Batya Swift Yasgur, MA, LSW

Extended-release injectable naltrexone combined with extended-release oral bupropion (NTX + BUPN) for moderate or severe methamphetamine use disorder was associated with a significant decrease in use of the drug, a new study showed.

Investigators leading the randomized clinical trial found a 27% increase in negative methamphetamine urine tests in the treatment group — indicating reduced use — compared with an 11% increase in negative urine tests in control participants.

“These findings have important implications for pharmacological treatment for methamphetamine use disorder. There is no FDA-approved medication for it, yet methamphetamine-involved overdoses have greatly increased over the past decade,” lead author Michael Li, MD, assistant professor-in-residence of family medicine at the David Geffen School of Medicine at UCLA, Los Angeles, said in a news release.

The study was published online in Addiction.

Methamphetamine use has increased worldwide, from 33 million users in 2010 to 34 million in 2020, with overdose deaths rising fivefold in the United States over the past decade, the authors wrote.

A previous open-label study of NTX + BUPN showed efficacy for treating severe methamphetamine use disorder, and NTX and BUPN have each shown efficacy separately for this indication. 

This new study is the second phase of the multicenter ADAPT-2 trial, conducted between 2017 and 2019 in 403 participants with methamphetamine use disorder. In the first stage, 109 people received NTX + BUPN and 294 received placebo.

The treatment group received extended-release NTX (380 mg) or placebo as an intramuscular injection on weeks 1, 4, 7, and 10. Extended-release BUPN or placebo tablets were administered weekly, with BUPN doses starting at 150 mg on day 1 and increasing to 450 mg by day 3. At week 13, participants received a tapering dose for 4 days before discontinuing.

As previously reported by this news organization, the two-drug combo was effective at reducing methamphetamine use at 6 weeks. The current analysis measured change in methamphetamine use during weeks 7-12 of the trial and in posttreatment weeks 13-16.

Participants in the intervention group during stage 1 showed an additional 9.2% increase (P = .038) during stage 2 in their probability of testing negative for methamphetamine. This represented a total increase of 27.1% in negative urine tests across the complete 12 weeks of treatment, compared with a total 11.4% increase in negative tests in the placebo group.

The 12-week increase in methamphetamine-negative urine tests in the intervention group was 15.8% greater (P = .006) than the increase in the placebo group.

There was no significant change in either group at posttreatment follow-up in weeks 13-16.

“Our findings suggest that ongoing NTX + BUPN treatment yields statistically significant reductions in methamphetamine use that continue from weeks 7 to 12,” the authors wrote. The lack of change in methamphetamine use from weeks 13-16 corresponds to the conclusion of treatment in week 12, they added.

It remains to be determined “whether continued use of NTX + BUPN treatment past 12 weeks would yield further reductions in use,” the authors wrote, noting that prior stimulant use disorder trials suggest that change in use is gradual and that sustained abstinence is unlikely in merely 12 weeks of a trial. Rather, it is dependent on treatment duration.

“This warrants future clinical trials to quantify changes in methamphetamine use beyond 12 weeks and to identify the optimal duration of treatment with this medication,” they concluded.

The study was funded by awards from the National Institute on Drug Abuse (NIDA), the US Department of Health and Human Services, the National Institute of Mental Health, and the O’Donnell Clinical Neuroscience Scholar Award from the University of Texas Southwestern Medical Center. Alkermes provided Vivitrol (naltrexone for extended-release injectable suspension) and matched placebo free of charge for use in this trial under a written agreement with NIDA. Dr. Li reports no relevant financial relationships. The other authors’ disclosures are listed on the original paper.

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

Extended-release injectable naltrexone combined with extended-release oral bupropion (NTX + BUPN) for moderate or severe methamphetamine use disorder was associated with a significant decrease in use of the drug, a new study showed.

Investigators leading the randomized clinical trial found a 27% increase in negative methamphetamine urine tests in the treatment group — indicating reduced use — compared with an 11% increase in negative urine tests in control participants.

“These findings have important implications for pharmacological treatment for methamphetamine use disorder. There is no FDA-approved medication for it, yet methamphetamine-involved overdoses have greatly increased over the past decade,” lead author Michael Li, MD, assistant professor-in-residence of family medicine at the David Geffen School of Medicine at UCLA, Los Angeles, said in a news release.

The study was published online in Addiction.

Methamphetamine use has increased worldwide, from 33 million users in 2010 to 34 million in 2020, with overdose deaths rising fivefold in the United States over the past decade, the authors wrote.

A previous open-label study of NTX + BUPN showed efficacy for treating severe methamphetamine use disorder, and NTX and BUPN have each shown efficacy separately for this indication. 

This new study is the second phase of the multicenter ADAPT-2 trial, conducted between 2017 and 2019 in 403 participants with methamphetamine use disorder. In the first stage, 109 people received NTX + BUPN and 294 received placebo.

The treatment group received extended-release NTX (380 mg) or placebo as an intramuscular injection on weeks 1, 4, 7, and 10. Extended-release BUPN or placebo tablets were administered weekly, with BUPN doses starting at 150 mg on day 1 and increasing to 450 mg by day 3. At week 13, participants received a tapering dose for 4 days before discontinuing.

As previously reported by this news organization, the two-drug combo was effective at reducing methamphetamine use at 6 weeks. The current analysis measured change in methamphetamine use during weeks 7-12 of the trial and in posttreatment weeks 13-16.

Participants in the intervention group during stage 1 showed an additional 9.2% increase (P = .038) during stage 2 in their probability of testing negative for methamphetamine. This represented a total increase of 27.1% in negative urine tests across the complete 12 weeks of treatment, compared with a total 11.4% increase in negative tests in the placebo group.

The 12-week increase in methamphetamine-negative urine tests in the intervention group was 15.8% greater (P = .006) than the increase in the placebo group.

There was no significant change in either group at posttreatment follow-up in weeks 13-16.

“Our findings suggest that ongoing NTX + BUPN treatment yields statistically significant reductions in methamphetamine use that continue from weeks 7 to 12,” the authors wrote. The lack of change in methamphetamine use from weeks 13-16 corresponds to the conclusion of treatment in week 12, they added.

It remains to be determined “whether continued use of NTX + BUPN treatment past 12 weeks would yield further reductions in use,” the authors wrote, noting that prior stimulant use disorder trials suggest that change in use is gradual and that sustained abstinence is unlikely in merely 12 weeks of a trial. Rather, it is dependent on treatment duration.

“This warrants future clinical trials to quantify changes in methamphetamine use beyond 12 weeks and to identify the optimal duration of treatment with this medication,” they concluded.

The study was funded by awards from the National Institute on Drug Abuse (NIDA), the US Department of Health and Human Services, the National Institute of Mental Health, and the O’Donnell Clinical Neuroscience Scholar Award from the University of Texas Southwestern Medical Center. Alkermes provided Vivitrol (naltrexone for extended-release injectable suspension) and matched placebo free of charge for use in this trial under a written agreement with NIDA. Dr. Li reports no relevant financial relationships. The other authors’ disclosures are listed on the original paper.

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

Extended-release injectable naltrexone combined with extended-release oral bupropion (NTX + BUPN) for moderate or severe methamphetamine use disorder was associated with a significant decrease in use of the drug, a new study showed.

Investigators leading the randomized clinical trial found a 27% increase in negative methamphetamine urine tests in the treatment group — indicating reduced use — compared with an 11% increase in negative urine tests in control participants.

“These findings have important implications for pharmacological treatment for methamphetamine use disorder. There is no FDA-approved medication for it, yet methamphetamine-involved overdoses have greatly increased over the past decade,” lead author Michael Li, MD, assistant professor-in-residence of family medicine at the David Geffen School of Medicine at UCLA, Los Angeles, said in a news release.

The study was published online in Addiction.

Methamphetamine use has increased worldwide, from 33 million users in 2010 to 34 million in 2020, with overdose deaths rising fivefold in the United States over the past decade, the authors wrote.

A previous open-label study of NTX + BUPN showed efficacy for treating severe methamphetamine use disorder, and NTX and BUPN have each shown efficacy separately for this indication. 

This new study is the second phase of the multicenter ADAPT-2 trial, conducted between 2017 and 2019 in 403 participants with methamphetamine use disorder. In the first stage, 109 people received NTX + BUPN and 294 received placebo.

The treatment group received extended-release NTX (380 mg) or placebo as an intramuscular injection on weeks 1, 4, 7, and 10. Extended-release BUPN or placebo tablets were administered weekly, with BUPN doses starting at 150 mg on day 1 and increasing to 450 mg by day 3. At week 13, participants received a tapering dose for 4 days before discontinuing.

As previously reported by this news organization, the two-drug combo was effective at reducing methamphetamine use at 6 weeks. The current analysis measured change in methamphetamine use during weeks 7-12 of the trial and in posttreatment weeks 13-16.

Participants in the intervention group during stage 1 showed an additional 9.2% increase (P = .038) during stage 2 in their probability of testing negative for methamphetamine. This represented a total increase of 27.1% in negative urine tests across the complete 12 weeks of treatment, compared with a total 11.4% increase in negative tests in the placebo group.

The 12-week increase in methamphetamine-negative urine tests in the intervention group was 15.8% greater (P = .006) than the increase in the placebo group.

There was no significant change in either group at posttreatment follow-up in weeks 13-16.

“Our findings suggest that ongoing NTX + BUPN treatment yields statistically significant reductions in methamphetamine use that continue from weeks 7 to 12,” the authors wrote. The lack of change in methamphetamine use from weeks 13-16 corresponds to the conclusion of treatment in week 12, they added.

It remains to be determined “whether continued use of NTX + BUPN treatment past 12 weeks would yield further reductions in use,” the authors wrote, noting that prior stimulant use disorder trials suggest that change in use is gradual and that sustained abstinence is unlikely in merely 12 weeks of a trial. Rather, it is dependent on treatment duration.

“This warrants future clinical trials to quantify changes in methamphetamine use beyond 12 weeks and to identify the optimal duration of treatment with this medication,” they concluded.

The study was funded by awards from the National Institute on Drug Abuse (NIDA), the US Department of Health and Human Services, the National Institute of Mental Health, and the O’Donnell Clinical Neuroscience Scholar Award from the University of Texas Southwestern Medical Center. Alkermes provided Vivitrol (naltrexone for extended-release injectable suspension) and matched placebo free of charge for use in this trial under a written agreement with NIDA. Dr. Li reports no relevant financial relationships. The other authors’ disclosures are listed on the original paper.

