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The psychopathic brain: New insight
Using MRI, researchers found that the striatum was about 10% larger on average in adults with psychopathic traits than in matched control persons and that this relationship was mediated by stimulation seeking and impulsivity.
The striatum is a subcortical region of the forebrain involved in the cognitive processing of reward-related information and motivational aspects of behavior.
“Our study’s results help advance our knowledge about what underlies antisocial behavior such as psychopathy,” co-author and neurocriminologist Olivia Choy, PhD, with Nanyang Technological University, Singapore, said in a news release.
“In addition to social environmental influences, it is important to consider that there can be differences in biology – in this case, the size of brain structures – between antisocial and non-antisocial individuals,” Dr. Choy added.
The study was published online in the Journal of Psychiatric Research.
Antisocial, egocentric
Individuals with psychopathic traits typically have an egocentric and antisocial personality. They generally lack remorse for their actions or empathy for others and often have criminal tendencies.
Some prior research suggests links between psychopathy and an overactive striatum, but it was unclear what role striatal volume plays in this behavior.
For the study, investigators assessed striatal volume using MRI in 120 adults living in the community, and they assessed psychopathy using the Psychopathy Checklist – Revised.
Correlational analyses showed that increased striatal volumes were associated with more psychopathic traits (P = .001) in both men and women.
Volumetric increases were found for all subregions of the striatum in psychopathic individuals, after controlling for age, substance dependence, substance abuse, antisocial personality disorder, attention-deficit/hyperactivity disorder, social adversity, and total brain volume.
An analysis of 18 psychopathic individuals showed that striatal volumes were increased 9.4%, compared with 18 propensity-matched control persons (P = .01).
Abnormal reward processing
Stimulation seeking and impulsivity partly mediated the striatal-psychopathy relationship, accounting for 49.4% of this association.
These findings “replicate and build on initial studies indicating striatal enlargement in adults with psychopathy, yielding an updated effect size of d = 0.48,” the researchers note.
The results are “consistent with the notion that striatal abnormalities in individuals with psychopathy partly reflect increased sensation-seeking and impulsivity and support the hypothesis of abnormal reward processing in psychopathy,” they add.
“We have always known that psychopaths go to extreme lengths to seek out rewards, including criminal activities that involve property, sex, and drugs,” co-author Adrian Raine, DPhil, department of criminology, psychiatry, and psychology, University of Pennsylvania, Philadelphia, said in a news release.
“We are now finding out a neurobiological underpinning of this impulsive and stimulating behavior in the form of enlargement to the striatum, a key brain area involved in rewards,” Dr. Raine added.
What causes striatal enlargement in individuals with psychopathy still needs to be determined.
In human development, the striatum typically becomes smaller as a child matures, suggesting that psychopathy is associated with differences in brain development, the researchers suggest.
“Because biological traits, such as the size of one’s striatum, can be inherited to child from parent, these findings give added support to neurodevelopmental perspectives of psychopathy – that the brains of these offenders do not develop normally throughout childhood and adolescence,” said Dr. Raine.
Larger studies needed
Commenting on the findings for this news organization, Terrie E. Moffitt, PhD, professor of psychology, Duke University, Durham, N.C., noted that there is “general consensus among brain-imaging researchers that testing brain-behavior relations requires very large samples in the thousands and also samples of research participants who represent the full extent of variation in the population as well as possible – from rich to poor, from well to unwell, from high IQ to low IQ, from strong mental health to mental illness, etc.
“It would be grand to see this study’s provocative finding replicated in a large, representative sampling design,” Dr. Moffitt said.
The study was supported in part by the National Institutes of Health. Dr. Choy, Dr. Raine, and Dr. Moffitt have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Using MRI, researchers found that the striatum was about 10% larger on average in adults with psychopathic traits than in matched control persons and that this relationship was mediated by stimulation seeking and impulsivity.
The striatum is a subcortical region of the forebrain involved in the cognitive processing of reward-related information and motivational aspects of behavior.
“Our study’s results help advance our knowledge about what underlies antisocial behavior such as psychopathy,” co-author and neurocriminologist Olivia Choy, PhD, with Nanyang Technological University, Singapore, said in a news release.
“In addition to social environmental influences, it is important to consider that there can be differences in biology – in this case, the size of brain structures – between antisocial and non-antisocial individuals,” Dr. Choy added.
The study was published online in the Journal of Psychiatric Research.
Antisocial, egocentric
Individuals with psychopathic traits typically have an egocentric and antisocial personality. They generally lack remorse for their actions or empathy for others and often have criminal tendencies.
Some prior research suggests links between psychopathy and an overactive striatum, but it was unclear what role striatal volume plays in this behavior.
For the study, investigators assessed striatal volume using MRI in 120 adults living in the community, and they assessed psychopathy using the Psychopathy Checklist – Revised.
Correlational analyses showed that increased striatal volumes were associated with more psychopathic traits (P = .001) in both men and women.
Volumetric increases were found for all subregions of the striatum in psychopathic individuals, after controlling for age, substance dependence, substance abuse, antisocial personality disorder, attention-deficit/hyperactivity disorder, social adversity, and total brain volume.
An analysis of 18 psychopathic individuals showed that striatal volumes were increased 9.4%, compared with 18 propensity-matched control persons (P = .01).
Abnormal reward processing
Stimulation seeking and impulsivity partly mediated the striatal-psychopathy relationship, accounting for 49.4% of this association.
These findings “replicate and build on initial studies indicating striatal enlargement in adults with psychopathy, yielding an updated effect size of d = 0.48,” the researchers note.
The results are “consistent with the notion that striatal abnormalities in individuals with psychopathy partly reflect increased sensation-seeking and impulsivity and support the hypothesis of abnormal reward processing in psychopathy,” they add.
“We have always known that psychopaths go to extreme lengths to seek out rewards, including criminal activities that involve property, sex, and drugs,” co-author Adrian Raine, DPhil, department of criminology, psychiatry, and psychology, University of Pennsylvania, Philadelphia, said in a news release.
“We are now finding out a neurobiological underpinning of this impulsive and stimulating behavior in the form of enlargement to the striatum, a key brain area involved in rewards,” Dr. Raine added.
What causes striatal enlargement in individuals with psychopathy still needs to be determined.
In human development, the striatum typically becomes smaller as a child matures, suggesting that psychopathy is associated with differences in brain development, the researchers suggest.
“Because biological traits, such as the size of one’s striatum, can be inherited to child from parent, these findings give added support to neurodevelopmental perspectives of psychopathy – that the brains of these offenders do not develop normally throughout childhood and adolescence,” said Dr. Raine.
Larger studies needed
Commenting on the findings for this news organization, Terrie E. Moffitt, PhD, professor of psychology, Duke University, Durham, N.C., noted that there is “general consensus among brain-imaging researchers that testing brain-behavior relations requires very large samples in the thousands and also samples of research participants who represent the full extent of variation in the population as well as possible – from rich to poor, from well to unwell, from high IQ to low IQ, from strong mental health to mental illness, etc.
“It would be grand to see this study’s provocative finding replicated in a large, representative sampling design,” Dr. Moffitt said.
The study was supported in part by the National Institutes of Health. Dr. Choy, Dr. Raine, and Dr. Moffitt have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Using MRI, researchers found that the striatum was about 10% larger on average in adults with psychopathic traits than in matched control persons and that this relationship was mediated by stimulation seeking and impulsivity.
The striatum is a subcortical region of the forebrain involved in the cognitive processing of reward-related information and motivational aspects of behavior.
“Our study’s results help advance our knowledge about what underlies antisocial behavior such as psychopathy,” co-author and neurocriminologist Olivia Choy, PhD, with Nanyang Technological University, Singapore, said in a news release.
“In addition to social environmental influences, it is important to consider that there can be differences in biology – in this case, the size of brain structures – between antisocial and non-antisocial individuals,” Dr. Choy added.
The study was published online in the Journal of Psychiatric Research.
Antisocial, egocentric
Individuals with psychopathic traits typically have an egocentric and antisocial personality. They generally lack remorse for their actions or empathy for others and often have criminal tendencies.
Some prior research suggests links between psychopathy and an overactive striatum, but it was unclear what role striatal volume plays in this behavior.
For the study, investigators assessed striatal volume using MRI in 120 adults living in the community, and they assessed psychopathy using the Psychopathy Checklist – Revised.
Correlational analyses showed that increased striatal volumes were associated with more psychopathic traits (P = .001) in both men and women.
Volumetric increases were found for all subregions of the striatum in psychopathic individuals, after controlling for age, substance dependence, substance abuse, antisocial personality disorder, attention-deficit/hyperactivity disorder, social adversity, and total brain volume.
An analysis of 18 psychopathic individuals showed that striatal volumes were increased 9.4%, compared with 18 propensity-matched control persons (P = .01).
Abnormal reward processing
Stimulation seeking and impulsivity partly mediated the striatal-psychopathy relationship, accounting for 49.4% of this association.
These findings “replicate and build on initial studies indicating striatal enlargement in adults with psychopathy, yielding an updated effect size of d = 0.48,” the researchers note.
The results are “consistent with the notion that striatal abnormalities in individuals with psychopathy partly reflect increased sensation-seeking and impulsivity and support the hypothesis of abnormal reward processing in psychopathy,” they add.
“We have always known that psychopaths go to extreme lengths to seek out rewards, including criminal activities that involve property, sex, and drugs,” co-author Adrian Raine, DPhil, department of criminology, psychiatry, and psychology, University of Pennsylvania, Philadelphia, said in a news release.
“We are now finding out a neurobiological underpinning of this impulsive and stimulating behavior in the form of enlargement to the striatum, a key brain area involved in rewards,” Dr. Raine added.
What causes striatal enlargement in individuals with psychopathy still needs to be determined.
In human development, the striatum typically becomes smaller as a child matures, suggesting that psychopathy is associated with differences in brain development, the researchers suggest.
“Because biological traits, such as the size of one’s striatum, can be inherited to child from parent, these findings give added support to neurodevelopmental perspectives of psychopathy – that the brains of these offenders do not develop normally throughout childhood and adolescence,” said Dr. Raine.
Larger studies needed
Commenting on the findings for this news organization, Terrie E. Moffitt, PhD, professor of psychology, Duke University, Durham, N.C., noted that there is “general consensus among brain-imaging researchers that testing brain-behavior relations requires very large samples in the thousands and also samples of research participants who represent the full extent of variation in the population as well as possible – from rich to poor, from well to unwell, from high IQ to low IQ, from strong mental health to mental illness, etc.
“It would be grand to see this study’s provocative finding replicated in a large, representative sampling design,” Dr. Moffitt said.
The study was supported in part by the National Institutes of Health. Dr. Choy, Dr. Raine, and Dr. Moffitt have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Neuropsychiatric risks of COVID-19: New data
The neuropsychiatric ramifications of severe COVID-19 infection appear to be no different than for other severe acute respiratory infections (SARI).
This suggests that disease severity, rather than pathogen, is the most relevant factor in new-onset neuropsychiatric illness, the investigators note.
The risk of new-onset neuropsychological illness after severe COVID-19 infection are “substantial, but similar to those after other severe respiratory infections,” study investigator Peter Watkinson, MD, Nuffield Department of Clinical Neurosciences, University of Oxford, and John Radcliffe Hospital, Oxford, England, told this news organization.
