Neurology

Noninvasive brain stimulation does not appear to augment cognitive behavioral therapy (CBT) in patients with major depressive disorder (MDD), new research shows.

Results of a multicenter, placebo-controlled randomized clinical trials showed adjunctive transcranial direct current stimulation (tDCS) was not superior to sham-tDCS plus CBT or CBT alone.

“Combining these interventions does not lead to added value. This is an example where negative findings guide the way of future studies. What we learned is that we might change things in a few dimensions,” study investigator Malek Bajbouj, MD, Charité University Hospital, Berlin, told this news organization.

Charité University Hospital, Berlin

Urgent need for better treatment

MDD affects 10% of the global population. However, up to 30% of patients have an inadequate response to standard treatment of CBT, pharmacotherapy, or a combination of the two, highlighting the need to develop more effective therapeutic strategies, the investigators note.

A noninvasive approach, tDCS, in healthy populations, has been shown to enhance cognitive function in brain regions that are also relevant for CBT. Specifically, the investigators point out that tDCS can “positively modulate neuronal activity in prefrontal structures central for affective and cognitive processes,” including emotion regulation, cognitive control working memory, and learning.

Based on this early data, the investigators conducted a randomized, placebo-controlled trial to determine whether tDCS combined with CBT might have clinically relevant synergistic effects.

The multicenter study included adults aged 20-65 years with a single or recurrent depressive episode who were either not receiving medication or receiving a stable regimen of selective serotonin reuptake inhibitors (SSRIs) or mirtazapine (Remeron).

A total of 148 participants (89 women, 59 men) with a mean age of 41 years were randomly assigned to receive CBT alone (n = 53), CBT+ tDCS (n = 48) or CBT + sham tDCS (n = 47).

Participants attended a 6-week group intervention of 12 sessions of CBT. If assigned, tDCS was applied simultaneously. Active tDCS included stimulation with an intensity of 2 milliamps for 30 minutes.

The study’s primary outcome was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to post treatment in the intention-to-treat sample. A total of 126 patients completed the study.

At baseline, the average MADRS score was 23.0. In each of the study groups, MADRS scores were reduced by a mean of 6.5 points (95% confidence interval, 3.82-9.14 points). The Cohen d value was -0.90 (95% CI, -1.43 to -0.50), indicating a significant effect over time, the researchers report. However, they add that “there was not significant effect of group and no significant interaction of group x time, indicating the estimated additive effects were not statistically significant.” 

Results suggest that more research is needed to optimize treatment synchronization to achieve synergies between noninvasive brain stimulation and psychotherapeutic interventions.
 

Beauty and promise

Commenting on the findings, Mark George, MD, director of the Medical University of South Carolina Center for Advanced Imaging Research and the Brain Stimulation Laboratory, Charleston, described the study as “a really good effort by a great group of researchers.”

It’s unclear, he added, why tDCS failed to augment CBT. “It may be about the nongeneralizability of tDCS to complex functions, it may be that they didn’t get the dose right, or it might be due to a placebo response,” he speculated.  

Furthermore, “tDCS is the most simple form of brain stimulation. The beauty and promise of tDCS is that it is so inexpensive and safe,” Dr. George added.

If proven effective, tDCS could potentially be used at home and rolled out as a frontline therapy for depression, he added. “Everybody wants the technology to work as an antidepressant, since it could have a very big positive public health impact,” said Dr. George.

Referring to previous research showing tDCS’ ability to improve specific brain functions in healthy controls, Dr. George noted that the potential of tDCS may be limited to augmenting specific brain functions such as memory but not more complex behaviors like depression.

However, Dr. George believes a more plausible explanation is that the optimal dose for tDCS has not yet been determined.

With other types of neuromodulation, such as electroconvulsive therapy, “we know that we’re in the brain with the right dose. But for tDCS, we don’t know that, and we’ve got to figure that out before it’s ever really going to make it [as a treatment],” he said.

“There have been great advances through the years in the field of brain stimulation and the treatment of depression. But rates of depression and suicide are continuing to grow, and we have not yet made a significant dent in treatment, in part because these technologies require equipment, [and] they’re expensive. So when we figure out tDCS, it will be a very important piece of our toolkit – a real game changer,” Dr. George added.

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

Noninvasive brain stimulation does not appear to augment cognitive behavioral therapy (CBT) in patients with major depressive disorder (MDD), new research shows.

Results of a multicenter, placebo-controlled randomized clinical trials showed adjunctive transcranial direct current stimulation (tDCS) was not superior to sham-tDCS plus CBT or CBT alone.

“Combining these interventions does not lead to added value. This is an example where negative findings guide the way of future studies. What we learned is that we might change things in a few dimensions,” study investigator Malek Bajbouj, MD, Charité University Hospital, Berlin, told this news organization.

Charité University Hospital, Berlin

Urgent need for better treatment

MDD affects 10% of the global population. However, up to 30% of patients have an inadequate response to standard treatment of CBT, pharmacotherapy, or a combination of the two, highlighting the need to develop more effective therapeutic strategies, the investigators note.

A noninvasive approach, tDCS, in healthy populations, has been shown to enhance cognitive function in brain regions that are also relevant for CBT. Specifically, the investigators point out that tDCS can “positively modulate neuronal activity in prefrontal structures central for affective and cognitive processes,” including emotion regulation, cognitive control working memory, and learning.

Based on this early data, the investigators conducted a randomized, placebo-controlled trial to determine whether tDCS combined with CBT might have clinically relevant synergistic effects.

The multicenter study included adults aged 20-65 years with a single or recurrent depressive episode who were either not receiving medication or receiving a stable regimen of selective serotonin reuptake inhibitors (SSRIs) or mirtazapine (Remeron).

A total of 148 participants (89 women, 59 men) with a mean age of 41 years were randomly assigned to receive CBT alone (n = 53), CBT+ tDCS (n = 48) or CBT + sham tDCS (n = 47).

Participants attended a 6-week group intervention of 12 sessions of CBT. If assigned, tDCS was applied simultaneously. Active tDCS included stimulation with an intensity of 2 milliamps for 30 minutes.

The study’s primary outcome was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to post treatment in the intention-to-treat sample. A total of 126 patients completed the study.

At baseline, the average MADRS score was 23.0. In each of the study groups, MADRS scores were reduced by a mean of 6.5 points (95% confidence interval, 3.82-9.14 points). The Cohen d value was -0.90 (95% CI, -1.43 to -0.50), indicating a significant effect over time, the researchers report. However, they add that “there was not significant effect of group and no significant interaction of group x time, indicating the estimated additive effects were not statistically significant.” 

Results suggest that more research is needed to optimize treatment synchronization to achieve synergies between noninvasive brain stimulation and psychotherapeutic interventions.
 

Beauty and promise

Commenting on the findings, Mark George, MD, director of the Medical University of South Carolina Center for Advanced Imaging Research and the Brain Stimulation Laboratory, Charleston, described the study as “a really good effort by a great group of researchers.”

It’s unclear, he added, why tDCS failed to augment CBT. “It may be about the nongeneralizability of tDCS to complex functions, it may be that they didn’t get the dose right, or it might be due to a placebo response,” he speculated.  

Furthermore, “tDCS is the most simple form of brain stimulation. The beauty and promise of tDCS is that it is so inexpensive and safe,” Dr. George added.

If proven effective, tDCS could potentially be used at home and rolled out as a frontline therapy for depression, he added. “Everybody wants the technology to work as an antidepressant, since it could have a very big positive public health impact,” said Dr. George.

Referring to previous research showing tDCS’ ability to improve specific brain functions in healthy controls, Dr. George noted that the potential of tDCS may be limited to augmenting specific brain functions such as memory but not more complex behaviors like depression.

However, Dr. George believes a more plausible explanation is that the optimal dose for tDCS has not yet been determined.

With other types of neuromodulation, such as electroconvulsive therapy, “we know that we’re in the brain with the right dose. But for tDCS, we don’t know that, and we’ve got to figure that out before it’s ever really going to make it [as a treatment],” he said.

“There have been great advances through the years in the field of brain stimulation and the treatment of depression. But rates of depression and suicide are continuing to grow, and we have not yet made a significant dent in treatment, in part because these technologies require equipment, [and] they’re expensive. So when we figure out tDCS, it will be a very important piece of our toolkit – a real game changer,” Dr. George added.

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

Noninvasive brain stimulation does not appear to augment cognitive behavioral therapy (CBT) in patients with major depressive disorder (MDD), new research shows.

Results of a multicenter, placebo-controlled randomized clinical trials showed adjunctive transcranial direct current stimulation (tDCS) was not superior to sham-tDCS plus CBT or CBT alone.

“Combining these interventions does not lead to added value. This is an example where negative findings guide the way of future studies. What we learned is that we might change things in a few dimensions,” study investigator Malek Bajbouj, MD, Charité University Hospital, Berlin, told this news organization.

Charité University Hospital, Berlin

Urgent need for better treatment

MDD affects 10% of the global population. However, up to 30% of patients have an inadequate response to standard treatment of CBT, pharmacotherapy, or a combination of the two, highlighting the need to develop more effective therapeutic strategies, the investigators note.

A noninvasive approach, tDCS, in healthy populations, has been shown to enhance cognitive function in brain regions that are also relevant for CBT. Specifically, the investigators point out that tDCS can “positively modulate neuronal activity in prefrontal structures central for affective and cognitive processes,” including emotion regulation, cognitive control working memory, and learning.

Based on this early data, the investigators conducted a randomized, placebo-controlled trial to determine whether tDCS combined with CBT might have clinically relevant synergistic effects.

The multicenter study included adults aged 20-65 years with a single or recurrent depressive episode who were either not receiving medication or receiving a stable regimen of selective serotonin reuptake inhibitors (SSRIs) or mirtazapine (Remeron).

A total of 148 participants (89 women, 59 men) with a mean age of 41 years were randomly assigned to receive CBT alone (n = 53), CBT+ tDCS (n = 48) or CBT + sham tDCS (n = 47).

Participants attended a 6-week group intervention of 12 sessions of CBT. If assigned, tDCS was applied simultaneously. Active tDCS included stimulation with an intensity of 2 milliamps for 30 minutes.

The study’s primary outcome was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to post treatment in the intention-to-treat sample. A total of 126 patients completed the study.

At baseline, the average MADRS score was 23.0. In each of the study groups, MADRS scores were reduced by a mean of 6.5 points (95% confidence interval, 3.82-9.14 points). The Cohen d value was -0.90 (95% CI, -1.43 to -0.50), indicating a significant effect over time, the researchers report. However, they add that “there was not significant effect of group and no significant interaction of group x time, indicating the estimated additive effects were not statistically significant.” 

Results suggest that more research is needed to optimize treatment synchronization to achieve synergies between noninvasive brain stimulation and psychotherapeutic interventions.
 

Beauty and promise

Commenting on the findings, Mark George, MD, director of the Medical University of South Carolina Center for Advanced Imaging Research and the Brain Stimulation Laboratory, Charleston, described the study as “a really good effort by a great group of researchers.”

It’s unclear, he added, why tDCS failed to augment CBT. “It may be about the nongeneralizability of tDCS to complex functions, it may be that they didn’t get the dose right, or it might be due to a placebo response,” he speculated.  

Furthermore, “tDCS is the most simple form of brain stimulation. The beauty and promise of tDCS is that it is so inexpensive and safe,” Dr. George added.

If proven effective, tDCS could potentially be used at home and rolled out as a frontline therapy for depression, he added. “Everybody wants the technology to work as an antidepressant, since it could have a very big positive public health impact,” said Dr. George.

Referring to previous research showing tDCS’ ability to improve specific brain functions in healthy controls, Dr. George noted that the potential of tDCS may be limited to augmenting specific brain functions such as memory but not more complex behaviors like depression.

However, Dr. George believes a more plausible explanation is that the optimal dose for tDCS has not yet been determined.

With other types of neuromodulation, such as electroconvulsive therapy, “we know that we’re in the brain with the right dose. But for tDCS, we don’t know that, and we’ve got to figure that out before it’s ever really going to make it [as a treatment],” he said.

“There have been great advances through the years in the field of brain stimulation and the treatment of depression. But rates of depression and suicide are continuing to grow, and we have not yet made a significant dent in treatment, in part because these technologies require equipment, [and] they’re expensive. So when we figure out tDCS, it will be a very important piece of our toolkit – a real game changer,” Dr. George added.

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

A large percentage of studies in neurology and psychiatry over the past decade have failed to account for differences between the sexes, according to a team of Canadian researchers.

In a survey of more than 3,000 papers published in six neuroscience and psychiatry journals from 2009 to 2019, researchers found that only 5% analyzed sex as a variable.

“Despite the fact there are papers that are using males and females in the studies, they’re not using the males and females in the way that would optimally find the possibility of sex differences,” lead author Liisa A.M. Galea, PhD, told this news organization. Dr. Galea is a professor and distinguished scholar at the Djavad Mowafaghian Center for Brain Health at the University of British Columbia in Vancouver.

The study was published online in Nature Communications.
 

Optimal design uncommon

Differences in how neurologic and psychiatric diseases affect men and women have been well documented. Women, for example, are more susceptible to severe stroke, and men are more prone to cognitive decline with schizophrenia. With Alzheimer’s disease, women typically have more severe cognitive defects.

The researchers surveyed 3,193 papers that included a multitude of studies. Although most of the papers reported studies that included both sexes, only 19% of surveyed studies used what Dr. Galea called an optimal design for the discovery of sex differences. “What I mean by ‘optimally’ is the design of the experiments and the analysis of sex as a variable,” she said. And in 2019, only 5% of the studies used sex as a variable for determining differences between the sexes, the study found.

In the current research, two authors read the methods and results of each study described in each paper, Dr. Galea said. The readers noted whether the paper reported the study sample size and whether the studies used a balanced design. The surveyed journals include Nature Neuroscience, Neuron, Journal of Neuroscience, Molecular Psychiatry, Biological Psychiatry, and Neuropsychopharmacology.
 

‘Not much is changing’

“I had a suspicion that this was happening,” Dr. Galea said. “I didn’t know that it’s so bad, to be fair.” The “good news story,” she said, is that more papers considered sex as a factor in the later years surveyed. In 2019, more than 95% of papers across both disciplines reported participants’ sex, compared with about 70% in 2009. However, less than 20% of the papers in all study years reported studies that used sex optimally to determine differences between the sexes.

“The other thing that shocked me,” Dr. Galea said, “was that even despite the fact that we saw this increase in the number of papers that were using males and females, we didn’t see the sort of corresponding increase in those that were using ‘optimal design’ or ‘optimal analysis,’ ” Dr. Galea said. In 2009, 14% of papers used optimal design and 2% used optimal analysis for determining sex differences. By 2019, those percentages were 19% and 5%, respectively.

But even the papers that used both sexes had shortcomings, the study found. Just over one-third of these papers (34.5%) didn’t use a balanced design. Just over one-quarter (25.9%) didn’t identify the sample size, a shortcoming that marked 18% of these studies in 2009 and 33% in 2019. Fifteen percent of papers examined included studies that used both sexes inconsistently.

“That matters, because other studies have found that about 20% of papers are doing some kind of analysis with sex, but we had a suspicion that a lot of studies would include sex as a covariate,” Dr. Galea said. “Essentially what that does is, you remove that variable from the data. So, any statistical variation due to sex is then gone.

“The problem with that,” she added, “is you’re not actually looking to see if there’s an influence of sex; you’re removing it.”

Dr. Galea noted that this study points to a need for funding agencies to demand that researchers meet their mandates on sex- and gender-based analysis. “Despite the mandates, not much is really changing as far as the analysis or design of experiments, and we need to figure out how to change that,” she said. “We need to figure out how to get researchers more interested to use the power of studying sex differences.”
 

‘Not surprising, but disappointing’

Vladimir Hachinski, MD, professor of neurology and epidemiology at Western University in London, Ont., and former editor in chief of Stroke, told this news organization that women have almost twice the life risk of developing dementia, are at higher risk of stroke below age 35 years, and have more severe strokes and higher rates of disability at any age.

Commenting on the current study, Dr. Hachinski said, “It’s not surprising, but it’s disappointing, because we’ve known the difference for a long time.” He added, “The paper is very important because we were not aware that it was that bad.”

Dr. Hachinski also stated, “This paper needs a lot of reading. It’s a great resource, and it should be highlighted as one of those things that needs to be addressed, because it matters.”

The study was funded by a Natural Sciences and Engineering Research Council of Canada grant and by the British Columbia Women’s Foundation. Dr. Galea and Hachinski had no relevant disclosures.

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

A large percentage of studies in neurology and psychiatry over the past decade have failed to account for differences between the sexes, according to a team of Canadian researchers.

In a survey of more than 3,000 papers published in six neuroscience and psychiatry journals from 2009 to 2019, researchers found that only 5% analyzed sex as a variable.

“Despite the fact there are papers that are using males and females in the studies, they’re not using the males and females in the way that would optimally find the possibility of sex differences,” lead author Liisa A.M. Galea, PhD, told this news organization. Dr. Galea is a professor and distinguished scholar at the Djavad Mowafaghian Center for Brain Health at the University of British Columbia in Vancouver.

The study was published online in Nature Communications.
 

Optimal design uncommon

Differences in how neurologic and psychiatric diseases affect men and women have been well documented. Women, for example, are more susceptible to severe stroke, and men are more prone to cognitive decline with schizophrenia. With Alzheimer’s disease, women typically have more severe cognitive defects.

The researchers surveyed 3,193 papers that included a multitude of studies. Although most of the papers reported studies that included both sexes, only 19% of surveyed studies used what Dr. Galea called an optimal design for the discovery of sex differences. “What I mean by ‘optimally’ is the design of the experiments and the analysis of sex as a variable,” she said. And in 2019, only 5% of the studies used sex as a variable for determining differences between the sexes, the study found.

In the current research, two authors read the methods and results of each study described in each paper, Dr. Galea said. The readers noted whether the paper reported the study sample size and whether the studies used a balanced design. The surveyed journals include Nature Neuroscience, Neuron, Journal of Neuroscience, Molecular Psychiatry, Biological Psychiatry, and Neuropsychopharmacology.
 

‘Not much is changing’

“I had a suspicion that this was happening,” Dr. Galea said. “I didn’t know that it’s so bad, to be fair.” The “good news story,” she said, is that more papers considered sex as a factor in the later years surveyed. In 2019, more than 95% of papers across both disciplines reported participants’ sex, compared with about 70% in 2009. However, less than 20% of the papers in all study years reported studies that used sex optimally to determine differences between the sexes.

“The other thing that shocked me,” Dr. Galea said, “was that even despite the fact that we saw this increase in the number of papers that were using males and females, we didn’t see the sort of corresponding increase in those that were using ‘optimal design’ or ‘optimal analysis,’ ” Dr. Galea said. In 2009, 14% of papers used optimal design and 2% used optimal analysis for determining sex differences. By 2019, those percentages were 19% and 5%, respectively.

