through August 2023. Participants underwent trio whole exome sequencing (trio-WES) paired with copy number variation sequencing (CNV-seq).

“To the best of our knowledge, this study represents the largest prospective examination of combined genetic testing methods in a GDD cohort,” the authors reported in JAMA Network Open.

GDD is a common neurodevelopmental disorder, marked by cognitive impairment, and affects about 1% of children, the paper states. Most children with GDD develop intellectual disability (ID) after 5 years of age, with implications for quality of life, their physical abilities, and social functioning. Early and accurate diagnosis followed by appropriately targeted treatment is critical, but lacking. Researchers note that there is lack of consensus among health care professionals on whether genetic testing is necessary.

Genetics are known to play a significant role in pathogenesis of GDD, but definitive biomarkers have been elusive.
 

Positive Detection Rate of 61%

In this study, the combined use of trio-WES with CNV-seq in children with early-stage GDD resulted in a positive detection rate of 61%, a significant improvement over performing individual tests, “enhancing the positive detection rate by 18%-40%,” the researchers wrote. The combined approach also saves families time and costs, they note, while leading to more comprehensive genetic analysis and fewer missed diagnoses.

The combined approach also addressed the limitations of trio-WES and CNV-seq used alone, the authors wrote. Because of technological constraints, trio-WES may miss 55% of CNV variations, and CNV-seq has a missed diagnosis rate of 3%.

The study included 434 patients with GDD (60% male; average age, 25 months) with diverse degrees of cognitive impairment: mild (23%); moderate (32%); severe (28%); and profound (17%).

Three characteristics were linked with higher likelihood of having genetic variants: Craniofacial abnormalities (odds ratio [OR], 2.27; 95% confidence interval [CI], 1.45-3.56); moderate or severe cognitive impairment (OR, 1.69; 95% CI, 1.05-2.70); and age between 12 and 24 months (OR, 1.57; 95% CI, 1.05-2.35).
 

Dopaminergic Pathway Promising for Treatment

Researchers also discovered that GDD-related genes were primarily enriched in lysosome, dopaminergic synapse, and lysine degradation pathways. Dopaminergic synapse emerged as a significant pathway linked with GDD.

“In this cohort study, our findings support the correlation between dopaminergic synapse and cognitive impairment, as substantiated by prior research and animal models. Therefore, targeting the dopaminergic pathway holds promise for treating GDD and ID,” the authors wrote.

However, the authors note in the limitations that they used only a subset of 100 patients with GDD to measure dopamine concentration.

“Expanding the sample size and conducting in vivo and in vitro experiments are necessary steps to verify whether dopamine can be targeted for clinical precision medical intervention in patients with GDD,” they wrote.

The authors reported no relevant financial relationships.

Using combined genetic testing in early childhood may decrease the misdiagnosis rate for Global Development Delay (GDD) and may help identify intervention targets, a new study suggests.

Researchers, led by Jiamei Zhang, MS, Department of Rehabilitation Medicine, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China, in a multicenter, prospective cohort study enrolled patients ages 12 to 60 months with GDD from six centers in China from July 2020 through August 2023. Participants underwent trio whole exome sequencing (trio-WES) paired with copy number variation sequencing (CNV-seq).

“To the best of our knowledge, this study represents the largest prospective examination of combined genetic testing methods in a GDD cohort,” the authors reported in JAMA Network Open.

GDD is a common neurodevelopmental disorder, marked by cognitive impairment, and affects about 1% of children, the paper states. Most children with GDD develop intellectual disability (ID) after 5 years of age, with implications for quality of life, their physical abilities, and social functioning. Early and accurate diagnosis followed by appropriately targeted treatment is critical, but lacking. Researchers note that there is lack of consensus among health care professionals on whether genetic testing is necessary.

Genetics are known to play a significant role in pathogenesis of GDD, but definitive biomarkers have been elusive.
 

Positive Detection Rate of 61%

In this study, the combined use of trio-WES with CNV-seq in children with early-stage GDD resulted in a positive detection rate of 61%, a significant improvement over performing individual tests, “enhancing the positive detection rate by 18%-40%,” the researchers wrote. The combined approach also saves families time and costs, they note, while leading to more comprehensive genetic analysis and fewer missed diagnoses.

The combined approach also addressed the limitations of trio-WES and CNV-seq used alone, the authors wrote. Because of technological constraints, trio-WES may miss 55% of CNV variations, and CNV-seq has a missed diagnosis rate of 3%.

The study included 434 patients with GDD (60% male; average age, 25 months) with diverse degrees of cognitive impairment: mild (23%); moderate (32%); severe (28%); and profound (17%).

Three characteristics were linked with higher likelihood of having genetic variants: Craniofacial abnormalities (odds ratio [OR], 2.27; 95% confidence interval [CI], 1.45-3.56); moderate or severe cognitive impairment (OR, 1.69; 95% CI, 1.05-2.70); and age between 12 and 24 months (OR, 1.57; 95% CI, 1.05-2.35).
 

Dopaminergic Pathway Promising for Treatment

Researchers also discovered that GDD-related genes were primarily enriched in lysosome, dopaminergic synapse, and lysine degradation pathways. Dopaminergic synapse emerged as a significant pathway linked with GDD.

“In this cohort study, our findings support the correlation between dopaminergic synapse and cognitive impairment, as substantiated by prior research and animal models. Therefore, targeting the dopaminergic pathway holds promise for treating GDD and ID,” the authors wrote.

However, the authors note in the limitations that they used only a subset of 100 patients with GDD to measure dopamine concentration.

“Expanding the sample size and conducting in vivo and in vitro experiments are necessary steps to verify whether dopamine can be targeted for clinical precision medical intervention in patients with GDD,” they wrote.

The authors reported no relevant financial relationships.

Using combined genetic testing in early childhood may decrease the misdiagnosis rate for Global Development Delay (GDD) and may help identify intervention targets, a new study suggests.