The study was published online in JAMA Psychiatry.
Significant mental health burden
Research has shown a significant burden of neuropsychological illness after severe COVID-19 infection. However, it’s unclear how this risk compares to SARI.
To investigate, Dr. Watkinson and colleagues evaluated electronic health record data on more than 8.3 million adults, including 16,679 (0.02%) who survived a hospital admission for SARI and 32,525 (0.03%) who survived a hospital stay for COVID-19.
Compared with the remaining population, risks of new anxiety disorder, dementia, psychotic disorder, depression, and bipolar disorder diagnoses were significantly and similarly increased in adults surviving hospitalization for either COVID-19 or SARI.
Compared with the wider population, survivors of severe SARI or COVID-19 were also at increased risk of starting treatment with antidepressants, hypnotics/anxiolytics, or antipsychotics.
When comparing survivors of SARI hospitalization to survivors of COVID-19 hospitalization, no significant differences were observed in the postdischarge rates of new-onset anxiety disorder, dementia, depression, or bipolar affective disorder.
The SARI and COVID groups also did not differ in terms of their postdischarge risks of antidepressant or hypnotic/anxiolytic use, but the COVID survivors had a 20% lower risk of starting an antipsychotic.
“In this cohort study, SARI were found to be associated with significant postacute neuropsychiatric morbidity, for which COVID-19 is not distinctly different,” Dr. Watkinson and colleagues write.
“These results may help refine our understanding of the post–severe COVID-19 phenotype and may inform post-discharge support for patients requiring hospital-based and intensive care for SARI regardless of causative pathogen,” they write.
Caveats, cautionary notes
Kevin McConway, PhD, emeritus professor of applied statistics at the Open University in Milton Keynes, England, described the study as “impressive.” However, he pointed out that the study’s observational design is a limitation.
“One can never be absolutely certain about the interpretation of findings of an observational study. What the research can’t tell us is what caused the increased psychiatric risks for people hospitalized with COVID-19 or some other serious respiratory disease,” Dr. McConway said.
“It can’t tell us what might happen in the future, when, we all hope, many fewer are being hospitalized with COVID-19 than was the case in those first two waves, and the current backlog of provision of some health services has decreased,” he added.
“So we can’t just say that, in general, serious COVID-19 has much the same neuropsychiatric consequences as other very serious respiratory illness. Maybe it does, maybe it doesn’t,” Dr. McConway cautioned.
Max Taquet, PhD, with the University of Oxford, noted that the study is limited to hospitalized adult patients, leaving open the question of risk in nonhospitalized individuals – which is the overwhelming majority of patients with COVID-19 – or in children.
Whether the neuropsychiatric risks have remained the same since the emergence of the Omicron variant also remains “an open question since all patients in this study were diagnosed before July 2021,” Dr. Taquet said in statement.
The study was funded by the Wellcome Trust, the John Fell Oxford University Press Research Fund, the Oxford Wellcome Institutional Strategic Support Fund and Cancer Research UK, through the Cancer Research UK Oxford Centre. Dr. Watkinson disclosed grants from the National Institute for Health Research and Sensyne Health outside the submitted work; and serving as chief medical officer for Sensyne Health prior to this work, as well as holding shares in the company. Dr. McConway is a trustee of the UK Science Media Centre and a member of its advisory committee. His comments were provided in his capacity as an independent professional statistician. Dr. Taquet has worked on similar studies trying to identify, quantify, and specify the neurological and psychiatric consequences of COVID-19.
A version of this article first appeared on Medscape.com.
The neuropsychiatric ramifications of severe COVID-19 infection appear to be no different than for other severe acute respiratory infections (SARI).
This suggests that disease severity, rather than pathogen, is the most relevant factor in new-onset neuropsychiatric illness, the investigators note.
The risk of new-onset neuropsychological illness after severe COVID-19 infection are “substantial, but similar to those after other severe respiratory infections,” study investigator Peter Watkinson, MD, Nuffield Department of Clinical Neurosciences, University of Oxford, and John Radcliffe Hospital, Oxford, England, told this news organization.
The study was published online in JAMA Psychiatry.
Significant mental health burden
Research has shown a significant burden of neuropsychological illness after severe COVID-19 infection. However, it’s unclear how this risk compares to SARI.
To investigate, Dr. Watkinson and colleagues evaluated electronic health record data on more than 8.3 million adults, including 16,679 (0.02%) who survived a hospital admission for SARI and 32,525 (0.03%) who survived a hospital stay for COVID-19.
Compared with the remaining population, risks of new anxiety disorder, dementia, psychotic disorder, depression, and bipolar disorder diagnoses were significantly and similarly increased in adults surviving hospitalization for either COVID-19 or SARI.
Compared with the wider population, survivors of severe SARI or COVID-19 were also at increased risk of starting treatment with antidepressants, hypnotics/anxiolytics, or antipsychotics.
When comparing survivors of SARI hospitalization to survivors of COVID-19 hospitalization, no significant differences were observed in the postdischarge rates of new-onset anxiety disorder, dementia, depression, or bipolar affective disorder.
The SARI and COVID groups also did not differ in terms of their postdischarge risks of antidepressant or hypnotic/anxiolytic use, but the COVID survivors had a 20% lower risk of starting an antipsychotic.
“In this cohort study, SARI were found to be associated with significant postacute neuropsychiatric morbidity, for which COVID-19 is not distinctly different,” Dr. Watkinson and colleagues write.
“These results may help refine our understanding of the post–severe COVID-19 phenotype and may inform post-discharge support for patients requiring hospital-based and intensive care for SARI regardless of causative pathogen,” they write.
Caveats, cautionary notes
Kevin McConway, PhD, emeritus professor of applied statistics at the Open University in Milton Keynes, England, described the study as “impressive.” However, he pointed out that the study’s observational design is a limitation.
“One can never be absolutely certain about the interpretation of findings of an observational study. What the research can’t tell us is what caused the increased psychiatric risks for people hospitalized with COVID-19 or some other serious respiratory disease,” Dr. McConway said.
“It can’t tell us what might happen in the future, when, we all hope, many fewer are being hospitalized with COVID-19 than was the case in those first two waves, and the current backlog of provision of some health services has decreased,” he added.
“So we can’t just say that, in general, serious COVID-19 has much the same neuropsychiatric consequences as other very serious respiratory illness. Maybe it does, maybe it doesn’t,” Dr. McConway cautioned.
Max Taquet, PhD, with the University of Oxford, noted that the study is limited to hospitalized adult patients, leaving open the question of risk in nonhospitalized individuals – which is the overwhelming majority of patients with COVID-19 – or in children.
Whether the neuropsychiatric risks have remained the same since the emergence of the Omicron variant also remains “an open question since all patients in this study were diagnosed before July 2021,” Dr. Taquet said in statement.
The study was funded by the Wellcome Trust, the John Fell Oxford University Press Research Fund, the Oxford Wellcome Institutional Strategic Support Fund and Cancer Research UK, through the Cancer Research UK Oxford Centre. Dr. Watkinson disclosed grants from the National Institute for Health Research and Sensyne Health outside the submitted work; and serving as chief medical officer for Sensyne Health prior to this work, as well as holding shares in the company. Dr. McConway is a trustee of the UK Science Media Centre and a member of its advisory committee. His comments were provided in his capacity as an independent professional statistician. Dr. Taquet has worked on similar studies trying to identify, quantify, and specify the neurological and psychiatric consequences of COVID-19.
A version of this article first appeared on Medscape.com.
The neuropsychiatric ramifications of severe COVID-19 infection appear to be no different than for other severe acute respiratory infections (SARI).
This suggests that disease severity, rather than pathogen, is the most relevant factor in new-onset neuropsychiatric illness, the investigators note.
The risk of new-onset neuropsychological illness after severe COVID-19 infection are “substantial, but similar to those after other severe respiratory infections,” study investigator Peter Watkinson, MD, Nuffield Department of Clinical Neurosciences, University of Oxford, and John Radcliffe Hospital, Oxford, England, told this news organization.
The study was published online in JAMA Psychiatry.
Significant mental health burden
Research has shown a significant burden of neuropsychological illness after severe COVID-19 infection. However, it’s unclear how this risk compares to SARI.
To investigate, Dr. Watkinson and colleagues evaluated electronic health record data on more than 8.3 million adults, including 16,679 (0.02%) who survived a hospital admission for SARI and 32,525 (0.03%) who survived a hospital stay for COVID-19.
Compared with the remaining population, risks of new anxiety disorder, dementia, psychotic disorder, depression, and bipolar disorder diagnoses were significantly and similarly increased in adults surviving hospitalization for either COVID-19 or SARI.
Compared with the wider population, survivors of severe SARI or COVID-19 were also at increased risk of starting treatment with antidepressants, hypnotics/anxiolytics, or antipsychotics.
When comparing survivors of SARI hospitalization to survivors of COVID-19 hospitalization, no significant differences were observed in the postdischarge rates of new-onset anxiety disorder, dementia, depression, or bipolar affective disorder.
The SARI and COVID groups also did not differ in terms of their postdischarge risks of antidepressant or hypnotic/anxiolytic use, but the COVID survivors had a 20% lower risk of starting an antipsychotic.
“In this cohort study, SARI were found to be associated with significant postacute neuropsychiatric morbidity, for which COVID-19 is not distinctly different,” Dr. Watkinson and colleagues write.
“These results may help refine our understanding of the post–severe COVID-19 phenotype and may inform post-discharge support for patients requiring hospital-based and intensive care for SARI regardless of causative pathogen,” they write.
Caveats, cautionary notes
Kevin McConway, PhD, emeritus professor of applied statistics at the Open University in Milton Keynes, England, described the study as “impressive.” However, he pointed out that the study’s observational design is a limitation.
“One can never be absolutely certain about the interpretation of findings of an observational study. What the research can’t tell us is what caused the increased psychiatric risks for people hospitalized with COVID-19 or some other serious respiratory disease,” Dr. McConway said.
“It can’t tell us what might happen in the future, when, we all hope, many fewer are being hospitalized with COVID-19 than was the case in those first two waves, and the current backlog of provision of some health services has decreased,” he added.
“So we can’t just say that, in general, serious COVID-19 has much the same neuropsychiatric consequences as other very serious respiratory illness. Maybe it does, maybe it doesn’t,” Dr. McConway cautioned.
Max Taquet, PhD, with the University of Oxford, noted that the study is limited to hospitalized adult patients, leaving open the question of risk in nonhospitalized individuals – which is the overwhelming majority of patients with COVID-19 – or in children.
Whether the neuropsychiatric risks have remained the same since the emergence of the Omicron variant also remains “an open question since all patients in this study were diagnosed before July 2021,” Dr. Taquet said in statement.
The study was funded by the Wellcome Trust, the John Fell Oxford University Press Research Fund, the Oxford Wellcome Institutional Strategic Support Fund and Cancer Research UK, through the Cancer Research UK Oxford Centre. Dr. Watkinson disclosed grants from the National Institute for Health Research and Sensyne Health outside the submitted work; and serving as chief medical officer for Sensyne Health prior to this work, as well as holding shares in the company. Dr. McConway is a trustee of the UK Science Media Centre and a member of its advisory committee. His comments were provided in his capacity as an independent professional statistician. Dr. Taquet has worked on similar studies trying to identify, quantify, and specify the neurological and psychiatric consequences of COVID-19.