But even the papers that used both sexes had shortcomings, the study found. Just over one-third of these papers (34.5%) didn’t use a balanced design. Just over one-quarter (25.9%) didn’t identify the sample size, a shortcoming that marked 18% of these studies in 2009 and 33% in 2019. Fifteen percent of papers examined included studies that used both sexes inconsistently.

“That matters, because other studies have found that about 20% of papers are doing some kind of analysis with sex, but we had a suspicion that a lot of studies would include sex as a covariate,” Dr. Galea said. “Essentially what that does is, you remove that variable from the data. So, any statistical variation due to sex is then gone.

“The problem with that,” she added, “is you’re not actually looking to see if there’s an influence of sex; you’re removing it.”

Dr. Galea noted that this study points to a need for funding agencies to demand that researchers meet their mandates on sex- and gender-based analysis. “Despite the mandates, not much is really changing as far as the analysis or design of experiments, and we need to figure out how to change that,” she said. “We need to figure out how to get researchers more interested to use the power of studying sex differences.”
 

‘Not surprising, but disappointing’

Vladimir Hachinski, MD, professor of neurology and epidemiology at Western University in London, Ont., and former editor in chief of Stroke, told this news organization that women have almost twice the life risk of developing dementia, are at higher risk of stroke below age 35 years, and have more severe strokes and higher rates of disability at any age.

Commenting on the current study, Dr. Hachinski said, “It’s not surprising, but it’s disappointing, because we’ve known the difference for a long time.” He added, “The paper is very important because we were not aware that it was that bad.”

Dr. Hachinski also stated, “This paper needs a lot of reading. It’s a great resource, and it should be highlighted as one of those things that needs to be addressed, because it matters.”

The study was funded by a Natural Sciences and Engineering Research Council of Canada grant and by the British Columbia Women’s Foundation. Dr. Galea and Hachinski had no relevant disclosures.

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

A large percentage of studies in neurology and psychiatry over the past decade have failed to account for differences between the sexes, according to a team of Canadian researchers.

In a survey of more than 3,000 papers published in six neuroscience and psychiatry journals from 2009 to 2019, researchers found that only 5% analyzed sex as a variable.

“Despite the fact there are papers that are using males and females in the studies, they’re not using the males and females in the way that would optimally find the possibility of sex differences,” lead author Liisa A.M. Galea, PhD, told this news organization. Dr. Galea is a professor and distinguished scholar at the Djavad Mowafaghian Center for Brain Health at the University of British Columbia in Vancouver.

The study was published online in Nature Communications.
 

Optimal design uncommon

Differences in how neurologic and psychiatric diseases affect men and women have been well documented. Women, for example, are more susceptible to severe stroke, and men are more prone to cognitive decline with schizophrenia. With Alzheimer’s disease, women typically have more severe cognitive defects.

The researchers surveyed 3,193 papers that included a multitude of studies. Although most of the papers reported studies that included both sexes, only 19% of surveyed studies used what Dr. Galea called an optimal design for the discovery of sex differences. “What I mean by ‘optimally’ is the design of the experiments and the analysis of sex as a variable,” she said. And in 2019, only 5% of the studies used sex as a variable for determining differences between the sexes, the study found.

In the current research, two authors read the methods and results of each study described in each paper, Dr. Galea said. The readers noted whether the paper reported the study sample size and whether the studies used a balanced design. The surveyed journals include Nature Neuroscience, Neuron, Journal of Neuroscience, Molecular Psychiatry, Biological Psychiatry, and Neuropsychopharmacology.
 

‘Not much is changing’

“I had a suspicion that this was happening,” Dr. Galea said. “I didn’t know that it’s so bad, to be fair.” The “good news story,” she said, is that more papers considered sex as a factor in the later years surveyed. In 2019, more than 95% of papers across both disciplines reported participants’ sex, compared with about 70% in 2009. However, less than 20% of the papers in all study years reported studies that used sex optimally to determine differences between the sexes.

“The other thing that shocked me,” Dr. Galea said, “was that even despite the fact that we saw this increase in the number of papers that were using males and females, we didn’t see the sort of corresponding increase in those that were using ‘optimal design’ or ‘optimal analysis,’ ” Dr. Galea said. In 2009, 14% of papers used optimal design and 2% used optimal analysis for determining sex differences. By 2019, those percentages were 19% and 5%, respectively.

But even the papers that used both sexes had shortcomings, the study found. Just over one-third of these papers (34.5%) didn’t use a balanced design. Just over one-quarter (25.9%) didn’t identify the sample size, a shortcoming that marked 18% of these studies in 2009 and 33% in 2019. Fifteen percent of papers examined included studies that used both sexes inconsistently.

“That matters, because other studies have found that about 20% of papers are doing some kind of analysis with sex, but we had a suspicion that a lot of studies would include sex as a covariate,” Dr. Galea said. “Essentially what that does is, you remove that variable from the data. So, any statistical variation due to sex is then gone.

“The problem with that,” she added, “is you’re not actually looking to see if there’s an influence of sex; you’re removing it.”

Dr. Galea noted that this study points to a need for funding agencies to demand that researchers meet their mandates on sex- and gender-based analysis. “Despite the mandates, not much is really changing as far as the analysis or design of experiments, and we need to figure out how to change that,” she said. “We need to figure out how to get researchers more interested to use the power of studying sex differences.”
 

‘Not surprising, but disappointing’

Vladimir Hachinski, MD, professor of neurology and epidemiology at Western University in London, Ont., and former editor in chief of Stroke, told this news organization that women have almost twice the life risk of developing dementia, are at higher risk of stroke below age 35 years, and have more severe strokes and higher rates of disability at any age.

Commenting on the current study, Dr. Hachinski said, “It’s not surprising, but it’s disappointing, because we’ve known the difference for a long time.” He added, “The paper is very important because we were not aware that it was that bad.”

Dr. Hachinski also stated, “This paper needs a lot of reading. It’s a great resource, and it should be highlighted as one of those things that needs to be addressed, because it matters.”

The study was funded by a Natural Sciences and Engineering Research Council of Canada grant and by the British Columbia Women’s Foundation. Dr. Galea and Hachinski had no relevant disclosures.

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

While previous research suggests that dietary supplementation with L-serine may be beneficial for patients with Alzheimer’s disease (AD), a new study cast doubt on the potential efficacy, and even the safety, of this treatment.

When given to patients with AD, L-serine supplements could be driving abnormally increased serine levels in the brain even higher, potentially accelerating neuronal death, according to study author Xu Chen, PhD, of the University of California, San Diego, and colleagues.

This conclusion conflicts with a 2020 study by Juliette Le Douce, PhD, and colleagues, who reported that oral L-serine supplementation may act as a “ready-to-use therapy” for AD, based on their findings that patients with AD had low levels of PHGDH, an enzyme necessary for synthesizing serine, and AD-like mice had low levels of serine.

Writing in Cell Metabolism, Dr. Chen and colleagues framed the present study, and their findings, in this context.

“In contrast to the work of Le Douce et al., here we report that PHGDH mRNA and protein levels are increased in the brains of two mouse models of AD and/or tauopathy, and are also progressively increased in human brains with no, early, and late AD pathology, as well as in people with no, asymptomatic, and symptomatic AD,” they wrote.

They suggested adjusting clinical recommendations for L-serine, the form of the amino acid commonly found in supplements. In the body, L-serine is converted to D-serine, which acts on the NMDA receptor (NMDAR).

‘Long-term use of D-serine contributes to neuronal death’ suggests research

“We feel oral L-serine as a ready-to-use therapy to AD warrants precaution,” Dr. Chen and colleagues wrote. “This is because despite being a cognitive enhancer, some [research] suggests that long-term use of D-serine contributes to neuronal death in AD through excitotoxicity. Furthermore, D-serine, as a co-agonist of NMDAR, would be expected to oppose NMDAR antagonists, which have proven clinical benefits in treating AD.”

According to principal author Sheng Zhong, PhD, of the University of California, San Diego, “Research is needed to test if targeting PHGDH can ameliorate cognitive decline in AD.”

Dr. Zhong also noted that the present findings support the “promise of using a specific RNA in blood as a biomarker for early detection of Alzheimer’s disease.” This approach is currently being validated at UCSD Shiley-Marcos Alzheimer’s Disease Research Center, he added.

Roles of PHGDH and serine in Alzheimer’s disease require further study

Commenting on both studies, Steve W. Barger, PhD, of the University of Arkansas for Medical Sciences, Little Rock, suggested that more work is needed to better understand the roles of PHGDH and serine in AD before clinical applications can be considered.

“In the end, these two studies fail to provide the clarity we need in designing evidence-based therapeutic hypotheses,” Dr. Barger said in an interview. “We still do not have a firm grasp on the role that D-serine plays in AD. Indeed, the evidence regarding even a single enzyme contributing to its levels is ambiguous.”

Dr. Barger, who has published extensively on the topic of neuronal death, with a particular focus on Alzheimer’s disease, noted that “determination of what happens to D-serine levels in AD has been of interest for decades,” but levels of the amino acid have been notoriously challenging to measure because “D-serine can disappear rapidly from the brain and its fluids after death.”

While Dr. Le Douce and colleagues did measure levels of serine in mice, Dr. Barger noted that the study by Dr. Chen and colleagues was conducted with more “quantitatively rigorous methods.” Even though Dr. Chen and colleagues “did not assay the levels of D-serine itself ... the implication of their findings is that PHGDH is poised to elevate this critical neurotransmitter,” leading to their conclusion that serine supplementation is “potentially dangerous.”

At this point, it may be too early to tell, according to Dr. Barger.

He suggested that conclusions drawn from PHGDH levels alone are “always limited,” and conclusions based on serine levels may be equally dubious, considering that the activities and effects of serine “are quite complex,” and may be influenced by other physiologic processes, including the effects of gut bacteria.

Instead, Dr. Barger suggested that changes in PHGDH and serine may be interpreted as signals coming from a more relevant process upstream: glucose metabolism.

“What we can say confidently is that the glucose metabolism that PHGDH connects to D-serine is most definitely a factor in AD,” he said. “Countless studies have documented what now appears to be a universal decline in glucose delivery to the cerebral cortex, even before frank dementia sets in.”

Dr. Barger noted that declining glucose delivery coincides with some of the earliest events in the development of AD, perhaps “linking accumulation of amyloid β-peptide to subsequent neurofibrillary tangles and tissue atrophy.”

Dr. Barger’s own work recently demonstrated that AD is associated with “an irregularity in the insertion of a specific glucose transporter (GLUT1) into the cell surface” of astrocytes.

“It could be more effective to direct therapeutic interventions at these events lying upstream of PHGDH or serine,” he concluded.

The study was partly supported by a Kreuger v. Wyeth research award. The investigators and Dr. Barger reported no conflicts of interest.

While previous research suggests that dietary supplementation with L-serine may be beneficial for patients with Alzheimer’s disease (AD), a new study cast doubt on the potential efficacy, and even the safety, of this treatment.

When given to patients with AD, L-serine supplements could be driving abnormally increased serine levels in the brain even higher, potentially accelerating neuronal death, according to study author Xu Chen, PhD, of the University of California, San Diego, and colleagues.

This conclusion conflicts with a 2020 study by Juliette Le Douce, PhD, and colleagues, who reported that oral L-serine supplementation may act as a “ready-to-use therapy” for AD, based on their findings that patients with AD had low levels of PHGDH, an enzyme necessary for synthesizing serine, and AD-like mice had low levels of serine.

Writing in Cell Metabolism, Dr. Chen and colleagues framed the present study, and their findings, in this context.

“In contrast to the work of Le Douce et al., here we report that PHGDH mRNA and protein levels are increased in the brains of two mouse models of AD and/or tauopathy, and are also progressively increased in human brains with no, early, and late AD pathology, as well as in people with no, asymptomatic, and symptomatic AD,” they wrote.

They suggested adjusting clinical recommendations for L-serine, the form of the amino acid commonly found in supplements. In the body, L-serine is converted to D-serine, which acts on the NMDA receptor (NMDAR).

‘Long-term use of D-serine contributes to neuronal death’ suggests research

“We feel oral L-serine as a ready-to-use therapy to AD warrants precaution,” Dr. Chen and colleagues wrote. “This is because despite being a cognitive enhancer, some [research] suggests that long-term use of D-serine contributes to neuronal death in AD through excitotoxicity. Furthermore, D-serine, as a co-agonist of NMDAR, would be expected to oppose NMDAR antagonists, which have proven clinical benefits in treating AD.”

According to principal author Sheng Zhong, PhD, of the University of California, San Diego, “Research is needed to test if targeting PHGDH can ameliorate cognitive decline in AD.”

Dr. Zhong also noted that the present findings support the “promise of using a specific RNA in blood as a biomarker for early detection of Alzheimer’s disease.” This approach is currently being validated at UCSD Shiley-Marcos Alzheimer’s Disease Research Center, he added.

Roles of PHGDH and serine in Alzheimer’s disease require further study

Commenting on both studies, Steve W. Barger, PhD, of the University of Arkansas for Medical Sciences, Little Rock, suggested that more work is needed to better understand the roles of PHGDH and serine in AD before clinical applications can be considered.

“In the end, these two studies fail to provide the clarity we need in designing evidence-based therapeutic hypotheses,” Dr. Barger said in an interview. “We still do not have a firm grasp on the role that D-serine plays in AD. Indeed, the evidence regarding even a single enzyme contributing to its levels is ambiguous.”

Dr. Barger, who has published extensively on the topic of neuronal death, with a particular focus on Alzheimer’s disease, noted that “determination of what happens to D-serine levels in AD has been of interest for decades,” but levels of the amino acid have been notoriously challenging to measure because “D-serine can disappear rapidly from the brain and its fluids after death.”

While Dr. Le Douce and colleagues did measure levels of serine in mice, Dr. Barger noted that the study by Dr. Chen and colleagues was conducted with more “quantitatively rigorous methods.” Even though Dr. Chen and colleagues “did not assay the levels of D-serine itself ... the implication of their findings is that PHGDH is poised to elevate this critical neurotransmitter,” leading to their conclusion that serine supplementation is “potentially dangerous.”

At this point, it may be too early to tell, according to Dr. Barger.

He suggested that conclusions drawn from PHGDH levels alone are “always limited,” and conclusions based on serine levels may be equally dubious, considering that the activities and effects of serine “are quite complex,” and may be influenced by other physiologic processes, including the effects of gut bacteria.

Instead, Dr. Barger suggested that changes in PHGDH and serine may be interpreted as signals coming from a more relevant process upstream: glucose metabolism.

“What we can say confidently is that the glucose metabolism that PHGDH connects to D-serine is most definitely a factor in AD,” he said. “Countless studies have documented what now appears to be a universal decline in glucose delivery to the cerebral cortex, even before frank dementia sets in.”

Dr. Barger noted that declining glucose delivery coincides with some of the earliest events in the development of AD, perhaps “linking accumulation of amyloid β-peptide to subsequent neurofibrillary tangles and tissue atrophy.”

Dr. Barger’s own work recently demonstrated that AD is associated with “an irregularity in the insertion of a specific glucose transporter (GLUT1) into the cell surface” of astrocytes.

“It could be more effective to direct therapeutic interventions at these events lying upstream of PHGDH or serine,” he concluded.

The study was partly supported by a Kreuger v. Wyeth research award. The investigators and Dr. Barger reported no conflicts of interest.

While previous research suggests that dietary supplementation with L-serine may be beneficial for patients with Alzheimer’s disease (AD), a new study cast doubt on the potential efficacy, and even the safety, of this treatment.

When given to patients with AD, L-serine supplements could be driving abnormally increased serine levels in the brain even higher, potentially accelerating neuronal death, according to study author Xu Chen, PhD, of the University of California, San Diego, and colleagues.

This conclusion conflicts with a 2020 study by Juliette Le Douce, PhD, and colleagues, who reported that oral L-serine supplementation may act as a “ready-to-use therapy” for AD, based on their findings that patients with AD had low levels of PHGDH, an enzyme necessary for synthesizing serine, and AD-like mice had low levels of serine.

Writing in Cell Metabolism, Dr. Chen and colleagues framed the present study, and their findings, in this context.

“In contrast to the work of Le Douce et al., here we report that PHGDH mRNA and protein levels are increased in the brains of two mouse models of AD and/or tauopathy, and are also progressively increased in human brains with no, early, and late AD pathology, as well as in people with no, asymptomatic, and symptomatic AD,” they wrote.

They suggested adjusting clinical recommendations for L-serine, the form of the amino acid commonly found in supplements. In the body, L-serine is converted to D-serine, which acts on the NMDA receptor (NMDAR).

‘Long-term use of D-serine contributes to neuronal death’ suggests research

“We feel oral L-serine as a ready-to-use therapy to AD warrants precaution,” Dr. Chen and colleagues wrote. “This is because despite being a cognitive enhancer, some [research] suggests that long-term use of D-serine contributes to neuronal death in AD through excitotoxicity. Furthermore, D-serine, as a co-agonist of NMDAR, would be expected to oppose NMDAR antagonists, which have proven clinical benefits in treating AD.”

According to principal author Sheng Zhong, PhD, of the University of California, San Diego, “Research is needed to test if targeting PHGDH can ameliorate cognitive decline in AD.”

Dr. Zhong also noted that the present findings support the “promise of using a specific RNA in blood as a biomarker for early detection of Alzheimer’s disease.” This approach is currently being validated at UCSD Shiley-Marcos Alzheimer’s Disease Research Center, he added.

Roles of PHGDH and serine in Alzheimer’s disease require further study

Commenting on both studies, Steve W. Barger, PhD, of the University of Arkansas for Medical Sciences, Little Rock, suggested that more work is needed to better understand the roles of PHGDH and serine in AD before clinical applications can be considered.

“In the end, these two studies fail to provide the clarity we need in designing evidence-based therapeutic hypotheses,” Dr. Barger said in an interview. “We still do not have a firm grasp on the role that D-serine plays in AD. Indeed, the evidence regarding even a single enzyme contributing to its levels is ambiguous.”

Dr. Barger, who has published extensively on the topic of neuronal death, with a particular focus on Alzheimer’s disease, noted that “determination of what happens to D-serine levels in AD has been of interest for decades,” but levels of the amino acid have been notoriously challenging to measure because “D-serine can disappear rapidly from the brain and its fluids after death.”

While Dr. Le Douce and colleagues did measure levels of serine in mice, Dr. Barger noted that the study by Dr. Chen and colleagues was conducted with more “quantitatively rigorous methods.” Even though Dr. Chen and colleagues “did not assay the levels of D-serine itself ... the implication of their findings is that PHGDH is poised to elevate this critical neurotransmitter,” leading to their conclusion that serine supplementation is “potentially dangerous.”