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.

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.

tetheshakebanagechishocakusochostapuchasluclarojagohathomoshaclowrodricruspagaphucibepatroclakaslepraphurijuvulestogiprashomosudadrogupodraphichijauithiwaseganunebospuwrachihusteclohiheslospomouauespeswavoslomeuaroclotroswushuchuchuvecuuubauaslap

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.

tetheshakebanagechishocakusochostapuchasluclarojagohathomoshaclowrodricruspagaphucibepatroclakaslepraphurijuvulestogiprashomosudadrogupodraphichijauithiwaseganunebospuwrachihusteclohiheslospomouauespeswavoslomeuaroclotroswushuchuchuvecuuubauaslap

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.

tetheshakebanagechishocakusochostapuchasluclarojagohathomoshaclowrodricruspagaphucibepatroclakaslepraphurijuvulestogiprashomosudadrogupodraphichijauithiwaseganunebospuwrachihusteclohiheslospomouauespeswavoslomeuaroclotroswushuchuchuvecuuubauaslap

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:

A new analysis of a national dataset of children in the United States shows that there were roughly one million more children with attention-deficit/hyperactivity disorder (ADHD) in 2022 than in 2016.

METHODOLOGY:

• Researchers used 2022 data from the National Survey of Children’s Health to estimate the prevalence of ever-diagnosed and current ADHD among US children between the ages of 3 and 18 years.
• They also estimated, among children with current ADHD, the severity of the condition and the presence of current co-occurring disorders and the receipt of medication and behavioral treatments.
• The researchers calculated overall weighted estimates as well as estimates for specific demographic and clinical subgroups (n = 45,169).

TAKEAWAY:

• The number of children who had ever received an ADHD diagnosis increased from 6.1 million in 2016 to 7.1 million in 2022, and the number with current ADHD increased from 5.4 million to 6.5 million.
• Of those with current ADHD in 2022, 58.1% had moderate or severe ADHD, and 77.9% had at least one co-occurring disorder.
• A total of 53.6% had received ADHD medication, 44.4% had received behavioral treatment in the past year, and 30.1% had received no ADHD-specific treatment.
• A similar percentage of children with ADHD were receiving behavioral treatment in 2022 as in 2016 (44.4% vs 46.7%, respectively), but treatment with ADHD medication was lower in 2022 than in 2016 (53.6% vs 62.0%, respectively).

IN PRACTICE:

The estimates “can be used by clinicians to understand current ADHD diagnosis and treatment utilization patterns to inform clinical practice, such as accounting for the frequency and management of co-occurring conditions and considering the notable percentage of children with ADHD not currently receiving ADHD treatment,” and can be used by policymakers, practitioners, and others “to plan for the needs of children with ADHD, such as by ensuring access to care and services for ADHD,” investigators wrote.

SOURCE:

Melissa L. Danielson, of the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, led the study, which was published online in the Journal of Clinical Child & Adolescent Psychology.

LIMITATIONS:

Indicators reported in the analysis were on the basis of the parent report, which may be limited by recall and reporting decisions and were not validated against medical records or clinical judgment. Moreover, details about the types of treatment were not included.

DISCLOSURES:

The work was authorized as part of the contributor’s official duties as an employee of the US Government, and therefore is a work of the US Government. The authors declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

A new analysis of a national dataset of children in the United States shows that there were roughly one million more children with attention-deficit/hyperactivity disorder (ADHD) in 2022 than in 2016.

METHODOLOGY:

• Researchers used 2022 data from the National Survey of Children’s Health to estimate the prevalence of ever-diagnosed and current ADHD among US children between the ages of 3 and 18 years.
• They also estimated, among children with current ADHD, the severity of the condition and the presence of current co-occurring disorders and the receipt of medication and behavioral treatments.
• The researchers calculated overall weighted estimates as well as estimates for specific demographic and clinical subgroups (n = 45,169).

TAKEAWAY:

• The number of children who had ever received an ADHD diagnosis increased from 6.1 million in 2016 to 7.1 million in 2022, and the number with current ADHD increased from 5.4 million to 6.5 million.
• Of those with current ADHD in 2022, 58.1% had moderate or severe ADHD, and 77.9% had at least one co-occurring disorder.
• A total of 53.6% had received ADHD medication, 44.4% had received behavioral treatment in the past year, and 30.1% had received no ADHD-specific treatment.
• A similar percentage of children with ADHD were receiving behavioral treatment in 2022 as in 2016 (44.4% vs 46.7%, respectively), but treatment with ADHD medication was lower in 2022 than in 2016 (53.6% vs 62.0%, respectively).

IN PRACTICE:

The estimates “can be used by clinicians to understand current ADHD diagnosis and treatment utilization patterns to inform clinical practice, such as accounting for the frequency and management of co-occurring conditions and considering the notable percentage of children with ADHD not currently receiving ADHD treatment,” and can be used by policymakers, practitioners, and others “to plan for the needs of children with ADHD, such as by ensuring access to care and services for ADHD,” investigators wrote.

SOURCE:

Melissa L. Danielson, of the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, led the study, which was published online in the Journal of Clinical Child & Adolescent Psychology.

LIMITATIONS:

Indicators reported in the analysis were on the basis of the parent report, which may be limited by recall and reporting decisions and were not validated against medical records or clinical judgment. Moreover, details about the types of treatment were not included.

DISCLOSURES:

The work was authorized as part of the contributor’s official duties as an employee of the US Government, and therefore is a work of the US Government. The authors declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

A new analysis of a national dataset of children in the United States shows that there were roughly one million more children with attention-deficit/hyperactivity disorder (ADHD) in 2022 than in 2016.

METHODOLOGY:

• Researchers used 2022 data from the National Survey of Children’s Health to estimate the prevalence of ever-diagnosed and current ADHD among US children between the ages of 3 and 18 years.
• They also estimated, among children with current ADHD, the severity of the condition and the presence of current co-occurring disorders and the receipt of medication and behavioral treatments.
• The researchers calculated overall weighted estimates as well as estimates for specific demographic and clinical subgroups (n = 45,169).

TAKEAWAY:

• The number of children who had ever received an ADHD diagnosis increased from 6.1 million in 2016 to 7.1 million in 2022, and the number with current ADHD increased from 5.4 million to 6.5 million.
• Of those with current ADHD in 2022, 58.1% had moderate or severe ADHD, and 77.9% had at least one co-occurring disorder.
• A total of 53.6% had received ADHD medication, 44.4% had received behavioral treatment in the past year, and 30.1% had received no ADHD-specific treatment.
• A similar percentage of children with ADHD were receiving behavioral treatment in 2022 as in 2016 (44.4% vs 46.7%, respectively), but treatment with ADHD medication was lower in 2022 than in 2016 (53.6% vs 62.0%, respectively).

IN PRACTICE:

The estimates “can be used by clinicians to understand current ADHD diagnosis and treatment utilization patterns to inform clinical practice, such as accounting for the frequency and management of co-occurring conditions and considering the notable percentage of children with ADHD not currently receiving ADHD treatment,” and can be used by policymakers, practitioners, and others “to plan for the needs of children with ADHD, such as by ensuring access to care and services for ADHD,” investigators wrote.

SOURCE:

Melissa L. Danielson, of the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, led the study, which was published online in the Journal of Clinical Child & Adolescent Psychology.

LIMITATIONS:

Indicators reported in the analysis were on the basis of the parent report, which may be limited by recall and reporting decisions and were not validated against medical records or clinical judgment. Moreover, details about the types of treatment were not included.

DISCLOSURES:

The work was authorized as part of the contributor’s official duties as an employee of the US Government, and therefore is a work of the US Government. The authors declared no relevant financial relationships.

A version of this article appeared on Medscape.com.

Reports from older adults and their partners of early memory issues are associated with higher levels of tau neurofibrillary tangles in the brain, new research suggests. 

The findings show that in addition to beta-amyloid, tau is implicated in cognitive decline even in the absence of overt clinical symptoms.

“Understanding the earliest signs of Alzheimer’s disease is even more important now that new disease-modifying drugs are becoming available,” study author 

Rebecca E. Amariglio, PhD, clinical neuropsychologist at Brigham and Women’s Hospital and the Massachusetts General Hospital and assistant professor in neurology at Harvard Medical School, Boston, said in a news release. “Our study found early suspicions of memory problems by both participants and the people who knew them well were linked to higher levels of tau tangles in the brain.”

The study was published online in Neurology.
 

Subjective Cognitive Decline

Beta-amyloid plaque accumulations and tau neurofibrillary tangles both underlie the clinical continuum of Alzheimer’s disease (AD). Previous studies have investigated beta-amyloid burden and self- and partner-reported cognitive decline, but fewer have examined regional tau.

Subjective cognitive decline may be an early sign of AD, but self-awareness declines as individuals become increasingly symptomatic. So, a report from a partner about the participant’s level of cognitive functioning is often required in studies of mild cognitive impairment and dementia. The relevance of this model during the preclinical stage is less clear.

For the multicohort, cross-sectional study, investigators studied 675 cognitively unimpaired older adults (mean age, 72 years; 59% female), including persons with nonelevated beta-amyloid levels and those with elevated beta-amyloid levels, as determined by PET. 

Participants brought a spouse, adult child, or other study partner with them to answer questions about the participant’s cognitive abilities and their ability to complete daily tasks. About 65% of participants lived with their partners and both completed the Cognitive Function Index (CFI) to assess cognitive decline, with higher scores indicating greater cognitive decline. 

Covariates included age, sex, education, and cohort as well as objective cognitive performance.
 

The Value of Partner Reporting

Investigators found that higher tau levels were associated with greater self- and partner-reported cognitive decline (P < .001 for both).

Significant associations between self- and partner-reported CFI measures were driven by elevated beta-amyloid levels, with continuous beta-amyloid levels showing an independent effect on CFI in addition to tau. 

“Our findings suggest that asking older people who have elevated Alzheimer’s disease biomarkers about subjective cognitive decline may be valuable for early detection,” Dr. Amariglio said.

Limitations include the fact that most participants were White and highly educated. Future studies should include participants from more diverse racial and ethnic groups and people with diverse levels of education, researchers noted.

“Although this study was cross-sectional, findings suggest that among older CU individuals who at risk for AD dementia, capturing self-report and study partner report of cognitive function may be valuable for understanding the relationship between early pathophysiologic progression and the emergence of functional impairment,” the authors concluded.