A version of this article first appeared on Medscape.com.
Most COVID-19 survivors return to work within 2 years
The burden of persistent COVID-19 symptoms appeared to improve over time, but a higher percentage of former patients reported poor health, compared with the general population. This suggests that some patients need more time to completely recover from COVID-19, wrote the authors of the new study, which was published in The Lancet Respiratory Medicine. Previous research has shown that the health effects of COVID-19 last for up to a year, but data from longer-term studies are limited, said Lixue Huang, MD, of Capital Medical University, Beijing, one of the study authors, and colleagues.
Methods and results
In the new study, the researchers reviewed data from 1,192 adult patients who were discharged from the hospital after surviving COVID-19 between Jan. 7, 2020, and May 29, 2020. The researchers measured the participants’ health outcomes at 6 months, 12 months, and 2 years after their onset of symptoms. A community-based dataset of 3,383 adults with no history of COVID-19 served as controls to measure the recovery of the COVID-19 patients. The median age of the patients at the time of hospital discharge was 57 years, and 46% were women. The median follow-up time after the onset of symptoms was 185 days, 349 days, and 685 days for the 6-month, 12-month, and 2-year visits, respectively. The researchers measured health outcomes using a 6-min walking distance (6MWD) test, laboratory tests, and questionnaires about symptoms, mental health, health-related quality of life, returning to work, and health care use since leaving the hospital.
Overall, the proportion of COVID-19 survivors with at least one symptom decreased from 68% at 6 months to 55% at 2 years (P < .0001). The most frequent symptoms were fatigue and muscle weakness, reported by approximately one-third of the patients (31%); sleep problems also were reported by 31% of the patients.
The proportion of individuals with poor results on the 6MWD decreased continuously over time, not only in COVID-19 survivors overall, but also in three subgroups of varying initial disease severity. Of the 494 survivors who reported working before becoming ill, 438 (89%) had returned to their original jobs 2 years later. The most common reasons for not returning to work were decreased physical function, unwillingness to return, and unemployment, the researchers noted.
However, at 2 years, COVID-19 survivors reported more pain and discomfort, as well as more anxiety and depression, compared with the controls (23% vs. 5% and 12% vs. 5%, respectively).
In addition, significantly more survivors who needed high levels of respiratory support while hospitalized had lung diffusion impairment (65%), reduced residual volume (62%), and total lung capacity (39%), compared with matched controls (36%, 20%, and 6%, respectively) at 2 years.
Long-COVID concerns
Approximately half of the survivors had symptoms of long COVID at 2 years. These individuals were more likely to report pain or discomfort or anxiety or depression, as well as mobility problems, compared to survivors without long COVID. Participants with long-COVID symptoms were more than twice as likely to have an outpatient clinic visit (odds ratio, 2.82), and not quite twice as likely to be rehospitalized (OR, 1.64).
“We found that [health-related quality of life], exercise capacity, and mental health continued to improve throughout the 2 years regardless of initial disease severity, but about half still had symptomatic sequelae at 2 years,” the researchers wrote in their paper.
Findings can inform doctor-patient discussions
“We are increasingly recognizing that the health effects of COVID-19 may persist beyond acute illness, therefore this is a timely study to assess the long-term impact of COVID-19 with a long follow-up period,” said Suman Pal, MD, an internal medicine physician at the University of New Mexico, Albuquerque, in an interview.
The findings are consistent with the existing literature, said Dr. Pal, who was not involved in the study. The data from the study “can help clinicians have discussions regarding expected recovery and long-term prognosis for patients with COVID-19,” he noted.
What patients should know is that “studies such as this can help COVID-19 survivors understand and monitor persistent symptoms they may experience, and bring them to the attention of their clinicians,” said Dr. Pal.
However, “As a single-center study with high attrition of subjects during the study period, the findings may not be generalizable,” Dr. Pal emphasized. “Larger-scale studies and patient registries distributed over different geographical areas and time periods will help obtain a better understanding of the nature and prevalence of long COVID,” he said.
The study findings were limited by several factors, including the lack of formerly hospitalized controls with respiratory infections other than COVID-19 to determine which outcomes are COVID-19 specific, the researchers noted. Other limitations included the use of data from only patients at a single center, and from the early stages of the pandemic, as well as the use of self-reports for comorbidities and health outcomes, they said.
However, the results represent the longest-known published longitudinal follow-up of patients who recovered from acute COVID-19, the researchers emphasized. Study strengths included the large sample size, longitudinal design, and long-term follow-up with non-COVID controls to determine outcomes. The researchers noted their plans to conduct annual follow-ups in the current study population. They added that more research is needed to explore rehabilitation programs to promote recovery for COVID-19 survivors and to reduce the effects of long COVID.
The study was supported by the Chinese Academy of Medical Sciences, National Natural Science Foundation of China, National Key Research and Development Program of China, National Administration of Traditional Chinese Medicine, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, China Evergrande Group, Jack Ma Foundation, Sino Biopharmaceutical, Ping An Insurance (Group), and New Sunshine Charity Foundation. The researchers and Dr. Pal had no financial conflicts to disclose.
This article was updated on 5/16/2022.
The burden of persistent COVID-19 symptoms appeared to improve over time, but a higher percentage of former patients reported poor health, compared with the general population. This suggests that some patients need more time to completely recover from COVID-19, wrote the authors of the new study, which was published in The Lancet Respiratory Medicine. Previous research has shown that the health effects of COVID-19 last for up to a year, but data from longer-term studies are limited, said Lixue Huang, MD, of Capital Medical University, Beijing, one of the study authors, and colleagues.
Methods and results
In the new study, the researchers reviewed data from 1,192 adult patients who were discharged from the hospital after surviving COVID-19 between Jan. 7, 2020, and May 29, 2020. The researchers measured the participants’ health outcomes at 6 months, 12 months, and 2 years after their onset of symptoms. A community-based dataset of 3,383 adults with no history of COVID-19 served as controls to measure the recovery of the COVID-19 patients. The median age of the patients at the time of hospital discharge was 57 years, and 46% were women. The median follow-up time after the onset of symptoms was 185 days, 349 days, and 685 days for the 6-month, 12-month, and 2-year visits, respectively. The researchers measured health outcomes using a 6-min walking distance (6MWD) test, laboratory tests, and questionnaires about symptoms, mental health, health-related quality of life, returning to work, and health care use since leaving the hospital.
Overall, the proportion of COVID-19 survivors with at least one symptom decreased from 68% at 6 months to 55% at 2 years (P < .0001). The most frequent symptoms were fatigue and muscle weakness, reported by approximately one-third of the patients (31%); sleep problems also were reported by 31% of the patients.
The proportion of individuals with poor results on the 6MWD decreased continuously over time, not only in COVID-19 survivors overall, but also in three subgroups of varying initial disease severity. Of the 494 survivors who reported working before becoming ill, 438 (89%) had returned to their original jobs 2 years later. The most common reasons for not returning to work were decreased physical function, unwillingness to return, and unemployment, the researchers noted.
However, at 2 years, COVID-19 survivors reported more pain and discomfort, as well as more anxiety and depression, compared with the controls (23% vs. 5% and 12% vs. 5%, respectively).
In addition, significantly more survivors who needed high levels of respiratory support while hospitalized had lung diffusion impairment (65%), reduced residual volume (62%), and total lung capacity (39%), compared with matched controls (36%, 20%, and 6%, respectively) at 2 years.
Long-COVID concerns
Approximately half of the survivors had symptoms of long COVID at 2 years. These individuals were more likely to report pain or discomfort or anxiety or depression, as well as mobility problems, compared to survivors without long COVID. Participants with long-COVID symptoms were more than twice as likely to have an outpatient clinic visit (odds ratio, 2.82), and not quite twice as likely to be rehospitalized (OR, 1.64).
“We found that [health-related quality of life], exercise capacity, and mental health continued to improve throughout the 2 years regardless of initial disease severity, but about half still had symptomatic sequelae at 2 years,” the researchers wrote in their paper.
Findings can inform doctor-patient discussions
“We are increasingly recognizing that the health effects of COVID-19 may persist beyond acute illness, therefore this is a timely study to assess the long-term impact of COVID-19 with a long follow-up period,” said Suman Pal, MD, an internal medicine physician at the University of New Mexico, Albuquerque, in an interview.
The findings are consistent with the existing literature, said Dr. Pal, who was not involved in the study. The data from the study “can help clinicians have discussions regarding expected recovery and long-term prognosis for patients with COVID-19,” he noted.
What patients should know is that “studies such as this can help COVID-19 survivors understand and monitor persistent symptoms they may experience, and bring them to the attention of their clinicians,” said Dr. Pal.
However, “As a single-center study with high attrition of subjects during the study period, the findings may not be generalizable,” Dr. Pal emphasized. “Larger-scale studies and patient registries distributed over different geographical areas and time periods will help obtain a better understanding of the nature and prevalence of long COVID,” he said.
The study findings were limited by several factors, including the lack of formerly hospitalized controls with respiratory infections other than COVID-19 to determine which outcomes are COVID-19 specific, the researchers noted. Other limitations included the use of data from only patients at a single center, and from the early stages of the pandemic, as well as the use of self-reports for comorbidities and health outcomes, they said.
However, the results represent the longest-known published longitudinal follow-up of patients who recovered from acute COVID-19, the researchers emphasized. Study strengths included the large sample size, longitudinal design, and long-term follow-up with non-COVID controls to determine outcomes. The researchers noted their plans to conduct annual follow-ups in the current study population. They added that more research is needed to explore rehabilitation programs to promote recovery for COVID-19 survivors and to reduce the effects of long COVID.
The study was supported by the Chinese Academy of Medical Sciences, National Natural Science Foundation of China, National Key Research and Development Program of China, National Administration of Traditional Chinese Medicine, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, China Evergrande Group, Jack Ma Foundation, Sino Biopharmaceutical, Ping An Insurance (Group), and New Sunshine Charity Foundation. The researchers and Dr. Pal had no financial conflicts to disclose.
This article was updated on 5/16/2022.
The burden of persistent COVID-19 symptoms appeared to improve over time, but a higher percentage of former patients reported poor health, compared with the general population. This suggests that some patients need more time to completely recover from COVID-19, wrote the authors of the new study, which was published in The Lancet Respiratory Medicine. Previous research has shown that the health effects of COVID-19 last for up to a year, but data from longer-term studies are limited, said Lixue Huang, MD, of Capital Medical University, Beijing, one of the study authors, and colleagues.
Methods and results
In the new study, the researchers reviewed data from 1,192 adult patients who were discharged from the hospital after surviving COVID-19 between Jan. 7, 2020, and May 29, 2020. The researchers measured the participants’ health outcomes at 6 months, 12 months, and 2 years after their onset of symptoms. A community-based dataset of 3,383 adults with no history of COVID-19 served as controls to measure the recovery of the COVID-19 patients. The median age of the patients at the time of hospital discharge was 57 years, and 46% were women. The median follow-up time after the onset of symptoms was 185 days, 349 days, and 685 days for the 6-month, 12-month, and 2-year visits, respectively. The researchers measured health outcomes using a 6-min walking distance (6MWD) test, laboratory tests, and questionnaires about symptoms, mental health, health-related quality of life, returning to work, and health care use since leaving the hospital.