Researchers, led by Jiamei Zhang, MS, Department of Rehabilitation Medicine, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China, in a multicenter, prospective cohort study enrolled patients ages 12 to 60 months with GDD from six centers in China from July 2020 through August 2023. Participants underwent trio whole exome sequencing (trio-WES) paired with copy number variation sequencing (CNV-seq).

“To the best of our knowledge, this study represents the largest prospective examination of combined genetic testing methods in a GDD cohort,” the authors reported in JAMA Network Open.

GDD is a common neurodevelopmental disorder, marked by cognitive impairment, and affects about 1% of children, the paper states. Most children with GDD develop intellectual disability (ID) after 5 years of age, with implications for quality of life, their physical abilities, and social functioning. Early and accurate diagnosis followed by appropriately targeted treatment is critical, but lacking. Researchers note that there is lack of consensus among health care professionals on whether genetic testing is necessary.

Genetics are known to play a significant role in pathogenesis of GDD, but definitive biomarkers have been elusive.
 

Positive Detection Rate of 61%

In this study, the combined use of trio-WES with CNV-seq in children with early-stage GDD resulted in a positive detection rate of 61%, a significant improvement over performing individual tests, “enhancing the positive detection rate by 18%-40%,” the researchers wrote. The combined approach also saves families time and costs, they note, while leading to more comprehensive genetic analysis and fewer missed diagnoses.

The combined approach also addressed the limitations of trio-WES and CNV-seq used alone, the authors wrote. Because of technological constraints, trio-WES may miss 55% of CNV variations, and CNV-seq has a missed diagnosis rate of 3%.

The study included 434 patients with GDD (60% male; average age, 25 months) with diverse degrees of cognitive impairment: mild (23%); moderate (32%); severe (28%); and profound (17%).

Three characteristics were linked with higher likelihood of having genetic variants: Craniofacial abnormalities (odds ratio [OR], 2.27; 95% confidence interval [CI], 1.45-3.56); moderate or severe cognitive impairment (OR, 1.69; 95% CI, 1.05-2.70); and age between 12 and 24 months (OR, 1.57; 95% CI, 1.05-2.35).
 

Dopaminergic Pathway Promising for Treatment

Researchers also discovered that GDD-related genes were primarily enriched in lysosome, dopaminergic synapse, and lysine degradation pathways. Dopaminergic synapse emerged as a significant pathway linked with GDD.

“In this cohort study, our findings support the correlation between dopaminergic synapse and cognitive impairment, as substantiated by prior research and animal models. Therefore, targeting the dopaminergic pathway holds promise for treating GDD and ID,” the authors wrote.

However, the authors note in the limitations that they used only a subset of 100 patients with GDD to measure dopamine concentration.

“Expanding the sample size and conducting in vivo and in vitro experiments are necessary steps to verify whether dopamine can be targeted for clinical precision medical intervention in patients with GDD,” they wrote.

The authors reported no relevant financial relationships.

Among stroke survivors with diabetes or obesity, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduced secondary stroke risk by up to 16%, according to authors of a recent meta-analysis. With benefits across administration routes, dosing regimens, type 2 diabetes status, and total and nonfatal strokes, the findings could improve GLP-1 RA implementation by stroke specialists in patients with stroke history and concurrent type 2 diabetes or obesity, authors said. The study was published online in the International Journal of Stoke.

Extending Longevity

Agents including GLP-1 RAs that have been found to reduce cardiovascular events among patients with type 2 diabetes and patients who are overweight or obese also reduce risk of recurrent stroke among patients with a history of stroke who are overweight, obese, or have metabolic disease, said American Heart Association (AHA) Chief Clinical Science Officer Mitchell S. V. Elkind, MD, who was not involved with the study but was asked to comment.

“Stroke is a leading cause of mortality and the leading cause of serious long-term disability,” he added, “so medications that help to reduce that risk can play an important role in improving overall health and well-being and hopefully reducing premature mortality.”

Investigators Anastasia Adamou, MD, an internal medicine resident at AHEPA University Hospital in Thessaloniki, Greece, and colleagues searched MEDLINE and Scopus for cardiovascular outcome trials involving adults randomly assigned to GLP-1 RAs or placebo through November 2023, ultimately analyzing 11 randomized controlled trials (RCTs).

Among 60,380 participants in the nine studies that assessed total strokes, 2.5% of the GLP-1 RA group experienced strokes during follow-up, versus 3% in the placebo group (relative risk [RR] 0.85, 95% confidence interval [CI] 0.77-0.93). Regarding secondary outcomes, the GLP-1 RA group showed a significantly lower rate of nonfatal strokes versus patients on placebo (RR 0.87, 95% CI 0.79-0.95). Conversely, investigators observed no significant risk difference among the groups regarding fatal strokes, probably due to the low rate of events — 0.3% and 0.4% for treated and untreated patients, respectively.

Subgroup analyses revealed no interaction between dosing frequency and total, nonfatal, or fatal strokes. The investigators observed no difference in nonfatal strokes among participants by type 2 diabetes status and medication administration route (oral versus subcutaneous).

“The oral administration route could provide the advantage of lower local ecchymoses and allergic reactions due to subcutaneous infusions,” Dr. Adamou said in an interview. But because oral administration demands daily intake, she added, treatment adherence might be affected. “For this reason, our team performed another subgroup analysis to compare the once-a-day to the once-a-month administration. No interaction effect was again presented between the two subgroups. This outcome allows for personalization of the administration method for each patient.”

Addressing Underutilization

Despite more than 2 decades of widespread use and well-established effects on body weight, HbA1c, and cardiovascular risk, GLP-1 RAs remain underutilized, authors wrote. This is especially true in primary care, noted one study published in Clinical Diabetes.

“GLP-1 RAs have been used for many years to treat diabetic patients,” said Dr. Adamou. But because their impact on cardiovascular health regardless of diabetic status is only recently known, she said, physicians are exercising caution when prescribing this medication to patients without diabetes. “This is why more studies need to be available, especially RCTs.”