At this point, it may be too early to tell, according to Dr. Barger.

He suggested that conclusions drawn from PHGDH levels alone are “always limited,” and conclusions based on serine levels may be equally dubious, considering that the activities and effects of serine “are quite complex,” and may be influenced by other physiologic processes, including the effects of gut bacteria.

Instead, Dr. Barger suggested that changes in PHGDH and serine may be interpreted as signals coming from a more relevant process upstream: glucose metabolism.

“What we can say confidently is that the glucose metabolism that PHGDH connects to D-serine is most definitely a factor in AD,” he said. “Countless studies have documented what now appears to be a universal decline in glucose delivery to the cerebral cortex, even before frank dementia sets in.”

Dr. Barger noted that declining glucose delivery coincides with some of the earliest events in the development of AD, perhaps “linking accumulation of amyloid β-peptide to subsequent neurofibrillary tangles and tissue atrophy.”

Dr. Barger’s own work recently demonstrated that AD is associated with “an irregularity in the insertion of a specific glucose transporter (GLUT1) into the cell surface” of astrocytes.

“It could be more effective to direct therapeutic interventions at these events lying upstream of PHGDH or serine,” he concluded.

The study was partly supported by a Kreuger v. Wyeth research award. The investigators and Dr. Barger reported no conflicts of interest.

SAN DIEGO – If a medical professional is trying to figure out the best medical treatment for a pregnant woman with headache, it may be helpful to review data from randomized clinical trials (RCTs). Well, make that data from the RCT. There’s just been one, Northwestern Medicine obstetrician-gynecologist Catherine Stika, MD, told colleagues at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Only a single efficacy RCT has examined headache in pregnancy, said Dr. Stika. “Overall, we have very limited data in pregnancy to tell us exactly what to do,” she added.

But ob.gyns. aren’t entirely in the dark, according to medical specialists who spoke at the session. Expert opinion and fetal safety data offer insight into the best treatments, as does a new ACOG clinical practice guideline on headaches during pregnancy and post partum that was coauthored by the speakers.

And there’s some good news: Pregnancy itself is often a good treatment for headaches.

Pregnant women often find relief from one kind of headache – migraine – as their estradiol levels rise, said Laura Mercer, MD, an ob.gyn. at the University of Arizona, Phoenix. “About half of patients will report that migraines are getting better as early as the first trimester, and upwards of 83% will say that their migraines are better by the time they’re in their third trimester,” she said. “What this means for us as obstetricians is that oftentimes we can actually discontinue preventative therapies for patients during pregnancy.”

But simply discontinuing every headache treatment during pregnancy may not be the right approach, Dr. Mercer said. Instead, she said, consider the benefits and risks.

Divalproex sodium (Depakote) and topiramate (Topamax) must be avoided because of fetal risk, she said. “In fact, we will prefer that people stop these medications before they discontinue their contraception if they’re planning on getting pregnant,” she said.

Other medications, such as ACE inhibitors and the herbal remedy feverfew, should not be used at any time during pregnancy, she said.

On the other hand, calcium channel blockers and antihistamines are alright to use in pregnancy, she said. “These two should be considered first-line because there’s no known risks for them.”

Beta-blockers also may be used “with some consideration to the known risks that we’re familiar with when we use them for other indications,” she said.

There are questions about the safety of oral magnesium in pregnancy, although it’s generally considered safe, she added, and “nerve blocks and nerve stimulators seem very promising and have little known risks.”

Dr. Mercer recommended gradually tapering most medications prior to conception. But it’s crucial to stop higher-risk drugs immediately once pregnancy is confirmed, she said.

In regard to acute headache, Dr. Stika urged caution if a patient reports taking a headache medication more than twice a week. “All the medications we use for the treatment of migraine, both in and outside of pregnancy, carry the risk of what’s called medication overuse” that can lead to rebound headaches, she said.

Excedrin Tension Headache may be used for headaches in pregnancy, she said, but not Excedrin Migraine since it includes aspirin. Triptans are not recommended as first-line therapy, she added, and they “should absolutely not be used in any pregnant patient with a history of known cardiac disease or hypertension.”

Dr. Stika added that ACOG advises against the use of drugs that contain butalbital, a barbiturate that’s combined with other agents to treat headache. “Butalbital is the drug that’s most closely associated with getting people into this medication overuse headache,” she said. “It’s even worse than opioids.”

Unlike multiple other countries and the entire European Union, the United States has not banned compounds that contain butalbital, she said.

In some cases, she said, patients may present to triage with vomiting, an inability to keep food down, and persistent headache despite treatment. “This is a really classic presentation.”

The ACOG clinical practice guideline offers a flow chart about what to do, she said. Hydration is key, she said, and various treatment options can help. A referral to neurology may be needed in extreme cases, she said. But “most of the time, you’re able to get rid of her headache.”

Dr. Mercer and Dr. Stika report no disclosures.

SAN DIEGO – If a medical professional is trying to figure out the best medical treatment for a pregnant woman with headache, it may be helpful to review data from randomized clinical trials (RCTs). Well, make that data from the RCT. There’s just been one, Northwestern Medicine obstetrician-gynecologist Catherine Stika, MD, told colleagues at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Only a single efficacy RCT has examined headache in pregnancy, said Dr. Stika. “Overall, we have very limited data in pregnancy to tell us exactly what to do,” she added.

But ob.gyns. aren’t entirely in the dark, according to medical specialists who spoke at the session. Expert opinion and fetal safety data offer insight into the best treatments, as does a new ACOG clinical practice guideline on headaches during pregnancy and post partum that was coauthored by the speakers.

And there’s some good news: Pregnancy itself is often a good treatment for headaches.

Pregnant women often find relief from one kind of headache – migraine – as their estradiol levels rise, said Laura Mercer, MD, an ob.gyn. at the University of Arizona, Phoenix. “About half of patients will report that migraines are getting better as early as the first trimester, and upwards of 83% will say that their migraines are better by the time they’re in their third trimester,” she said. “What this means for us as obstetricians is that oftentimes we can actually discontinue preventative therapies for patients during pregnancy.”

But simply discontinuing every headache treatment during pregnancy may not be the right approach, Dr. Mercer said. Instead, she said, consider the benefits and risks.

Divalproex sodium (Depakote) and topiramate (Topamax) must be avoided because of fetal risk, she said. “In fact, we will prefer that people stop these medications before they discontinue their contraception if they’re planning on getting pregnant,” she said.

Other medications, such as ACE inhibitors and the herbal remedy feverfew, should not be used at any time during pregnancy, she said.

On the other hand, calcium channel blockers and antihistamines are alright to use in pregnancy, she said. “These two should be considered first-line because there’s no known risks for them.”

Beta-blockers also may be used “with some consideration to the known risks that we’re familiar with when we use them for other indications,” she said.

There are questions about the safety of oral magnesium in pregnancy, although it’s generally considered safe, she added, and “nerve blocks and nerve stimulators seem very promising and have little known risks.”

Dr. Mercer recommended gradually tapering most medications prior to conception. But it’s crucial to stop higher-risk drugs immediately once pregnancy is confirmed, she said.

In regard to acute headache, Dr. Stika urged caution if a patient reports taking a headache medication more than twice a week. “All the medications we use for the treatment of migraine, both in and outside of pregnancy, carry the risk of what’s called medication overuse” that can lead to rebound headaches, she said.

Excedrin Tension Headache may be used for headaches in pregnancy, she said, but not Excedrin Migraine since it includes aspirin. Triptans are not recommended as first-line therapy, she added, and they “should absolutely not be used in any pregnant patient with a history of known cardiac disease or hypertension.”

Dr. Stika added that ACOG advises against the use of drugs that contain butalbital, a barbiturate that’s combined with other agents to treat headache. “Butalbital is the drug that’s most closely associated with getting people into this medication overuse headache,” she said. “It’s even worse than opioids.”

Unlike multiple other countries and the entire European Union, the United States has not banned compounds that contain butalbital, she said.

In some cases, she said, patients may present to triage with vomiting, an inability to keep food down, and persistent headache despite treatment. “This is a really classic presentation.”

The ACOG clinical practice guideline offers a flow chart about what to do, she said. Hydration is key, she said, and various treatment options can help. A referral to neurology may be needed in extreme cases, she said. But “most of the time, you’re able to get rid of her headache.”

Dr. Mercer and Dr. Stika report no disclosures.

SAN DIEGO – If a medical professional is trying to figure out the best medical treatment for a pregnant woman with headache, it may be helpful to review data from randomized clinical trials (RCTs). Well, make that data from the RCT. There’s just been one, Northwestern Medicine obstetrician-gynecologist Catherine Stika, MD, told colleagues at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Only a single efficacy RCT has examined headache in pregnancy, said Dr. Stika. “Overall, we have very limited data in pregnancy to tell us exactly what to do,” she added.

But ob.gyns. aren’t entirely in the dark, according to medical specialists who spoke at the session. Expert opinion and fetal safety data offer insight into the best treatments, as does a new ACOG clinical practice guideline on headaches during pregnancy and post partum that was coauthored by the speakers.

And there’s some good news: Pregnancy itself is often a good treatment for headaches.

Pregnant women often find relief from one kind of headache – migraine – as their estradiol levels rise, said Laura Mercer, MD, an ob.gyn. at the University of Arizona, Phoenix. “About half of patients will report that migraines are getting better as early as the first trimester, and upwards of 83% will say that their migraines are better by the time they’re in their third trimester,” she said. “What this means for us as obstetricians is that oftentimes we can actually discontinue preventative therapies for patients during pregnancy.”

But simply discontinuing every headache treatment during pregnancy may not be the right approach, Dr. Mercer said. Instead, she said, consider the benefits and risks.

Divalproex sodium (Depakote) and topiramate (Topamax) must be avoided because of fetal risk, she said. “In fact, we will prefer that people stop these medications before they discontinue their contraception if they’re planning on getting pregnant,” she said.

Other medications, such as ACE inhibitors and the herbal remedy feverfew, should not be used at any time during pregnancy, she said.

On the other hand, calcium channel blockers and antihistamines are alright to use in pregnancy, she said. “These two should be considered first-line because there’s no known risks for them.”

Beta-blockers also may be used “with some consideration to the known risks that we’re familiar with when we use them for other indications,” she said.

There are questions about the safety of oral magnesium in pregnancy, although it’s generally considered safe, she added, and “nerve blocks and nerve stimulators seem very promising and have little known risks.”

Dr. Mercer recommended gradually tapering most medications prior to conception. But it’s crucial to stop higher-risk drugs immediately once pregnancy is confirmed, she said.

In regard to acute headache, Dr. Stika urged caution if a patient reports taking a headache medication more than twice a week. “All the medications we use for the treatment of migraine, both in and outside of pregnancy, carry the risk of what’s called medication overuse” that can lead to rebound headaches, she said.

Excedrin Tension Headache may be used for headaches in pregnancy, she said, but not Excedrin Migraine since it includes aspirin. Triptans are not recommended as first-line therapy, she added, and they “should absolutely not be used in any pregnant patient with a history of known cardiac disease or hypertension.”

Dr. Stika added that ACOG advises against the use of drugs that contain butalbital, a barbiturate that’s combined with other agents to treat headache. “Butalbital is the drug that’s most closely associated with getting people into this medication overuse headache,” she said. “It’s even worse than opioids.”

Unlike multiple other countries and the entire European Union, the United States has not banned compounds that contain butalbital, she said.

In some cases, she said, patients may present to triage with vomiting, an inability to keep food down, and persistent headache despite treatment. “This is a really classic presentation.”

The ACOG clinical practice guideline offers a flow chart about what to do, she said. Hydration is key, she said, and various treatment options can help. A referral to neurology may be needed in extreme cases, she said. But “most of the time, you’re able to get rid of her headache.”

Dr. Mercer and Dr. Stika report no disclosures.

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.¹ Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),² and direct-to-consumer (DTC) services that provide these results as part of large panels.³ Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.³ A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 1⁴), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).⁵ That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).⁶ In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,^7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway¹⁰).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.¹¹ While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.¹²

Continue to: 7 clinical scenarios and how to approach them

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 2^13-16.

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 1⁴ for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.¹⁷ For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,⁴ estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.¹⁸ But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.^19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.²

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.²¹ Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.^2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.²⁴ Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.^25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.²⁷

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.²⁸ Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.²⁹ Interventions that personalize and validate an individual’s experience can help address internalized stigma.³⁰ Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.³¹ It would be prudent to address proper blood pressure control³² and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).^13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.^15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.³³ But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).³⁴ Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.³⁵ Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.^6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; Stites@UPenn.edu

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.¹ Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),² and direct-to-consumer (DTC) services that provide these results as part of large panels.³ Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.³ A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 1⁴), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).⁵ That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).⁶ In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,^7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway¹⁰).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.¹¹ While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.¹²

Continue to: 7 clinical scenarios and how to approach them

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 2^13-16.

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 1⁴ for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.¹⁷ For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,⁴ estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.¹⁸ But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.^19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.²

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.²¹ Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.^2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.²⁴ Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.^25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.²⁷

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.²⁸ Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.²⁹ Interventions that personalize and validate an individual’s experience can help address internalized stigma.³⁰ Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.³¹ It would be prudent to address proper blood pressure control³² and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).^13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.^15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.³³ But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).³⁴ Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.³⁵ Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.^6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; Stites@UPenn.edu

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.¹ Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),² and direct-to-consumer (DTC) services that provide these results as part of large panels.³ Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.³ A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 1⁴), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).⁵ That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).⁶ In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,^7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway¹⁰).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.¹¹ While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.¹²

Continue to: 7 clinical scenarios and how to approach them

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 2^13-16.

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 1⁴ for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.¹⁷ For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,⁴ estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.¹⁸ But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.^19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.²

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.²¹ Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.^2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.²⁴ Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.^25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.²⁷

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.²⁸ Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.²⁹ Interventions that personalize and validate an individual’s experience can help address internalized stigma.³⁰ Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.³¹ It would be prudent to address proper blood pressure control³² and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).^13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.^15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.³³ But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).³⁴ Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.³⁵ Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.^6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; Stites@UPenn.edu

Higher industriousness was associated with a 25% reduced risk of concurrent motoric cognitive risk syndrome (MCR), based on data from approximately 6,000 individuals.

Previous research supports an association between conscientiousness and a lower risk of MCR, a form of predementia that involves slow gait speed and cognitive complaints, wrote Yannick Stephan, PhD, of the University of Montpellier (France), and colleagues. However, the specific facets of conscientiousness that impact MCR have not been examined.

In a study published in the Journal of Psychiatric Research, the authors reviewed data from 6,001 dementia-free adults aged 65-99 years who were enrolled in the Health and Retirement Study, a nationally representative longitudinal study of adults aged 50 years and older in the United States.

Baseline data were collected between 2008 and 2010, and participants were assessed for MCR at follow-up points during 2012-2014 and 2016-2018. Six facets of conscientiousness were assessed using a 24-item scale that has been used in previous studies. The six facets were industriousness, self-control, order, traditionalism, virtue, and responsibility. The researchers controlled for variables including demographic factors, cognition, physical activity, disease burden, depressive symptoms, and body mass index.

Overall, increased industriousness was significantly associated with a lower likelihood of concurrent MCR (odds ratio, 0.75) and a reduced risk of incident MCR (hazard ratio, 0.63,; P < .001 for both).

The conscientiousness facets of order, self-control, and responsibility also were associated with a lower likelihood of both concurrent and incident MCR, with ORs ranging from 0.82-0.88 for concurrent and HRs ranging from 0.72-0.82 for incident.

Traditionalism and virtue were significantly associated with a lower risk of incident MCR, but not concurrent MCR (HR, 0.84; P < .01 for both).

The mechanism of action for the association may be explained by several cognitive, health-related, behavioral, and psychological pathways, the researchers wrote. With regard to industriousness, the relationship could be partly explained by cognition, physical activity, disease burden, BMI, and depressive symptoms. However, industriousness also has been associated with a reduced risk of systemic inflammation, which may in turn reduce MCR risk. Also, data suggest that industriousness and MCR share a common genetic cause.

The study findings were limited by several factors including the observational design and the positive selection effect from patients with complete follow-up data, as these patients likely have higher levels of order, industriousness, and responsibility, the researchers noted. However, the results support those from previous studies and were strengthened by the large sample and examination of six facets of conscientiousness.

“This study thus provides a more detailed understanding of the specific components of conscientiousness that are associated with risk of MCR among older adults,” and the facets could be targeted in interventions to reduce both MCR and dementia, they concluded.

The Health and Retirement Study is supported by the National Institute on Aging and conducted by the University of Michigan. The current study was supported in part by the National Institutes of Health. The researchers had no financial conflicts to disclose.

Higher industriousness was associated with a 25% reduced risk of concurrent motoric cognitive risk syndrome (MCR), based on data from approximately 6,000 individuals.

Previous research supports an association between conscientiousness and a lower risk of MCR, a form of predementia that involves slow gait speed and cognitive complaints, wrote Yannick Stephan, PhD, of the University of Montpellier (France), and colleagues. However, the specific facets of conscientiousness that impact MCR have not been examined.

In a study published in the Journal of Psychiatric Research, the authors reviewed data from 6,001 dementia-free adults aged 65-99 years who were enrolled in the Health and Retirement Study, a nationally representative longitudinal study of adults aged 50 years and older in the United States.

Baseline data were collected between 2008 and 2010, and participants were assessed for MCR at follow-up points during 2012-2014 and 2016-2018. Six facets of conscientiousness were assessed using a 24-item scale that has been used in previous studies. The six facets were industriousness, self-control, order, traditionalism, virtue, and responsibility. The researchers controlled for variables including demographic factors, cognition, physical activity, disease burden, depressive symptoms, and body mass index.

Overall, increased industriousness was significantly associated with a lower likelihood of concurrent MCR (odds ratio, 0.75) and a reduced risk of incident MCR (hazard ratio, 0.63,; P < .001 for both).

The conscientiousness facets of order, self-control, and responsibility also were associated with a lower likelihood of both concurrent and incident MCR, with ORs ranging from 0.82-0.88 for concurrent and HRs ranging from 0.72-0.82 for incident.

Traditionalism and virtue were significantly associated with a lower risk of incident MCR, but not concurrent MCR (HR, 0.84; P < .01 for both).

The mechanism of action for the association may be explained by several cognitive, health-related, behavioral, and psychological pathways, the researchers wrote. With regard to industriousness, the relationship could be partly explained by cognition, physical activity, disease burden, BMI, and depressive symptoms. However, industriousness also has been associated with a reduced risk of systemic inflammation, which may in turn reduce MCR risk. Also, data suggest that industriousness and MCR share a common genetic cause.

The study findings were limited by several factors including the observational design and the positive selection effect from patients with complete follow-up data, as these patients likely have higher levels of order, industriousness, and responsibility, the researchers noted. However, the results support those from previous studies and were strengthened by the large sample and examination of six facets of conscientiousness.