Overall, the proportion of COVID-19 survivors with at least one symptom decreased from 68% at 6 months to 55% at 2 years (P < .0001). The most frequent symptoms were fatigue and muscle weakness, reported by approximately one-third of the patients (31%); sleep problems also were reported by 31% of the patients.
The proportion of individuals with poor results on the 6MWD decreased continuously over time, not only in COVID-19 survivors overall, but also in three subgroups of varying initial disease severity. Of the 494 survivors who reported working before becoming ill, 438 (89%) had returned to their original jobs 2 years later. The most common reasons for not returning to work were decreased physical function, unwillingness to return, and unemployment, the researchers noted.
However, at 2 years, COVID-19 survivors reported more pain and discomfort, as well as more anxiety and depression, compared with the controls (23% vs. 5% and 12% vs. 5%, respectively).
In addition, significantly more survivors who needed high levels of respiratory support while hospitalized had lung diffusion impairment (65%), reduced residual volume (62%), and total lung capacity (39%), compared with matched controls (36%, 20%, and 6%, respectively) at 2 years.
Long-COVID concerns
Approximately half of the survivors had symptoms of long COVID at 2 years. These individuals were more likely to report pain or discomfort or anxiety or depression, as well as mobility problems, compared to survivors without long COVID. Participants with long-COVID symptoms were more than twice as likely to have an outpatient clinic visit (odds ratio, 2.82), and not quite twice as likely to be rehospitalized (OR, 1.64).
“We found that [health-related quality of life], exercise capacity, and mental health continued to improve throughout the 2 years regardless of initial disease severity, but about half still had symptomatic sequelae at 2 years,” the researchers wrote in their paper.
Findings can inform doctor-patient discussions
“We are increasingly recognizing that the health effects of COVID-19 may persist beyond acute illness, therefore this is a timely study to assess the long-term impact of COVID-19 with a long follow-up period,” said Suman Pal, MD, an internal medicine physician at the University of New Mexico, Albuquerque, in an interview.
The findings are consistent with the existing literature, said Dr. Pal, who was not involved in the study. The data from the study “can help clinicians have discussions regarding expected recovery and long-term prognosis for patients with COVID-19,” he noted.
What patients should know is that “studies such as this can help COVID-19 survivors understand and monitor persistent symptoms they may experience, and bring them to the attention of their clinicians,” said Dr. Pal.
However, “As a single-center study with high attrition of subjects during the study period, the findings may not be generalizable,” Dr. Pal emphasized. “Larger-scale studies and patient registries distributed over different geographical areas and time periods will help obtain a better understanding of the nature and prevalence of long COVID,” he said.
The study findings were limited by several factors, including the lack of formerly hospitalized controls with respiratory infections other than COVID-19 to determine which outcomes are COVID-19 specific, the researchers noted. Other limitations included the use of data from only patients at a single center, and from the early stages of the pandemic, as well as the use of self-reports for comorbidities and health outcomes, they said.
However, the results represent the longest-known published longitudinal follow-up of patients who recovered from acute COVID-19, the researchers emphasized. Study strengths included the large sample size, longitudinal design, and long-term follow-up with non-COVID controls to determine outcomes. The researchers noted their plans to conduct annual follow-ups in the current study population. They added that more research is needed to explore rehabilitation programs to promote recovery for COVID-19 survivors and to reduce the effects of long COVID.
The study was supported by the Chinese Academy of Medical Sciences, National Natural Science Foundation of China, National Key Research and Development Program of China, National Administration of Traditional Chinese Medicine, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, China Evergrande Group, Jack Ma Foundation, Sino Biopharmaceutical, Ping An Insurance (Group), and New Sunshine Charity Foundation. The researchers and Dr. Pal had no financial conflicts to disclose.
This article was updated on 5/16/2022.
FROM THE LANCET RESPIRATORY MEDICINE
Myositis guidelines aim to standardize adult and pediatric care
All patients with idiopathic inflammatory myopathies (IIM) should be screened for swallowing difficulties, according to the first evidence-based guideline to be produced.
The guideline, which has been developed by a working group of the British Society for Rheumatology (BSR), also advises that all diagnosed patients should have their myositis antibody levels checked and have their overall well-being assessed. Other recommendations for all patients include the use of glucocorticoids to reduce muscle inflammation and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for long-term treatment.
“Finally, now, we’re able to standardize the way we treat adults and children with IIM,” senior guideline author Hector Chinoy, PhD, said at the society’s annual meeting.
It has been a long labor of love, however, taking 4 years to get the guideline published, said Dr. Chinoy, professor of rheumatology and neuromuscular disease at the University of Manchester (England), and a consultant at Salford (England) Royal Hospital.
“We’re not covering diagnosis, classification, or the investigation of suspected IIM,” said Dr. Chinoy. Inclusion body myositis also is not included.
Altogether, there are 13 recommendations that have been developed using a PICO (patient or population, intervention, comparison, outcome) format, graded based on the quality of the available evidence, and then voted on by the working group members to give a score of the strength of agreement. Dr. Chinoy noted that there was a checklist included in the Supplementary Data section of the guideline to help follow the recommendations.
“The target audience for the guideline reflects the variety of clinicians caring for patients with IIM,” Dr. Chinoy said. So that is not just pediatric and adult rheumatologists, but also neurologists, dermatologists, respiratory physicians, oncologists, gastroenterologists, cardiologists, and of course other health care professionals. This includes rheumatology and neurology nurses, psychologists, speech and language therapists, and podiatrists, as well as rheumatology specialist pharmacists, physiotherapists, and occupational therapists.
With reference to the latter, Liza McCann, MBBS, who co-led the development of the guideline, said in a statement released by the BSR that the guideline “highlights the importance of exercise, led and monitored by specialist physiotherapists and occupational therapists.”
Dr. McCann, a consultant pediatric rheumatologist at Alder Hey Hospital, Liverpool, England, and Honorary Clinical Lecturer at the University of Liverpool, added that the guidelines also cover “the need to address psychological wellbeing as an integral part of treatment, in parallel with pharmacological therapies.”
Recommendation highlights
Some of the highlights of the recommendations include the use of high-dose glucocorticoids to manage skeletal muscle inflammation at the time of treatment induction, with specific guidance on the different doses to use in adults and in children. There also is guidance on the use of csDMARDs in both populations and what to use if there is refractory disease – with the strongest evidence supporting the use of intravenous immunoglobulin (IVIG) or cyclophosphamide, and possibly rituximab and abatacept.
“There is insufficient evidence to recommend JAK inhibition,” Dr. Chinoy said. The data search used to develop the guideline had a cutoff of October 2020, but even now there is only anecdotal evidence from case studies, he added.
Importantly, the guidelines recognize that childhood IIM differs from adult disease and call for children to be managed by pediatric specialists.
“Routine assessment of dysphagia should be considered in all patients,” Dr. Chinoy said, “so ask the question.” The recommendation is that a swallowing assessment should involve a speech and language therapist or gastroenterologist, and that IVIG be considered for active disease and dysphagia that is resistant to other treatments.
There also are recommendations to screen adult patients for interstitial lung disease, consider fracture risk, and screen adult patients for cancer if they have specific risk factors that include older age at onset, male gender, dysphagia, and rapid disease onset, among others.
Separate cancer screening guidelines on cards
“Around one in four patients with myositis will develop cancer within the 3 years either before or after myositis onset,” Alexander Oldroyd, MBChB, PhD, said in a separate presentation at the BSR annual meeting.
“It’s a hugely increased risk compared to the general population, and a great worry for patients,” he added. Exactly why there is an increased risk is not known, but “there’s a big link between the biological onset of cancer and myositis.”
Dr. Oldroyd, who is an NIHR Academic Clinical Lecturer at the University of Manchester in England and a coauthor of the BSR myositis guideline, is part of a special interest group set up by the International Myositis Assessment and Clinical Studies Group (IMACS) that is in the process of developing separate guidelines for cancer screening in people newly diagnosed with IIM.
The aim was to produce evidence-based recommendations that were both “pragmatic and practical,” that could help clinicians answer patient’s questions on their risk and how best and how often to screen them, Dr. Oldroyd explained. Importantly, IMACS has endeavored to create recommendations that should be applicable across different countries and health care systems.
“We had to acknowledge that there’s not a lot of evidence base there,” Dr. Oldroyd said, noting that he and colleagues conducted a systematic literature review and meta-analysis and used a Delphi process to draft 20 recommendations. These cover identifying risk factors for cancer in people with myositis and categorizing people into low, medium, and high-risk categories. The recommendations also cover what should constitute basic and enhanced screening, and how often someone should be screened.
Moreover, the authors make recommendations on the use of imaging modalities such as PET and CT scans, as well as upper and lower gastrointestinal endoscopy and naso-endoscopy.
“As rheumatologists, we don’t talk about cancer a lot,” Dr. Oldroyd said. “We pick up a lot of incidental cancers, but we don’t usually talk about cancer screening with patients.” That’s something that needs to change, he said.
“It’s important – just get it out in the open, talk to people about it,” Dr. Oldroyd said.
“Tell them what you’re wanting to do, how you’re wanting to investigate for it, clearly communicate their risk,” he said. “But also acknowledge the limited evidence as well, and clearly communicate the results.”
Dr. Chinoy acknowledged he had received fees for presentations (UCB, Biogen), consultancy (Alexion, Novartis, Eli Lilly, Orphazyme, AstraZeneca), or grant support (Eli Lilly, UCB) that had been paid via his institution for the purpose of furthering myositis research. Dr. Oldroyd had no conflicts of interest to disclose.
All patients with idiopathic inflammatory myopathies (IIM) should be screened for swallowing difficulties, according to the first evidence-based guideline to be produced.
The guideline, which has been developed by a working group of the British Society for Rheumatology (BSR), also advises that all diagnosed patients should have their myositis antibody levels checked and have their overall well-being assessed. Other recommendations for all patients include the use of glucocorticoids to reduce muscle inflammation and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for long-term treatment.
“Finally, now, we’re able to standardize the way we treat adults and children with IIM,” senior guideline author Hector Chinoy, PhD, said at the society’s annual meeting.
It has been a long labor of love, however, taking 4 years to get the guideline published, said Dr. Chinoy, professor of rheumatology and neuromuscular disease at the University of Manchester (England), and a consultant at Salford (England) Royal Hospital.
“We’re not covering diagnosis, classification, or the investigation of suspected IIM,” said Dr. Chinoy. Inclusion body myositis also is not included.
Altogether, there are 13 recommendations that have been developed using a PICO (patient or population, intervention, comparison, outcome) format, graded based on the quality of the available evidence, and then voted on by the working group members to give a score of the strength of agreement. Dr. Chinoy noted that there was a checklist included in the Supplementary Data section of the guideline to help follow the recommendations.
“The target audience for the guideline reflects the variety of clinicians caring for patients with IIM,” Dr. Chinoy said. So that is not just pediatric and adult rheumatologists, but also neurologists, dermatologists, respiratory physicians, oncologists, gastroenterologists, cardiologists, and of course other health care professionals. This includes rheumatology and neurology nurses, psychologists, speech and language therapists, and podiatrists, as well as rheumatology specialist pharmacists, physiotherapists, and occupational therapists.