Most neurologists traditionally have left management of type 2 diabetes and other metabolic disorders to primary care doctors, said Dr. Elkind. “However, these medications are increasingly important to vascular risk reduction and should be considered part of the stroke specialist’s armamentarium.”

Vascular neurologists can play an important role in managing metabolic disease and obesity by recommending GLP-1 RAs for patients with a history of stroke, or by initiating these medications themselves, Dr. Elkind said. “These drugs are likely to become an important part of stroke patients’ medication regimens, along with antithrombotic agents, blood pressure control, and statins. Neurologists are well-positioned to educate other physicians about the important connections among brain, heart, and metabolic health.”

To that end, he said, the AHA will update guidelines for both primary and secondary stroke prevention as warranted by evidence supporting GLP-1 RAs and other medications that could impact stroke risk in type 2 diabetes and related metabolic disorders. However, no guidelines concerning use of GLP-1 RAs for secondary stroke prevention in obesity exist. Here, said Dr. Elkind, the AHA will continue building on its innovative Cardiovascular-Kidney Metabolic Health program, which includes clinical suggestions and may include more formal clinical practice guidelines as the evidence evolves.

Among the main drivers of the initiative, he said, is the recognition that cardiovascular disease — including stroke — is the major cause of death and morbidity among patients with obesity, type 2 diabetes, and metabolic disorders. “Stroke should be considered an important part of overall cardiovascular risk, and the findings that these drugs can help to reduce the risk of stroke specifically is an important additional reason for their use.”

Dr. Elkind and Dr. Adamou reported no conflicting interests. The authors received no financial support for the study.

Among stroke survivors with diabetes or obesity, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduced secondary stroke risk by up to 16%, according to authors of a recent meta-analysis. With benefits across administration routes, dosing regimens, type 2 diabetes status, and total and nonfatal strokes, the findings could improve GLP-1 RA implementation by stroke specialists in patients with stroke history and concurrent type 2 diabetes or obesity, authors said. The study was published online in the International Journal of Stoke.

Extending Longevity

Agents including GLP-1 RAs that have been found to reduce cardiovascular events among patients with type 2 diabetes and patients who are overweight or obese also reduce risk of recurrent stroke among patients with a history of stroke who are overweight, obese, or have metabolic disease, said American Heart Association (AHA) Chief Clinical Science Officer Mitchell S. V. Elkind, MD, who was not involved with the study but was asked to comment.

“Stroke is a leading cause of mortality and the leading cause of serious long-term disability,” he added, “so medications that help to reduce that risk can play an important role in improving overall health and well-being and hopefully reducing premature mortality.”

Investigators Anastasia Adamou, MD, an internal medicine resident at AHEPA University Hospital in Thessaloniki, Greece, and colleagues searched MEDLINE and Scopus for cardiovascular outcome trials involving adults randomly assigned to GLP-1 RAs or placebo through November 2023, ultimately analyzing 11 randomized controlled trials (RCTs).

Among 60,380 participants in the nine studies that assessed total strokes, 2.5% of the GLP-1 RA group experienced strokes during follow-up, versus 3% in the placebo group (relative risk [RR] 0.85, 95% confidence interval [CI] 0.77-0.93). Regarding secondary outcomes, the GLP-1 RA group showed a significantly lower rate of nonfatal strokes versus patients on placebo (RR 0.87, 95% CI 0.79-0.95). Conversely, investigators observed no significant risk difference among the groups regarding fatal strokes, probably due to the low rate of events — 0.3% and 0.4% for treated and untreated patients, respectively.

Subgroup analyses revealed no interaction between dosing frequency and total, nonfatal, or fatal strokes. The investigators observed no difference in nonfatal strokes among participants by type 2 diabetes status and medication administration route (oral versus subcutaneous).

“The oral administration route could provide the advantage of lower local ecchymoses and allergic reactions due to subcutaneous infusions,” Dr. Adamou said in an interview. But because oral administration demands daily intake, she added, treatment adherence might be affected. “For this reason, our team performed another subgroup analysis to compare the once-a-day to the once-a-month administration. No interaction effect was again presented between the two subgroups. This outcome allows for personalization of the administration method for each patient.”

Addressing Underutilization

Despite more than 2 decades of widespread use and well-established effects on body weight, HbA1c, and cardiovascular risk, GLP-1 RAs remain underutilized, authors wrote. This is especially true in primary care, noted one study published in Clinical Diabetes.

“GLP-1 RAs have been used for many years to treat diabetic patients,” said Dr. Adamou. But because their impact on cardiovascular health regardless of diabetic status is only recently known, she said, physicians are exercising caution when prescribing this medication to patients without diabetes. “This is why more studies need to be available, especially RCTs.”

Most neurologists traditionally have left management of type 2 diabetes and other metabolic disorders to primary care doctors, said Dr. Elkind. “However, these medications are increasingly important to vascular risk reduction and should be considered part of the stroke specialist’s armamentarium.”

Vascular neurologists can play an important role in managing metabolic disease and obesity by recommending GLP-1 RAs for patients with a history of stroke, or by initiating these medications themselves, Dr. Elkind said. “These drugs are likely to become an important part of stroke patients’ medication regimens, along with antithrombotic agents, blood pressure control, and statins. Neurologists are well-positioned to educate other physicians about the important connections among brain, heart, and metabolic health.”

To that end, he said, the AHA will update guidelines for both primary and secondary stroke prevention as warranted by evidence supporting GLP-1 RAs and other medications that could impact stroke risk in type 2 diabetes and related metabolic disorders. However, no guidelines concerning use of GLP-1 RAs for secondary stroke prevention in obesity exist. Here, said Dr. Elkind, the AHA will continue building on its innovative Cardiovascular-Kidney Metabolic Health program, which includes clinical suggestions and may include more formal clinical practice guidelines as the evidence evolves.