“This study thus provides a more detailed understanding of the specific components of conscientiousness that are associated with risk of MCR among older adults,” and the facets could be targeted in interventions to reduce both MCR and dementia, they concluded.

The Health and Retirement Study is supported by the National Institute on Aging and conducted by the University of Michigan. The current study was supported in part by the National Institutes of Health. The researchers had no financial conflicts to disclose.

Higher industriousness was associated with a 25% reduced risk of concurrent motoric cognitive risk syndrome (MCR), based on data from approximately 6,000 individuals.

Previous research supports an association between conscientiousness and a lower risk of MCR, a form of predementia that involves slow gait speed and cognitive complaints, wrote Yannick Stephan, PhD, of the University of Montpellier (France), and colleagues. However, the specific facets of conscientiousness that impact MCR have not been examined.

In a study published in the Journal of Psychiatric Research, the authors reviewed data from 6,001 dementia-free adults aged 65-99 years who were enrolled in the Health and Retirement Study, a nationally representative longitudinal study of adults aged 50 years and older in the United States.

Baseline data were collected between 2008 and 2010, and participants were assessed for MCR at follow-up points during 2012-2014 and 2016-2018. Six facets of conscientiousness were assessed using a 24-item scale that has been used in previous studies. The six facets were industriousness, self-control, order, traditionalism, virtue, and responsibility. The researchers controlled for variables including demographic factors, cognition, physical activity, disease burden, depressive symptoms, and body mass index.

Overall, increased industriousness was significantly associated with a lower likelihood of concurrent MCR (odds ratio, 0.75) and a reduced risk of incident MCR (hazard ratio, 0.63,; P < .001 for both).

The conscientiousness facets of order, self-control, and responsibility also were associated with a lower likelihood of both concurrent and incident MCR, with ORs ranging from 0.82-0.88 for concurrent and HRs ranging from 0.72-0.82 for incident.

Traditionalism and virtue were significantly associated with a lower risk of incident MCR, but not concurrent MCR (HR, 0.84; P < .01 for both).

The mechanism of action for the association may be explained by several cognitive, health-related, behavioral, and psychological pathways, the researchers wrote. With regard to industriousness, the relationship could be partly explained by cognition, physical activity, disease burden, BMI, and depressive symptoms. However, industriousness also has been associated with a reduced risk of systemic inflammation, which may in turn reduce MCR risk. Also, data suggest that industriousness and MCR share a common genetic cause.

The study findings were limited by several factors including the observational design and the positive selection effect from patients with complete follow-up data, as these patients likely have higher levels of order, industriousness, and responsibility, the researchers noted. However, the results support those from previous studies and were strengthened by the large sample and examination of six facets of conscientiousness.

“This study thus provides a more detailed understanding of the specific components of conscientiousness that are associated with risk of MCR among older adults,” and the facets could be targeted in interventions to reduce both MCR and dementia, they concluded.

The Health and Retirement Study is supported by the National Institute on Aging and conducted by the University of Michigan. The current study was supported in part by the National Institutes of Health. The researchers had no financial conflicts to disclose.

As many as 240,000 people per year in the United States experience a transient ischemic attack (TIA),^1,2 which is now defined by the American Heart Association and American Stroke Association as a “transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction.”³ An older definition of TIA was based on the duration of the event (ie, resolution of symptoms at 24 hours); in the updated (2009) definition, the diagnostic criterion is the extent of focal tissue damage.³ Using the 2009 definition might mean a decrease in the number of patients who have a diagnosis of a TIA and an increase in the number who are determined to have had a stroke because an infarction is found on initial imaging.

Guided by the 2009 revised definition of a TIA, we review here the work-up and treatment of TIA, emphasizing immediacy of management to (1) prevent further tissue damage and (2) decrease the risk of a second event.

Copyright Scott Bodell

CASE

Martin L, 69 years old, retired, a nonsmoker, and with a history of peripheral arterial disease and hypercholesterolemia, presents to the emergency department (ED) of a rural hospital complaining of slurred speech and left-side facial numbness. He had an episode of facial numbness that lasted 30 minutes, then resolved, each of the 2 previous evenings; he did not seek care at those times. Now, in the ED, Mr. L is normotensive.

The patient’s medication history includes a selective serotonin reuptake inhibitor and melatonin to improve sleep. He reports having discontinued a statin because he could not tolerate its adverse effects.

What immediate steps are recommended for Mr. L’s care?

Common event callsfor quick action

A TIA is the strongest predictor of subsequent stroke and stroke-related death; the highest period of risk of these devastating outcomes is immediately following a TIA.^1,2,4,5 It is essential, therefore, for the physician who sees a patient with a current complaint or recent history of suspected focal neurologic deficits to direct that patient to an ED for an accurate diagnosis and, as appropriate, early treatment for the best possible outcome.

A TIA is the strongest predictor of subsequent stroke and stroke-related death; the highest period of risk of these devastating outcomes is immediately following a TIA.

Imaging—preferably, diffusion-­weighted magnetic resonance imaging (DW-MRI), the gold standard for diagnosing stroke (see “Diagnosis includes ruling out mimics”)^2,3—should be performed as soon as the patient with a suspected TIA arrives in the ED. Imaging should not be held while waiting for a stroke to declare itself—ie, by allowing symptoms to persist for longer than 24 hours. ⁶

Continue to: Late presentation

Late presentation. Some patients present ≥ 48 hours after onset of early symptoms of a TIA; for them, the work-up is the same as for prompt presentation but can be completed in the outpatient clinic—as long as the patient is stable clinically and imaging is accessible there. DW-MRI should be completed within 48 hours after late presentation. In such cases, the patient should be cautioned regarding risks and any recurrence of symptoms.^7,8

Diagnosis includes ruling out mimics

All patients in whom a stroke is suspected should be evaluated on an emergency basis with brain imaging upon arrival at the hospital, before any therapy is initiated. As noted, DW-MRI is the preferred modality; noncontrast computed tomography (CT) or CT angiography can be used if MRI is unavailable.^2,3

Mimics. Stroke has many mimics; quickly eliminating them from the differential diagnosis is important so that appropriate therapy can be initiated. Mimics usually have a prolonged presentation of symptoms, whereas the presentation of a TIA is usually abrupt. The 3 more common diagnoses that mimic a TIA are migraine with aura, seizure, and syncope.^9,10 Symptoms that generally are not associated with a TIA are chest pain, generalized weakness, and confusion.¹¹ A complete history and physical exam provide the path to the imaging, laboratory, and cardiac testing that is needed to differentiate these diagnoses from a TIA.

A thorough history is best obtained from the patient and a witness, if available, and should include identification of any focal neurologic deficits and the duration and time to resolution of symptoms. Obtain a history of risk factors for ischemia—tobacco use, diabetes, obesity, dyslipidemia, hypertension, previous TIA or stroke, atrial fibrillation, and any coagulopathy. Ask questions about a family history of TIA, stroke, and coagulopathy.¹¹

A comprehensive physical exam, including vital signs, cardiac exam, a check for carotid bruits, and complete neurologic exam, should be performed. Most patients present with concerns for unilateral weakness and changes in speech, which are usually associated with infarction on DW-MRI.¹² The most common findings on physical exam include cranial nerve abnormalities, such as diplopia, hemianopia, monocular blindness, disconjugate gaze, facial drooping, lateral tongue movement, dysphagia, and vestibular dysfunction. Cerebellar abnormalities are also often noted, including past pointing, dystaxia, ataxia, nystagmus, and motor abnormalities (eg, spasticity, clonus, or unilateral weakness in the face or extremities).¹¹

Electrocardiography at the bedside can confirm atrial fibrillation or another arrhythmia quickly.

Essential laboratory testing includes measurement of blood glucose and serum electrolytes to determine if these particular imbalances are the cause of symptoms. The presence of a hypercoaguable state is determined by a complete blood count and coagulation studies.^3,13 Urine toxicology should also be obtained to rule out other causes of symptoms. A lipid profile is beneficial for making long-term treatment decisions.

Continue to: ABCD2 score

ABCD2 score. Patients who have had a TIA and present within 72 hours after symptoms have resolved should be hospitalized if they have an ABCD2 (Age, Blood pressure [BP], Clinical presentation, Diabetes mellitus [type 1 or 2], Duration of symptoms) prediction system score > 3.¹⁴ ABCD2 criteria can be used to help identify patients who are at higher risk of stroke or need further therapy (TABLE 1).^14,15

Send a patient with a current complaint or recent history of suspected focal neurologic deficits to an ED for accurate diagnosis of a possible TIA and, as appropriate, early treatment.

The ABCD2 score is also used to determine whether a patient needs dual antiplatelet therapy. Patients who score at the higher end of the ABCD2 system usually have an increased risk of stroke, longer hospitalization, and greater disability.

CASE

In the ED, Mr. L is immediately assessed and airlifted to a larger regional medical center, where MRI confirms a stroke.

Management

Initial management of a TIA is aimed at reducing the risk of recurrent TIA or stroke. Early medical and possibly surgical treatment are key for preventing stroke and improving outcomes. The first 48 hours after a TIA are the most critical because the incidence of recurrent TIA or stroke is highest during this period.^16-18

What is the accepted strategy for early treatment?

Initial treatment must include antiplatelet therapy, BP management, anticoagulation, statin therapy, and carotid endarterectomy as indicated.^2,19,20 Control of hypertension and anticoagulation decrease the risk of recurrent stroke by the largest margin²⁰; both are “A”-level Strength of Recommendation Taxonomy interventions.^2,3

Step 1: Antiplatelet therapy. After initial imaging is complete and if there are no contraindications, antiplatelet agents are recommended for patients who have had a noncardioembolic TIA. The American Heart Association and American Stroke Association recommend either aspirin, clopidogrel, dipyridamole + aspirin (available in a single capsule [Aggrenox]), or clopidogrel + aspirin as first-line therapy.^2,20 The choice of agent needs to be individualized, based on tolerability and adverse effects (TABLE 2^2,20,21).

A meta-analysis of antiplatelet therapy reviewed the optimum dosing of each medication.^21,22 Reduction of the risk of ischemic stroke with aspirin is 21% to 22% at the optimal dosing of 75 to 150 mg/d, which also reduces the risk of gastrointestinal bleeding.

Continue to: For a patient who has...

For a patient who has an ABCD2 score ≥ 4, has had a prior TIA, or has large-vessel disease, dual antiplatelet therapy is recommended for the first 21 days, with a subsequent return to monotherapy. Dual antiplatelet therapy of clopidogrel + aspirin increases the risk of adverse reactions and has not been shown to have greater long-term benefit^23-25 (TABLE 2^2,20,21).

Step 2: BP management. This is the next immediate step. As many as 80% of patients who present with a TIA have elevated BP upon admission. BP needs to be treated and carefully monitored during this early treatment phase. The recommendation is for a systolic BP < 185 mm Hg and a diastolic BP < 110 mm Hg.²⁴

Step 3: Anticoagulation. Treatment with warfarin or a direct oral anticoagulant (DOAC) is recommended for patients who have the potential for forming emboli—eg, in the setting of atrial fibrillation, ventricular thrombus, mechanical heart valve, or venous thromboembolism.

Step 4. High-intensity statin. A statin agent is recommended as part of immediate and long-term medical management, regardless of the low-density lipoprotein cholesterol (LDL-C) level, to reduce the risk of stroke.^2,24

Carotid artery management. Surgical intervention is not always considered a component of immediate medical management. However, guidelines recommend that carotid endarterectomy or stenting be considered in patients who have stenosis > 70%.²

CASE

Mr. L is admitted to the hospital and undergoes neurosurgical intervention. Medical management is instituted.

Long-term management and secondary prevention

The main risk factors for stroke can be divided into modifiable, vascular, and unmodifiable. Addressing both modifiable and vascular risks is important for secondary prevention.

Continue to: Modifiable and vascular risk factors

 

 

Modifiable and vascular risk factors

Modifiable risk factors for stroke include hypertension, diabetes, dyslipidemia, smoking, and physical activity; the most important of these, for preventing subsequent stroke after an initial TIA, is hypertension.²⁶

The 2 more significant vascular risk factors for stroke are carotid artery stenosis and atrial fibrillation.

Hypertension. Improving control of hypertension can improve secondary risk reduction for recurrent stroke. Control of both systolic and diastolic BP is important in this regard, with larger systolic BP reductions having a greater impact on decreasing the risk of recurrent stroke.²⁴ Evidence supports lowering BP to improve secondary risk reduction in people with and without diagnosed hypertension: The goal is to lower systolic BP by ≥ 10 mm Hg and diastolic BP by 5 mm Hg.²⁴ No particular class of antihypertensive is recommended in the first line, although preliminary evidence shows that a diuretic, with or without an angiotensin-converting enzyme inhibitor, might be more beneficial than other options.²⁴

Diabetes. The risk of cardiovascular disease, including stroke, is higher in people with diabetes. Evidence shows that various (but not all) agents in 2 pharmaceutical classes—glucagon-like peptide-1 (GLP-1) receptor agonists and the sodium glucose-2 cotransporter (SGLT2) inhibitors—reduce the risk of major cardiovascular events and improve secondary prevention of recurrent stroke:

• EMPA-REG OUTCOME (ClinicalTrials.gov Identifier: NCT01131676) was the first trial to show cardiovascular benefit from an SGLT2 inhibitor (empagliflozin); subsequent studies confirmed the cardiovascular benefits found in EMPA-REG OUTCOME.^27,28
• The ELIXA trial (ClinicalTrials.gov Identifier: NCT01147250) was the first to show cardiovascular benefit from a GLP-1 receptor agonist (lixisenatide); subsequent studies supported this finding.^29,30

Appropriate agents in these 2 classes should be considered as first-line or adjunctive in patients with both diabetes and known cardiovascular disease, as long as there are no contraindications.^27,28

Pioglitazone, a thiazolidinedione-class antidiabetic agent, was once considered a potential option to improve secondary prevention of stroke. However, the thiazolidinediones are generally no longer considered; instead, the SGLT2 inhibitors and GLP-1 receptor agonists are favored.³¹

Evidence demonstrates the effect of hyperglycemia on cardiovascular events; however, it is important to note that hypoglycemia can result in symptoms and focal changes that mimic a stroke. In addition, some evidence suggests that hypoglycemia can increase cardiovascular risk—thereby supporting the importance of strict control of diabetes and maintenance of euglycemia in reducing overall cardiovascular risk.³²

Continue to: Lipids

Lipids. The SPARCL trial (ClinicalTrials.gov Identifier: NCT00147602) was the first study to demonstrate the benefit of high-­intensity statin therapy—specifically, atorvastatin 80 mg/d—for secondary prevention for recurrent stroke.³³ The recommendation is to use high-intensity statin therapy to decrease the risk of recurrent stroke by reducing the level of LDL-C—by ≥ 50% or to < 70 mg/dL, for maximum risk reduction.^24,34

Common conditions that mimic a TIA are migraine with aura, seizure, and syncope; a TIA is generally not associated with chest pain, generalized weakness, or confusion.

The IMPROVE-IT trial (ClinicalTrials.gov Identifier: NCT00202878) demonstrated the benefit of adding ezetimibe, 10 mg/d, to a moderate-to-high-intensity statin (simvastatin, 40-80 mg/d) to reduce the risk of recurrent stroke.³⁵

Results of recent studies support the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for regulating levels of LDL-C, as an additional option to consider—if needed to further reduce the LDL-C level or if statins are contraindicated in a particular patient.³⁴

Smoking cessation. Cigarette smoking is known to increase the risk of ischemic stroke; newer evidence shows that second-hand exposure to smoke also increases the risk of ischemic stroke.^36,37 Although these studies focused on primary prevention of ischemic stroke, the data can reasonably be applied to secondary prevention.³⁸ The recommendation for secondary prevention is to quit smoking and avoid secondhand smoke.²⁴

Alcohol. Evidence demonstrates that heavy alcohol consumption and alcoholism increase the risk of stroke; similar to what is known about smoking, most available data relate to primary prevention.³⁸ The recommendation for providing secondary stroke prevention is to stop or decrease alcohol intake.²⁴

Weight reduction. Obesity (body mass index > 30) increases the risk of ischemic stroke. However, there is, as yet, no evidence that weight loss diminishes the risk of subsequent stroke for secondary prevention.²⁴

Physical activity. Aerobic exercise and strength-training programs after a stroke improve cardiovascular health and mobility. There is no evidence that exercise leads to a reduction in the risk of subsequent stroke.²⁴

Continue to: Nutrition

Nutrition. No current randomized controlled trials are focused on the relationship between diet and recurrent stroke for purposes of prevention; however, evidence for both BP and lipid control incorporate dietary guidance. Recommendations include reducing intake of saturated fats and of sodium (the latter, to < 2.3 g/d) and increasing intake of fruits and vegetables, both of which are beneficial for controlling BP and lipid levels and promoting overall cardiovascular health.³⁸

Carotid artery stenosis. Several randomized controlled trials have demonstrated benefit from treating carotid stenosis (> 70% stenosis but not < 50%) with carotid endarterectomy to reduce the risk of recurrent stroke after TIA.² The ideal timing of carotid endarterectomy is still being studied; however, available evidence supports intervention within 2 to 6 weeks after TIA or stroke.²⁵ Studies are ongoing that compare carotid angioplasty and stenting against carotid endarterectomy. Medical therapy, with antiplatelet agents and statins, is recommended after carotid endarterectomy.²⁵

Atrial fibrillation increases the risk of recurrent stroke after a TIA, and is the most important indication for secondary stroke prevention with anticoagulation therapy:

• Warfarin. Several studies have shown that warfarin provides a 68% relative risk reduction and a 1.4% absolute risk reduction in the annual stroke rate.²⁴ To achieve this reduction in risk, the optimal international normalized ratio is 2.5 (range, 2-3).²⁴
• Aspirin provides a 13% relative risk reduction for recurrent stroke, although there is evidence that long-term anticoagulation provides more benefit than aspirin after a TIA.^39-41 Optimal dosing of aspirin ranges from 75-100 mg/d; greatest benefit is likely in the 12 weeks after stroke, when the risk of recurrent stroke is highest.^31,41,42
• DOACs have similar efficacy to warfarin but more rapid onset, lower risk of bleeding, fewer drug interactions, and no requirement for monitoring—often making them a more tolerable long-term choice. Options are rivaroxaban 20 mg/d, dabigatran 150 mg twice daily, apixaban 5 mg twice daily, and edoxaban 60 mg/d.³⁹

Initial treatment of a TIA must include antiplatelet therapy, BP management, anticoagulation, and statin therapy; carotid endarterectomy might also be indicated.

When to start anticoagulation and the choice of agent should be weighed against a risk of bleeding, which is highest after the initial stroke. Cost is also a consideration: DOACs are more expensive than warfarin.