With reference to the latter, Liza McCann, MBBS, who co-led the development of the guideline, said in a statement released by the BSR that the guideline “highlights the importance of exercise, led and monitored by specialist physiotherapists and occupational therapists.”
Dr. McCann, a consultant pediatric rheumatologist at Alder Hey Hospital, Liverpool, England, and Honorary Clinical Lecturer at the University of Liverpool, added that the guidelines also cover “the need to address psychological wellbeing as an integral part of treatment, in parallel with pharmacological therapies.”
Recommendation highlights
Some of the highlights of the recommendations include the use of high-dose glucocorticoids to manage skeletal muscle inflammation at the time of treatment induction, with specific guidance on the different doses to use in adults and in children. There also is guidance on the use of csDMARDs in both populations and what to use if there is refractory disease – with the strongest evidence supporting the use of intravenous immunoglobulin (IVIG) or cyclophosphamide, and possibly rituximab and abatacept.
“There is insufficient evidence to recommend JAK inhibition,” Dr. Chinoy said. The data search used to develop the guideline had a cutoff of October 2020, but even now there is only anecdotal evidence from case studies, he added.
Importantly, the guidelines recognize that childhood IIM differs from adult disease and call for children to be managed by pediatric specialists.
“Routine assessment of dysphagia should be considered in all patients,” Dr. Chinoy said, “so ask the question.” The recommendation is that a swallowing assessment should involve a speech and language therapist or gastroenterologist, and that IVIG be considered for active disease and dysphagia that is resistant to other treatments.
There also are recommendations to screen adult patients for interstitial lung disease, consider fracture risk, and screen adult patients for cancer if they have specific risk factors that include older age at onset, male gender, dysphagia, and rapid disease onset, among others.
Separate cancer screening guidelines on cards
“Around one in four patients with myositis will develop cancer within the 3 years either before or after myositis onset,” Alexander Oldroyd, MBChB, PhD, said in a separate presentation at the BSR annual meeting.
“It’s a hugely increased risk compared to the general population, and a great worry for patients,” he added. Exactly why there is an increased risk is not known, but “there’s a big link between the biological onset of cancer and myositis.”
Dr. Oldroyd, who is an NIHR Academic Clinical Lecturer at the University of Manchester in England and a coauthor of the BSR myositis guideline, is part of a special interest group set up by the International Myositis Assessment and Clinical Studies Group (IMACS) that is in the process of developing separate guidelines for cancer screening in people newly diagnosed with IIM.
The aim was to produce evidence-based recommendations that were both “pragmatic and practical,” that could help clinicians answer patient’s questions on their risk and how best and how often to screen them, Dr. Oldroyd explained. Importantly, IMACS has endeavored to create recommendations that should be applicable across different countries and health care systems.
“We had to acknowledge that there’s not a lot of evidence base there,” Dr. Oldroyd said, noting that he and colleagues conducted a systematic literature review and meta-analysis and used a Delphi process to draft 20 recommendations. These cover identifying risk factors for cancer in people with myositis and categorizing people into low, medium, and high-risk categories. The recommendations also cover what should constitute basic and enhanced screening, and how often someone should be screened.
Moreover, the authors make recommendations on the use of imaging modalities such as PET and CT scans, as well as upper and lower gastrointestinal endoscopy and naso-endoscopy.
“As rheumatologists, we don’t talk about cancer a lot,” Dr. Oldroyd said. “We pick up a lot of incidental cancers, but we don’t usually talk about cancer screening with patients.” That’s something that needs to change, he said.
“It’s important – just get it out in the open, talk to people about it,” Dr. Oldroyd said.
“Tell them what you’re wanting to do, how you’re wanting to investigate for it, clearly communicate their risk,” he said. “But also acknowledge the limited evidence as well, and clearly communicate the results.”
Dr. Chinoy acknowledged he had received fees for presentations (UCB, Biogen), consultancy (Alexion, Novartis, Eli Lilly, Orphazyme, AstraZeneca), or grant support (Eli Lilly, UCB) that had been paid via his institution for the purpose of furthering myositis research. Dr. Oldroyd had no conflicts of interest to disclose.
All patients with idiopathic inflammatory myopathies (IIM) should be screened for swallowing difficulties, according to the first evidence-based guideline to be produced.
The guideline, which has been developed by a working group of the British Society for Rheumatology (BSR), also advises that all diagnosed patients should have their myositis antibody levels checked and have their overall well-being assessed. Other recommendations for all patients include the use of glucocorticoids to reduce muscle inflammation and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for long-term treatment.
“Finally, now, we’re able to standardize the way we treat adults and children with IIM,” senior guideline author Hector Chinoy, PhD, said at the society’s annual meeting.
It has been a long labor of love, however, taking 4 years to get the guideline published, said Dr. Chinoy, professor of rheumatology and neuromuscular disease at the University of Manchester (England), and a consultant at Salford (England) Royal Hospital.
“We’re not covering diagnosis, classification, or the investigation of suspected IIM,” said Dr. Chinoy. Inclusion body myositis also is not included.
Altogether, there are 13 recommendations that have been developed using a PICO (patient or population, intervention, comparison, outcome) format, graded based on the quality of the available evidence, and then voted on by the working group members to give a score of the strength of agreement. Dr. Chinoy noted that there was a checklist included in the Supplementary Data section of the guideline to help follow the recommendations.
“The target audience for the guideline reflects the variety of clinicians caring for patients with IIM,” Dr. Chinoy said. So that is not just pediatric and adult rheumatologists, but also neurologists, dermatologists, respiratory physicians, oncologists, gastroenterologists, cardiologists, and of course other health care professionals. This includes rheumatology and neurology nurses, psychologists, speech and language therapists, and podiatrists, as well as rheumatology specialist pharmacists, physiotherapists, and occupational therapists.
With reference to the latter, Liza McCann, MBBS, who co-led the development of the guideline, said in a statement released by the BSR that the guideline “highlights the importance of exercise, led and monitored by specialist physiotherapists and occupational therapists.”
Dr. McCann, a consultant pediatric rheumatologist at Alder Hey Hospital, Liverpool, England, and Honorary Clinical Lecturer at the University of Liverpool, added that the guidelines also cover “the need to address psychological wellbeing as an integral part of treatment, in parallel with pharmacological therapies.”
Recommendation highlights
Some of the highlights of the recommendations include the use of high-dose glucocorticoids to manage skeletal muscle inflammation at the time of treatment induction, with specific guidance on the different doses to use in adults and in children. There also is guidance on the use of csDMARDs in both populations and what to use if there is refractory disease – with the strongest evidence supporting the use of intravenous immunoglobulin (IVIG) or cyclophosphamide, and possibly rituximab and abatacept.
“There is insufficient evidence to recommend JAK inhibition,” Dr. Chinoy said. The data search used to develop the guideline had a cutoff of October 2020, but even now there is only anecdotal evidence from case studies, he added.
Importantly, the guidelines recognize that childhood IIM differs from adult disease and call for children to be managed by pediatric specialists.
“Routine assessment of dysphagia should be considered in all patients,” Dr. Chinoy said, “so ask the question.” The recommendation is that a swallowing assessment should involve a speech and language therapist or gastroenterologist, and that IVIG be considered for active disease and dysphagia that is resistant to other treatments.
There also are recommendations to screen adult patients for interstitial lung disease, consider fracture risk, and screen adult patients for cancer if they have specific risk factors that include older age at onset, male gender, dysphagia, and rapid disease onset, among others.
Separate cancer screening guidelines on cards
“Around one in four patients with myositis will develop cancer within the 3 years either before or after myositis onset,” Alexander Oldroyd, MBChB, PhD, said in a separate presentation at the BSR annual meeting.
“It’s a hugely increased risk compared to the general population, and a great worry for patients,” he added. Exactly why there is an increased risk is not known, but “there’s a big link between the biological onset of cancer and myositis.”
Dr. Oldroyd, who is an NIHR Academic Clinical Lecturer at the University of Manchester in England and a coauthor of the BSR myositis guideline, is part of a special interest group set up by the International Myositis Assessment and Clinical Studies Group (IMACS) that is in the process of developing separate guidelines for cancer screening in people newly diagnosed with IIM.
The aim was to produce evidence-based recommendations that were both “pragmatic and practical,” that could help clinicians answer patient’s questions on their risk and how best and how often to screen them, Dr. Oldroyd explained. Importantly, IMACS has endeavored to create recommendations that should be applicable across different countries and health care systems.
“We had to acknowledge that there’s not a lot of evidence base there,” Dr. Oldroyd said, noting that he and colleagues conducted a systematic literature review and meta-analysis and used a Delphi process to draft 20 recommendations. These cover identifying risk factors for cancer in people with myositis and categorizing people into low, medium, and high-risk categories. The recommendations also cover what should constitute basic and enhanced screening, and how often someone should be screened.
Moreover, the authors make recommendations on the use of imaging modalities such as PET and CT scans, as well as upper and lower gastrointestinal endoscopy and naso-endoscopy.
“As rheumatologists, we don’t talk about cancer a lot,” Dr. Oldroyd said. “We pick up a lot of incidental cancers, but we don’t usually talk about cancer screening with patients.” That’s something that needs to change, he said.
“It’s important – just get it out in the open, talk to people about it,” Dr. Oldroyd said.
“Tell them what you’re wanting to do, how you’re wanting to investigate for it, clearly communicate their risk,” he said. “But also acknowledge the limited evidence as well, and clearly communicate the results.”
Dr. Chinoy acknowledged he had received fees for presentations (UCB, Biogen), consultancy (Alexion, Novartis, Eli Lilly, Orphazyme, AstraZeneca), or grant support (Eli Lilly, UCB) that had been paid via his institution for the purpose of furthering myositis research. Dr. Oldroyd had no conflicts of interest to disclose.
FROM BSR 2022
Exenatide linked to less hyperglycemia after stroke
Treatment with the diabetes drug exenatide was associated with a significant decrease in hyperglycemia in acute stroke patients, a new study shows.
The research could offer clinicians an alternative to insulin therapy to treat hyperglycemia and reduce glucose levels, which are elevated in up to 60% of stroke patients and associated with worse outcomes after stroke.
“Use of these diabetes drugs to control glucose in acute stroke has enormous potential,” said lead researcher Christopher Bladin, PhD, professor of neurology at Monash University and Eastern Health Clinical School, Australia.
The findings were presented at the European Stroke Organisation Conference (ESOC) 2022 annual meeting in Lyon, France.
A better fix than insulin?
Hyperglycemia is common in stroke patients, including those who have no prior history of diabetes. Among stroke patients with normal blood glucose upon admission, about 30% will develop hyperglycemia within 48 hours of stroke onset.
Previous research suggests that hyperglycemia is a poor prognostic factor in patients with stroke and may reduce the efficacy of reperfusion therapies such as thrombolysis and mechanical thrombectomy.
“We’ve been looking for different ways of treating hyperglycemia for quite some time, and one of the obvious ways is to use insulin therapy,” Dr. Bladin said. “But as we’ve seen from multiple studies, insulin therapy is difficult.”
Insulin treatment is resource-heavy, significantly increases the risk for hypoglycemia, and some studies suggest the therapy isn’t associated with better outcomes.