The study was funded in part by the National Institute on Aging, Eli Lily, and the Alzheimer’s Association, among others. Dr. Amariglio receives research funding from the National Institute on Aging. Complete study funding and other authors’ disclosures are listed in the original paper.

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

Reports from older adults and their partners of early memory issues are associated with higher levels of tau neurofibrillary tangles in the brain, new research suggests. 

The findings show that in addition to beta-amyloid, tau is implicated in cognitive decline even in the absence of overt clinical symptoms.

“Understanding the earliest signs of Alzheimer’s disease is even more important now that new disease-modifying drugs are becoming available,” study author 

Rebecca E. Amariglio, PhD, clinical neuropsychologist at Brigham and Women’s Hospital and the Massachusetts General Hospital and assistant professor in neurology at Harvard Medical School, Boston, said in a news release. “Our study found early suspicions of memory problems by both participants and the people who knew them well were linked to higher levels of tau tangles in the brain.”

The study was published online in Neurology.
 

Subjective Cognitive Decline

Beta-amyloid plaque accumulations and tau neurofibrillary tangles both underlie the clinical continuum of Alzheimer’s disease (AD). Previous studies have investigated beta-amyloid burden and self- and partner-reported cognitive decline, but fewer have examined regional tau.

Subjective cognitive decline may be an early sign of AD, but self-awareness declines as individuals become increasingly symptomatic. So, a report from a partner about the participant’s level of cognitive functioning is often required in studies of mild cognitive impairment and dementia. The relevance of this model during the preclinical stage is less clear.

For the multicohort, cross-sectional study, investigators studied 675 cognitively unimpaired older adults (mean age, 72 years; 59% female), including persons with nonelevated beta-amyloid levels and those with elevated beta-amyloid levels, as determined by PET. 

Participants brought a spouse, adult child, or other study partner with them to answer questions about the participant’s cognitive abilities and their ability to complete daily tasks. About 65% of participants lived with their partners and both completed the Cognitive Function Index (CFI) to assess cognitive decline, with higher scores indicating greater cognitive decline. 

Covariates included age, sex, education, and cohort as well as objective cognitive performance.
 

The Value of Partner Reporting

Investigators found that higher tau levels were associated with greater self- and partner-reported cognitive decline (P < .001 for both).

Significant associations between self- and partner-reported CFI measures were driven by elevated beta-amyloid levels, with continuous beta-amyloid levels showing an independent effect on CFI in addition to tau. 

“Our findings suggest that asking older people who have elevated Alzheimer’s disease biomarkers about subjective cognitive decline may be valuable for early detection,” Dr. Amariglio said.

Limitations include the fact that most participants were White and highly educated. Future studies should include participants from more diverse racial and ethnic groups and people with diverse levels of education, researchers noted.

“Although this study was cross-sectional, findings suggest that among older CU individuals who at risk for AD dementia, capturing self-report and study partner report of cognitive function may be valuable for understanding the relationship between early pathophysiologic progression and the emergence of functional impairment,” the authors concluded.

The study was funded in part by the National Institute on Aging, Eli Lily, and the Alzheimer’s Association, among others. Dr. Amariglio receives research funding from the National Institute on Aging. Complete study funding and other authors’ disclosures are listed in the original paper.

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

Reports from older adults and their partners of early memory issues are associated with higher levels of tau neurofibrillary tangles in the brain, new research suggests. 

The findings show that in addition to beta-amyloid, tau is implicated in cognitive decline even in the absence of overt clinical symptoms.

“Understanding the earliest signs of Alzheimer’s disease is even more important now that new disease-modifying drugs are becoming available,” study author 

Rebecca E. Amariglio, PhD, clinical neuropsychologist at Brigham and Women’s Hospital and the Massachusetts General Hospital and assistant professor in neurology at Harvard Medical School, Boston, said in a news release. “Our study found early suspicions of memory problems by both participants and the people who knew them well were linked to higher levels of tau tangles in the brain.”

The study was published online in Neurology.
 

Subjective Cognitive Decline

Beta-amyloid plaque accumulations and tau neurofibrillary tangles both underlie the clinical continuum of Alzheimer’s disease (AD). Previous studies have investigated beta-amyloid burden and self- and partner-reported cognitive decline, but fewer have examined regional tau.

Subjective cognitive decline may be an early sign of AD, but self-awareness declines as individuals become increasingly symptomatic. So, a report from a partner about the participant’s level of cognitive functioning is often required in studies of mild cognitive impairment and dementia. The relevance of this model during the preclinical stage is less clear.

For the multicohort, cross-sectional study, investigators studied 675 cognitively unimpaired older adults (mean age, 72 years; 59% female), including persons with nonelevated beta-amyloid levels and those with elevated beta-amyloid levels, as determined by PET. 

Participants brought a spouse, adult child, or other study partner with them to answer questions about the participant’s cognitive abilities and their ability to complete daily tasks. About 65% of participants lived with their partners and both completed the Cognitive Function Index (CFI) to assess cognitive decline, with higher scores indicating greater cognitive decline. 

Covariates included age, sex, education, and cohort as well as objective cognitive performance.
 

The Value of Partner Reporting

Investigators found that higher tau levels were associated with greater self- and partner-reported cognitive decline (P < .001 for both).

Significant associations between self- and partner-reported CFI measures were driven by elevated beta-amyloid levels, with continuous beta-amyloid levels showing an independent effect on CFI in addition to tau. 

“Our findings suggest that asking older people who have elevated Alzheimer’s disease biomarkers about subjective cognitive decline may be valuable for early detection,” Dr. Amariglio said.

Limitations include the fact that most participants were White and highly educated. Future studies should include participants from more diverse racial and ethnic groups and people with diverse levels of education, researchers noted.

“Although this study was cross-sectional, findings suggest that among older CU individuals who at risk for AD dementia, capturing self-report and study partner report of cognitive function may be valuable for understanding the relationship between early pathophysiologic progression and the emergence of functional impairment,” the authors concluded.

The study was funded in part by the National Institute on Aging, Eli Lily, and the Alzheimer’s Association, among others. Dr. Amariglio receives research funding from the National Institute on Aging. Complete study funding and other authors’ disclosures are listed in the original paper.

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

Nearly one-fifth of suicides in the United States occur in people who were incarcerated in the previous year, a new study showed.

An analysis of more than seven million recently incarcerated US adults revealed a nearly ninefold increased risk for suicide within 1 year after release and an almost sevenfold higher risk during the 2 years following release compared with nonincarcerated people.

The findings suggest that recent incarceration should be considered a risk factor for suicide, investigators said.

“Suicide prevention efforts should focus on people who have spent at least 1 night in jail in the past year,” investigator Ted R. Miller, PhD, of the Pacific Institute for Research and Evaluation, Beltsville, Maryland, and Curtin University School of Public Health, Silver Spring, Maryland, and colleagues wrote. “Health systems could develop infrastructure to identify these high-risk adults and provide community-based suicide screening and prevention.” 

The study was published online on May 10, 2024, in JAMA Network Open.

To address the lack of data on suicide risk after recent incarceration, researchers used estimates from meta-analyses and jail census counts.

In 2019, a little more than seven million people (77% male), or 2.8% of the US adult population, were released from US jails at least once, typically after brief pretrial stays. Of those, 9121 died by suicide.

Compared with suicide risk in people who had never been incarcerated, risk was nearly nine times higher within 1 year of release (relative risk [RR], 8.95; 95% CI, 7.21-10.69) and nearly seven times higher during the second year after release (RR, 6.98; 95% CI, 4.21-9.76), researchers found.

Over a quarter (27%) of all adult suicides in the United States occurred in formerly incarcerated people within 2 years of jail release, and one fifth occurred within 1 year of release.

“The results suggest that better integration of suicide risk detection and prevention across health and criminal justice systems is critical to advancing population-level suicide-prevention efforts,” the authors wrote.

High volumes of jail admissions and discharges, short jail stays, and understaffing limit the capacity of many jails to coordinate care with outside health agencies, researchers acknowledged.

“The suicide rate after the return to the community after jail stay is higher than the suicide rate in jail, but local jails have limited capacity to coordinate postrelease health activities,” authors wrote. “Thus, a comprehensive approach to reducing the population-level US suicide rate would include health systems screening their subscribers or patients for recent arrest or police involvement and reaching out to those recently released to prevent suicide.”

In an accompanying editorial, Stuart A. Kinner, PhD, and Rohan Borschmann, PhD, both with the Melbourne School of Population and Global Health, University of Melbourne, Australia, noted that people who experience incarceration “are distinguished by complex health problems that necessitate coordinated, multisectoral care.”

“Miller and colleagues’ findings provide further evidence that incarceration serves as an important marker for disease vulnerability and risk,” Dr. Kinner and Borschmann wrote. “Yet, all too often, the health care provided to these individuals before, during, and after incarceration is underresourced, interrupted, and fragmented.”

Coordinating care for recently incarcerated individuals will require a coordinated effort by all stakeholders, including those in the criminal justice system, they argued.

“The systems that incarcerate 7.1 million people in the United States each year should not be given a get-out-of-jail-free card,” they wrote.

This study was supported by grants from the National Institutes of Mental Health (NIMH)/National Institutes of Health (NIH) and from the National Center for Health and Justice Integration for Suicide Prevention. Dr. Miller reported receiving grants from the NIMH/NIH with his employer as a subcontractor during the conduct of the study and a contract from government plaintiffs in Opioid Litigation: Epidemiology/Abatement Planning outside the submitted work. The other authors’ disclosures are listed on the original paper. Dr. Kinner and Borschmann declared no relevant financial relationships. 
 

A version of this article appeared on Medscape.com.

Nearly one-fifth of suicides in the United States occur in people who were incarcerated in the previous year, a new study showed.

An analysis of more than seven million recently incarcerated US adults revealed a nearly ninefold increased risk for suicide within 1 year after release and an almost sevenfold higher risk during the 2 years following release compared with nonincarcerated people.

The findings suggest that recent incarceration should be considered a risk factor for suicide, investigators said.

“Suicide prevention efforts should focus on people who have spent at least 1 night in jail in the past year,” investigator Ted R. Miller, PhD, of the Pacific Institute for Research and Evaluation, Beltsville, Maryland, and Curtin University School of Public Health, Silver Spring, Maryland, and colleagues wrote. “Health systems could develop infrastructure to identify these high-risk adults and provide community-based suicide screening and prevention.” 

The study was published online on May 10, 2024, in JAMA Network Open.

To address the lack of data on suicide risk after recent incarceration, researchers used estimates from meta-analyses and jail census counts.