CASE

Mr. L is discharged 3 days after carotid endarterectomy and free of residual deficits. He is started on dual antiplatelet therapy (aspirin + clopidogrel) for 21 days, to be followed by a return to monotherapy. He is restarted on a high-intensity statin. He is instructed to resume taking the selective serotonin reuptake inhibitor and melatonin for sleep, as needed. Last, he is told to schedule follow-up with his primary care physician in 7 to 10 days to begin post-stroke care.

Final thoughts

Primary care physicians are often the first point of contact for patients with current or remote TIA symptoms. Based on that ­provider–patient relationship, evidence supports several recommendations for diagnosing and treating a TIA and for reducing the risk of recurrent stroke after TIA. Addressing each of these areas, in this order, is imperative to reduce the risk of recurrent stroke and improve overall cardiovascular outcomes:

• Obtain an accurate diagnosis of a TIA, using DW-MRI or comparable brain imaging, to allow for prompt intervention.
• Initiate BP management promptly in the acute setting and establish optimal BP control over the long term.
• Begin appropriate antiplatelet therapy.
• When indicated (eg, atrial fibrillation), begin anticoagulation therapy with a DOAC or warfarin.
• Begin high-intensity statin therapy.
• Consider treating patients with diabetes using an SGLT2 inhibitor or GLP-1 receptor agonist.
• Encourage smoking cessation, prescribe quit-smoking medications, or refer a smoker for behavioral support.

Education. Last, it is important to educate patients—especially those who have risk factors for a TIA or stroke—about the presentation of events, so that they know to seek immediate medical attention.

CORRESPONDENCE
Kristen Rundell, MD, Department of Family and Community Medicine, University of Arizona College of Medicine, 655 North Alvernon Way, Suite 228, Tucson, AZ 85711; kristenrundell@arizona.edu

As many as 240,000 people per year in the United States experience a transient ischemic attack (TIA),^1,2 which is now defined by the American Heart Association and American Stroke Association as a “transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction.”³ An older definition of TIA was based on the duration of the event (ie, resolution of symptoms at 24 hours); in the updated (2009) definition, the diagnostic criterion is the extent of focal tissue damage.³ Using the 2009 definition might mean a decrease in the number of patients who have a diagnosis of a TIA and an increase in the number who are determined to have had a stroke because an infarction is found on initial imaging.

Guided by the 2009 revised definition of a TIA, we review here the work-up and treatment of TIA, emphasizing immediacy of management to (1) prevent further tissue damage and (2) decrease the risk of a second event.

Copyright Scott Bodell

CASE

Martin L, 69 years old, retired, a nonsmoker, and with a history of peripheral arterial disease and hypercholesterolemia, presents to the emergency department (ED) of a rural hospital complaining of slurred speech and left-side facial numbness. He had an episode of facial numbness that lasted 30 minutes, then resolved, each of the 2 previous evenings; he did not seek care at those times. Now, in the ED, Mr. L is normotensive.

The patient’s medication history includes a selective serotonin reuptake inhibitor and melatonin to improve sleep. He reports having discontinued a statin because he could not tolerate its adverse effects.

What immediate steps are recommended for Mr. L’s care?

Common event callsfor quick action

A TIA is the strongest predictor of subsequent stroke and stroke-related death; the highest period of risk of these devastating outcomes is immediately following a TIA.^1,2,4,5 It is essential, therefore, for the physician who sees a patient with a current complaint or recent history of suspected focal neurologic deficits to direct that patient to an ED for an accurate diagnosis and, as appropriate, early treatment for the best possible outcome.

A TIA is the strongest predictor of subsequent stroke and stroke-related death; the highest period of risk of these devastating outcomes is immediately following a TIA.

Imaging—preferably, diffusion-­weighted magnetic resonance imaging (DW-MRI), the gold standard for diagnosing stroke (see “Diagnosis includes ruling out mimics”)^2,3—should be performed as soon as the patient with a suspected TIA arrives in the ED. Imaging should not be held while waiting for a stroke to declare itself—ie, by allowing symptoms to persist for longer than 24 hours. ⁶

Continue to: Late presentation

Late presentation. Some patients present ≥ 48 hours after onset of early symptoms of a TIA; for them, the work-up is the same as for prompt presentation but can be completed in the outpatient clinic—as long as the patient is stable clinically and imaging is accessible there. DW-MRI should be completed within 48 hours after late presentation. In such cases, the patient should be cautioned regarding risks and any recurrence of symptoms.^7,8

Diagnosis includes ruling out mimics

All patients in whom a stroke is suspected should be evaluated on an emergency basis with brain imaging upon arrival at the hospital, before any therapy is initiated. As noted, DW-MRI is the preferred modality; noncontrast computed tomography (CT) or CT angiography can be used if MRI is unavailable.^2,3

Mimics. Stroke has many mimics; quickly eliminating them from the differential diagnosis is important so that appropriate therapy can be initiated. Mimics usually have a prolonged presentation of symptoms, whereas the presentation of a TIA is usually abrupt. The 3 more common diagnoses that mimic a TIA are migraine with aura, seizure, and syncope.^9,10 Symptoms that generally are not associated with a TIA are chest pain, generalized weakness, and confusion.¹¹ A complete history and physical exam provide the path to the imaging, laboratory, and cardiac testing that is needed to differentiate these diagnoses from a TIA.

A thorough history is best obtained from the patient and a witness, if available, and should include identification of any focal neurologic deficits and the duration and time to resolution of symptoms. Obtain a history of risk factors for ischemia—tobacco use, diabetes, obesity, dyslipidemia, hypertension, previous TIA or stroke, atrial fibrillation, and any coagulopathy. Ask questions about a family history of TIA, stroke, and coagulopathy.¹¹

A comprehensive physical exam, including vital signs, cardiac exam, a check for carotid bruits, and complete neurologic exam, should be performed. Most patients present with concerns for unilateral weakness and changes in speech, which are usually associated with infarction on DW-MRI.¹² The most common findings on physical exam include cranial nerve abnormalities, such as diplopia, hemianopia, monocular blindness, disconjugate gaze, facial drooping, lateral tongue movement, dysphagia, and vestibular dysfunction. Cerebellar abnormalities are also often noted, including past pointing, dystaxia, ataxia, nystagmus, and motor abnormalities (eg, spasticity, clonus, or unilateral weakness in the face or extremities).¹¹

Electrocardiography at the bedside can confirm atrial fibrillation or another arrhythmia quickly.

Essential laboratory testing includes measurement of blood glucose and serum electrolytes to determine if these particular imbalances are the cause of symptoms. The presence of a hypercoaguable state is determined by a complete blood count and coagulation studies.^3,13 Urine toxicology should also be obtained to rule out other causes of symptoms. A lipid profile is beneficial for making long-term treatment decisions.

Continue to: ABCD2 score

ABCD2 score. Patients who have had a TIA and present within 72 hours after symptoms have resolved should be hospitalized if they have an ABCD2 (Age, Blood pressure [BP], Clinical presentation, Diabetes mellitus [type 1 or 2], Duration of symptoms) prediction system score > 3.¹⁴ ABCD2 criteria can be used to help identify patients who are at higher risk of stroke or need further therapy (TABLE 1).^14,15

Send a patient with a current complaint or recent history of suspected focal neurologic deficits to an ED for accurate diagnosis of a possible TIA and, as appropriate, early treatment.

The ABCD2 score is also used to determine whether a patient needs dual antiplatelet therapy. Patients who score at the higher end of the ABCD2 system usually have an increased risk of stroke, longer hospitalization, and greater disability.

CASE

In the ED, Mr. L is immediately assessed and airlifted to a larger regional medical center, where MRI confirms a stroke.

Management

Initial management of a TIA is aimed at reducing the risk of recurrent TIA or stroke. Early medical and possibly surgical treatment are key for preventing stroke and improving outcomes. The first 48 hours after a TIA are the most critical because the incidence of recurrent TIA or stroke is highest during this period.^16-18

What is the accepted strategy for early treatment?

Initial treatment must include antiplatelet therapy, BP management, anticoagulation, statin therapy, and carotid endarterectomy as indicated.^2,19,20 Control of hypertension and anticoagulation decrease the risk of recurrent stroke by the largest margin²⁰; both are “A”-level Strength of Recommendation Taxonomy interventions.^2,3

Step 1: Antiplatelet therapy. After initial imaging is complete and if there are no contraindications, antiplatelet agents are recommended for patients who have had a noncardioembolic TIA. The American Heart Association and American Stroke Association recommend either aspirin, clopidogrel, dipyridamole + aspirin (available in a single capsule [Aggrenox]), or clopidogrel + aspirin as first-line therapy.^2,20 The choice of agent needs to be individualized, based on tolerability and adverse effects (TABLE 2^2,20,21).

A meta-analysis of antiplatelet therapy reviewed the optimum dosing of each medication.^21,22 Reduction of the risk of ischemic stroke with aspirin is 21% to 22% at the optimal dosing of 75 to 150 mg/d, which also reduces the risk of gastrointestinal bleeding.

Continue to: For a patient who has...

For a patient who has an ABCD2 score ≥ 4, has had a prior TIA, or has large-vessel disease, dual antiplatelet therapy is recommended for the first 21 days, with a subsequent return to monotherapy. Dual antiplatelet therapy of clopidogrel + aspirin increases the risk of adverse reactions and has not been shown to have greater long-term benefit^23-25 (TABLE 2^2,20,21).

Step 2: BP management. This is the next immediate step. As many as 80% of patients who present with a TIA have elevated BP upon admission. BP needs to be treated and carefully monitored during this early treatment phase. The recommendation is for a systolic BP < 185 mm Hg and a diastolic BP < 110 mm Hg.²⁴

Step 3: Anticoagulation. Treatment with warfarin or a direct oral anticoagulant (DOAC) is recommended for patients who have the potential for forming emboli—eg, in the setting of atrial fibrillation, ventricular thrombus, mechanical heart valve, or venous thromboembolism.

Step 4. High-intensity statin. A statin agent is recommended as part of immediate and long-term medical management, regardless of the low-density lipoprotein cholesterol (LDL-C) level, to reduce the risk of stroke.^2,24

Carotid artery management. Surgical intervention is not always considered a component of immediate medical management. However, guidelines recommend that carotid endarterectomy or stenting be considered in patients who have stenosis > 70%.²

CASE

Mr. L is admitted to the hospital and undergoes neurosurgical intervention. Medical management is instituted.

Long-term management and secondary prevention

The main risk factors for stroke can be divided into modifiable, vascular, and unmodifiable. Addressing both modifiable and vascular risks is important for secondary prevention.

Continue to: Modifiable and vascular risk factors

 

 

Modifiable and vascular risk factors

Modifiable risk factors for stroke include hypertension, diabetes, dyslipidemia, smoking, and physical activity; the most important of these, for preventing subsequent stroke after an initial TIA, is hypertension.²⁶

The 2 more significant vascular risk factors for stroke are carotid artery stenosis and atrial fibrillation.

Hypertension. Improving control of hypertension can improve secondary risk reduction for recurrent stroke. Control of both systolic and diastolic BP is important in this regard, with larger systolic BP reductions having a greater impact on decreasing the risk of recurrent stroke.²⁴ Evidence supports lowering BP to improve secondary risk reduction in people with and without diagnosed hypertension: The goal is to lower systolic BP by ≥ 10 mm Hg and diastolic BP by 5 mm Hg.²⁴ No particular class of antihypertensive is recommended in the first line, although preliminary evidence shows that a diuretic, with or without an angiotensin-converting enzyme inhibitor, might be more beneficial than other options.²⁴

Diabetes. The risk of cardiovascular disease, including stroke, is higher in people with diabetes. Evidence shows that various (but not all) agents in 2 pharmaceutical classes—glucagon-like peptide-1 (GLP-1) receptor agonists and the sodium glucose-2 cotransporter (SGLT2) inhibitors—reduce the risk of major cardiovascular events and improve secondary prevention of recurrent stroke:

• EMPA-REG OUTCOME (ClinicalTrials.gov Identifier: NCT01131676) was the first trial to show cardiovascular benefit from an SGLT2 inhibitor (empagliflozin); subsequent studies confirmed the cardiovascular benefits found in EMPA-REG OUTCOME.^27,28
• The ELIXA trial (ClinicalTrials.gov Identifier: NCT01147250) was the first to show cardiovascular benefit from a GLP-1 receptor agonist (lixisenatide); subsequent studies supported this finding.^29,30

Appropriate agents in these 2 classes should be considered as first-line or adjunctive in patients with both diabetes and known cardiovascular disease, as long as there are no contraindications.^27,28

Pioglitazone, a thiazolidinedione-class antidiabetic agent, was once considered a potential option to improve secondary prevention of stroke. However, the thiazolidinediones are generally no longer considered; instead, the SGLT2 inhibitors and GLP-1 receptor agonists are favored.³¹

Evidence demonstrates the effect of hyperglycemia on cardiovascular events; however, it is important to note that hypoglycemia can result in symptoms and focal changes that mimic a stroke. In addition, some evidence suggests that hypoglycemia can increase cardiovascular risk—thereby supporting the importance of strict control of diabetes and maintenance of euglycemia in reducing overall cardiovascular risk.³²

Continue to: Lipids

Lipids. The SPARCL trial (ClinicalTrials.gov Identifier: NCT00147602) was the first study to demonstrate the benefit of high-­intensity statin therapy—specifically, atorvastatin 80 mg/d—for secondary prevention for recurrent stroke.³³ The recommendation is to use high-intensity statin therapy to decrease the risk of recurrent stroke by reducing the level of LDL-C—by ≥ 50% or to < 70 mg/dL, for maximum risk reduction.^24,34

Common conditions that mimic a TIA are migraine with aura, seizure, and syncope; a TIA is generally not associated with chest pain, generalized weakness, or confusion.

The IMPROVE-IT trial (ClinicalTrials.gov Identifier: NCT00202878) demonstrated the benefit of adding ezetimibe, 10 mg/d, to a moderate-to-high-intensity statin (simvastatin, 40-80 mg/d) to reduce the risk of recurrent stroke.³⁵

Results of recent studies support the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for regulating levels of LDL-C, as an additional option to consider—if needed to further reduce the LDL-C level or if statins are contraindicated in a particular patient.³⁴

Smoking cessation. Cigarette smoking is known to increase the risk of ischemic stroke; newer evidence shows that second-hand exposure to smoke also increases the risk of ischemic stroke.^36,37 Although these studies focused on primary prevention of ischemic stroke, the data can reasonably be applied to secondary prevention.³⁸ The recommendation for secondary prevention is to quit smoking and avoid secondhand smoke.²⁴

Alcohol. Evidence demonstrates that heavy alcohol consumption and alcoholism increase the risk of stroke; similar to what is known about smoking, most available data relate to primary prevention.³⁸ The recommendation for providing secondary stroke prevention is to stop or decrease alcohol intake.²⁴

Weight reduction. Obesity (body mass index > 30) increases the risk of ischemic stroke. However, there is, as yet, no evidence that weight loss diminishes the risk of subsequent stroke for secondary prevention.²⁴

Physical activity. Aerobic exercise and strength-training programs after a stroke improve cardiovascular health and mobility. There is no evidence that exercise leads to a reduction in the risk of subsequent stroke.²⁴

Continue to: Nutrition

Nutrition. No current randomized controlled trials are focused on the relationship between diet and recurrent stroke for purposes of prevention; however, evidence for both BP and lipid control incorporate dietary guidance. Recommendations include reducing intake of saturated fats and of sodium (the latter, to < 2.3 g/d) and increasing intake of fruits and vegetables, both of which are beneficial for controlling BP and lipid levels and promoting overall cardiovascular health.³⁸

Carotid artery stenosis. Several randomized controlled trials have demonstrated benefit from treating carotid stenosis (> 70% stenosis but not < 50%) with carotid endarterectomy to reduce the risk of recurrent stroke after TIA.² The ideal timing of carotid endarterectomy is still being studied; however, available evidence supports intervention within 2 to 6 weeks after TIA or stroke.²⁵ Studies are ongoing that compare carotid angioplasty and stenting against carotid endarterectomy. Medical therapy, with antiplatelet agents and statins, is recommended after carotid endarterectomy.²⁵

Atrial fibrillation increases the risk of recurrent stroke after a TIA, and is the most important indication for secondary stroke prevention with anticoagulation therapy:

• Warfarin. Several studies have shown that warfarin provides a 68% relative risk reduction and a 1.4% absolute risk reduction in the annual stroke rate.²⁴ To achieve this reduction in risk, the optimal international normalized ratio is 2.5 (range, 2-3).²⁴
• Aspirin provides a 13% relative risk reduction for recurrent stroke, although there is evidence that long-term anticoagulation provides more benefit than aspirin after a TIA.^39-41 Optimal dosing of aspirin ranges from 75-100 mg/d; greatest benefit is likely in the 12 weeks after stroke, when the risk of recurrent stroke is highest.^31,41,42
• DOACs have similar efficacy to warfarin but more rapid onset, lower risk of bleeding, fewer drug interactions, and no requirement for monitoring—often making them a more tolerable long-term choice. Options are rivaroxaban 20 mg/d, dabigatran 150 mg twice daily, apixaban 5 mg twice daily, and edoxaban 60 mg/d.³⁹

Initial treatment of a TIA must include antiplatelet therapy, BP management, anticoagulation, and statin therapy; carotid endarterectomy might also be indicated.

When to start anticoagulation and the choice of agent should be weighed against a risk of bleeding, which is highest after the initial stroke. Cost is also a consideration: DOACs are more expensive than warfarin.

CASE

Mr. L is discharged 3 days after carotid endarterectomy and free of residual deficits. He is started on dual antiplatelet therapy (aspirin + clopidogrel) for 21 days, to be followed by a return to monotherapy. He is restarted on a high-intensity statin. He is instructed to resume taking the selective serotonin reuptake inhibitor and melatonin for sleep, as needed. Last, he is told to schedule follow-up with his primary care physician in 7 to 10 days to begin post-stroke care.

Final thoughts

Primary care physicians are often the first point of contact for patients with current or remote TIA symptoms. Based on that ­provider–patient relationship, evidence supports several recommendations for diagnosing and treating a TIA and for reducing the risk of recurrent stroke after TIA. Addressing each of these areas, in this order, is imperative to reduce the risk of recurrent stroke and improve overall cardiovascular outcomes:

• Obtain an accurate diagnosis of a TIA, using DW-MRI or comparable brain imaging, to allow for prompt intervention.
• Initiate BP management promptly in the acute setting and establish optimal BP control over the long term.
• Begin appropriate antiplatelet therapy.
• When indicated (eg, atrial fibrillation), begin anticoagulation therapy with a DOAC or warfarin.
• Begin high-intensity statin therapy.
• Consider treating patients with diabetes using an SGLT2 inhibitor or GLP-1 receptor agonist.
• Encourage smoking cessation, prescribe quit-smoking medications, or refer a smoker for behavioral support.