An advantage to a GLP-1 agonist-like exenatide, Dr. Bladin added, is that it’s glucose-dependent. As the glucose level falls, the drug’s efficacy diminishes. It is delivered via an autoinjector and easy to administer.
A case for more study
To study exenatide’s efficacy in reducing hyperglycemia and improving neurologic outcomes, researchers developed the phase 2, international, multicenter, randomized controlled TEXAIS trial.
The study enrolled 350 patients following an ischemic stroke. Within 9 hours of stroke onset, patients received either standard care or a subcutaneous injection of 5 mg of exenatide twice daily for 5 days.
On admission, 42% of patients had hyperglycemia, defined as blood glucose > 7.0 mmol/L.
The study’s primary outcome was at least an 8-point improvement in National Institutes of Health Stroke Scale (NIHSS) score by 7 days after treatment with exenatide. Although there was a trend toward better scores with exenatide, the score was not significantly different between groups (56.7% with standard care versus 61.2% with exenatide; adjusted odds ratio, 1.22; P = .38).
However, when the researchers examined hyperglycemia frequency, they found significantly lower incidence in patients treated with exenatide (P = .002).
There were no cases of hypoglycemia in either group, and only 4% of the study group reported nausea or vomiting.
“Clearly exenatide is having some benefit in terms of keeping glucose under control, reducing hyperglycemia,” Dr. Bladin said. “It certainly lends itself to a larger phase 3 study which can look at this more completely.”
Value to clinicians
Commenting on the findings, Yvonne Chun, PhD, honorary senior clinical lecturer at University of Edinburgh, noted that, even though the study didn’t find a significant association with improved neurological outcomes, the reduced risk for hypoglycemia makes exenatide an attractive alternative to insulin therapy in stroke patients.
“The results are of value to clinicians, as exenatide could potentially be a safer medication to administer than an insulin infusion in acute stroke patients with hyperglycemia,” Dr. Chun said. “There is less risk of hypoglycemia with exenatide compared to standard care.”
However, Dr. Chun noted that more study is needed before exenatide can replace standard care. Dr. Bladin agrees and would like to pursue a phase 3 trial with a modified design to answer questions raised by Dr. Chun and others.
“The next phase could consider changing the primary outcome to an ordinal shift analysis on modified Rankin Scale – a very commonly used primary outcome in stroke clinical trials to assess improvement in disability,” Dr. Chun said. “The primary outcome used in the presented trial – an 8-point improvement on NIHSS – seemed too ambitious and does not inform disability of the patient post stroke.”
Dr. Bladin said he would also like to see the next phase enroll more patients, examine a higher dose of exenatide, and include better stratification of patients with a history of diabetes. Such a trial could yield findings demonstrating the drug’s effectiveness at reducing hyperglycemia and improving outcomes after stroke, he said.
“I can see the day patients will come in with acute stroke, and as they’re coming into the emergency department, they’ll simply get their shot of exenatide because we know it’s safe to use, and it doesn’t cause hypoglycemia,” Dr. Bladin said. “And from the moment that patient arrives the glucose control is underway.”
Dr. Bladin and Dr. Chun reported no relevant financial relationships. Study funding was not disclosed.
A version of this article first appeared on Medscape.com.
Treatment with the diabetes drug exenatide was associated with a significant decrease in hyperglycemia in acute stroke patients, a new study shows.
The research could offer clinicians an alternative to insulin therapy to treat hyperglycemia and reduce glucose levels, which are elevated in up to 60% of stroke patients and associated with worse outcomes after stroke.
“Use of these diabetes drugs to control glucose in acute stroke has enormous potential,” said lead researcher Christopher Bladin, PhD, professor of neurology at Monash University and Eastern Health Clinical School, Australia.
The findings were presented at the European Stroke Organisation Conference (ESOC) 2022 annual meeting in Lyon, France.
A better fix than insulin?
Hyperglycemia is common in stroke patients, including those who have no prior history of diabetes. Among stroke patients with normal blood glucose upon admission, about 30% will develop hyperglycemia within 48 hours of stroke onset.
Previous research suggests that hyperglycemia is a poor prognostic factor in patients with stroke and may reduce the efficacy of reperfusion therapies such as thrombolysis and mechanical thrombectomy.
“We’ve been looking for different ways of treating hyperglycemia for quite some time, and one of the obvious ways is to use insulin therapy,” Dr. Bladin said. “But as we’ve seen from multiple studies, insulin therapy is difficult.”
Insulin treatment is resource-heavy, significantly increases the risk for hypoglycemia, and some studies suggest the therapy isn’t associated with better outcomes.
An advantage to a GLP-1 agonist-like exenatide, Dr. Bladin added, is that it’s glucose-dependent. As the glucose level falls, the drug’s efficacy diminishes. It is delivered via an autoinjector and easy to administer.
A case for more study
To study exenatide’s efficacy in reducing hyperglycemia and improving neurologic outcomes, researchers developed the phase 2, international, multicenter, randomized controlled TEXAIS trial.
The study enrolled 350 patients following an ischemic stroke. Within 9 hours of stroke onset, patients received either standard care or a subcutaneous injection of 5 mg of exenatide twice daily for 5 days.
On admission, 42% of patients had hyperglycemia, defined as blood glucose > 7.0 mmol/L.
The study’s primary outcome was at least an 8-point improvement in National Institutes of Health Stroke Scale (NIHSS) score by 7 days after treatment with exenatide. Although there was a trend toward better scores with exenatide, the score was not significantly different between groups (56.7% with standard care versus 61.2% with exenatide; adjusted odds ratio, 1.22; P = .38).
However, when the researchers examined hyperglycemia frequency, they found significantly lower incidence in patients treated with exenatide (P = .002).
There were no cases of hypoglycemia in either group, and only 4% of the study group reported nausea or vomiting.
“Clearly exenatide is having some benefit in terms of keeping glucose under control, reducing hyperglycemia,” Dr. Bladin said. “It certainly lends itself to a larger phase 3 study which can look at this more completely.”
Value to clinicians
Commenting on the findings, Yvonne Chun, PhD, honorary senior clinical lecturer at University of Edinburgh, noted that, even though the study didn’t find a significant association with improved neurological outcomes, the reduced risk for hypoglycemia makes exenatide an attractive alternative to insulin therapy in stroke patients.
“The results are of value to clinicians, as exenatide could potentially be a safer medication to administer than an insulin infusion in acute stroke patients with hyperglycemia,” Dr. Chun said. “There is less risk of hypoglycemia with exenatide compared to standard care.”
However, Dr. Chun noted that more study is needed before exenatide can replace standard care. Dr. Bladin agrees and would like to pursue a phase 3 trial with a modified design to answer questions raised by Dr. Chun and others.
“The next phase could consider changing the primary outcome to an ordinal shift analysis on modified Rankin Scale – a very commonly used primary outcome in stroke clinical trials to assess improvement in disability,” Dr. Chun said. “The primary outcome used in the presented trial – an 8-point improvement on NIHSS – seemed too ambitious and does not inform disability of the patient post stroke.”
Dr. Bladin said he would also like to see the next phase enroll more patients, examine a higher dose of exenatide, and include better stratification of patients with a history of diabetes. Such a trial could yield findings demonstrating the drug’s effectiveness at reducing hyperglycemia and improving outcomes after stroke, he said.
“I can see the day patients will come in with acute stroke, and as they’re coming into the emergency department, they’ll simply get their shot of exenatide because we know it’s safe to use, and it doesn’t cause hypoglycemia,” Dr. Bladin said. “And from the moment that patient arrives the glucose control is underway.”
Dr. Bladin and Dr. Chun reported no relevant financial relationships. Study funding was not disclosed.
A version of this article first appeared on Medscape.com.
Treatment with the diabetes drug exenatide was associated with a significant decrease in hyperglycemia in acute stroke patients, a new study shows.
The research could offer clinicians an alternative to insulin therapy to treat hyperglycemia and reduce glucose levels, which are elevated in up to 60% of stroke patients and associated with worse outcomes after stroke.
“Use of these diabetes drugs to control glucose in acute stroke has enormous potential,” said lead researcher Christopher Bladin, PhD, professor of neurology at Monash University and Eastern Health Clinical School, Australia.
The findings were presented at the European Stroke Organisation Conference (ESOC) 2022 annual meeting in Lyon, France.
A better fix than insulin?
Hyperglycemia is common in stroke patients, including those who have no prior history of diabetes. Among stroke patients with normal blood glucose upon admission, about 30% will develop hyperglycemia within 48 hours of stroke onset.
Previous research suggests that hyperglycemia is a poor prognostic factor in patients with stroke and may reduce the efficacy of reperfusion therapies such as thrombolysis and mechanical thrombectomy.
“We’ve been looking for different ways of treating hyperglycemia for quite some time, and one of the obvious ways is to use insulin therapy,” Dr. Bladin said. “But as we’ve seen from multiple studies, insulin therapy is difficult.”
Insulin treatment is resource-heavy, significantly increases the risk for hypoglycemia, and some studies suggest the therapy isn’t associated with better outcomes.
An advantage to a GLP-1 agonist-like exenatide, Dr. Bladin added, is that it’s glucose-dependent. As the glucose level falls, the drug’s efficacy diminishes. It is delivered via an autoinjector and easy to administer.
A case for more study
To study exenatide’s efficacy in reducing hyperglycemia and improving neurologic outcomes, researchers developed the phase 2, international, multicenter, randomized controlled TEXAIS trial.
The study enrolled 350 patients following an ischemic stroke. Within 9 hours of stroke onset, patients received either standard care or a subcutaneous injection of 5 mg of exenatide twice daily for 5 days.
On admission, 42% of patients had hyperglycemia, defined as blood glucose > 7.0 mmol/L.
The study’s primary outcome was at least an 8-point improvement in National Institutes of Health Stroke Scale (NIHSS) score by 7 days after treatment with exenatide. Although there was a trend toward better scores with exenatide, the score was not significantly different between groups (56.7% with standard care versus 61.2% with exenatide; adjusted odds ratio, 1.22; P = .38).
However, when the researchers examined hyperglycemia frequency, they found significantly lower incidence in patients treated with exenatide (P = .002).
There were no cases of hypoglycemia in either group, and only 4% of the study group reported nausea or vomiting.
“Clearly exenatide is having some benefit in terms of keeping glucose under control, reducing hyperglycemia,” Dr. Bladin said. “It certainly lends itself to a larger phase 3 study which can look at this more completely.”
Value to clinicians
Commenting on the findings, Yvonne Chun, PhD, honorary senior clinical lecturer at University of Edinburgh, noted that, even though the study didn’t find a significant association with improved neurological outcomes, the reduced risk for hypoglycemia makes exenatide an attractive alternative to insulin therapy in stroke patients.
“The results are of value to clinicians, as exenatide could potentially be a safer medication to administer than an insulin infusion in acute stroke patients with hyperglycemia,” Dr. Chun said. “There is less risk of hypoglycemia with exenatide compared to standard care.”
However, Dr. Chun noted that more study is needed before exenatide can replace standard care. Dr. Bladin agrees and would like to pursue a phase 3 trial with a modified design to answer questions raised by Dr. Chun and others.