In 2019, a little more than seven million people (77% male), or 2.8% of the US adult population, were released from US jails at least once, typically after brief pretrial stays. Of those, 9121 died by suicide.

Compared with suicide risk in people who had never been incarcerated, risk was nearly nine times higher within 1 year of release (relative risk [RR], 8.95; 95% CI, 7.21-10.69) and nearly seven times higher during the second year after release (RR, 6.98; 95% CI, 4.21-9.76), researchers found.

Over a quarter (27%) of all adult suicides in the United States occurred in formerly incarcerated people within 2 years of jail release, and one fifth occurred within 1 year of release.

“The results suggest that better integration of suicide risk detection and prevention across health and criminal justice systems is critical to advancing population-level suicide-prevention efforts,” the authors wrote.

High volumes of jail admissions and discharges, short jail stays, and understaffing limit the capacity of many jails to coordinate care with outside health agencies, researchers acknowledged.

“The suicide rate after the return to the community after jail stay is higher than the suicide rate in jail, but local jails have limited capacity to coordinate postrelease health activities,” authors wrote. “Thus, a comprehensive approach to reducing the population-level US suicide rate would include health systems screening their subscribers or patients for recent arrest or police involvement and reaching out to those recently released to prevent suicide.”

In an accompanying editorial, Stuart A. Kinner, PhD, and Rohan Borschmann, PhD, both with the Melbourne School of Population and Global Health, University of Melbourne, Australia, noted that people who experience incarceration “are distinguished by complex health problems that necessitate coordinated, multisectoral care.”

“Miller and colleagues’ findings provide further evidence that incarceration serves as an important marker for disease vulnerability and risk,” Dr. Kinner and Borschmann wrote. “Yet, all too often, the health care provided to these individuals before, during, and after incarceration is underresourced, interrupted, and fragmented.”

Coordinating care for recently incarcerated individuals will require a coordinated effort by all stakeholders, including those in the criminal justice system, they argued.

“The systems that incarcerate 7.1 million people in the United States each year should not be given a get-out-of-jail-free card,” they wrote.

This study was supported by grants from the National Institutes of Mental Health (NIMH)/National Institutes of Health (NIH) and from the National Center for Health and Justice Integration for Suicide Prevention. Dr. Miller reported receiving grants from the NIMH/NIH with his employer as a subcontractor during the conduct of the study and a contract from government plaintiffs in Opioid Litigation: Epidemiology/Abatement Planning outside the submitted work. The other authors’ disclosures are listed on the original paper. Dr. Kinner and Borschmann declared no relevant financial relationships. 
 

A version of this article appeared on Medscape.com.

Nearly one-fifth of suicides in the United States occur in people who were incarcerated in the previous year, a new study showed.

An analysis of more than seven million recently incarcerated US adults revealed a nearly ninefold increased risk for suicide within 1 year after release and an almost sevenfold higher risk during the 2 years following release compared with nonincarcerated people.

The findings suggest that recent incarceration should be considered a risk factor for suicide, investigators said.

“Suicide prevention efforts should focus on people who have spent at least 1 night in jail in the past year,” investigator Ted R. Miller, PhD, of the Pacific Institute for Research and Evaluation, Beltsville, Maryland, and Curtin University School of Public Health, Silver Spring, Maryland, and colleagues wrote. “Health systems could develop infrastructure to identify these high-risk adults and provide community-based suicide screening and prevention.” 

The study was published online on May 10, 2024, in JAMA Network Open.

To address the lack of data on suicide risk after recent incarceration, researchers used estimates from meta-analyses and jail census counts.

In 2019, a little more than seven million people (77% male), or 2.8% of the US adult population, were released from US jails at least once, typically after brief pretrial stays. Of those, 9121 died by suicide.

Compared with suicide risk in people who had never been incarcerated, risk was nearly nine times higher within 1 year of release (relative risk [RR], 8.95; 95% CI, 7.21-10.69) and nearly seven times higher during the second year after release (RR, 6.98; 95% CI, 4.21-9.76), researchers found.

Over a quarter (27%) of all adult suicides in the United States occurred in formerly incarcerated people within 2 years of jail release, and one fifth occurred within 1 year of release.

“The results suggest that better integration of suicide risk detection and prevention across health and criminal justice systems is critical to advancing population-level suicide-prevention efforts,” the authors wrote.

High volumes of jail admissions and discharges, short jail stays, and understaffing limit the capacity of many jails to coordinate care with outside health agencies, researchers acknowledged.

“The suicide rate after the return to the community after jail stay is higher than the suicide rate in jail, but local jails have limited capacity to coordinate postrelease health activities,” authors wrote. “Thus, a comprehensive approach to reducing the population-level US suicide rate would include health systems screening their subscribers or patients for recent arrest or police involvement and reaching out to those recently released to prevent suicide.”

In an accompanying editorial, Stuart A. Kinner, PhD, and Rohan Borschmann, PhD, both with the Melbourne School of Population and Global Health, University of Melbourne, Australia, noted that people who experience incarceration “are distinguished by complex health problems that necessitate coordinated, multisectoral care.”

“Miller and colleagues’ findings provide further evidence that incarceration serves as an important marker for disease vulnerability and risk,” Dr. Kinner and Borschmann wrote. “Yet, all too often, the health care provided to these individuals before, during, and after incarceration is underresourced, interrupted, and fragmented.”

Coordinating care for recently incarcerated individuals will require a coordinated effort by all stakeholders, including those in the criminal justice system, they argued.

“The systems that incarcerate 7.1 million people in the United States each year should not be given a get-out-of-jail-free card,” they wrote.

This study was supported by grants from the National Institutes of Mental Health (NIMH)/National Institutes of Health (NIH) and from the National Center for Health and Justice Integration for Suicide Prevention. Dr. Miller reported receiving grants from the NIMH/NIH with his employer as a subcontractor during the conduct of the study and a contract from government plaintiffs in Opioid Litigation: Epidemiology/Abatement Planning outside the submitted work. The other authors’ disclosures are listed on the original paper. Dr. Kinner and Borschmann declared no relevant financial relationships. 
 

A version of this article appeared on Medscape.com.

Although the prevalence of migraine in the United States has remained stable over the past three decades, migraine-related disability has nearly doubled during that time, a new systematic review showed.

“The disability trend could reflect changes in reporting, study methodology, social, and societal changes, or changes in exacerbating or remediating factors that make migraine more disabling,” wrote lead investigator Fred Cohen, MD, of Center for Headache and Facial Pain, Department of Neurology, Icahn School of Medicine, Mount Sinai, New York City, and colleagues.

The study was published online in Headache.

Researchers conducted a systematic review of population-based US epidemiologic studies focusing on the prevalence and/or burden of migraine, all published before February 2022. Studies on migraine, episodic migraine, and/or chronic migraine were included.

The primary measure of disease burden was the Migraine Disability Assessment Scale (MIDAS), which measures days lost to migraine over a 3-month period in three domains and defines groups with moderate or severe disability (grades III and IV, respectively), using cut-scores.

Of 1609 studies initially reviewed, the researchers included 26 publications from 11 US population-based studies.

For the past 30 years, the prevalence of migraine in the population has remained largely stable, ranging from 12% to 15% in the overall population, from 17% to 19% in women, and from 6% to 7% in men.

In adults overall, chronic migraine prevalence is 0.91% (1.3% in women and 0.5% in men), while in adolescents, the prevalence is 0.8%.

Although prevalence remained roughly the same during the 30 years, the proportion of people with migraine and moderate to severe MIDAS disability (grades III-IV) has trended upward across studies during part of the study period, increasing from 22% in 2005 to 42% in 2018.

Throughout the years studied, a consistently higher proportion of women versus men were assigned MIDAS grades III-IV.

Although researchers said the exact reason for the increase is unknown, possible explanations include changes in study methodology from mailed questionnaires to web surveys or the decline in participation rate in web surveys. It is also possible that people with migraine may be more willing to report disability than they used to be, authors wrote.

Increased MIDAS scores may be attributable to some environmental risk factor that exacerbates migraine without modifying its prevalence, such as worsening air quality, an increase in natural disasters, or increased opioid use for migraine, they added.

The reason for increased moderate to severe disability in women may be attributable to the fact that migraine is “most common in mid-life, a period characterized by familial and work responsibilities, which may engender a higher risk of burden for working women,” authors wrote. The link between migraine attacks and menstrual cycles may also explain observed gender differences in disability.

In general, the most frequently reported burdens associated with migraine included missed work and school and family and social functioning.

It is “surprising that improvements in treatment have not been associated with reductions in disability,” researchers noted.

No financial support was provided for this study. Dr. Cohen serves as an assistant editor for Headache. He has received honoraria from Springer Nature and MedLink Neurology. Other authors’ disclosures are listed on the original paper.
 

A version of this article appeared on Medscape.com.

Although the prevalence of migraine in the United States has remained stable over the past three decades, migraine-related disability has nearly doubled during that time, a new systematic review showed.

“The disability trend could reflect changes in reporting, study methodology, social, and societal changes, or changes in exacerbating or remediating factors that make migraine more disabling,” wrote lead investigator Fred Cohen, MD, of Center for Headache and Facial Pain, Department of Neurology, Icahn School of Medicine, Mount Sinai, New York City, and colleagues.

The study was published online in Headache.

Researchers conducted a systematic review of population-based US epidemiologic studies focusing on the prevalence and/or burden of migraine, all published before February 2022. Studies on migraine, episodic migraine, and/or chronic migraine were included.

The primary measure of disease burden was the Migraine Disability Assessment Scale (MIDAS), which measures days lost to migraine over a 3-month period in three domains and defines groups with moderate or severe disability (grades III and IV, respectively), using cut-scores.

Of 1609 studies initially reviewed, the researchers included 26 publications from 11 US population-based studies.

For the past 30 years, the prevalence of migraine in the population has remained largely stable, ranging from 12% to 15% in the overall population, from 17% to 19% in women, and from 6% to 7% in men.

In adults overall, chronic migraine prevalence is 0.91% (1.3% in women and 0.5% in men), while in adolescents, the prevalence is 0.8%.

Although prevalence remained roughly the same during the 30 years, the proportion of people with migraine and moderate to severe MIDAS disability (grades III-IV) has trended upward across studies during part of the study period, increasing from 22% in 2005 to 42% in 2018.

Throughout the years studied, a consistently higher proportion of women versus men were assigned MIDAS grades III-IV.