Among the main drivers of the initiative, he said, is the recognition that cardiovascular disease — including stroke — is the major cause of death and morbidity among patients with obesity, type 2 diabetes, and metabolic disorders. “Stroke should be considered an important part of overall cardiovascular risk, and the findings that these drugs can help to reduce the risk of stroke specifically is an important additional reason for their use.”

Dr. Elkind and Dr. Adamou reported no conflicting interests. The authors received no financial support for the study.

Among stroke survivors with diabetes or obesity, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduced secondary stroke risk by up to 16%, according to authors of a recent meta-analysis. With benefits across administration routes, dosing regimens, type 2 diabetes status, and total and nonfatal strokes, the findings could improve GLP-1 RA implementation by stroke specialists in patients with stroke history and concurrent type 2 diabetes or obesity, authors said. The study was published online in the International Journal of Stoke.

Extending Longevity

Agents including GLP-1 RAs that have been found to reduce cardiovascular events among patients with type 2 diabetes and patients who are overweight or obese also reduce risk of recurrent stroke among patients with a history of stroke who are overweight, obese, or have metabolic disease, said American Heart Association (AHA) Chief Clinical Science Officer Mitchell S. V. Elkind, MD, who was not involved with the study but was asked to comment.

“Stroke is a leading cause of mortality and the leading cause of serious long-term disability,” he added, “so medications that help to reduce that risk can play an important role in improving overall health and well-being and hopefully reducing premature mortality.”

Investigators Anastasia Adamou, MD, an internal medicine resident at AHEPA University Hospital in Thessaloniki, Greece, and colleagues searched MEDLINE and Scopus for cardiovascular outcome trials involving adults randomly assigned to GLP-1 RAs or placebo through November 2023, ultimately analyzing 11 randomized controlled trials (RCTs).

Among 60,380 participants in the nine studies that assessed total strokes, 2.5% of the GLP-1 RA group experienced strokes during follow-up, versus 3% in the placebo group (relative risk [RR] 0.85, 95% confidence interval [CI] 0.77-0.93). Regarding secondary outcomes, the GLP-1 RA group showed a significantly lower rate of nonfatal strokes versus patients on placebo (RR 0.87, 95% CI 0.79-0.95). Conversely, investigators observed no significant risk difference among the groups regarding fatal strokes, probably due to the low rate of events — 0.3% and 0.4% for treated and untreated patients, respectively.

Subgroup analyses revealed no interaction between dosing frequency and total, nonfatal, or fatal strokes. The investigators observed no difference in nonfatal strokes among participants by type 2 diabetes status and medication administration route (oral versus subcutaneous).

“The oral administration route could provide the advantage of lower local ecchymoses and allergic reactions due to subcutaneous infusions,” Dr. Adamou said in an interview. But because oral administration demands daily intake, she added, treatment adherence might be affected. “For this reason, our team performed another subgroup analysis to compare the once-a-day to the once-a-month administration. No interaction effect was again presented between the two subgroups. This outcome allows for personalization of the administration method for each patient.”

Addressing Underutilization

Despite more than 2 decades of widespread use and well-established effects on body weight, HbA1c, and cardiovascular risk, GLP-1 RAs remain underutilized, authors wrote. This is especially true in primary care, noted one study published in Clinical Diabetes.

“GLP-1 RAs have been used for many years to treat diabetic patients,” said Dr. Adamou. But because their impact on cardiovascular health regardless of diabetic status is only recently known, she said, physicians are exercising caution when prescribing this medication to patients without diabetes. “This is why more studies need to be available, especially RCTs.”

Most neurologists traditionally have left management of type 2 diabetes and other metabolic disorders to primary care doctors, said Dr. Elkind. “However, these medications are increasingly important to vascular risk reduction and should be considered part of the stroke specialist’s armamentarium.”

Vascular neurologists can play an important role in managing metabolic disease and obesity by recommending GLP-1 RAs for patients with a history of stroke, or by initiating these medications themselves, Dr. Elkind said. “These drugs are likely to become an important part of stroke patients’ medication regimens, along with antithrombotic agents, blood pressure control, and statins. Neurologists are well-positioned to educate other physicians about the important connections among brain, heart, and metabolic health.”

To that end, he said, the AHA will update guidelines for both primary and secondary stroke prevention as warranted by evidence supporting GLP-1 RAs and other medications that could impact stroke risk in type 2 diabetes and related metabolic disorders. However, no guidelines concerning use of GLP-1 RAs for secondary stroke prevention in obesity exist. Here, said Dr. Elkind, the AHA will continue building on its innovative Cardiovascular-Kidney Metabolic Health program, which includes clinical suggestions and may include more formal clinical practice guidelines as the evidence evolves.

Among the main drivers of the initiative, he said, is the recognition that cardiovascular disease — including stroke — is the major cause of death and morbidity among patients with obesity, type 2 diabetes, and metabolic disorders. “Stroke should be considered an important part of overall cardiovascular risk, and the findings that these drugs can help to reduce the risk of stroke specifically is an important additional reason for their use.”

Dr. Elkind and Dr. Adamou reported no conflicting interests. The authors received no financial support for the study.

TOPLINE:

Nearly 13% of older adults in the United States were treated for traumatic brain injury (TBI) over an 18-year period, a new study showed.

METHODOLOGY:

• Researchers analyzed data from approximately 9200 Medicare enrollees who were part of the Health and Retirement Study (HRS), aged 65 years and older, from 2000 to 2018.
• The baseline date was the date of the first age eligible HRS core interview in the community in 2000 or later.
• Incident TBI cases came from an updated list of the International Classification of Diseases (ICD), 9th and 10th edition codes, from the Defense and Veterans Brain Injury Center and the Armed Forces Health Surveillance Branch for TBI surveillance.
• Codes corresponded with emergency department, CT, and/or fMRI visits.

TAKEAWAY:

• Almost 13% of older individuals (n = 797) experienced TBI during the study, highlighting its significant prevalence in this population.
• Older adults (mean age at baseline, 75 years) who experienced TBI during the study period were more likely to be women and White individuals as well as individuals having higher levels of education and normal cognition (P < .001), challenging previous assumptions about risk factors.
• The study underscored the need for targeted interventions and research focused on TBI prevention and postdischarge care in older adults.