“The next phase could consider changing the primary outcome to an ordinal shift analysis on modified Rankin Scale – a very commonly used primary outcome in stroke clinical trials to assess improvement in disability,” Dr. Chun said. “The primary outcome used in the presented trial – an 8-point improvement on NIHSS – seemed too ambitious and does not inform disability of the patient post stroke.”
Dr. Bladin said he would also like to see the next phase enroll more patients, examine a higher dose of exenatide, and include better stratification of patients with a history of diabetes. Such a trial could yield findings demonstrating the drug’s effectiveness at reducing hyperglycemia and improving outcomes after stroke, he said.
“I can see the day patients will come in with acute stroke, and as they’re coming into the emergency department, they’ll simply get their shot of exenatide because we know it’s safe to use, and it doesn’t cause hypoglycemia,” Dr. Bladin said. “And from the moment that patient arrives the glucose control is underway.”
Dr. Bladin and Dr. Chun reported no relevant financial relationships. Study funding was not disclosed.
A version of this article first appeared on Medscape.com.
FROM ESOC 2022
Does noninvasive brain stimulation augment CBT for depression?
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.
The study was published online in JAMA Psychiatry.
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.
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.
The study was published online in JAMA Psychiatry.
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.
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.
The study was published online in JAMA Psychiatry.
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.
FROM JAMA PSYCHIATRY
Neurology, psychiatry studies overlook sex as a variable
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.
“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.
“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.
“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.
FROM NATURE COMMUNICATIONS
Study casts doubt on safety, efficacy of L-serine supplementation for AD
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.
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.
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.
FROM CELL METABOLISM
Headache in pregnancy: New ACOG guidelines offer insight
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.
AT ACOG 2022
Patients asking about APOE gene test results? Here’s what to tell them
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 213-16.
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
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.
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.
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).
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; [email protected]
1. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2018;14:535-562. doi: 10.1016/j.jalz.2018.02.018 PMCID:PMC5958625
2. Langlois CM, Bradbury A, Wood EM, et al. Alzheimer’s Prevention Initiative Generation Program: development of an APOE genetic counseling and disclosure process in the context of clinical trials. Alzheimers Dement Transl Res Clin Interv. 2019;5:705-716. doi: 10.1016/j.trci.2019.09.013
3. Frank L, Wesson Ashford J, Bayley PJ, et al. Genetic risk of Alzheimer’s disease: three wishes now that the genie is out of the bottle. J Alzheimers Dis. 2018;66:421-423. doi: 10.3233/JAD-180629
4. Qian J, Wolters FJ, Beiser A, et al. APOE-related risk of mild cognitive impairment and dementia for prevention trials: an analysis of four cohorts. PLOS Med. 2017;14:e1002254. doi: 10.1371/journal.pmed.1002254
5. Sperling RA, Jack CR, Black SE, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7:367-385. doi: 10.1016/j.jalz.2011.05.2351
6. FDA. November 6, 2020: Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting Announcement. Published November 12, 2020. Accessed January 14, 2021. www.fda.gov/advisory-committees/advisory-committee-calendar/november-6-2020-meeting-peripheral-and-central-nervous-system-drugs-advisory-committee-meeting
7. Cummings J. Why aducanumab is important. Nat Med. 2021;27:1498-1498. doi: 10.1038/s41591-021-01478-4
8. Alexander GC, Karlawish J. The problem of aducanumab for the treatment of Alzheimer disease. Ann Intern Med. 2021;174:1303-1304. doi: 10.7326/M21-2603
9. Mullard A. More Alzheimer’s drugs head for FDA review: what scientists are watching. Nature. 2021;599:544-545. doi: 10.1038/d41586-021-03410-9
10. Rosenberg A, Mangialasche F, Ngandu T, et al. Multidomain interventions to prevent cognitive impairment, Alzheimer’s disease, and dementia: from finger to world-wide fingers. J Prev Alzheimers Dis. 2019:1-8. doi: 10.14283/jpad.2019.41
11. FDA. Commissioner of the FDA allows marketing of first direct-to-consumer tests that provide genetic risk information for certain conditions. Published March 24, 2020. Accessed November 7, 2020. www.fda.gov/news-events/press-announcements/fda-allows-marketing-first-direct-consumer-tests-provide-genetic-risk-information-certain-conditions
12. Blell M, Hunter MA. Direct-to-consumer genetic testing’s red herring: “genetic ancestry” and personalized medicine. Front Med. 2019;6:48. doi: 10.3389/fmed.2019.00048
13. Ekstrand B, Scheers N, Rasmussen MK, et al. Brain foods - the role of diet in brain performance and health. Nutr Rev. 2021;79:693-708. doi: 10.1093/nutrit/nuaa091
14. Cherian L, Wang Y, Fakuda K, et al. Mediterranean-Dash Intervention for Neurodegenerative Delay (MIND) diet slows cognitive decline after stroke. J Prev Alzheimers Dis. 2019;6:267-273. doi: 10.14283/jpad.2019.28
15. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet. 2020;396:413-446. doi: 10.1016/S0140-6736(20)30367-6
16. Livingston PG, Sommerlad A, Orgeta V, et al. The Lancet International Commission on Dementia Prevention and Care. 2017. Accessed March 30, 2022. https://discovery.ucl.ac.uk/id/eprint/1567635/1/Livingston_Dementia_prevention_intervention_care.pdf
17. Peters U. What is the function of confirmation bias? Erkenntnis. April 2020. doi: 10.1007/s10670-020-00252-1
18. Barnes LL, Bennett DA. Cognitive resilience in APOE*ε4 carriers—is race important? Nat Rev Neurol. 2015;11:190-191. doi: 10.1038/nrneurol.2015.38
19. Farrer LA. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA. 1997;278:1349. doi: 10.1001/jama.1997.03550160069041
20. Evans DA, Bennett DA, Wilson RS, et al. Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status. Arch Neurol. 2003;60:185. doi: 10.1001/archneur.60.2.185
21. Chung WW, Chen CA, Cupples LA, et al. A new scale measuring psychologic impact of genetic susceptibility testing for Alzheimer disease. Alzheimer Dis Assoc Disord. 2009;23:50-56. doi: 10.1097/WAD.0b013e318188429e
22. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606-613. doi: 10.1046/j.1525-1497.2001.016009606.x
23. Yesavage JA, Sheikh JI. 9/Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. Clin Gerontol. 1986;5:165-173. doi: 10.1300/J018v05n01_09
24. Green RC, Roberts JS, Cupples LA, et al. Disclosure of APOE genotype for risk of Alzheimer’s disease. N Engl J Med. 2009;361:245-254. doi: 10.1056/NEJMoa0809578
25. Lineweaver TT, Bondi MW, Galasko D, et al. Effect of knowledge of APOE genotype on subjective and objective memory performance in healthy older adults. Am J Psychiatry. 2014;171:201-208. doi: 10.1176/appi.ajp.2013.12121590
26. Karlawish J. Understanding the impact of learning an amyloid PET scan result: preliminary findings from the SOKRATES study. Alzheimers Dement J Alzheimers Assoc. 2016;12:P325. doi: 10.1016/j.jalz.2016.06.594
27. Stites SD. Cognitively healthy individuals want to know their risk for Alzheimer’s disease: what should we do? J Alzheimers Dis. 2018;62:499-502. doi: 10.3233/JAD-171089
28. Milne S, Lomax C, Freeston MH. A review of the relationship between intolerance of uncertainty and threat appraisal in anxiety. Cogn Behav Ther. 2019;12:e38. doi: 10.1017/S1754470X19000230
29. Hebert EA, Dugas MJ. Behavioral experiments for intolerance of uncertainty: challenging the unknown in the treatment of generalized anxiety disorder. Cogn Behav Pract. 2019;26:421-436. doi: 10.1016/j.cbpra.2018.07.007
30. Stites SD, Karlawish, J. Stigma of Alzheimer’s disease dementia: considerations for practice. Pract Neurol. Published June 2018. Accessed January 31, 2019. http://practicalneurology.com/2018/06/stigma-of-alzheimers-disease-dementia/
31. Solomon A, Turunen H, Ngandu T, et al. Effect of the apolipoprotein E genotype on cognitive change during a multidomain lifestyle intervention: a subgroup analysis of a randomized clinical trial. JAMA Neurol. 2018;75:462. doi: 10.1001/jamaneurol.2017.4365
32. Peters R, Warwick J, Anstey KJ, et al. Blood pressure and dementia: what the SPRINT-MIND trial adds and what we still need to know. Neurology. 2019;92:1017-1018. doi: 10.1212/WNL.0000000000007543
33. Musunuru K, Hershberger RE, Day SM, et al. Genetic testing for inherited cardiovascular diseases: a Scientific Statement from the American Heart Association. Circ Genom Precis Med. 2020;13: e000067. doi: 10.1161/HCG.0000000000000067
34. Margaglione M, Seripa D, Gravina C, et al. Prevalence of apolipoprotein E alleles in healthy subjects and survivors of ischemic stroke. Stroke. 1998;29:399-403. doi: 10.1161/01.STR.29.2.399
35. National Institute on Aging. Alzheimer’s disease genetics fact sheet. Reviewed December 24, 2019. Accessed April 10, 2022. www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet
36. Belluck P, Kaplan S, Robbins R. How Aduhelm, an unproven Alzheimer’s drug, got approved. The New York Times. Published July 19, 2021. Updated Oct. 20, 2021. Accessed December 1, 2021. www.nytimes.com/2021/07/19/health/alzheimers-drug-aduhelm-fda.html
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 213-16.
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
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.
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.
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).
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; [email protected]
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 213-16.
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
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.
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.
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).