Although researchers said the exact reason for the increase is unknown, possible explanations include changes in study methodology from mailed questionnaires to web surveys or the decline in participation rate in web surveys. It is also possible that people with migraine may be more willing to report disability than they used to be, authors wrote.

Increased MIDAS scores may be attributable to some environmental risk factor that exacerbates migraine without modifying its prevalence, such as worsening air quality, an increase in natural disasters, or increased opioid use for migraine, they added.

The reason for increased moderate to severe disability in women may be attributable to the fact that migraine is “most common in mid-life, a period characterized by familial and work responsibilities, which may engender a higher risk of burden for working women,” authors wrote. The link between migraine attacks and menstrual cycles may also explain observed gender differences in disability.

In general, the most frequently reported burdens associated with migraine included missed work and school and family and social functioning.

It is “surprising that improvements in treatment have not been associated with reductions in disability,” researchers noted.

No financial support was provided for this study. Dr. Cohen serves as an assistant editor for Headache. He has received honoraria from Springer Nature and MedLink Neurology. Other authors’ disclosures are listed on the original paper.
 

A version of this article appeared on Medscape.com.

Although the prevalence of migraine in the United States has remained stable over the past three decades, migraine-related disability has nearly doubled during that time, a new systematic review showed.

“The disability trend could reflect changes in reporting, study methodology, social, and societal changes, or changes in exacerbating or remediating factors that make migraine more disabling,” wrote lead investigator Fred Cohen, MD, of Center for Headache and Facial Pain, Department of Neurology, Icahn School of Medicine, Mount Sinai, New York City, and colleagues.

The study was published online in Headache.

Researchers conducted a systematic review of population-based US epidemiologic studies focusing on the prevalence and/or burden of migraine, all published before February 2022. Studies on migraine, episodic migraine, and/or chronic migraine were included.

The primary measure of disease burden was the Migraine Disability Assessment Scale (MIDAS), which measures days lost to migraine over a 3-month period in three domains and defines groups with moderate or severe disability (grades III and IV, respectively), using cut-scores.

Of 1609 studies initially reviewed, the researchers included 26 publications from 11 US population-based studies.

For the past 30 years, the prevalence of migraine in the population has remained largely stable, ranging from 12% to 15% in the overall population, from 17% to 19% in women, and from 6% to 7% in men.

In adults overall, chronic migraine prevalence is 0.91% (1.3% in women and 0.5% in men), while in adolescents, the prevalence is 0.8%.

Although prevalence remained roughly the same during the 30 years, the proportion of people with migraine and moderate to severe MIDAS disability (grades III-IV) has trended upward across studies during part of the study period, increasing from 22% in 2005 to 42% in 2018.

Throughout the years studied, a consistently higher proportion of women versus men were assigned MIDAS grades III-IV.

Although researchers said the exact reason for the increase is unknown, possible explanations include changes in study methodology from mailed questionnaires to web surveys or the decline in participation rate in web surveys. It is also possible that people with migraine may be more willing to report disability than they used to be, authors wrote.

Increased MIDAS scores may be attributable to some environmental risk factor that exacerbates migraine without modifying its prevalence, such as worsening air quality, an increase in natural disasters, or increased opioid use for migraine, they added.

The reason for increased moderate to severe disability in women may be attributable to the fact that migraine is “most common in mid-life, a period characterized by familial and work responsibilities, which may engender a higher risk of burden for working women,” authors wrote. The link between migraine attacks and menstrual cycles may also explain observed gender differences in disability.

In general, the most frequently reported burdens associated with migraine included missed work and school and family and social functioning.

It is “surprising that improvements in treatment have not been associated with reductions in disability,” researchers noted.

No financial support was provided for this study. Dr. Cohen serves as an assistant editor for Headache. He has received honoraria from Springer Nature and MedLink Neurology. Other authors’ disclosures are listed on the original paper.
 

A version of this article appeared on Medscape.com.

New expert guidance to help clinicians manage the treatment of patients with epilepsy during pregnancy has been released.

Issued by the American Academy of Neurology, the American Epilepsy Society, and the Society for Maternal-Fetal Medicine, the new practice guideline covers the use of antiseizure medications (ASMs) and folic acid supplementation before conception and during pregnancy.

“Most children born to people with epilepsy are healthy, but there is a small risk of pregnancy-related problems, partly due to seizures and partly due to the effects of antiseizure medications,” the guidelines’ lead author Alison M. Pack, MD, MPH, professor of neurology and chief of the Epilepsy and Sleep Division, Columbia University, New York City, said in a news release.

“This guideline provides recommendations regarding the effects of antiseizure medications and folic acid supplementation on malformations at birth and the development of children during pregnancy, so that doctors and people with epilepsy can determine which treatments may be best for them,” she added. 

The guideline was published online in Neurology.
 

Why Now? 

The new guideline updates the 2009 guidance on epilepsy management during pregnancy. Since then, Dr. Pack told this news organization, there has been a wealth of new data on differential effects of different ASMs — notably, lamotrigine and levetiracetam — the most commonly prescribed medications in this population.

“In this guideline, we were able to assess differential effects of different ASMs on outcomes of interest, including major congenital malformations [MCMs], perinatal outcomes, and neurodevelopmental outcomes. In addition, we looked at the effect of folic acid supplementation on each of these outcomes,” she said.

The overarching goals of care for patients are to “optimize health outcomes both for individuals and their future offspring,” the authors wrote. Shared decision-making, they add, leads to better decision-making by providing a better understanding of the available treatment options and their potential risks, resulting in enhanced decision-making that aligns with personal values.

Clinicians should recommend ASMs that optimize seizure control and fetal outcomes, in the event of a pregnancy, at the earliest possible preconception time, the guideline authors note.

“Overall, treating clinicians need to balance treating the person with epilepsy to control convulsive seizures (generalized tonic-clonic seizures and focal-to-bilateral tonic-clonic seizures) to minimize potential risks to the birth parent and the possible risks of certain ASMs on the fetus if pregnancy occurs,” they wrote.

If a patient is already pregnant, the experts recommend that clinicians “exercise caution” in removing or replacing an ASM that controls convulsive seizures, even if it’s “not an optimal choice” for the fetus. 

In addition, they advise that ASM levels should be monitored throughout the pregnancy, guided by individual ASM pharmacokinetics and an individual patient’s clinical presentation. ASM dose, they note, should be adjusted during pregnancy in response to decreasing serum ASM levels or worsening seizure control.

The authors point out that there are limited data on “pregnancy-related outcomes with respect to acetazolamide, eslicarbazepine, ethosuximide, lacosamide, nitrazepam, perampanel, piracetam, pregabalin, rufinamide, stiripentol, tiagabine, and vigabatrin.”

Patients should be informed that the birth prevalence of any major congenital malformation in the general population ranges between 2.4% and 2.9%.
 

If Feasible, Avoid Valproic Acid 

“One of the most important take-home messages is that valproic acid has the highest unadjusted birth prevalence of all major congenital malformations — 9.7% — and the highest unadjusted birth prevalence of neural tube defects at 1.4%,” Dr. Pack said. As a result, the guideline authors advise against using valproic acid, if clinically feasible.

Valproic acid also has the highest prevalence of negative neurodevelopmental outcomes, including a reduction in global IQ and an increased prevalence of autism spectrum disorder (ASD). Patients should be counseled accordingly and advised of the increased risk for ASD and decreased IQ resulting from valproic acid.

Clinicians should consider using lamotrigine, levetiracetam, or oxcarbazepine when appropriate. Serum concentrations of most ASMs have a “defined therapeutic window” for effective seizure control and that concentration may decrease during pregnancy, particularly with lamotrigine and levetiracetam, the authors note.

Phenobarbital, topiramate, and valproic acid should because of the increased risk for cardiac malformations, oral clefts, and urogenital and renal malformations.

Fetal screening for major congenital malformations is recommended to enable early detection and timely intervention in patients treated with any ASM during pregnancy Patients receiving phenobarbital during pregnancy should also undergo fetal cardiac screenings.

Valproic acid and topiramate are also associated with children who are small for their gestational age. To enable early identification of fetal growth restriction, patients taking valproic acid or topiramate should be monitored. In addition, children exposed to these medications in utero should be monitored during childhood to ensure they are meeting age-appropriate developmental milestones. 

Folic acid taken during pregnancy can reduce the prevalence of negative neurodevelopment outcomes, but not major congenital malformations, Dr. Pack noted. 

“Due to limited available data, we were unable to define an optimal dose of folic acid supplementation beyond at least 0.4 mg/d,” Dr. Pack said. “Future studies, preferably randomized clinical trials, are needed to better define the optimal dose.”

She emphasized that epilepsy is one of the most common neurologic disorders, and 1 in 5 of those affected are people of childbearing potential. Understanding the effects of ASMs on pregnancy outcomes is critical for physicians who manage these patients.
 

Uncertainty Remains 

Commenting for this news organization, Kimford Meador, MD, a professor in the Department of Neurology and Neurological Sciences at Stanford University School of Medicine , Stanford Neuroscience Health Center, Palo Alto, California, noted that the new guidelines reflect the gains in knowledge since 2009 and that the recommendations are “reasonable, based on available data.”

However, “one very important point is how much remains unknown,” said Dr. Meador, who was not involved in writing the current guideline. “Many ASMs have no data, and several have estimates based on small samples or a single observational study.” Thus, “the risks for the majority of ASMs are uncertain.”

Given that randomized trials “are not possible in this population, and that all observational studies are subject to residual confounding, a reliable signal across multiple studies in humans is required to be certain of findings,” he stated.

This practice guideline was developed with financial support from the American Academy of Neurology. Dr. Pack serves on the editorial board for the journal Epilepsy Currents, receives royalties from UpToDate, receives funding from the National Institutes of Health for serving as coinvestigator and site principal investigator for the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, and receives funding from Bayer for serving as a co-investigator on a study on women with epilepsy initiating a progestin intrauterine device. One of Dr. Pack’s immediate family members has received personal compensation for serving as an employee of REGENEXBIO. The other authors’ disclosures are listed on the original paper. Dr. Meador has received research support from the National Institutes of Health, Veterans Administration, Eisai, Inc, and Suno Medtronic Navigation, Inc, and the Epilepsy Study Consortium pays Dr. Meador’s university for his research on the Human Epilepsy Project and consultant time related to Eisai, UCB Pharma, and Xenon.

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

New expert guidance to help clinicians manage the treatment of patients with epilepsy during pregnancy has been released.