Education. Last, it is important to educate patients—especially those who have risk factors for a TIA or stroke—about the presentation of events, so that they know to seek immediate medical attention.

CORRESPONDENCE
Kristen Rundell, MD, Department of Family and Community Medicine, University of Arizona College of Medicine, 655 North Alvernon Way, Suite 228, Tucson, AZ 85711; kristenrundell@arizona.edu

As many as 240,000 people per year in the United States experience a transient ischemic attack (TIA),^1,2 which is now defined by the American Heart Association and American Stroke Association as a “transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction.”³ An older definition of TIA was based on the duration of the event (ie, resolution of symptoms at 24 hours); in the updated (2009) definition, the diagnostic criterion is the extent of focal tissue damage.³ Using the 2009 definition might mean a decrease in the number of patients who have a diagnosis of a TIA and an increase in the number who are determined to have had a stroke because an infarction is found on initial imaging.

Guided by the 2009 revised definition of a TIA, we review here the work-up and treatment of TIA, emphasizing immediacy of management to (1) prevent further tissue damage and (2) decrease the risk of a second event.

Copyright Scott Bodell

CASE

Martin L, 69 years old, retired, a nonsmoker, and with a history of peripheral arterial disease and hypercholesterolemia, presents to the emergency department (ED) of a rural hospital complaining of slurred speech and left-side facial numbness. He had an episode of facial numbness that lasted 30 minutes, then resolved, each of the 2 previous evenings; he did not seek care at those times. Now, in the ED, Mr. L is normotensive.

The patient’s medication history includes a selective serotonin reuptake inhibitor and melatonin to improve sleep. He reports having discontinued a statin because he could not tolerate its adverse effects.

What immediate steps are recommended for Mr. L’s care?

Common event callsfor quick action

A TIA is the strongest predictor of subsequent stroke and stroke-related death; the highest period of risk of these devastating outcomes is immediately following a TIA.^1,2,4,5 It is essential, therefore, for the physician who sees a patient with a current complaint or recent history of suspected focal neurologic deficits to direct that patient to an ED for an accurate diagnosis and, as appropriate, early treatment for the best possible outcome.

A TIA is the strongest predictor of subsequent stroke and stroke-related death; the highest period of risk of these devastating outcomes is immediately following a TIA.

Imaging—preferably, diffusion-­weighted magnetic resonance imaging (DW-MRI), the gold standard for diagnosing stroke (see “Diagnosis includes ruling out mimics”)^2,3—should be performed as soon as the patient with a suspected TIA arrives in the ED. Imaging should not be held while waiting for a stroke to declare itself—ie, by allowing symptoms to persist for longer than 24 hours. ⁶

Continue to: Late presentation

Late presentation. Some patients present ≥ 48 hours after onset of early symptoms of a TIA; for them, the work-up is the same as for prompt presentation but can be completed in the outpatient clinic—as long as the patient is stable clinically and imaging is accessible there. DW-MRI should be completed within 48 hours after late presentation. In such cases, the patient should be cautioned regarding risks and any recurrence of symptoms.^7,8

Diagnosis includes ruling out mimics

All patients in whom a stroke is suspected should be evaluated on an emergency basis with brain imaging upon arrival at the hospital, before any therapy is initiated. As noted, DW-MRI is the preferred modality; noncontrast computed tomography (CT) or CT angiography can be used if MRI is unavailable.^2,3

Mimics. Stroke has many mimics; quickly eliminating them from the differential diagnosis is important so that appropriate therapy can be initiated. Mimics usually have a prolonged presentation of symptoms, whereas the presentation of a TIA is usually abrupt. The 3 more common diagnoses that mimic a TIA are migraine with aura, seizure, and syncope.^9,10 Symptoms that generally are not associated with a TIA are chest pain, generalized weakness, and confusion.¹¹ A complete history and physical exam provide the path to the imaging, laboratory, and cardiac testing that is needed to differentiate these diagnoses from a TIA.

A thorough history is best obtained from the patient and a witness, if available, and should include identification of any focal neurologic deficits and the duration and time to resolution of symptoms. Obtain a history of risk factors for ischemia—tobacco use, diabetes, obesity, dyslipidemia, hypertension, previous TIA or stroke, atrial fibrillation, and any coagulopathy. Ask questions about a family history of TIA, stroke, and coagulopathy.¹¹

A comprehensive physical exam, including vital signs, cardiac exam, a check for carotid bruits, and complete neurologic exam, should be performed. Most patients present with concerns for unilateral weakness and changes in speech, which are usually associated with infarction on DW-MRI.¹² The most common findings on physical exam include cranial nerve abnormalities, such as diplopia, hemianopia, monocular blindness, disconjugate gaze, facial drooping, lateral tongue movement, dysphagia, and vestibular dysfunction. Cerebellar abnormalities are also often noted, including past pointing, dystaxia, ataxia, nystagmus, and motor abnormalities (eg, spasticity, clonus, or unilateral weakness in the face or extremities).¹¹

Electrocardiography at the bedside can confirm atrial fibrillation or another arrhythmia quickly.

Essential laboratory testing includes measurement of blood glucose and serum electrolytes to determine if these particular imbalances are the cause of symptoms. The presence of a hypercoaguable state is determined by a complete blood count and coagulation studies.^3,13 Urine toxicology should also be obtained to rule out other causes of symptoms. A lipid profile is beneficial for making long-term treatment decisions.

Continue to: ABCD2 score

ABCD2 score. Patients who have had a TIA and present within 72 hours after symptoms have resolved should be hospitalized if they have an ABCD2 (Age, Blood pressure [BP], Clinical presentation, Diabetes mellitus [type 1 or 2], Duration of symptoms) prediction system score > 3.¹⁴ ABCD2 criteria can be used to help identify patients who are at higher risk of stroke or need further therapy (TABLE 1).^14,15

Send a patient with a current complaint or recent history of suspected focal neurologic deficits to an ED for accurate diagnosis of a possible TIA and, as appropriate, early treatment.

The ABCD2 score is also used to determine whether a patient needs dual antiplatelet therapy. Patients who score at the higher end of the ABCD2 system usually have an increased risk of stroke, longer hospitalization, and greater disability.

CASE

In the ED, Mr. L is immediately assessed and airlifted to a larger regional medical center, where MRI confirms a stroke.

Management

Initial management of a TIA is aimed at reducing the risk of recurrent TIA or stroke. Early medical and possibly surgical treatment are key for preventing stroke and improving outcomes. The first 48 hours after a TIA are the most critical because the incidence of recurrent TIA or stroke is highest during this period.^16-18

What is the accepted strategy for early treatment?

Initial treatment must include antiplatelet therapy, BP management, anticoagulation, statin therapy, and carotid endarterectomy as indicated.^2,19,20 Control of hypertension and anticoagulation decrease the risk of recurrent stroke by the largest margin²⁰; both are “A”-level Strength of Recommendation Taxonomy interventions.^2,3

Step 1: Antiplatelet therapy. After initial imaging is complete and if there are no contraindications, antiplatelet agents are recommended for patients who have had a noncardioembolic TIA. The American Heart Association and American Stroke Association recommend either aspirin, clopidogrel, dipyridamole + aspirin (available in a single capsule [Aggrenox]), or clopidogrel + aspirin as first-line therapy.^2,20 The choice of agent needs to be individualized, based on tolerability and adverse effects (TABLE 2^2,20,21).

A meta-analysis of antiplatelet therapy reviewed the optimum dosing of each medication.^21,22 Reduction of the risk of ischemic stroke with aspirin is 21% to 22% at the optimal dosing of 75 to 150 mg/d, which also reduces the risk of gastrointestinal bleeding.

Continue to: For a patient who has...

For a patient who has an ABCD2 score ≥ 4, has had a prior TIA, or has large-vessel disease, dual antiplatelet therapy is recommended for the first 21 days, with a subsequent return to monotherapy. Dual antiplatelet therapy of clopidogrel + aspirin increases the risk of adverse reactions and has not been shown to have greater long-term benefit^23-25 (TABLE 2^2,20,21).

Step 2: BP management. This is the next immediate step. As many as 80% of patients who present with a TIA have elevated BP upon admission. BP needs to be treated and carefully monitored during this early treatment phase. The recommendation is for a systolic BP < 185 mm Hg and a diastolic BP < 110 mm Hg.²⁴

Step 3: Anticoagulation. Treatment with warfarin or a direct oral anticoagulant (DOAC) is recommended for patients who have the potential for forming emboli—eg, in the setting of atrial fibrillation, ventricular thrombus, mechanical heart valve, or venous thromboembolism.

Step 4. High-intensity statin. A statin agent is recommended as part of immediate and long-term medical management, regardless of the low-density lipoprotein cholesterol (LDL-C) level, to reduce the risk of stroke.^2,24

Carotid artery management. Surgical intervention is not always considered a component of immediate medical management. However, guidelines recommend that carotid endarterectomy or stenting be considered in patients who have stenosis > 70%.²

CASE

Mr. L is admitted to the hospital and undergoes neurosurgical intervention. Medical management is instituted.

Long-term management and secondary prevention

The main risk factors for stroke can be divided into modifiable, vascular, and unmodifiable. Addressing both modifiable and vascular risks is important for secondary prevention.

Continue to: Modifiable and vascular risk factors

 

 

Modifiable and vascular risk factors

Modifiable risk factors for stroke include hypertension, diabetes, dyslipidemia, smoking, and physical activity; the most important of these, for preventing subsequent stroke after an initial TIA, is hypertension.²⁶

The 2 more significant vascular risk factors for stroke are carotid artery stenosis and atrial fibrillation.

Hypertension. Improving control of hypertension can improve secondary risk reduction for recurrent stroke. Control of both systolic and diastolic BP is important in this regard, with larger systolic BP reductions having a greater impact on decreasing the risk of recurrent stroke.²⁴ Evidence supports lowering BP to improve secondary risk reduction in people with and without diagnosed hypertension: The goal is to lower systolic BP by ≥ 10 mm Hg and diastolic BP by 5 mm Hg.²⁴ No particular class of antihypertensive is recommended in the first line, although preliminary evidence shows that a diuretic, with or without an angiotensin-converting enzyme inhibitor, might be more beneficial than other options.²⁴

Diabetes. The risk of cardiovascular disease, including stroke, is higher in people with diabetes. Evidence shows that various (but not all) agents in 2 pharmaceutical classes—glucagon-like peptide-1 (GLP-1) receptor agonists and the sodium glucose-2 cotransporter (SGLT2) inhibitors—reduce the risk of major cardiovascular events and improve secondary prevention of recurrent stroke:

• EMPA-REG OUTCOME (ClinicalTrials.gov Identifier: NCT01131676) was the first trial to show cardiovascular benefit from an SGLT2 inhibitor (empagliflozin); subsequent studies confirmed the cardiovascular benefits found in EMPA-REG OUTCOME.^27,28
• The ELIXA trial (ClinicalTrials.gov Identifier: NCT01147250) was the first to show cardiovascular benefit from a GLP-1 receptor agonist (lixisenatide); subsequent studies supported this finding.^29,30

Appropriate agents in these 2 classes should be considered as first-line or adjunctive in patients with both diabetes and known cardiovascular disease, as long as there are no contraindications.^27,28

Pioglitazone, a thiazolidinedione-class antidiabetic agent, was once considered a potential option to improve secondary prevention of stroke. However, the thiazolidinediones are generally no longer considered; instead, the SGLT2 inhibitors and GLP-1 receptor agonists are favored.³¹

Evidence demonstrates the effect of hyperglycemia on cardiovascular events; however, it is important to note that hypoglycemia can result in symptoms and focal changes that mimic a stroke. In addition, some evidence suggests that hypoglycemia can increase cardiovascular risk—thereby supporting the importance of strict control of diabetes and maintenance of euglycemia in reducing overall cardiovascular risk.³²

Continue to: Lipids

Lipids. The SPARCL trial (ClinicalTrials.gov Identifier: NCT00147602) was the first study to demonstrate the benefit of high-­intensity statin therapy—specifically, atorvastatin 80 mg/d—for secondary prevention for recurrent stroke.³³ The recommendation is to use high-intensity statin therapy to decrease the risk of recurrent stroke by reducing the level of LDL-C—by ≥ 50% or to < 70 mg/dL, for maximum risk reduction.^24,34

Common conditions that mimic a TIA are migraine with aura, seizure, and syncope; a TIA is generally not associated with chest pain, generalized weakness, or confusion.

The IMPROVE-IT trial (ClinicalTrials.gov Identifier: NCT00202878) demonstrated the benefit of adding ezetimibe, 10 mg/d, to a moderate-to-high-intensity statin (simvastatin, 40-80 mg/d) to reduce the risk of recurrent stroke.³⁵

Results of recent studies support the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for regulating levels of LDL-C, as an additional option to consider—if needed to further reduce the LDL-C level or if statins are contraindicated in a particular patient.³⁴

Smoking cessation. Cigarette smoking is known to increase the risk of ischemic stroke; newer evidence shows that second-hand exposure to smoke also increases the risk of ischemic stroke.^36,37 Although these studies focused on primary prevention of ischemic stroke, the data can reasonably be applied to secondary prevention.³⁸ The recommendation for secondary prevention is to quit smoking and avoid secondhand smoke.²⁴

Alcohol. Evidence demonstrates that heavy alcohol consumption and alcoholism increase the risk of stroke; similar to what is known about smoking, most available data relate to primary prevention.³⁸ The recommendation for providing secondary stroke prevention is to stop or decrease alcohol intake.²⁴

Weight reduction. Obesity (body mass index > 30) increases the risk of ischemic stroke. However, there is, as yet, no evidence that weight loss diminishes the risk of subsequent stroke for secondary prevention.²⁴

Physical activity. Aerobic exercise and strength-training programs after a stroke improve cardiovascular health and mobility. There is no evidence that exercise leads to a reduction in the risk of subsequent stroke.²⁴

Continue to: Nutrition

Nutrition. No current randomized controlled trials are focused on the relationship between diet and recurrent stroke for purposes of prevention; however, evidence for both BP and lipid control incorporate dietary guidance. Recommendations include reducing intake of saturated fats and of sodium (the latter, to < 2.3 g/d) and increasing intake of fruits and vegetables, both of which are beneficial for controlling BP and lipid levels and promoting overall cardiovascular health.³⁸

Carotid artery stenosis. Several randomized controlled trials have demonstrated benefit from treating carotid stenosis (> 70% stenosis but not < 50%) with carotid endarterectomy to reduce the risk of recurrent stroke after TIA.² The ideal timing of carotid endarterectomy is still being studied; however, available evidence supports intervention within 2 to 6 weeks after TIA or stroke.²⁵ Studies are ongoing that compare carotid angioplasty and stenting against carotid endarterectomy. Medical therapy, with antiplatelet agents and statins, is recommended after carotid endarterectomy.²⁵

Atrial fibrillation increases the risk of recurrent stroke after a TIA, and is the most important indication for secondary stroke prevention with anticoagulation therapy:

• Warfarin. Several studies have shown that warfarin provides a 68% relative risk reduction and a 1.4% absolute risk reduction in the annual stroke rate.²⁴ To achieve this reduction in risk, the optimal international normalized ratio is 2.5 (range, 2-3).²⁴
• Aspirin provides a 13% relative risk reduction for recurrent stroke, although there is evidence that long-term anticoagulation provides more benefit than aspirin after a TIA.^39-41 Optimal dosing of aspirin ranges from 75-100 mg/d; greatest benefit is likely in the 12 weeks after stroke, when the risk of recurrent stroke is highest.^31,41,42
• DOACs have similar efficacy to warfarin but more rapid onset, lower risk of bleeding, fewer drug interactions, and no requirement for monitoring—often making them a more tolerable long-term choice. Options are rivaroxaban 20 mg/d, dabigatran 150 mg twice daily, apixaban 5 mg twice daily, and edoxaban 60 mg/d.³⁹

Initial treatment of a TIA must include antiplatelet therapy, BP management, anticoagulation, and statin therapy; carotid endarterectomy might also be indicated.

When to start anticoagulation and the choice of agent should be weighed against a risk of bleeding, which is highest after the initial stroke. Cost is also a consideration: DOACs are more expensive than warfarin.

CASE

Mr. L is discharged 3 days after carotid endarterectomy and free of residual deficits. He is started on dual antiplatelet therapy (aspirin + clopidogrel) for 21 days, to be followed by a return to monotherapy. He is restarted on a high-intensity statin. He is instructed to resume taking the selective serotonin reuptake inhibitor and melatonin for sleep, as needed. Last, he is told to schedule follow-up with his primary care physician in 7 to 10 days to begin post-stroke care.

Final thoughts

Primary care physicians are often the first point of contact for patients with current or remote TIA symptoms. Based on that ­provider–patient relationship, evidence supports several recommendations for diagnosing and treating a TIA and for reducing the risk of recurrent stroke after TIA. Addressing each of these areas, in this order, is imperative to reduce the risk of recurrent stroke and improve overall cardiovascular outcomes:

• Obtain an accurate diagnosis of a TIA, using DW-MRI or comparable brain imaging, to allow for prompt intervention.
• Initiate BP management promptly in the acute setting and establish optimal BP control over the long term.
• Begin appropriate antiplatelet therapy.
• When indicated (eg, atrial fibrillation), begin anticoagulation therapy with a DOAC or warfarin.
• Begin high-intensity statin therapy.
• Consider treating patients with diabetes using an SGLT2 inhibitor or GLP-1 receptor agonist.
• Encourage smoking cessation, prescribe quit-smoking medications, or refer a smoker for behavioral support.

Education. Last, it is important to educate patients—especially those who have risk factors for a TIA or stroke—about the presentation of events, so that they know to seek immediate medical attention.

CORRESPONDENCE
Kristen Rundell, MD, Department of Family and Community Medicine, University of Arizona College of Medicine, 655 North Alvernon Way, Suite 228, Tucson, AZ 85711; kristenrundell@arizona.edu

An at-home investigational device is a promising noninvasive therapeutic approach for anxiety disorders, results from an open-label pilot trial suggest.

The small study showed users of the Mechanical Affective Touch Therapy (MATT) had improved anxiety and depression symptoms, which corresponded to positive changes in alpha and theta oscillatory activity.

Butler Hospital

Robust safety profile

Therapeutic noninvasive peripheral nerve stimulation is under investigation for anxiety as well as pain and depression. Nerve activation is achieved by delivering electrical or mechanical energy, although most devices to date have used electrical stimulation.

Although electrical stimulation is considered low risk, mechanical stimulation that activates somatosensory pathways has an even more robust safety profile, the investigators note.

The MATT device targets C-tactile fibers (CT) specialized unmyelinated Group C peripheral nerve fibers that fire when stroked at velocities perceived as pleasurable or comforting.

To use the device, participants wear a headset with a small vibrating piece that sits on the mastoid bone behind each ear. These pieces deliver gentle vibrations that can be adjusted by patients.  