IN PRACTICE:

“The number of people 65 and older with TBI is shockingly high,” senior author Raquel Gardner, MD, said in a press release. “We need evidence-based guidelines to inform postdischarge care of this very large Medicare population and more research on post-TBI dementia prevention and repeat injury prevention.”

SOURCE:

The study was led by Erica Kornblith, PhD, of the University of California, San Francisco. It was published online in JAMA Network Open.

LIMITATIONS:

The study’s reliance on ICD codes for TBI identification may not capture the full spectrum of TBI severity. Self-reported data on sociodemographic factors may have introduced bias, affecting the accuracy of associations with TBI incidence. In addition, the findings’ generalizability may be limited due to the study’s focus on Medicare enrollees, potentially excluding those from diverse socioeconomic backgrounds.

DISCLOSURES:

The study was funded by the Alzheimer’s Association, the US Department of Veterans Affairs, the National Institute on Aging, and the Department of Defense. Disclosures are noted in the original study.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

Nearly 13% of older adults in the United States were treated for traumatic brain injury (TBI) over an 18-year period, a new study showed.

METHODOLOGY:

• Researchers analyzed data from approximately 9200 Medicare enrollees who were part of the Health and Retirement Study (HRS), aged 65 years and older, from 2000 to 2018.
• The baseline date was the date of the first age eligible HRS core interview in the community in 2000 or later.
• Incident TBI cases came from an updated list of the International Classification of Diseases (ICD), 9th and 10th edition codes, from the Defense and Veterans Brain Injury Center and the Armed Forces Health Surveillance Branch for TBI surveillance.
• Codes corresponded with emergency department, CT, and/or fMRI visits.

TAKEAWAY:

• Almost 13% of older individuals (n = 797) experienced TBI during the study, highlighting its significant prevalence in this population.
• Older adults (mean age at baseline, 75 years) who experienced TBI during the study period were more likely to be women and White individuals as well as individuals having higher levels of education and normal cognition (P < .001), challenging previous assumptions about risk factors.
• The study underscored the need for targeted interventions and research focused on TBI prevention and postdischarge care in older adults.

IN PRACTICE:

“The number of people 65 and older with TBI is shockingly high,” senior author Raquel Gardner, MD, said in a press release. “We need evidence-based guidelines to inform postdischarge care of this very large Medicare population and more research on post-TBI dementia prevention and repeat injury prevention.”

SOURCE:

The study was led by Erica Kornblith, PhD, of the University of California, San Francisco. It was published online in JAMA Network Open.

LIMITATIONS:

The study’s reliance on ICD codes for TBI identification may not capture the full spectrum of TBI severity. Self-reported data on sociodemographic factors may have introduced bias, affecting the accuracy of associations with TBI incidence. In addition, the findings’ generalizability may be limited due to the study’s focus on Medicare enrollees, potentially excluding those from diverse socioeconomic backgrounds.

DISCLOSURES:

The study was funded by the Alzheimer’s Association, the US Department of Veterans Affairs, the National Institute on Aging, and the Department of Defense. Disclosures are noted in the original study.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

Nearly 13% of older adults in the United States were treated for traumatic brain injury (TBI) over an 18-year period, a new study showed.

METHODOLOGY:

• Researchers analyzed data from approximately 9200 Medicare enrollees who were part of the Health and Retirement Study (HRS), aged 65 years and older, from 2000 to 2018.
• The baseline date was the date of the first age eligible HRS core interview in the community in 2000 or later.
• Incident TBI cases came from an updated list of the International Classification of Diseases (ICD), 9th and 10th edition codes, from the Defense and Veterans Brain Injury Center and the Armed Forces Health Surveillance Branch for TBI surveillance.
• Codes corresponded with emergency department, CT, and/or fMRI visits.

TAKEAWAY:

• Almost 13% of older individuals (n = 797) experienced TBI during the study, highlighting its significant prevalence in this population.
• Older adults (mean age at baseline, 75 years) who experienced TBI during the study period were more likely to be women and White individuals as well as individuals having higher levels of education and normal cognition (P < .001), challenging previous assumptions about risk factors.
• The study underscored the need for targeted interventions and research focused on TBI prevention and postdischarge care in older adults.

IN PRACTICE:

“The number of people 65 and older with TBI is shockingly high,” senior author Raquel Gardner, MD, said in a press release. “We need evidence-based guidelines to inform postdischarge care of this very large Medicare population and more research on post-TBI dementia prevention and repeat injury prevention.”

SOURCE:

The study was led by Erica Kornblith, PhD, of the University of California, San Francisco. It was published online in JAMA Network Open.

LIMITATIONS:

The study’s reliance on ICD codes for TBI identification may not capture the full spectrum of TBI severity. Self-reported data on sociodemographic factors may have introduced bias, affecting the accuracy of associations with TBI incidence. In addition, the findings’ generalizability may be limited due to the study’s focus on Medicare enrollees, potentially excluding those from diverse socioeconomic backgrounds.

DISCLOSURES:

The study was funded by the Alzheimer’s Association, the US Department of Veterans Affairs, the National Institute on Aging, and the Department of Defense. Disclosures are noted in the original study.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

Women who had overweight or obesity as teens or young adults had more than a twofold increased risk for stroke before age 55, new research suggested.

An analysis of more than five decades of health data on 10,000 adults revealed that close to 5% experienced a stroke during the follow-up period, with the risk for ischemic stroke being more than twice as high in women who had obesity as teens or young adults. The risk was even higher for hemorrhagic stroke in both men and women with a history of obesity in youth.

“Our findings suggest that being overweight may have long-term health effects, even if the excess weight is temporary,” lead author Ursula Mikkola, BM, an investigator in the Research Unit of Population Health at the University of Oulu, Oulu, Finland, said in a news release.