Issued by the American Academy of Neurology, the American Epilepsy Society, and the Society for Maternal-Fetal Medicine, the new practice guideline covers the use of antiseizure medications (ASMs) and folic acid supplementation before conception and during pregnancy.

“Most children born to people with epilepsy are healthy, but there is a small risk of pregnancy-related problems, partly due to seizures and partly due to the effects of antiseizure medications,” the guidelines’ lead author Alison M. Pack, MD, MPH, professor of neurology and chief of the Epilepsy and Sleep Division, Columbia University, New York City, said in a news release.

“This guideline provides recommendations regarding the effects of antiseizure medications and folic acid supplementation on malformations at birth and the development of children during pregnancy, so that doctors and people with epilepsy can determine which treatments may be best for them,” she added. 

The guideline was published online in Neurology.
 

Why Now? 

The new guideline updates the 2009 guidance on epilepsy management during pregnancy. Since then, Dr. Pack told this news organization, there has been a wealth of new data on differential effects of different ASMs — notably, lamotrigine and levetiracetam — the most commonly prescribed medications in this population.

“In this guideline, we were able to assess differential effects of different ASMs on outcomes of interest, including major congenital malformations [MCMs], perinatal outcomes, and neurodevelopmental outcomes. In addition, we looked at the effect of folic acid supplementation on each of these outcomes,” she said.

The overarching goals of care for patients are to “optimize health outcomes both for individuals and their future offspring,” the authors wrote. Shared decision-making, they add, leads to better decision-making by providing a better understanding of the available treatment options and their potential risks, resulting in enhanced decision-making that aligns with personal values.

Clinicians should recommend ASMs that optimize seizure control and fetal outcomes, in the event of a pregnancy, at the earliest possible preconception time, the guideline authors note.

“Overall, treating clinicians need to balance treating the person with epilepsy to control convulsive seizures (generalized tonic-clonic seizures and focal-to-bilateral tonic-clonic seizures) to minimize potential risks to the birth parent and the possible risks of certain ASMs on the fetus if pregnancy occurs,” they wrote.

If a patient is already pregnant, the experts recommend that clinicians “exercise caution” in removing or replacing an ASM that controls convulsive seizures, even if it’s “not an optimal choice” for the fetus. 

In addition, they advise that ASM levels should be monitored throughout the pregnancy, guided by individual ASM pharmacokinetics and an individual patient’s clinical presentation. ASM dose, they note, should be adjusted during pregnancy in response to decreasing serum ASM levels or worsening seizure control.

The authors point out that there are limited data on “pregnancy-related outcomes with respect to acetazolamide, eslicarbazepine, ethosuximide, lacosamide, nitrazepam, perampanel, piracetam, pregabalin, rufinamide, stiripentol, tiagabine, and vigabatrin.”

Patients should be informed that the birth prevalence of any major congenital malformation in the general population ranges between 2.4% and 2.9%.
 

If Feasible, Avoid Valproic Acid 

“One of the most important take-home messages is that valproic acid has the highest unadjusted birth prevalence of all major congenital malformations — 9.7% — and the highest unadjusted birth prevalence of neural tube defects at 1.4%,” Dr. Pack said. As a result, the guideline authors advise against using valproic acid, if clinically feasible.

Valproic acid also has the highest prevalence of negative neurodevelopmental outcomes, including a reduction in global IQ and an increased prevalence of autism spectrum disorder (ASD). Patients should be counseled accordingly and advised of the increased risk for ASD and decreased IQ resulting from valproic acid.

Clinicians should consider using lamotrigine, levetiracetam, or oxcarbazepine when appropriate. Serum concentrations of most ASMs have a “defined therapeutic window” for effective seizure control and that concentration may decrease during pregnancy, particularly with lamotrigine and levetiracetam, the authors note.

Phenobarbital, topiramate, and valproic acid should because of the increased risk for cardiac malformations, oral clefts, and urogenital and renal malformations.

Fetal screening for major congenital malformations is recommended to enable early detection and timely intervention in patients treated with any ASM during pregnancy Patients receiving phenobarbital during pregnancy should also undergo fetal cardiac screenings.

Valproic acid and topiramate are also associated with children who are small for their gestational age. To enable early identification of fetal growth restriction, patients taking valproic acid or topiramate should be monitored. In addition, children exposed to these medications in utero should be monitored during childhood to ensure they are meeting age-appropriate developmental milestones. 

Folic acid taken during pregnancy can reduce the prevalence of negative neurodevelopment outcomes, but not major congenital malformations, Dr. Pack noted. 

“Due to limited available data, we were unable to define an optimal dose of folic acid supplementation beyond at least 0.4 mg/d,” Dr. Pack said. “Future studies, preferably randomized clinical trials, are needed to better define the optimal dose.”

She emphasized that epilepsy is one of the most common neurologic disorders, and 1 in 5 of those affected are people of childbearing potential. Understanding the effects of ASMs on pregnancy outcomes is critical for physicians who manage these patients.
 

Uncertainty Remains 

Commenting for this news organization, Kimford Meador, MD, a professor in the Department of Neurology and Neurological Sciences at Stanford University School of Medicine , Stanford Neuroscience Health Center, Palo Alto, California, noted that the new guidelines reflect the gains in knowledge since 2009 and that the recommendations are “reasonable, based on available data.”

However, “one very important point is how much remains unknown,” said Dr. Meador, who was not involved in writing the current guideline. “Many ASMs have no data, and several have estimates based on small samples or a single observational study.” Thus, “the risks for the majority of ASMs are uncertain.”

Given that randomized trials “are not possible in this population, and that all observational studies are subject to residual confounding, a reliable signal across multiple studies in humans is required to be certain of findings,” he stated.

This practice guideline was developed with financial support from the American Academy of Neurology. Dr. Pack serves on the editorial board for the journal Epilepsy Currents, receives royalties from UpToDate, receives funding from the National Institutes of Health for serving as coinvestigator and site principal investigator for the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, and receives funding from Bayer for serving as a co-investigator on a study on women with epilepsy initiating a progestin intrauterine device. One of Dr. Pack’s immediate family members has received personal compensation for serving as an employee of REGENEXBIO. The other authors’ disclosures are listed on the original paper. Dr. Meador has received research support from the National Institutes of Health, Veterans Administration, Eisai, Inc, and Suno Medtronic Navigation, Inc, and the Epilepsy Study Consortium pays Dr. Meador’s university for his research on the Human Epilepsy Project and consultant time related to Eisai, UCB Pharma, and Xenon.

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

New expert guidance to help clinicians manage the treatment of patients with epilepsy during pregnancy has been released.

Issued by the American Academy of Neurology, the American Epilepsy Society, and the Society for Maternal-Fetal Medicine, the new practice guideline covers the use of antiseizure medications (ASMs) and folic acid supplementation before conception and during pregnancy.

“Most children born to people with epilepsy are healthy, but there is a small risk of pregnancy-related problems, partly due to seizures and partly due to the effects of antiseizure medications,” the guidelines’ lead author Alison M. Pack, MD, MPH, professor of neurology and chief of the Epilepsy and Sleep Division, Columbia University, New York City, said in a news release.

“This guideline provides recommendations regarding the effects of antiseizure medications and folic acid supplementation on malformations at birth and the development of children during pregnancy, so that doctors and people with epilepsy can determine which treatments may be best for them,” she added. 

The guideline was published online in Neurology.
 

Why Now? 

The new guideline updates the 2009 guidance on epilepsy management during pregnancy. Since then, Dr. Pack told this news organization, there has been a wealth of new data on differential effects of different ASMs — notably, lamotrigine and levetiracetam — the most commonly prescribed medications in this population.

“In this guideline, we were able to assess differential effects of different ASMs on outcomes of interest, including major congenital malformations [MCMs], perinatal outcomes, and neurodevelopmental outcomes. In addition, we looked at the effect of folic acid supplementation on each of these outcomes,” she said.

The overarching goals of care for patients are to “optimize health outcomes both for individuals and their future offspring,” the authors wrote. Shared decision-making, they add, leads to better decision-making by providing a better understanding of the available treatment options and their potential risks, resulting in enhanced decision-making that aligns with personal values.

Clinicians should recommend ASMs that optimize seizure control and fetal outcomes, in the event of a pregnancy, at the earliest possible preconception time, the guideline authors note.

“Overall, treating clinicians need to balance treating the person with epilepsy to control convulsive seizures (generalized tonic-clonic seizures and focal-to-bilateral tonic-clonic seizures) to minimize potential risks to the birth parent and the possible risks of certain ASMs on the fetus if pregnancy occurs,” they wrote.

If a patient is already pregnant, the experts recommend that clinicians “exercise caution” in removing or replacing an ASM that controls convulsive seizures, even if it’s “not an optimal choice” for the fetus. 

In addition, they advise that ASM levels should be monitored throughout the pregnancy, guided by individual ASM pharmacokinetics and an individual patient’s clinical presentation. ASM dose, they note, should be adjusted during pregnancy in response to decreasing serum ASM levels or worsening seizure control.

The authors point out that there are limited data on “pregnancy-related outcomes with respect to acetazolamide, eslicarbazepine, ethosuximide, lacosamide, nitrazepam, perampanel, piracetam, pregabalin, rufinamide, stiripentol, tiagabine, and vigabatrin.”

Patients should be informed that the birth prevalence of any major congenital malformation in the general population ranges between 2.4% and 2.9%.
 

If Feasible, Avoid Valproic Acid 

“One of the most important take-home messages is that valproic acid has the highest unadjusted birth prevalence of all major congenital malformations — 9.7% — and the highest unadjusted birth prevalence of neural tube defects at 1.4%,” Dr. Pack said. As a result, the guideline authors advise against using valproic acid, if clinically feasible.

Valproic acid also has the highest prevalence of negative neurodevelopmental outcomes, including a reduction in global IQ and an increased prevalence of autism spectrum disorder (ASD). Patients should be counseled accordingly and advised of the increased risk for ASD and decreased IQ resulting from valproic acid.

Clinicians should consider using lamotrigine, levetiracetam, or oxcarbazepine when appropriate. Serum concentrations of most ASMs have a “defined therapeutic window” for effective seizure control and that concentration may decrease during pregnancy, particularly with lamotrigine and levetiracetam, the authors note.

Phenobarbital, topiramate, and valproic acid should because of the increased risk for cardiac malformations, oral clefts, and urogenital and renal malformations.

Fetal screening for major congenital malformations is recommended to enable early detection and timely intervention in patients treated with any ASM during pregnancy Patients receiving phenobarbital during pregnancy should also undergo fetal cardiac screenings.