During development of the MATT stimulation, researchers noted that an isochronic 10 Hz wave, cycling 2 seconds on and 2 seconds off, induced a state of relaxation and increased occipital alpha oscillations in pilot study participants.

The current study was designed to confirm preliminary efficacy and feasibility signals. The sample included 22 patients (mean age 37.3 years, 72.7% female, 77.3% White). All study participants were diagnosed with an anxiety disorder and had at least moderately severe anxiety symptoms. Some also had symptoms of panic or depression.

Many participants were on medications that weren’t effective, and they wanted to find a nondrug method of relieving their symptoms, said Dr. Carpenter.
 

What’s the mechanism?

Participants learned how to administer the stimulation and adjust the intensity of vibrations to a level where it was consistently detectable but not uncomfortable. Then they received a MATT device to use at home at least twice daily for 20 minutes.

Patients kept daily diaries documenting device use, adverse effects, and technological problems. In-person assessments were held at 2 and 4 weeks.

Researchers collected resting EEG immediately before, and after, the second stimulation session and again following 4 weeks of MATT use.

At baseline and after 2 and 4 weeks, patients self-reported anxiety using the 7-item Generalized Anxiety Disorder (GAD-7) scale, depression with the Beck Depression Inventory (BDI), and stress using the Perceived Stress Scale (PSS). They also reported symptoms with the Depression, Anxiety, Stress Scale (DASS).

Researchers also investigated “interoceptive awareness” or being mindful of your body and internal feelings. For this, they had participants complete the 32-item Multidimensional Assessment of Interoceptive Awareness pre- and post treatment.

Interoceptive awareness “is a whole new area of interest in neuroscience and brain health,” said Dr. Carpenter. “The hypothesis was that one way this device might work is that vibrations would travel to the insular cortex, the part of the brain that involves mindfulness and self-awareness.”
 

Symptom reduction

In the completer sample of 17 participants, mean scores on anxiety and depression symptoms fell significantly from baseline to 4 weeks (all P < .01). For example, the GAD-7 mean score fell from 14.3 to 7.1 and the BDI mean score from 30.6 to 14.8.

The study also showed that mindfulness was enhanced. The MAIA total score increased from 83.1 to 93.5 (P = .014).

Device users had increased alpha and theta brainwave activity, findings that “go along with the concept of decreased anxiety,” said Dr. Carpenter. She noted a recent study of the same patient population showed the device enhanced functional brain connectivity.

This current study was too small to pick up signals showing the device was effective in any particular subpopulation, said Dr. Carpenter.

Unlike other stimulation interventions that require clinic visits, patients use the MATT in the comfort of their own home and at their own convenience.

However, there are still questions surrounding the use of the noninvasive device. For example, said Dr. Carpenter, it’s unclear if it would be more effective if combined with psychotherapy or whether patients can use it while sleeping and driving. A next step could be a sham-controlled trial, she said.

The study was supported by Affect Neuro, developer of MATT therapy, and the National Institute of General Medical Sciences. Dr. Carpenter reports receiving a consultancy fee from Affect Neuro.

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

An at-home investigational device is a promising noninvasive therapeutic approach for anxiety disorders, results from an open-label pilot trial suggest.

The small study showed users of the Mechanical Affective Touch Therapy (MATT) had improved anxiety and depression symptoms, which corresponded to positive changes in alpha and theta oscillatory activity.

Butler Hospital

Robust safety profile

Therapeutic noninvasive peripheral nerve stimulation is under investigation for anxiety as well as pain and depression. Nerve activation is achieved by delivering electrical or mechanical energy, although most devices to date have used electrical stimulation.

Although electrical stimulation is considered low risk, mechanical stimulation that activates somatosensory pathways has an even more robust safety profile, the investigators note.

The MATT device targets C-tactile fibers (CT) specialized unmyelinated Group C peripheral nerve fibers that fire when stroked at velocities perceived as pleasurable or comforting.

To use the device, participants wear a headset with a small vibrating piece that sits on the mastoid bone behind each ear. These pieces deliver gentle vibrations that can be adjusted by patients.  

During development of the MATT stimulation, researchers noted that an isochronic 10 Hz wave, cycling 2 seconds on and 2 seconds off, induced a state of relaxation and increased occipital alpha oscillations in pilot study participants.

The current study was designed to confirm preliminary efficacy and feasibility signals. The sample included 22 patients (mean age 37.3 years, 72.7% female, 77.3% White). All study participants were diagnosed with an anxiety disorder and had at least moderately severe anxiety symptoms. Some also had symptoms of panic or depression.

Many participants were on medications that weren’t effective, and they wanted to find a nondrug method of relieving their symptoms, said Dr. Carpenter.
 

What’s the mechanism?

Participants learned how to administer the stimulation and adjust the intensity of vibrations to a level where it was consistently detectable but not uncomfortable. Then they received a MATT device to use at home at least twice daily for 20 minutes.

Patients kept daily diaries documenting device use, adverse effects, and technological problems. In-person assessments were held at 2 and 4 weeks.

Researchers collected resting EEG immediately before, and after, the second stimulation session and again following 4 weeks of MATT use.

At baseline and after 2 and 4 weeks, patients self-reported anxiety using the 7-item Generalized Anxiety Disorder (GAD-7) scale, depression with the Beck Depression Inventory (BDI), and stress using the Perceived Stress Scale (PSS). They also reported symptoms with the Depression, Anxiety, Stress Scale (DASS).

Researchers also investigated “interoceptive awareness” or being mindful of your body and internal feelings. For this, they had participants complete the 32-item Multidimensional Assessment of Interoceptive Awareness pre- and post treatment.

Interoceptive awareness “is a whole new area of interest in neuroscience and brain health,” said Dr. Carpenter. “The hypothesis was that one way this device might work is that vibrations would travel to the insular cortex, the part of the brain that involves mindfulness and self-awareness.”
 

Symptom reduction

In the completer sample of 17 participants, mean scores on anxiety and depression symptoms fell significantly from baseline to 4 weeks (all P < .01). For example, the GAD-7 mean score fell from 14.3 to 7.1 and the BDI mean score from 30.6 to 14.8.

The study also showed that mindfulness was enhanced. The MAIA total score increased from 83.1 to 93.5 (P = .014).

Device users had increased alpha and theta brainwave activity, findings that “go along with the concept of decreased anxiety,” said Dr. Carpenter. She noted a recent study of the same patient population showed the device enhanced functional brain connectivity.

This current study was too small to pick up signals showing the device was effective in any particular subpopulation, said Dr. Carpenter.

Unlike other stimulation interventions that require clinic visits, patients use the MATT in the comfort of their own home and at their own convenience.

However, there are still questions surrounding the use of the noninvasive device. For example, said Dr. Carpenter, it’s unclear if it would be more effective if combined with psychotherapy or whether patients can use it while sleeping and driving. A next step could be a sham-controlled trial, she said.

The study was supported by Affect Neuro, developer of MATT therapy, and the National Institute of General Medical Sciences. Dr. Carpenter reports receiving a consultancy fee from Affect Neuro.

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

An at-home investigational device is a promising noninvasive therapeutic approach for anxiety disorders, results from an open-label pilot trial suggest.

The small study showed users of the Mechanical Affective Touch Therapy (MATT) had improved anxiety and depression symptoms, which corresponded to positive changes in alpha and theta oscillatory activity.

Butler Hospital

Robust safety profile

Therapeutic noninvasive peripheral nerve stimulation is under investigation for anxiety as well as pain and depression. Nerve activation is achieved by delivering electrical or mechanical energy, although most devices to date have used electrical stimulation.

Although electrical stimulation is considered low risk, mechanical stimulation that activates somatosensory pathways has an even more robust safety profile, the investigators note.

The MATT device targets C-tactile fibers (CT) specialized unmyelinated Group C peripheral nerve fibers that fire when stroked at velocities perceived as pleasurable or comforting.

To use the device, participants wear a headset with a small vibrating piece that sits on the mastoid bone behind each ear. These pieces deliver gentle vibrations that can be adjusted by patients.  

During development of the MATT stimulation, researchers noted that an isochronic 10 Hz wave, cycling 2 seconds on and 2 seconds off, induced a state of relaxation and increased occipital alpha oscillations in pilot study participants.

The current study was designed to confirm preliminary efficacy and feasibility signals. The sample included 22 patients (mean age 37.3 years, 72.7% female, 77.3% White). All study participants were diagnosed with an anxiety disorder and had at least moderately severe anxiety symptoms. Some also had symptoms of panic or depression.

Many participants were on medications that weren’t effective, and they wanted to find a nondrug method of relieving their symptoms, said Dr. Carpenter.
 

What’s the mechanism?

Participants learned how to administer the stimulation and adjust the intensity of vibrations to a level where it was consistently detectable but not uncomfortable. Then they received a MATT device to use at home at least twice daily for 20 minutes.

Patients kept daily diaries documenting device use, adverse effects, and technological problems. In-person assessments were held at 2 and 4 weeks.

Researchers collected resting EEG immediately before, and after, the second stimulation session and again following 4 weeks of MATT use.

At baseline and after 2 and 4 weeks, patients self-reported anxiety using the 7-item Generalized Anxiety Disorder (GAD-7) scale, depression with the Beck Depression Inventory (BDI), and stress using the Perceived Stress Scale (PSS). They also reported symptoms with the Depression, Anxiety, Stress Scale (DASS).

Researchers also investigated “interoceptive awareness” or being mindful of your body and internal feelings. For this, they had participants complete the 32-item Multidimensional Assessment of Interoceptive Awareness pre- and post treatment.

Interoceptive awareness “is a whole new area of interest in neuroscience and brain health,” said Dr. Carpenter. “The hypothesis was that one way this device might work is that vibrations would travel to the insular cortex, the part of the brain that involves mindfulness and self-awareness.”
 

Symptom reduction

In the completer sample of 17 participants, mean scores on anxiety and depression symptoms fell significantly from baseline to 4 weeks (all P < .01). For example, the GAD-7 mean score fell from 14.3 to 7.1 and the BDI mean score from 30.6 to 14.8.

The study also showed that mindfulness was enhanced. The MAIA total score increased from 83.1 to 93.5 (P = .014).

Device users had increased alpha and theta brainwave activity, findings that “go along with the concept of decreased anxiety,” said Dr. Carpenter. She noted a recent study of the same patient population showed the device enhanced functional brain connectivity.

This current study was too small to pick up signals showing the device was effective in any particular subpopulation, said Dr. Carpenter.

Unlike other stimulation interventions that require clinic visits, patients use the MATT in the comfort of their own home and at their own convenience.

However, there are still questions surrounding the use of the noninvasive device. For example, said Dr. Carpenter, it’s unclear if it would be more effective if combined with psychotherapy or whether patients can use it while sleeping and driving. A next step could be a sham-controlled trial, she said.

The study was supported by Affect Neuro, developer of MATT therapy, and the National Institute of General Medical Sciences. Dr. Carpenter reports receiving a consultancy fee from Affect Neuro.

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

Higher levels of specific carotenoid antioxidants in blood may help guard against age-related dementia, new research suggests.

Investigators found that individuals with the highest serum levels of lutein + zeaxanthin and beta-cryptoxanthin at baseline were less likely to have dementia decades later than were their peers with lower levels of these antioxidants.

Lutein and zeaxanthin are found in green leafy vegetables such as kale, spinach, broccoli, and peas. Beta-cryptoxanthin is found in fruits such as oranges, papaya, tangerines, and persimmons.

“Antioxidants may help protect the brain from oxidative stress, which can cause cell damage,” first author May A. Beydoun, PhD, with the National Institute on Aging (NIA), said in a news release. 

“This is the first nationally representative study to analyze blood levels of antioxidants in relation to dementia risk,” NIA scientific director Luigi Ferrucci, MD, said in an interview.

“Blood test results may be more representative of the actual antioxidant level than a person’s report of what kind of foods they regularly consume,” Dr. Ferrucci added.

The study was published online in Neurology.
 

Reduced dementia risk

The researchers tested associations and interactions of serum vitamins A, C and E, and total and individual serum carotenoids and interactions with incident Alzheimer’s disease (AD) and all-cause dementia.

They analyzed data from 7,283 participants in the Third National Health and Nutrition Examination Survey (NHANES III) who were at least 45 years old at baseline and followed for an average of 16-17 years.

They found serum levels of lutein + zeaxanthin were associated with reduced risk of all-cause dementia among people aged 65 and older in models adjusted for lifestyle.

For lutein + zeaxanthin, every standard deviation (SD) increase (roughly 15.4 µmol/liter) was associated with a 7% decrease in risk for dementia (hazard ratio [HR] 0.93; 95% confidence interval [CI], 0.87-0.99, P = .037). This association was attenuated somewhat after adjustment for socioeconomic status.

Serum levels of beta-cryptoxanthin showed a “strong” inverse relationship with all-cause dementia in age- and sex-adjusted models.

For beta-cryptoxanthin, every SD increase (roughly 8.6 µmol/liter) was associated with a 14% reduced risk for dementia in people aged 45 and older (HR, 0.86; 95% CI, 0.80-0.93, P < .001) and 65 and older (HR, 0.86; 95% CI, 0.80-0.93, P = .001).

This relationship remained strong in models adjusted for sociodemographic and socioeconomic factors but attenuated in subsequent models.

No associations were found for lycopene, alpha-carotene, beta-carotene, or vitamins A, C, or E in the fully adjusted models.

Antagonistic interactions were observed for vitamin A and alpha-carotene, vitamin A and beta-carotene, vitamin E and lycopene, and lycopene and beta-carotene, suggesting putative protective effects of one antioxidant at lower levels of the other, the researchers noted.

“This analysis of an observational study found that the most important carotenoids in potentially protecting the brain may be lutein + zeaxanthin and beta-cryptoxanthin. However, randomized controlled trials are needed to prove causality,” said Dr. Ferrucci.

“Experts do not yet know the daily level of antioxidant intake to promote healthy aging of the brain. More research is needed to establish the necessary level of antioxidant intake – through the diet and/or supplements – to promote brain health and healthy aging,” he added.
 

An important step forward

In an accompanying editorial, Babak Hooshmand, MD, PhD, and Miia Kivipelto, MD, PhD, with Karolinska Institute, Stockholm, noted that while nutrition and dietary components are “potential targets” for dementia risk reduction, observational studies to date have reported “inconsistent findings.”

This study is “an important step towards exploring the complex relationship between antioxidants and dementia because it accounts for factors that could possibly influence the associations and considers interactions between different components,” they wrote.

The findings are “challenging,” they added, because they may lead to the hypothesis that inhibition of oxidative damage by antioxidants might have beneficial effects on preventing dementia.

However, clinical trials of antioxidant supplementation have been mainly “disappointing” and a recent Cochrane review found a lack of evidence for supplement use to preserve cognitive function or prevent dementia, Dr. Hooshmand and Dr. Kivipelto noted.

They added that the study contributes to the belief that antioxidants don’t act independently of each other or other factors, including socioeconomic status and lifestyle, in the mediation of dementia risk.

“A careful examination of the evidence is required to learn how antioxidants influence the complex pathology of dementia, because it appears to be more to it than meets the eye,”they concluded.

The research was supported in part by the Intramural Research Program of the National Institutes of Health and the National Institute on Aging. Dr. Beydoun, Dr. Ferrucci, and Dr. Hooshmand report no relevant disclosures. Dr. Kivipelto has supported advisory boards for Combinostics, Roche, and Biogen.

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

Higher levels of specific carotenoid antioxidants in blood may help guard against age-related dementia, new research suggests.

Investigators found that individuals with the highest serum levels of lutein + zeaxanthin and beta-cryptoxanthin at baseline were less likely to have dementia decades later than were their peers with lower levels of these antioxidants.

Lutein and zeaxanthin are found in green leafy vegetables such as kale, spinach, broccoli, and peas. Beta-cryptoxanthin is found in fruits such as oranges, papaya, tangerines, and persimmons.

“Antioxidants may help protect the brain from oxidative stress, which can cause cell damage,” first author May A. Beydoun, PhD, with the National Institute on Aging (NIA), said in a news release. 

“This is the first nationally representative study to analyze blood levels of antioxidants in relation to dementia risk,” NIA scientific director Luigi Ferrucci, MD, said in an interview.

“Blood test results may be more representative of the actual antioxidant level than a person’s report of what kind of foods they regularly consume,” Dr. Ferrucci added.

The study was published online in Neurology.
 

Reduced dementia risk

The researchers tested associations and interactions of serum vitamins A, C and E, and total and individual serum carotenoids and interactions with incident Alzheimer’s disease (AD) and all-cause dementia.

They analyzed data from 7,283 participants in the Third National Health and Nutrition Examination Survey (NHANES III) who were at least 45 years old at baseline and followed for an average of 16-17 years.

They found serum levels of lutein + zeaxanthin were associated with reduced risk of all-cause dementia among people aged 65 and older in models adjusted for lifestyle.

For lutein + zeaxanthin, every standard deviation (SD) increase (roughly 15.4 µmol/liter) was associated with a 7% decrease in risk for dementia (hazard ratio [HR] 0.93; 95% confidence interval [CI], 0.87-0.99, P = .037). This association was attenuated somewhat after adjustment for socioeconomic status.

Serum levels of beta-cryptoxanthin showed a “strong” inverse relationship with all-cause dementia in age- and sex-adjusted models.

For beta-cryptoxanthin, every SD increase (roughly 8.6 µmol/liter) was associated with a 14% reduced risk for dementia in people aged 45 and older (HR, 0.86; 95% CI, 0.80-0.93, P < .001) and 65 and older (HR, 0.86; 95% CI, 0.80-0.93, P = .001).

This relationship remained strong in models adjusted for sociodemographic and socioeconomic factors but attenuated in subsequent models.

No associations were found for lycopene, alpha-carotene, beta-carotene, or vitamins A, C, or E in the fully adjusted models.

Antagonistic interactions were observed for vitamin A and alpha-carotene, vitamin A and beta-carotene, vitamin E and lycopene, and lycopene and beta-carotene, suggesting putative protective effects of one antioxidant at lower levels of the other, the researchers noted.

“This analysis of an observational study found that the most important carotenoids in potentially protecting the brain may be lutein + zeaxanthin and beta-cryptoxanthin. However, randomized controlled trials are needed to prove causality,” said Dr. Ferrucci.

“Experts do not yet know the daily level of antioxidant intake to promote healthy aging of the brain. More research is needed to establish the necessary level of antioxidant intake – through the diet and/or supplements – to promote brain health and healthy aging,” he added.
 

An important step forward

In an accompanying editorial, Babak Hooshmand, MD, PhD, and Miia Kivipelto, MD, PhD, with Karolinska Institute, Stockholm, noted that while nutrition and dietary components are “potential targets” for dementia risk reduction, observational studies to date have reported “inconsistent findings.”