Gender Differences

Childhood obesity has been associated with a heightened risk for cerebrovascular disease later in life, but most studies have focused on body mass index (BMI) at a single time point without considering its fluctuations throughout life, the investigators noted.

For the study, investigators used data from the Northern Finland Birth Cohort 1966, a prospective, general population-based birth cohort that followed 10,491 individuals (5185 women) until 2020 or the first stroke, death, or moving abroad, whichever came first.

Mean (SD) follow-up for each participant was 39 years from age 14 onward and 23 years from age 31 onward. The analysis was conducted between 1980 and 2020.

BMI data were collected from participants at the age of 14 and 31 years. Age 14 covariates included smoking, parental socioeconomic status, and age at menarche (for girls). Age 31 covariates included smoking and participants’ educational level.

During the follow-up period, 4.7% of participants experienced stroke. Of these events, 31% were ischemic strokes and 40% were transient ischemic attacks. The remainder were hemorrhagic or other cerebrovascular events.

Using normal weight as a reference, researchers found that the risk for ischemic stroke was over twice as high for women who had been overweight at ages 14 (hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.44-4.31) and 31 (HR, 2.13; 95% CI, 1.14-3.97) years. The risk was also considerably higher for women who had obesity at ages 14 (HR, 1.87; 95% CI, 0.76-4.58) and 31 (HR, 2.67; 95% CI, 1.26-5.65) years.

The risk for hemorrhagic stroke was even higher, both among women (HR, 3.49; 95% CI, 1.13-10.7) and men (HR, 5.75; 95% CI, 1.43-23.1) who had obesity at age 31.

No similar associations were found among men, and the findings were independent of earlier or later BMI.

The risk for any cerebrovascular disease related to overweight at age 14 was twice as high among girls vs boys (HR, 2.09; 95% CI, 1.06-4.15), and the risk for ischemic stroke related to obesity at age 31 was nearly seven times higher among women vs men (HR, 6.96; 95% CI, 1.36-35.7).

“Stroke at a young age is rare, so the difference of just a few strokes could have an outsized impact on the risk estimates,” the study authors said. “Also, BMI relies solely on a person’s height and weight; therefore, a high BMI may be a misleading way to define obesity, especially in muscular people who may carry little fat even while weighing more.”
 

Caveats

In an accompanying editorial, Larry Goldstein, MD, chair of the Department of Neurology, University of Kentucky, Lexington, Kentucky, and codirector of the Kentucky Neuroscience Institute, said the study “provides additional evidence of an association between overweight/obesity and stroke in young adults.”

However, Dr. Goldstein added that “while it is tempting to assume that reductions in overweight/obesity in younger populations would translate to lower stroke rates in young adults, this remains to be proven.”

Moreover, it is “always important to acknowledge that associations found in observational studies may not reflect causality.”

This study was supported by Orion Research Foundation, Päivikki and Sakari Sohlberg Foundation, and Paulo Foundation. Dr. Mikkola reported no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Goldstein reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Women who had overweight or obesity as teens or young adults had more than a twofold increased risk for stroke before age 55, new research suggested.

An analysis of more than five decades of health data on 10,000 adults revealed that close to 5% experienced a stroke during the follow-up period, with the risk for ischemic stroke being more than twice as high in women who had obesity as teens or young adults. The risk was even higher for hemorrhagic stroke in both men and women with a history of obesity in youth.

“Our findings suggest that being overweight may have long-term health effects, even if the excess weight is temporary,” lead author Ursula Mikkola, BM, an investigator in the Research Unit of Population Health at the University of Oulu, Oulu, Finland, said in a news release.

Gender Differences

Childhood obesity has been associated with a heightened risk for cerebrovascular disease later in life, but most studies have focused on body mass index (BMI) at a single time point without considering its fluctuations throughout life, the investigators noted.

For the study, investigators used data from the Northern Finland Birth Cohort 1966, a prospective, general population-based birth cohort that followed 10,491 individuals (5185 women) until 2020 or the first stroke, death, or moving abroad, whichever came first.

Mean (SD) follow-up for each participant was 39 years from age 14 onward and 23 years from age 31 onward. The analysis was conducted between 1980 and 2020.

BMI data were collected from participants at the age of 14 and 31 years. Age 14 covariates included smoking, parental socioeconomic status, and age at menarche (for girls). Age 31 covariates included smoking and participants’ educational level.

During the follow-up period, 4.7% of participants experienced stroke. Of these events, 31% were ischemic strokes and 40% were transient ischemic attacks. The remainder were hemorrhagic or other cerebrovascular events.

Using normal weight as a reference, researchers found that the risk for ischemic stroke was over twice as high for women who had been overweight at ages 14 (hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.44-4.31) and 31 (HR, 2.13; 95% CI, 1.14-3.97) years. The risk was also considerably higher for women who had obesity at ages 14 (HR, 1.87; 95% CI, 0.76-4.58) and 31 (HR, 2.67; 95% CI, 1.26-5.65) years.

The risk for hemorrhagic stroke was even higher, both among women (HR, 3.49; 95% CI, 1.13-10.7) and men (HR, 5.75; 95% CI, 1.43-23.1) who had obesity at age 31.

No similar associations were found among men, and the findings were independent of earlier or later BMI.

The risk for any cerebrovascular disease related to overweight at age 14 was twice as high among girls vs boys (HR, 2.09; 95% CI, 1.06-4.15), and the risk for ischemic stroke related to obesity at age 31 was nearly seven times higher among women vs men (HR, 6.96; 95% CI, 1.36-35.7).

“Stroke at a young age is rare, so the difference of just a few strokes could have an outsized impact on the risk estimates,” the study authors said. “Also, BMI relies solely on a person’s height and weight; therefore, a high BMI may be a misleading way to define obesity, especially in muscular people who may carry little fat even while weighing more.”
 