Valproic acid and topiramate are also associated with children who are small for their gestational age. To enable early identification of fetal growth restriction, patients taking valproic acid or topiramate should be monitored. In addition, children exposed to these medications in utero should be monitored during childhood to ensure they are meeting age-appropriate developmental milestones. 

Folic acid taken during pregnancy can reduce the prevalence of negative neurodevelopment outcomes, but not major congenital malformations, Dr. Pack noted. 

“Due to limited available data, we were unable to define an optimal dose of folic acid supplementation beyond at least 0.4 mg/d,” Dr. Pack said. “Future studies, preferably randomized clinical trials, are needed to better define the optimal dose.”

She emphasized that epilepsy is one of the most common neurologic disorders, and 1 in 5 of those affected are people of childbearing potential. Understanding the effects of ASMs on pregnancy outcomes is critical for physicians who manage these patients.
 

Uncertainty Remains 

Commenting for this news organization, Kimford Meador, MD, a professor in the Department of Neurology and Neurological Sciences at Stanford University School of Medicine , Stanford Neuroscience Health Center, Palo Alto, California, noted that the new guidelines reflect the gains in knowledge since 2009 and that the recommendations are “reasonable, based on available data.”

However, “one very important point is how much remains unknown,” said Dr. Meador, who was not involved in writing the current guideline. “Many ASMs have no data, and several have estimates based on small samples or a single observational study.” Thus, “the risks for the majority of ASMs are uncertain.”

Given that randomized trials “are not possible in this population, and that all observational studies are subject to residual confounding, a reliable signal across multiple studies in humans is required to be certain of findings,” he stated.

This practice guideline was developed with financial support from the American Academy of Neurology. Dr. Pack serves on the editorial board for the journal Epilepsy Currents, receives royalties from UpToDate, receives funding from the National Institutes of Health for serving as coinvestigator and site principal investigator for the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, and receives funding from Bayer for serving as a co-investigator on a study on women with epilepsy initiating a progestin intrauterine device. One of Dr. Pack’s immediate family members has received personal compensation for serving as an employee of REGENEXBIO. The other authors’ disclosures are listed on the original paper. Dr. Meador has received research support from the National Institutes of Health, Veterans Administration, Eisai, Inc, and Suno Medtronic Navigation, Inc, and the Epilepsy Study Consortium pays Dr. Meador’s university for his research on the Human Epilepsy Project and consultant time related to Eisai, UCB Pharma, and Xenon.

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

Warning letters to primary care physicians (PCPs) regarding overprescription of quetiapine were helpful in reducing overprescribing of this agent, new research suggested.

Investigators analyzed data from an earlier trial that compared prescribing patterns in 5055 PCPs who receive a placebo letter or three warning letters informing them that their prescribing of quetiapine was high and under review by Medicare. Patients in question all had dementia and were either living in nursing homes or in the community.

The intervention reduced quetiapine use among all patients with dementia, with no detectable adverse effects on cognitive function, behavioral symptoms, depression, metabolic diagnoses, hospitalization, or death.

“This study found that overprescribing warning letters to PCPs safely reduced quetiapine prescribing to their patients with dementia,” wrote investigators led by Adam Sacarny, PhD, of the Department of Health Policy and Management, Mailman School of Public Health, Columbia University, New York. 

“This intervention and other[s] like it may be useful for future efforts to promote guideline-concordant care,” they added.

The study was published online in JAMA Network Open.
 

Off-Label Prescribing Common

The off-label use of antipsychotics in patients with dementia is fairly common, the investigators noted, affecting roughly one in seven nursing home residents and a similar number of community-dwelling older adults with dementia.

The agents are often prescribed to treat behavioral symptoms associated with dementia, including agitation and aggression. Although some evidence supports this use, antipsychotics in dementia patients can also cause an increased risk for weight gain, cognitive decline, falls and other injuries, cerebrovascular events, and mortality.

While some professional societies have called for “judicious use of antipsychotics in dementia care,” there is little evidence that reducing antipsychotic use in people with dementia might result in a benefit, investigators wrote.

The researchers analyzed data from a previous trial that focused on quetiapine, which is the most prescribed antipsychotic in the United States and is frequently used for patients with dementia.

In the original study, 2528 PCPs received a placebo letter and 2527 received three warning letters sent by the Centers for Medicare & Medicaid Services (CMS), which identified the highest-volume PCP prescribers of quetiapine.

The warning letters stated that the recipient’s quetiapine prescribing was high relative to their peers and was under review by Medicare. The placebo letter clarified an unrelated regulation. 

The current secondary analysis followed the providers and a cohort of their patients from their first receipt of the letters in 2015 through April 2017. The current evaluation analyzes patients’ outcomes through December 2018, utilizing Medicare fee-for-service claims, Minimum Data Set nursing home assessment, and Medicare enrollment data.
 

Low-Cost, Effective Intervention

While the original study focused on total quetiapine prescribing by study PCPs, the current analysis focused on patients’ total quetiapine use per 90-day period. Additional secondary outcomes included measures of cognitive function and behavioral symptoms, indicators of depression, metabolic diagnoses, indicators of use of hospital and healthcare services, and death.

PCPs in the study had a total of 84,881 patients with dementia living in nursing homes and 261,288 living in the community. At baseline, there were 92,874 patients (mean age, 82 years; 69% female).

The warning letters were associated with reduced quetiapine use among both nursing home patients and community-dwelling patients (adjusted difference, –0.7 days; P = .02 and adjusted difference, −1.5 days; P < .001, respectively).

Among nursing home patients, there were no statistically significant adverse changes in cognitive of behavioral health measures that coincided with reduction in quetiapine use.

Although a higher percentage of treatment vs control patients reported weight loss, the difference was not significant, and rates of metabolic diagnoses were similar in both groups. There were also no significant differences between the groups in emergency department use, inpatient hospital admission, or use of restraints.

Results were similar for patients living in the community.

Additionally, no adverse effects on more severe health endpoints, including rates of hospital use or entry to nursing facilities, were detected. Importantly, the risk for death was statistically significantly lower for patients whose PCPs had received warning letters vs control patients (P = .04).

The analysis “provides evidence that a low-cost letter intervention informed by behavioral science can reduce prescribing of quetiapine to patients with dementia in nursing home and community settings,” the authors wrote.

Researchers did not directly observe the administration of the medication but instead used prescription drug fills as a proxy. Moreover, they could not observe results for patients enrolled in Medicare Advantage, and claims-based and assessment-based outcomes might have been subject to measurement errors and under-ascertainment of diagnoses.

The authors received support from the National Institute on Aging. They reported no relevant financial relationships.

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

Warning letters to primary care physicians (PCPs) regarding overprescription of quetiapine were helpful in reducing overprescribing of this agent, new research suggested.

Investigators analyzed data from an earlier trial that compared prescribing patterns in 5055 PCPs who receive a placebo letter or three warning letters informing them that their prescribing of quetiapine was high and under review by Medicare. Patients in question all had dementia and were either living in nursing homes or in the community.

The intervention reduced quetiapine use among all patients with dementia, with no detectable adverse effects on cognitive function, behavioral symptoms, depression, metabolic diagnoses, hospitalization, or death.

“This study found that overprescribing warning letters to PCPs safely reduced quetiapine prescribing to their patients with dementia,” wrote investigators led by Adam Sacarny, PhD, of the Department of Health Policy and Management, Mailman School of Public Health, Columbia University, New York. 

“This intervention and other[s] like it may be useful for future efforts to promote guideline-concordant care,” they added.

The study was published online in JAMA Network Open.
 

Off-Label Prescribing Common

The off-label use of antipsychotics in patients with dementia is fairly common, the investigators noted, affecting roughly one in seven nursing home residents and a similar number of community-dwelling older adults with dementia.

The agents are often prescribed to treat behavioral symptoms associated with dementia, including agitation and aggression. Although some evidence supports this use, antipsychotics in dementia patients can also cause an increased risk for weight gain, cognitive decline, falls and other injuries, cerebrovascular events, and mortality.

While some professional societies have called for “judicious use of antipsychotics in dementia care,” there is little evidence that reducing antipsychotic use in people with dementia might result in a benefit, investigators wrote.

The researchers analyzed data from a previous trial that focused on quetiapine, which is the most prescribed antipsychotic in the United States and is frequently used for patients with dementia.

In the original study, 2528 PCPs received a placebo letter and 2527 received three warning letters sent by the Centers for Medicare & Medicaid Services (CMS), which identified the highest-volume PCP prescribers of quetiapine.

The warning letters stated that the recipient’s quetiapine prescribing was high relative to their peers and was under review by Medicare. The placebo letter clarified an unrelated regulation. 

The current secondary analysis followed the providers and a cohort of their patients from their first receipt of the letters in 2015 through April 2017. The current evaluation analyzes patients’ outcomes through December 2018, utilizing Medicare fee-for-service claims, Minimum Data Set nursing home assessment, and Medicare enrollment data.
 

Low-Cost, Effective Intervention

While the original study focused on total quetiapine prescribing by study PCPs, the current analysis focused on patients’ total quetiapine use per 90-day period. Additional secondary outcomes included measures of cognitive function and behavioral symptoms, indicators of depression, metabolic diagnoses, indicators of use of hospital and healthcare services, and death.

PCPs in the study had a total of 84,881 patients with dementia living in nursing homes and 261,288 living in the community. At baseline, there were 92,874 patients (mean age, 82 years; 69% female).

The warning letters were associated with reduced quetiapine use among both nursing home patients and community-dwelling patients (adjusted difference, –0.7 days; P = .02 and adjusted difference, −1.5 days; P < .001, respectively).

Among nursing home patients, there were no statistically significant adverse changes in cognitive of behavioral health measures that coincided with reduction in quetiapine use.

Although a higher percentage of treatment vs control patients reported weight loss, the difference was not significant, and rates of metabolic diagnoses were similar in both groups. There were also no significant differences between the groups in emergency department use, inpatient hospital admission, or use of restraints.

Results were similar for patients living in the community.

Additionally, no adverse effects on more severe health endpoints, including rates of hospital use or entry to nursing facilities, were detected. Importantly, the risk for death was statistically significantly lower for patients whose PCPs had received warning letters vs control patients (P = .04).

The analysis “provides evidence that a low-cost letter intervention informed by behavioral science can reduce prescribing of quetiapine to patients with dementia in nursing home and community settings,” the authors wrote.