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; [email protected]
1. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2018;14:535-562. doi: 10.1016/j.jalz.2018.02.018 PMCID:PMC5958625
2. Langlois CM, Bradbury A, Wood EM, et al. Alzheimer’s Prevention Initiative Generation Program: development of an APOE genetic counseling and disclosure process in the context of clinical trials. Alzheimers Dement Transl Res Clin Interv. 2019;5:705-716. doi: 10.1016/j.trci.2019.09.013
3. Frank L, Wesson Ashford J, Bayley PJ, et al. Genetic risk of Alzheimer’s disease: three wishes now that the genie is out of the bottle. J Alzheimers Dis. 2018;66:421-423. doi: 10.3233/JAD-180629
4. Qian J, Wolters FJ, Beiser A, et al. APOE-related risk of mild cognitive impairment and dementia for prevention trials: an analysis of four cohorts. PLOS Med. 2017;14:e1002254. doi: 10.1371/journal.pmed.1002254
5. Sperling RA, Jack CR, Black SE, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7:367-385. doi: 10.1016/j.jalz.2011.05.2351
6. FDA. November 6, 2020: Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting Announcement. Published November 12, 2020. Accessed January 14, 2021. www.fda.gov/advisory-committees/advisory-committee-calendar/november-6-2020-meeting-peripheral-and-central-nervous-system-drugs-advisory-committee-meeting
7. Cummings J. Why aducanumab is important. Nat Med. 2021;27:1498-1498. doi: 10.1038/s41591-021-01478-4
8. Alexander GC, Karlawish J. The problem of aducanumab for the treatment of Alzheimer disease. Ann Intern Med. 2021;174:1303-1304. doi: 10.7326/M21-2603
9. Mullard A. More Alzheimer’s drugs head for FDA review: what scientists are watching. Nature. 2021;599:544-545. doi: 10.1038/d41586-021-03410-9
10. Rosenberg A, Mangialasche F, Ngandu T, et al. Multidomain interventions to prevent cognitive impairment, Alzheimer’s disease, and dementia: from finger to world-wide fingers. J Prev Alzheimers Dis. 2019:1-8. doi: 10.14283/jpad.2019.41
11. FDA. Commissioner of the FDA allows marketing of first direct-to-consumer tests that provide genetic risk information for certain conditions. Published March 24, 2020. Accessed November 7, 2020. www.fda.gov/news-events/press-announcements/fda-allows-marketing-first-direct-consumer-tests-provide-genetic-risk-information-certain-conditions
12. Blell M, Hunter MA. Direct-to-consumer genetic testing’s red herring: “genetic ancestry” and personalized medicine. Front Med. 2019;6:48. doi: 10.3389/fmed.2019.00048
13. Ekstrand B, Scheers N, Rasmussen MK, et al. Brain foods - the role of diet in brain performance and health. Nutr Rev. 2021;79:693-708. doi: 10.1093/nutrit/nuaa091
14. Cherian L, Wang Y, Fakuda K, et al. Mediterranean-Dash Intervention for Neurodegenerative Delay (MIND) diet slows cognitive decline after stroke. J Prev Alzheimers Dis. 2019;6:267-273. doi: 10.14283/jpad.2019.28
15. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet. 2020;396:413-446. doi: 10.1016/S0140-6736(20)30367-6
16. Livingston PG, Sommerlad A, Orgeta V, et al. The Lancet International Commission on Dementia Prevention and Care. 2017. Accessed March 30, 2022. https://discovery.ucl.ac.uk/id/eprint/1567635/1/Livingston_Dementia_prevention_intervention_care.pdf
17. Peters U. What is the function of confirmation bias? Erkenntnis. April 2020. doi: 10.1007/s10670-020-00252-1
18. Barnes LL, Bennett DA. Cognitive resilience in APOE*ε4 carriers—is race important? Nat Rev Neurol. 2015;11:190-191. doi: 10.1038/nrneurol.2015.38
19. Farrer LA. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA. 1997;278:1349. doi: 10.1001/jama.1997.03550160069041
20. Evans DA, Bennett DA, Wilson RS, et al. Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status. Arch Neurol. 2003;60:185. doi: 10.1001/archneur.60.2.185
21. Chung WW, Chen CA, Cupples LA, et al. A new scale measuring psychologic impact of genetic susceptibility testing for Alzheimer disease. Alzheimer Dis Assoc Disord. 2009;23:50-56. doi: 10.1097/WAD.0b013e318188429e
22. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606-613. doi: 10.1046/j.1525-1497.2001.016009606.x
23. Yesavage JA, Sheikh JI. 9/Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. Clin Gerontol. 1986;5:165-173. doi: 10.1300/J018v05n01_09
24. Green RC, Roberts JS, Cupples LA, et al. Disclosure of APOE genotype for risk of Alzheimer’s disease. N Engl J Med. 2009;361:245-254. doi: 10.1056/NEJMoa0809578
25. Lineweaver TT, Bondi MW, Galasko D, et al. Effect of knowledge of APOE genotype on subjective and objective memory performance in healthy older adults. Am J Psychiatry. 2014;171:201-208. doi: 10.1176/appi.ajp.2013.12121590
26. Karlawish J. Understanding the impact of learning an amyloid PET scan result: preliminary findings from the SOKRATES study. Alzheimers Dement J Alzheimers Assoc. 2016;12:P325. doi: 10.1016/j.jalz.2016.06.594
27. Stites SD. Cognitively healthy individuals want to know their risk for Alzheimer’s disease: what should we do? J Alzheimers Dis. 2018;62:499-502. doi: 10.3233/JAD-171089
28. Milne S, Lomax C, Freeston MH. A review of the relationship between intolerance of uncertainty and threat appraisal in anxiety. Cogn Behav Ther. 2019;12:e38. doi: 10.1017/S1754470X19000230
29. Hebert EA, Dugas MJ. Behavioral experiments for intolerance of uncertainty: challenging the unknown in the treatment of generalized anxiety disorder. Cogn Behav Pract. 2019;26:421-436. doi: 10.1016/j.cbpra.2018.07.007
30. Stites SD, Karlawish, J. Stigma of Alzheimer’s disease dementia: considerations for practice. Pract Neurol. Published June 2018. Accessed January 31, 2019. http://practicalneurology.com/2018/06/stigma-of-alzheimers-disease-dementia/
31. Solomon A, Turunen H, Ngandu T, et al. Effect of the apolipoprotein E genotype on cognitive change during a multidomain lifestyle intervention: a subgroup analysis of a randomized clinical trial. JAMA Neurol. 2018;75:462. doi: 10.1001/jamaneurol.2017.4365
32. Peters R, Warwick J, Anstey KJ, et al. Blood pressure and dementia: what the SPRINT-MIND trial adds and what we still need to know. Neurology. 2019;92:1017-1018. doi: 10.1212/WNL.0000000000007543
33. Musunuru K, Hershberger RE, Day SM, et al. Genetic testing for inherited cardiovascular diseases: a Scientific Statement from the American Heart Association. Circ Genom Precis Med. 2020;13: e000067. doi: 10.1161/HCG.0000000000000067
34. Margaglione M, Seripa D, Gravina C, et al. Prevalence of apolipoprotein E alleles in healthy subjects and survivors of ischemic stroke. Stroke. 1998;29:399-403. doi: 10.1161/01.STR.29.2.399
35. National Institute on Aging. Alzheimer’s disease genetics fact sheet. Reviewed December 24, 2019. Accessed April 10, 2022. www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet
36. Belluck P, Kaplan S, Robbins R. How Aduhelm, an unproven Alzheimer’s drug, got approved. The New York Times. Published July 19, 2021. Updated Oct. 20, 2021. Accessed December 1, 2021. www.nytimes.com/2021/07/19/health/alzheimers-drug-aduhelm-fda.html
1. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2018;14:535-562. doi: 10.1016/j.jalz.2018.02.018 PMCID:PMC5958625
2. Langlois CM, Bradbury A, Wood EM, et al. Alzheimer’s Prevention Initiative Generation Program: development of an APOE genetic counseling and disclosure process in the context of clinical trials. Alzheimers Dement Transl Res Clin Interv. 2019;5:705-716. doi: 10.1016/j.trci.2019.09.013
3. Frank L, Wesson Ashford J, Bayley PJ, et al. Genetic risk of Alzheimer’s disease: three wishes now that the genie is out of the bottle. J Alzheimers Dis. 2018;66:421-423. doi: 10.3233/JAD-180629
4. Qian J, Wolters FJ, Beiser A, et al. APOE-related risk of mild cognitive impairment and dementia for prevention trials: an analysis of four cohorts. PLOS Med. 2017;14:e1002254. doi: 10.1371/journal.pmed.1002254
5. Sperling RA, Jack CR, Black SE, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7:367-385. doi: 10.1016/j.jalz.2011.05.2351
6. FDA. November 6, 2020: Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting Announcement. Published November 12, 2020. Accessed January 14, 2021. www.fda.gov/advisory-committees/advisory-committee-calendar/november-6-2020-meeting-peripheral-and-central-nervous-system-drugs-advisory-committee-meeting
7. Cummings J. Why aducanumab is important. Nat Med. 2021;27:1498-1498. doi: 10.1038/s41591-021-01478-4
8. Alexander GC, Karlawish J. The problem of aducanumab for the treatment of Alzheimer disease. Ann Intern Med. 2021;174:1303-1304. doi: 10.7326/M21-2603
9. Mullard A. More Alzheimer’s drugs head for FDA review: what scientists are watching. Nature. 2021;599:544-545. doi: 10.1038/d41586-021-03410-9
10. Rosenberg A, Mangialasche F, Ngandu T, et al. Multidomain interventions to prevent cognitive impairment, Alzheimer’s disease, and dementia: from finger to world-wide fingers. J Prev Alzheimers Dis. 2019:1-8. doi: 10.14283/jpad.2019.41
11. FDA. Commissioner of the FDA allows marketing of first direct-to-consumer tests that provide genetic risk information for certain conditions. Published March 24, 2020. Accessed November 7, 2020. www.fda.gov/news-events/press-announcements/fda-allows-marketing-first-direct-consumer-tests-provide-genetic-risk-information-certain-conditions
12. Blell M, Hunter MA. Direct-to-consumer genetic testing’s red herring: “genetic ancestry” and personalized medicine. Front Med. 2019;6:48. doi: 10.3389/fmed.2019.00048
13. Ekstrand B, Scheers N, Rasmussen MK, et al. Brain foods - the role of diet in brain performance and health. Nutr Rev. 2021;79:693-708. doi: 10.1093/nutrit/nuaa091
14. Cherian L, Wang Y, Fakuda K, et al. Mediterranean-Dash Intervention for Neurodegenerative Delay (MIND) diet slows cognitive decline after stroke. J Prev Alzheimers Dis. 2019;6:267-273. doi: 10.14283/jpad.2019.28
15. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet. 2020;396:413-446. doi: 10.1016/S0140-6736(20)30367-6
16. Livingston PG, Sommerlad A, Orgeta V, et al. The Lancet International Commission on Dementia Prevention and Care. 2017. Accessed March 30, 2022. https://discovery.ucl.ac.uk/id/eprint/1567635/1/Livingston_Dementia_prevention_intervention_care.pdf
17. Peters U. What is the function of confirmation bias? Erkenntnis. April 2020. doi: 10.1007/s10670-020-00252-1
18. Barnes LL, Bennett DA. Cognitive resilience in APOE*ε4 carriers—is race important? Nat Rev Neurol. 2015;11:190-191. doi: 10.1038/nrneurol.2015.38
19. Farrer LA. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA. 1997;278:1349. doi: 10.1001/jama.1997.03550160069041
20. Evans DA, Bennett DA, Wilson RS, et al. Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status. Arch Neurol. 2003;60:185. doi: 10.1001/archneur.60.2.185
21. Chung WW, Chen CA, Cupples LA, et al. A new scale measuring psychologic impact of genetic susceptibility testing for Alzheimer disease. Alzheimer Dis Assoc Disord. 2009;23:50-56. doi: 10.1097/WAD.0b013e318188429e
22. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606-613. doi: 10.1046/j.1525-1497.2001.016009606.x
23. Yesavage JA, Sheikh JI. 9/Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. Clin Gerontol. 1986;5:165-173. doi: 10.1300/J018v05n01_09
24. Green RC, Roberts JS, Cupples LA, et al. Disclosure of APOE genotype for risk of Alzheimer’s disease. N Engl J Med. 2009;361:245-254. doi: 10.1056/NEJMoa0809578
25. Lineweaver TT, Bondi MW, Galasko D, et al. Effect of knowledge of APOE genotype on subjective and objective memory performance in healthy older adults. Am J Psychiatry. 2014;171:201-208. doi: 10.1176/appi.ajp.2013.12121590
26. Karlawish J. Understanding the impact of learning an amyloid PET scan result: preliminary findings from the SOKRATES study. Alzheimers Dement J Alzheimers Assoc. 2016;12:P325. doi: 10.1016/j.jalz.2016.06.594
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