This study is “an important step towards exploring the complex relationship between antioxidants and dementia because it accounts for factors that could possibly influence the associations and considers interactions between different components,” they wrote.

The findings are “challenging,” they added, because they may lead to the hypothesis that inhibition of oxidative damage by antioxidants might have beneficial effects on preventing dementia.

However, clinical trials of antioxidant supplementation have been mainly “disappointing” and a recent Cochrane review found a lack of evidence for supplement use to preserve cognitive function or prevent dementia, Dr. Hooshmand and Dr. Kivipelto noted.

They added that the study contributes to the belief that antioxidants don’t act independently of each other or other factors, including socioeconomic status and lifestyle, in the mediation of dementia risk.

“A careful examination of the evidence is required to learn how antioxidants influence the complex pathology of dementia, because it appears to be more to it than meets the eye,”they concluded.

The research was supported in part by the Intramural Research Program of the National Institutes of Health and the National Institute on Aging. Dr. Beydoun, Dr. Ferrucci, and Dr. Hooshmand report no relevant disclosures. Dr. Kivipelto has supported advisory boards for Combinostics, Roche, and Biogen.

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

Higher levels of specific carotenoid antioxidants in blood may help guard against age-related dementia, new research suggests.

Investigators found that individuals with the highest serum levels of lutein + zeaxanthin and beta-cryptoxanthin at baseline were less likely to have dementia decades later than were their peers with lower levels of these antioxidants.

Lutein and zeaxanthin are found in green leafy vegetables such as kale, spinach, broccoli, and peas. Beta-cryptoxanthin is found in fruits such as oranges, papaya, tangerines, and persimmons.

“Antioxidants may help protect the brain from oxidative stress, which can cause cell damage,” first author May A. Beydoun, PhD, with the National Institute on Aging (NIA), said in a news release. 

“This is the first nationally representative study to analyze blood levels of antioxidants in relation to dementia risk,” NIA scientific director Luigi Ferrucci, MD, said in an interview.

“Blood test results may be more representative of the actual antioxidant level than a person’s report of what kind of foods they regularly consume,” Dr. Ferrucci added.

The study was published online in Neurology.
 

Reduced dementia risk

The researchers tested associations and interactions of serum vitamins A, C and E, and total and individual serum carotenoids and interactions with incident Alzheimer’s disease (AD) and all-cause dementia.

They analyzed data from 7,283 participants in the Third National Health and Nutrition Examination Survey (NHANES III) who were at least 45 years old at baseline and followed for an average of 16-17 years.

They found serum levels of lutein + zeaxanthin were associated with reduced risk of all-cause dementia among people aged 65 and older in models adjusted for lifestyle.

For lutein + zeaxanthin, every standard deviation (SD) increase (roughly 15.4 µmol/liter) was associated with a 7% decrease in risk for dementia (hazard ratio [HR] 0.93; 95% confidence interval [CI], 0.87-0.99, P = .037). This association was attenuated somewhat after adjustment for socioeconomic status.

Serum levels of beta-cryptoxanthin showed a “strong” inverse relationship with all-cause dementia in age- and sex-adjusted models.

For beta-cryptoxanthin, every SD increase (roughly 8.6 µmol/liter) was associated with a 14% reduced risk for dementia in people aged 45 and older (HR, 0.86; 95% CI, 0.80-0.93, P < .001) and 65 and older (HR, 0.86; 95% CI, 0.80-0.93, P = .001).

This relationship remained strong in models adjusted for sociodemographic and socioeconomic factors but attenuated in subsequent models.

No associations were found for lycopene, alpha-carotene, beta-carotene, or vitamins A, C, or E in the fully adjusted models.

Antagonistic interactions were observed for vitamin A and alpha-carotene, vitamin A and beta-carotene, vitamin E and lycopene, and lycopene and beta-carotene, suggesting putative protective effects of one antioxidant at lower levels of the other, the researchers noted.

“This analysis of an observational study found that the most important carotenoids in potentially protecting the brain may be lutein + zeaxanthin and beta-cryptoxanthin. However, randomized controlled trials are needed to prove causality,” said Dr. Ferrucci.

“Experts do not yet know the daily level of antioxidant intake to promote healthy aging of the brain. More research is needed to establish the necessary level of antioxidant intake – through the diet and/or supplements – to promote brain health and healthy aging,” he added.
 

An important step forward

In an accompanying editorial, Babak Hooshmand, MD, PhD, and Miia Kivipelto, MD, PhD, with Karolinska Institute, Stockholm, noted that while nutrition and dietary components are “potential targets” for dementia risk reduction, observational studies to date have reported “inconsistent findings.”

This study is “an important step towards exploring the complex relationship between antioxidants and dementia because it accounts for factors that could possibly influence the associations and considers interactions between different components,” they wrote.

The findings are “challenging,” they added, because they may lead to the hypothesis that inhibition of oxidative damage by antioxidants might have beneficial effects on preventing dementia.

However, clinical trials of antioxidant supplementation have been mainly “disappointing” and a recent Cochrane review found a lack of evidence for supplement use to preserve cognitive function or prevent dementia, Dr. Hooshmand and Dr. Kivipelto noted.

They added that the study contributes to the belief that antioxidants don’t act independently of each other or other factors, including socioeconomic status and lifestyle, in the mediation of dementia risk.

“A careful examination of the evidence is required to learn how antioxidants influence the complex pathology of dementia, because it appears to be more to it than meets the eye,”they concluded.

The research was supported in part by the Intramural Research Program of the National Institutes of Health and the National Institute on Aging. Dr. Beydoun, Dr. Ferrucci, and Dr. Hooshmand report no relevant disclosures. Dr. Kivipelto has supported advisory boards for Combinostics, Roche, and Biogen.

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

The use of isotretinoin to treat acne was not associated with an increase in adverse neuropsychiatric outcomes, compared with the use of oral antibiotics, in a large retrospective cohort study published in the British Journal of Dermatology.

Although severe neuropsychiatric effects associated with isotretinoin therapy in patients with acne have been reported, “the evidence base ... is mixed and inconclusive,” and many studies are small, Seena Fazel, MBChB, MD, of the department of psychiatry, Oxford University, England, and co-authors write in the study.

The study results suggest that isotretinoin is conferring protection against adverse neuropsychiatric outcomes, particularly when compared with using oral antibiotics to treat acne, Dr. Fazel, professor of forensic psychiatry at Oxford University and the study’s senior author, said in an interview.

In the study, the investigators reviewed electronic health records (2013-2019) from a primarily United States–based dataset (TriNetX) of patients with acne aged 12-27 who had been followed for up to 1 year after their prescriptions had been dispensed.

There were four arms: those prescribed isotretinoin (30,866), oral antibiotics (44,748), topical anti-acne treatments (108,367), and those who had not been prescribed any acne treatment (78,666). The primary outcomes were diagnoses of a neuropsychiatric disorder (psychotic, mood, anxiety, personality, behavioral, and sleep disorders; and non-fatal self-harm) within one year of being prescribed treatment.

After using propensity score matching to adjust for confounders at baseline, the investigators determined that the odds ratio for any incident neuropsychiatric outcomes among patients with acne treated with isotretinoin was 0.80 (95% confidence interval, 0.74-0.87), compared with patients on oral antibiotics; 0.94 (95% CI, 0.87-1.02), compared with patients on topical anti-acne medications; and 1.06 (95% CI, 0.97-1.16), compared with those without a prescription for anti-acne medicines.

Side effects of isotretinoin – such as headache, dry mouth, and fatigue – were higher among those on isotretinoin than in the other three groups.

The authors concluded that isotretinoin was not independently linked to excess adverse neuropsychiatric outcomes at a population level. “We observed a consistent association between increasing acne severity as indicated by anti-acne treatment options and incidence of adverse neuropsychiatric outcomes, but the findings showed that isotretinoin exposure did not add to the risk of neuropsychiatric adverse outcomes over and above what was associated with oral antibiotics,” they write.

Isotretinoin treatment “appeared to mitigate the excess neuropsychiatric risk associated with recalcitrant moderate-to-severe acne,” they add.

The dermatology community has been interested in the impact isotretinoin has on mental health, and “I think clinically, they see that people get better on isotretinoin and their mental health improves,” Dr. Fazel told this news organization.

Asked to comment on the study results, John Barbieri, MD, MBA, director of the Advanced Acne Therapeutics Clinic, Brigham and Women’s Hospital, Boston, commended the investigators for the design of the trial.

“One of the strengths of this study is that they use a technique called propensity-score matching, where you try to make the groups of patients similar with respect to their other characteristics to minimize the risks of confounding and bias in the study, which I think is a real strength,” he told this news organization. “The other thing that they do, which I think is a strength, is to think about the impact of acne severity on these outcomes, because we know acne itself is associated with depression and risk for suicide and other neuropsychiatric outcomes.”

Including a cohort of patients who had acne and received oral antibiotics for comparison “is a nice way to address the potential for confounding by severity and confounding by indication,” Dr. Barbieri said. “Those who get antibiotics usually have more severe acne. They may not have it as severely as those who get isotretinoin, but it is a nice approach to account for background levels of depression and neuropsychiatric outcomes in patients with acne. I think that is a real strength of the study. This is one of the best studies to have looked at this question.” 

However, although the study found that isotretinoin decreased the excess psychiatric risk associated with refractory moderate-to-severe acne, it does not rule out the possibility that individuals may experience an adverse psychiatric outcome while on isotretinoin, Dr. Barbieri said.

“While I think on a population level, we absolutely can feel reassured by these data, I do think there are individual patients who have idiosyncratic, unpredictable reactions to isotretinoin where they have mood changes, whether it be irritability, depression, or other mood changes,” he cautioned. “Given the association of acne itself with mental health comorbidities, it is important to screen for comorbidities such as depression in all patients with acne.”

The study was funded by the Wellcome Trust, which provided Dr. Fazel and the first author with financial support for the study. One author is an employee of TriNetX; the other authors had no relevant disclosures. Dr. Barbieri reported no financial disclosures. He is cochair of the AAD’s Acne Guidelines Workgroup and associate editor at JAMA Dermatology.

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

The use of isotretinoin to treat acne was not associated with an increase in adverse neuropsychiatric outcomes, compared with the use of oral antibiotics, in a large retrospective cohort study published in the British Journal of Dermatology.

Although severe neuropsychiatric effects associated with isotretinoin therapy in patients with acne have been reported, “the evidence base ... is mixed and inconclusive,” and many studies are small, Seena Fazel, MBChB, MD, of the department of psychiatry, Oxford University, England, and co-authors write in the study.

The study results suggest that isotretinoin is conferring protection against adverse neuropsychiatric outcomes, particularly when compared with using oral antibiotics to treat acne, Dr. Fazel, professor of forensic psychiatry at Oxford University and the study’s senior author, said in an interview.

In the study, the investigators reviewed electronic health records (2013-2019) from a primarily United States–based dataset (TriNetX) of patients with acne aged 12-27 who had been followed for up to 1 year after their prescriptions had been dispensed.

There were four arms: those prescribed isotretinoin (30,866), oral antibiotics (44,748), topical anti-acne treatments (108,367), and those who had not been prescribed any acne treatment (78,666). The primary outcomes were diagnoses of a neuropsychiatric disorder (psychotic, mood, anxiety, personality, behavioral, and sleep disorders; and non-fatal self-harm) within one year of being prescribed treatment.

After using propensity score matching to adjust for confounders at baseline, the investigators determined that the odds ratio for any incident neuropsychiatric outcomes among patients with acne treated with isotretinoin was 0.80 (95% confidence interval, 0.74-0.87), compared with patients on oral antibiotics; 0.94 (95% CI, 0.87-1.02), compared with patients on topical anti-acne medications; and 1.06 (95% CI, 0.97-1.16), compared with those without a prescription for anti-acne medicines.

Side effects of isotretinoin – such as headache, dry mouth, and fatigue – were higher among those on isotretinoin than in the other three groups.

The authors concluded that isotretinoin was not independently linked to excess adverse neuropsychiatric outcomes at a population level. “We observed a consistent association between increasing acne severity as indicated by anti-acne treatment options and incidence of adverse neuropsychiatric outcomes, but the findings showed that isotretinoin exposure did not add to the risk of neuropsychiatric adverse outcomes over and above what was associated with oral antibiotics,” they write.

Isotretinoin treatment “appeared to mitigate the excess neuropsychiatric risk associated with recalcitrant moderate-to-severe acne,” they add.

The dermatology community has been interested in the impact isotretinoin has on mental health, and “I think clinically, they see that people get better on isotretinoin and their mental health improves,” Dr. Fazel told this news organization.

Asked to comment on the study results, John Barbieri, MD, MBA, director of the Advanced Acne Therapeutics Clinic, Brigham and Women’s Hospital, Boston, commended the investigators for the design of the trial.

“One of the strengths of this study is that they use a technique called propensity-score matching, where you try to make the groups of patients similar with respect to their other characteristics to minimize the risks of confounding and bias in the study, which I think is a real strength,” he told this news organization. “The other thing that they do, which I think is a strength, is to think about the impact of acne severity on these outcomes, because we know acne itself is associated with depression and risk for suicide and other neuropsychiatric outcomes.”

Including a cohort of patients who had acne and received oral antibiotics for comparison “is a nice way to address the potential for confounding by severity and confounding by indication,” Dr. Barbieri said. “Those who get antibiotics usually have more severe acne. They may not have it as severely as those who get isotretinoin, but it is a nice approach to account for background levels of depression and neuropsychiatric outcomes in patients with acne. I think that is a real strength of the study. This is one of the best studies to have looked at this question.” 

However, although the study found that isotretinoin decreased the excess psychiatric risk associated with refractory moderate-to-severe acne, it does not rule out the possibility that individuals may experience an adverse psychiatric outcome while on isotretinoin, Dr. Barbieri said.

“While I think on a population level, we absolutely can feel reassured by these data, I do think there are individual patients who have idiosyncratic, unpredictable reactions to isotretinoin where they have mood changes, whether it be irritability, depression, or other mood changes,” he cautioned. “Given the association of acne itself with mental health comorbidities, it is important to screen for comorbidities such as depression in all patients with acne.”

The study was funded by the Wellcome Trust, which provided Dr. Fazel and the first author with financial support for the study. One author is an employee of TriNetX; the other authors had no relevant disclosures. Dr. Barbieri reported no financial disclosures. He is cochair of the AAD’s Acne Guidelines Workgroup and associate editor at JAMA Dermatology.

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

The use of isotretinoin to treat acne was not associated with an increase in adverse neuropsychiatric outcomes, compared with the use of oral antibiotics, in a large retrospective cohort study published in the British Journal of Dermatology.

Although severe neuropsychiatric effects associated with isotretinoin therapy in patients with acne have been reported, “the evidence base ... is mixed and inconclusive,” and many studies are small, Seena Fazel, MBChB, MD, of the department of psychiatry, Oxford University, England, and co-authors write in the study.

The study results suggest that isotretinoin is conferring protection against adverse neuropsychiatric outcomes, particularly when compared with using oral antibiotics to treat acne, Dr. Fazel, professor of forensic psychiatry at Oxford University and the study’s senior author, said in an interview.

In the study, the investigators reviewed electronic health records (2013-2019) from a primarily United States–based dataset (TriNetX) of patients with acne aged 12-27 who had been followed for up to 1 year after their prescriptions had been dispensed.

There were four arms: those prescribed isotretinoin (30,866), oral antibiotics (44,748), topical anti-acne treatments (108,367), and those who had not been prescribed any acne treatment (78,666). The primary outcomes were diagnoses of a neuropsychiatric disorder (psychotic, mood, anxiety, personality, behavioral, and sleep disorders; and non-fatal self-harm) within one year of being prescribed treatment.

After using propensity score matching to adjust for confounders at baseline, the investigators determined that the odds ratio for any incident neuropsychiatric outcomes among patients with acne treated with isotretinoin was 0.80 (95% confidence interval, 0.74-0.87), compared with patients on oral antibiotics; 0.94 (95% CI, 0.87-1.02), compared with patients on topical anti-acne medications; and 1.06 (95% CI, 0.97-1.16), compared with those without a prescription for anti-acne medicines.

Side effects of isotretinoin – such as headache, dry mouth, and fatigue – were higher among those on isotretinoin than in the other three groups.

The authors concluded that isotretinoin was not independently linked to excess adverse neuropsychiatric outcomes at a population level. “We observed a consistent association between increasing acne severity as indicated by anti-acne treatment options and incidence of adverse neuropsychiatric outcomes, but the findings showed that isotretinoin exposure did not add to the risk of neuropsychiatric adverse outcomes over and above what was associated with oral antibiotics,” they write.

Isotretinoin treatment “appeared to mitigate the excess neuropsychiatric risk associated with recalcitrant moderate-to-severe acne,” they add.

The dermatology community has been interested in the impact isotretinoin has on mental health, and “I think clinically, they see that people get better on isotretinoin and their mental health improves,” Dr. Fazel told this news organization.

Asked to comment on the study results, John Barbieri, MD, MBA, director of the Advanced Acne Therapeutics Clinic, Brigham and Women’s Hospital, Boston, commended the investigators for the design of the trial.

“One of the strengths of this study is that they use a technique called propensity-score matching, where you try to make the groups of patients similar with respect to their other characteristics to minimize the risks of confounding and bias in the study, which I think is a real strength,” he told this news organization. “The other thing that they do, which I think is a strength, is to think about the impact of acne severity on these outcomes, because we know acne itself is associated with depression and risk for suicide and other neuropsychiatric outcomes.”

Including a cohort of patients who had acne and received oral antibiotics for comparison “is a nice way to address the potential for confounding by severity and confounding by indication,” Dr. Barbieri said. “Those who get antibiotics usually have more severe acne. They may not have it as severely as those who get isotretinoin, but it is a nice approach to account for background levels of depression and neuropsychiatric outcomes in patients with acne. I think that is a real strength of the study. This is one of the best studies to have looked at this question.” 

However, although the study found that isotretinoin decreased the excess psychiatric risk associated with refractory moderate-to-severe acne, it does not rule out the possibility that individuals may experience an adverse psychiatric outcome while on isotretinoin, Dr. Barbieri said.

“While I think on a population level, we absolutely can feel reassured by these data, I do think there are individual patients who have idiosyncratic, unpredictable reactions to isotretinoin where they have mood changes, whether it be irritability, depression, or other mood changes,” he cautioned. “Given the association of acne itself with mental health comorbidities, it is important to screen for comorbidities such as depression in all patients with acne.”

The study was funded by the Wellcome Trust, which provided Dr. Fazel and the first author with financial support for the study. One author is an employee of TriNetX; the other authors had no relevant disclosures. Dr. Barbieri reported no financial disclosures. He is cochair of the AAD’s Acne Guidelines Workgroup and associate editor at JAMA Dermatology.

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