Researchers did not directly observe the administration of the medication but instead used prescription drug fills as a proxy. Moreover, they could not observe results for patients enrolled in Medicare Advantage, and claims-based and assessment-based outcomes might have been subject to measurement errors and under-ascertainment of diagnoses.

The authors received support from the National Institute on Aging. They reported no relevant financial relationships.

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

Warning letters to primary care physicians (PCPs) regarding overprescription of quetiapine were helpful in reducing overprescribing of this agent, new research suggested.

Investigators analyzed data from an earlier trial that compared prescribing patterns in 5055 PCPs who receive a placebo letter or three warning letters informing them that their prescribing of quetiapine was high and under review by Medicare. Patients in question all had dementia and were either living in nursing homes or in the community.

The intervention reduced quetiapine use among all patients with dementia, with no detectable adverse effects on cognitive function, behavioral symptoms, depression, metabolic diagnoses, hospitalization, or death.

“This study found that overprescribing warning letters to PCPs safely reduced quetiapine prescribing to their patients with dementia,” wrote investigators led by Adam Sacarny, PhD, of the Department of Health Policy and Management, Mailman School of Public Health, Columbia University, New York. 

“This intervention and other[s] like it may be useful for future efforts to promote guideline-concordant care,” they added.

The study was published online in JAMA Network Open.
 

Off-Label Prescribing Common

The off-label use of antipsychotics in patients with dementia is fairly common, the investigators noted, affecting roughly one in seven nursing home residents and a similar number of community-dwelling older adults with dementia.

The agents are often prescribed to treat behavioral symptoms associated with dementia, including agitation and aggression. Although some evidence supports this use, antipsychotics in dementia patients can also cause an increased risk for weight gain, cognitive decline, falls and other injuries, cerebrovascular events, and mortality.

While some professional societies have called for “judicious use of antipsychotics in dementia care,” there is little evidence that reducing antipsychotic use in people with dementia might result in a benefit, investigators wrote.

The researchers analyzed data from a previous trial that focused on quetiapine, which is the most prescribed antipsychotic in the United States and is frequently used for patients with dementia.

In the original study, 2528 PCPs received a placebo letter and 2527 received three warning letters sent by the Centers for Medicare & Medicaid Services (CMS), which identified the highest-volume PCP prescribers of quetiapine.

The warning letters stated that the recipient’s quetiapine prescribing was high relative to their peers and was under review by Medicare. The placebo letter clarified an unrelated regulation. 

The current secondary analysis followed the providers and a cohort of their patients from their first receipt of the letters in 2015 through April 2017. The current evaluation analyzes patients’ outcomes through December 2018, utilizing Medicare fee-for-service claims, Minimum Data Set nursing home assessment, and Medicare enrollment data.
 

Low-Cost, Effective Intervention

While the original study focused on total quetiapine prescribing by study PCPs, the current analysis focused on patients’ total quetiapine use per 90-day period. Additional secondary outcomes included measures of cognitive function and behavioral symptoms, indicators of depression, metabolic diagnoses, indicators of use of hospital and healthcare services, and death.

PCPs in the study had a total of 84,881 patients with dementia living in nursing homes and 261,288 living in the community. At baseline, there were 92,874 patients (mean age, 82 years; 69% female).

The warning letters were associated with reduced quetiapine use among both nursing home patients and community-dwelling patients (adjusted difference, –0.7 days; P = .02 and adjusted difference, −1.5 days; P < .001, respectively).

Among nursing home patients, there were no statistically significant adverse changes in cognitive of behavioral health measures that coincided with reduction in quetiapine use.

Although a higher percentage of treatment vs control patients reported weight loss, the difference was not significant, and rates of metabolic diagnoses were similar in both groups. There were also no significant differences between the groups in emergency department use, inpatient hospital admission, or use of restraints.

Results were similar for patients living in the community.

Additionally, no adverse effects on more severe health endpoints, including rates of hospital use or entry to nursing facilities, were detected. Importantly, the risk for death was statistically significantly lower for patients whose PCPs had received warning letters vs control patients (P = .04).

The analysis “provides evidence that a low-cost letter intervention informed by behavioral science can reduce prescribing of quetiapine to patients with dementia in nursing home and community settings,” the authors wrote.

Researchers did not directly observe the administration of the medication but instead used prescription drug fills as a proxy. Moreover, they could not observe results for patients enrolled in Medicare Advantage, and claims-based and assessment-based outcomes might have been subject to measurement errors and under-ascertainment of diagnoses.

The authors received support from the National Institute on Aging. They reported no relevant financial relationships.

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

TOPLINE:

Mental health distress increased disproportionately among transgender and gender-nonconforming US adults between 2014 and 2021 compared with their cisgender counterparts, a new study suggested. Investigators said the findings among an historically marginalized segment of society point to a need to address a growing inequality in mental health.

METHODOLOGY:

• Investigators drew on 2014-2021 US Behavioral Risk Factor Surveillance System (BRFSS) survey data, using logistic and ordinary least squares regression to document temporal trends in the transgender-cisgender disparity in self-reports of the number of poor mental health days in the past month and frequent mental distress.
• They included 43 states that implemented the optional sexual orientation and gender identity module in the BRFSS.
• Outcomes included the number of poor mental health days in the past month, as well as frequent mental distress (≥ 14 poor mental health days in the past month).

TAKEAWAY:

• Even in 2014, there was a discrepancy between cisgender and transgender and gender-nonconforming individuals in the reported mean of poor mental health days (3.68 vs 5.42).
• The size of this disparity, adjusted by differences in observable characteristics, increased by 2.75 days (95% CI, 0.58-4.91) over the study period.
• The inequality in mental health status between cisgender and transgender and nonconforming adults grew from 11.4% vs 18.9% in 2014, respectively, to 14.6% vs 32.9% in 2021, respectively.

IN PRACTICE:

“Our findings demonstrate sizable and worsening inequities in mental health across gender identity,” the authors wrote. “Mental health and primary care providers must be prepared to address the unique psychosocial needs of gender minority adults. Furthermore, our findings highlight the need for action to reduce these disparities.”

SOURCE:

Samuel Mann, PhD, of the RAND Corporation, was the corresponding author of the study. It was published online on April 10 in the American Journal of Public Health.

LIMITATIONS:

Measures of mental health were derived from self-reports. In addition, data from seven states were missing because these states did not include sexual orientation and gender identity in the BRFSS. And the BRFSS does not survey people who are unhoused, incarcerated, or in group living quarters.

DISCLOSURES:

No source of study funding was listed. The authors disclosed no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Mental health distress increased disproportionately among transgender and gender-nonconforming US adults between 2014 and 2021 compared with their cisgender counterparts, a new study suggested. Investigators said the findings among an historically marginalized segment of society point to a need to address a growing inequality in mental health.

METHODOLOGY:

• Investigators drew on 2014-2021 US Behavioral Risk Factor Surveillance System (BRFSS) survey data, using logistic and ordinary least squares regression to document temporal trends in the transgender-cisgender disparity in self-reports of the number of poor mental health days in the past month and frequent mental distress.
• They included 43 states that implemented the optional sexual orientation and gender identity module in the BRFSS.
• Outcomes included the number of poor mental health days in the past month, as well as frequent mental distress (≥ 14 poor mental health days in the past month).

TAKEAWAY:

• Even in 2014, there was a discrepancy between cisgender and transgender and gender-nonconforming individuals in the reported mean of poor mental health days (3.68 vs 5.42).
• The size of this disparity, adjusted by differences in observable characteristics, increased by 2.75 days (95% CI, 0.58-4.91) over the study period.
• The inequality in mental health status between cisgender and transgender and nonconforming adults grew from 11.4% vs 18.9% in 2014, respectively, to 14.6% vs 32.9% in 2021, respectively.

IN PRACTICE:

“Our findings demonstrate sizable and worsening inequities in mental health across gender identity,” the authors wrote. “Mental health and primary care providers must be prepared to address the unique psychosocial needs of gender minority adults. Furthermore, our findings highlight the need for action to reduce these disparities.”

SOURCE:

Samuel Mann, PhD, of the RAND Corporation, was the corresponding author of the study. It was published online on April 10 in the American Journal of Public Health.

LIMITATIONS:

Measures of mental health were derived from self-reports. In addition, data from seven states were missing because these states did not include sexual orientation and gender identity in the BRFSS. And the BRFSS does not survey people who are unhoused, incarcerated, or in group living quarters.

DISCLOSURES:

No source of study funding was listed. The authors disclosed no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Mental health distress increased disproportionately among transgender and gender-nonconforming US adults between 2014 and 2021 compared with their cisgender counterparts, a new study suggested. Investigators said the findings among an historically marginalized segment of society point to a need to address a growing inequality in mental health.

METHODOLOGY:

• Investigators drew on 2014-2021 US Behavioral Risk Factor Surveillance System (BRFSS) survey data, using logistic and ordinary least squares regression to document temporal trends in the transgender-cisgender disparity in self-reports of the number of poor mental health days in the past month and frequent mental distress.
• They included 43 states that implemented the optional sexual orientation and gender identity module in the BRFSS.
• Outcomes included the number of poor mental health days in the past month, as well as frequent mental distress (≥ 14 poor mental health days in the past month).

TAKEAWAY:

• Even in 2014, there was a discrepancy between cisgender and transgender and gender-nonconforming individuals in the reported mean of poor mental health days (3.68 vs 5.42).
• The size of this disparity, adjusted by differences in observable characteristics, increased by 2.75 days (95% CI, 0.58-4.91) over the study period.
• The inequality in mental health status between cisgender and transgender and nonconforming adults grew from 11.4% vs 18.9% in 2014, respectively, to 14.6% vs 32.9% in 2021, respectively.

IN PRACTICE:

“Our findings demonstrate sizable and worsening inequities in mental health across gender identity,” the authors wrote. “Mental health and primary care providers must be prepared to address the unique psychosocial needs of gender minority adults. Furthermore, our findings highlight the need for action to reduce these disparities.”

SOURCE:

Samuel Mann, PhD, of the RAND Corporation, was the corresponding author of the study. It was published online on April 10 in the American Journal of Public Health.

LIMITATIONS:

Measures of mental health were derived from self-reports. In addition, data from seven states were missing because these states did not include sexual orientation and gender identity in the BRFSS. And the BRFSS does not survey people who are unhoused, incarcerated, or in group living quarters.

DISCLOSURES:

No source of study funding was listed. The authors disclosed no relevant financial relationships.
 

A version of this article appeared on Medscape.com.