Caveats

In an accompanying editorial, Larry Goldstein, MD, chair of the Department of Neurology, University of Kentucky, Lexington, Kentucky, and codirector of the Kentucky Neuroscience Institute, said the study “provides additional evidence of an association between overweight/obesity and stroke in young adults.”

However, Dr. Goldstein added that “while it is tempting to assume that reductions in overweight/obesity in younger populations would translate to lower stroke rates in young adults, this remains to be proven.”

Moreover, it is “always important to acknowledge that associations found in observational studies may not reflect causality.”

This study was supported by Orion Research Foundation, Päivikki and Sakari Sohlberg Foundation, and Paulo Foundation. Dr. Mikkola reported no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Goldstein reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Women who had overweight or obesity as teens or young adults had more than a twofold increased risk for stroke before age 55, new research suggested.

An analysis of more than five decades of health data on 10,000 adults revealed that close to 5% experienced a stroke during the follow-up period, with the risk for ischemic stroke being more than twice as high in women who had obesity as teens or young adults. The risk was even higher for hemorrhagic stroke in both men and women with a history of obesity in youth.

“Our findings suggest that being overweight may have long-term health effects, even if the excess weight is temporary,” lead author Ursula Mikkola, BM, an investigator in the Research Unit of Population Health at the University of Oulu, Oulu, Finland, said in a news release.

Gender Differences

Childhood obesity has been associated with a heightened risk for cerebrovascular disease later in life, but most studies have focused on body mass index (BMI) at a single time point without considering its fluctuations throughout life, the investigators noted.

For the study, investigators used data from the Northern Finland Birth Cohort 1966, a prospective, general population-based birth cohort that followed 10,491 individuals (5185 women) until 2020 or the first stroke, death, or moving abroad, whichever came first.

Mean (SD) follow-up for each participant was 39 years from age 14 onward and 23 years from age 31 onward. The analysis was conducted between 1980 and 2020.

BMI data were collected from participants at the age of 14 and 31 years. Age 14 covariates included smoking, parental socioeconomic status, and age at menarche (for girls). Age 31 covariates included smoking and participants’ educational level.

During the follow-up period, 4.7% of participants experienced stroke. Of these events, 31% were ischemic strokes and 40% were transient ischemic attacks. The remainder were hemorrhagic or other cerebrovascular events.

Using normal weight as a reference, researchers found that the risk for ischemic stroke was over twice as high for women who had been overweight at ages 14 (hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.44-4.31) and 31 (HR, 2.13; 95% CI, 1.14-3.97) years. The risk was also considerably higher for women who had obesity at ages 14 (HR, 1.87; 95% CI, 0.76-4.58) and 31 (HR, 2.67; 95% CI, 1.26-5.65) years.

The risk for hemorrhagic stroke was even higher, both among women (HR, 3.49; 95% CI, 1.13-10.7) and men (HR, 5.75; 95% CI, 1.43-23.1) who had obesity at age 31.

No similar associations were found among men, and the findings were independent of earlier or later BMI.

The risk for any cerebrovascular disease related to overweight at age 14 was twice as high among girls vs boys (HR, 2.09; 95% CI, 1.06-4.15), and the risk for ischemic stroke related to obesity at age 31 was nearly seven times higher among women vs men (HR, 6.96; 95% CI, 1.36-35.7).

“Stroke at a young age is rare, so the difference of just a few strokes could have an outsized impact on the risk estimates,” the study authors said. “Also, BMI relies solely on a person’s height and weight; therefore, a high BMI may be a misleading way to define obesity, especially in muscular people who may carry little fat even while weighing more.”
 

Caveats

In an accompanying editorial, Larry Goldstein, MD, chair of the Department of Neurology, University of Kentucky, Lexington, Kentucky, and codirector of the Kentucky Neuroscience Institute, said the study “provides additional evidence of an association between overweight/obesity and stroke in young adults.”

However, Dr. Goldstein added that “while it is tempting to assume that reductions in overweight/obesity in younger populations would translate to lower stroke rates in young adults, this remains to be proven.”

Moreover, it is “always important to acknowledge that associations found in observational studies may not reflect causality.”

This study was supported by Orion Research Foundation, Päivikki and Sakari Sohlberg Foundation, and Paulo Foundation. Dr. Mikkola reported no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Goldstein reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

High-frequency electric nerve block significantly reduced postamputation pain in a new study, presenting a potential new therapeutic option for amputees.

METHODOLOGY:

• The study enrolled 180 patients with unilateral lower limb amputations who were experiencing severe post-procedure pain.
• Participants were randomized 1:1 to receive 3 months of treatment with either a high-frequency nerve block (Altius; Neuros Medical) or an active sham.
• Effectiveness was measured by the percentage of participants achieving at least a 50% reduction in pain in more than half of the treatment sessions.
• The researchers attempted to control for variables including pain type and baseline pain intensity.

TAKEAWAY:

• A total of 24.7% of patients in the group that received the nerve block were responders at 30 minutes post-treatment, significantly higher than 7.1% in the control group (P = .002).
• The rate of response rose to 46.8% in the treatment group at 120 minutes, compared with 22.2% in the sham group (P = .001).
• Patients who received the nerve block reported a greater improvement in their score on the Brief Pain Inventory than those in the sham arm — 2.3 ± 0.29 vs 1.3 ± 0.26, respectively (P = .01).
• Use of opioids trended toward a greater reduction in the treatment group, although that finding was not statistically significant.

IN PRACTICE:

The results suggested “high-frequency electric nerve block could be a viable option for managing chronic post-amputation pain, potentially improving patients’ quality of life and reducing reliance on opioids,” the authors wrote. “The study addresses a critical gap in treatment options for amputees suffering from persistent pain, offering evidence for a novel therapeutic approach.”

“We have never seen a study of this magnitude and rigor in this patient population,” said lead author Leonardo Kapural, MD, PhD, of the Carolinas Pain Institute in Winston-Salem, North Carolina, in a press release about the data. “The data demonstrated clear and lasting benefit of treatment for pain reduction and functional outcomes at 3 months, creating great optimism for the long-term study results. These findings represent a significant advancement for an at-risk and underserved patient population in desperate need of reliable and effective treatment.”

SOURCE:

The study was led by Leonardo Kapural, MD, PhD, of the Carolinas Pain Institute in Winston-Salem, North Carolina, and was published online in the Journal of Pain Research.

LIMITATIONS:

The sample size of 180 participants may limit the generalizability of the findings to all amputees. A 3-month duration for assessing treatment efficacy may not capture long-term outcomes and effects. The active-sham control design, while rigorous, may not fully account for the placebo effects inherent in pain perception studies.

DISCLOSURES:

The QUEST study was funded by Neuros Medical Inc. Dr. Kapural reported personal fees from various medical companies, unrelated to this work. No other conflicts of interest were reported in this work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

High-frequency electric nerve block significantly reduced postamputation pain in a new study, presenting a potential new therapeutic option for amputees.

METHODOLOGY:

• The study enrolled 180 patients with unilateral lower limb amputations who were experiencing severe post-procedure pain.
• Participants were randomized 1:1 to receive 3 months of treatment with either a high-frequency nerve block (Altius; Neuros Medical) or an active sham.
• Effectiveness was measured by the percentage of participants achieving at least a 50% reduction in pain in more than half of the treatment sessions.
• The researchers attempted to control for variables including pain type and baseline pain intensity.

TAKEAWAY:

• A total of 24.7% of patients in the group that received the nerve block were responders at 30 minutes post-treatment, significantly higher than 7.1% in the control group (P = .002).
• The rate of response rose to 46.8% in the treatment group at 120 minutes, compared with 22.2% in the sham group (P = .001).
• Patients who received the nerve block reported a greater improvement in their score on the Brief Pain Inventory than those in the sham arm — 2.3 ± 0.29 vs 1.3 ± 0.26, respectively (P = .01).
• Use of opioids trended toward a greater reduction in the treatment group, although that finding was not statistically significant.

IN PRACTICE:

The results suggested “high-frequency electric nerve block could be a viable option for managing chronic post-amputation pain, potentially improving patients’ quality of life and reducing reliance on opioids,” the authors wrote. “The study addresses a critical gap in treatment options for amputees suffering from persistent pain, offering evidence for a novel therapeutic approach.”

“We have never seen a study of this magnitude and rigor in this patient population,” said lead author Leonardo Kapural, MD, PhD, of the Carolinas Pain Institute in Winston-Salem, North Carolina, in a press release about the data. “The data demonstrated clear and lasting benefit of treatment for pain reduction and functional outcomes at 3 months, creating great optimism for the long-term study results. These findings represent a significant advancement for an at-risk and underserved patient population in desperate need of reliable and effective treatment.”

SOURCE:

The study was led by Leonardo Kapural, MD, PhD, of the Carolinas Pain Institute in Winston-Salem, North Carolina, and was published online in the Journal of Pain Research.

LIMITATIONS:

The sample size of 180 participants may limit the generalizability of the findings to all amputees. A 3-month duration for assessing treatment efficacy may not capture long-term outcomes and effects. The active-sham control design, while rigorous, may not fully account for the placebo effects inherent in pain perception studies.

DISCLOSURES:

The QUEST study was funded by Neuros Medical Inc. Dr. Kapural reported personal fees from various medical companies, unrelated to this work. No other conflicts of interest were reported in this work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

High-frequency electric nerve block significantly reduced postamputation pain in a new study, presenting a potential new therapeutic option for amputees.

METHODOLOGY:

• The study enrolled 180 patients with unilateral lower limb amputations who were experiencing severe post-procedure pain.
• Participants were randomized 1:1 to receive 3 months of treatment with either a high-frequency nerve block (Altius; Neuros Medical) or an active sham.
• Effectiveness was measured by the percentage of participants achieving at least a 50% reduction in pain in more than half of the treatment sessions.
• The researchers attempted to control for variables including pain type and baseline pain intensity.

TAKEAWAY:

• A total of 24.7% of patients in the group that received the nerve block were responders at 30 minutes post-treatment, significantly higher than 7.1% in the control group (P = .002).
• The rate of response rose to 46.8% in the treatment group at 120 minutes, compared with 22.2% in the sham group (P = .001).
• Patients who received the nerve block reported a greater improvement in their score on the Brief Pain Inventory than those in the sham arm — 2.3 ± 0.29 vs 1.3 ± 0.26, respectively (P = .01).
• Use of opioids trended toward a greater reduction in the treatment group, although that finding was not statistically significant.

IN PRACTICE:

The results suggested “high-frequency electric nerve block could be a viable option for managing chronic post-amputation pain, potentially improving patients’ quality of life and reducing reliance on opioids,” the authors wrote. “The study addresses a critical gap in treatment options for amputees suffering from persistent pain, offering evidence for a novel therapeutic approach.”

“We have never seen a study of this magnitude and rigor in this patient population,” said lead author Leonardo Kapural, MD, PhD, of the Carolinas Pain Institute in Winston-Salem, North Carolina, in a press release about the data. “The data demonstrated clear and lasting benefit of treatment for pain reduction and functional outcomes at 3 months, creating great optimism for the long-term study results. These findings represent a significant advancement for an at-risk and underserved patient population in desperate need of reliable and effective treatment.”

SOURCE:

The study was led by Leonardo Kapural, MD, PhD, of the Carolinas Pain Institute in Winston-Salem, North Carolina, and was published online in the Journal of Pain Research.

LIMITATIONS:

The sample size of 180 participants may limit the generalizability of the findings to all amputees. A 3-month duration for assessing treatment efficacy may not capture long-term outcomes and effects. The active-sham control design, while rigorous, may not fully account for the placebo effects inherent in pain perception studies.

DISCLOSURES:

The QUEST study was funded by Neuros Medical Inc. Dr. Kapural reported personal fees from various medical companies, unrelated to this work. No other conflicts of interest were reported in this work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.