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A healthy heart in youth protects the brain later on
, new research suggests. New findings from the Coronary Artery Risk Development in Young Adults (CARDIA) study show that individuals who had better cardiovascular health in their 20s scored higher on tests of thinking and memory 30 years later than their peers who had poorer cardiovascular health as young adults.
“We have learned that midlife vascular risk factors, rather than risk factors in older age, are particularly associated with cognition in older age,” study author Farzaneh Sorond, MD, PhD, Northwestern University Feinberg School of Medicine, Chicago, Illinois, told Medscape Medical News
“Our findings from the CARDIA study expand this knowledge and show that vascular health during young adulthood, rather than midlife, is also specifically associated with brain vascular health and cognitive function” in later life, Dr. Sorond said.
“These results indicate that people need to pay close attention to their health even in their early 20s,” she added in a statement.
The findings were released February 26 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage.
Early prevention key
The analysis examined data from 189 participants (45% women, 45% black) in the CARDIA study who were followed for 30 years. The mean age at baseline was 24 years.
Vascular risk factors were assessed eight times during the 30-year study period. A cardiovascular health score (range, 0 – 10) was calculated on the basis of smoking status, body mass index, blood pressure, total cholesterol level, and fasting glucose level.
At the final assessment, which was conducted 30 years after baseline, dynamic cerebral autoregulation was calculated as the transfer function phase of the spontaneous oscillations in blood pressure and flow velocity in the middle cerebral artery using transcranial Doppler ultrasound.
Cognition was assessed using a series of standard neuropsychological tests. Multivariate linear regression models were used to assess the association of heart health at each visit with cerebral autoregulation and cognition.
Results showed that the participants with better cardiovascular health at the beginning of the study were more likely to have higher cognitive test scores 30 years later in comparison with those with worse cardiovascular health.
For example, on a test of attention skills in which scores ranged from 7 to 103, each point higher on the cardiovascular health score was associated with a 2.2-point higher score in attention skills. These results held up after adjustment for other factors that could affect cognitive test scores, such as education level.
Better cardiovascular health at baseline and at 7 years was also associated with significantly better dynamic cerebral autoregulation.
“Our findings suggest that the earlier vascular risk factors are modified and addressed, the more likely that they will impact brain health across life span,” Dr. Sorond said.
“Moreover, these findings underscore the importance of primordial prevention and addressing the significant knowledge gap that currently exist in this domain,” she added.
Good for the heart, good for the brain
Commenting on the findings, Rebecca Edelmayer, PhD, director of scientific engagement for the Alzheimer’s Association, said that the longitudinal study adds to the growing body of research showing that “what is good for the heart is also good for the brain.”
“This is still a relatively small study, and larger studies have been published that show similar results,” said Dr. Edelmayer, who was not involved with the research.
She noted that results of the large SPRINT-MIND trial, published last year in JAMA and reported by Medscape Medical News, “provided the strongest evidence to date about reducing risk of mild cognitive impairment through the management of high blood pressure.”
The Alzheimer’s Association has provided seed funding for SPRINT-MIND 2.0, a 2-year extension of the study to evaluate whether intensive blood pressure management reduces risk for all-cause dementia.
Support for the current study was provided by the National Institutes of Health, the National Heart, Lung, and Blood Institute, the University of Alabama at Birmingham, Northwestern University, the University of Minnesota, and the Kaiser Foundation Research Institute. Drs. Sorond and Edelmayer have reported no relevant financial relationships.
This article first appeared on Medscape.com.
, new research suggests. New findings from the Coronary Artery Risk Development in Young Adults (CARDIA) study show that individuals who had better cardiovascular health in their 20s scored higher on tests of thinking and memory 30 years later than their peers who had poorer cardiovascular health as young adults.
“We have learned that midlife vascular risk factors, rather than risk factors in older age, are particularly associated with cognition in older age,” study author Farzaneh Sorond, MD, PhD, Northwestern University Feinberg School of Medicine, Chicago, Illinois, told Medscape Medical News
“Our findings from the CARDIA study expand this knowledge and show that vascular health during young adulthood, rather than midlife, is also specifically associated with brain vascular health and cognitive function” in later life, Dr. Sorond said.
“These results indicate that people need to pay close attention to their health even in their early 20s,” she added in a statement.
The findings were released February 26 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage.
Early prevention key
The analysis examined data from 189 participants (45% women, 45% black) in the CARDIA study who were followed for 30 years. The mean age at baseline was 24 years.
Vascular risk factors were assessed eight times during the 30-year study period. A cardiovascular health score (range, 0 – 10) was calculated on the basis of smoking status, body mass index, blood pressure, total cholesterol level, and fasting glucose level.
At the final assessment, which was conducted 30 years after baseline, dynamic cerebral autoregulation was calculated as the transfer function phase of the spontaneous oscillations in blood pressure and flow velocity in the middle cerebral artery using transcranial Doppler ultrasound.
Cognition was assessed using a series of standard neuropsychological tests. Multivariate linear regression models were used to assess the association of heart health at each visit with cerebral autoregulation and cognition.
Results showed that the participants with better cardiovascular health at the beginning of the study were more likely to have higher cognitive test scores 30 years later in comparison with those with worse cardiovascular health.
For example, on a test of attention skills in which scores ranged from 7 to 103, each point higher on the cardiovascular health score was associated with a 2.2-point higher score in attention skills. These results held up after adjustment for other factors that could affect cognitive test scores, such as education level.
Better cardiovascular health at baseline and at 7 years was also associated with significantly better dynamic cerebral autoregulation.
“Our findings suggest that the earlier vascular risk factors are modified and addressed, the more likely that they will impact brain health across life span,” Dr. Sorond said.
“Moreover, these findings underscore the importance of primordial prevention and addressing the significant knowledge gap that currently exist in this domain,” she added.
Good for the heart, good for the brain
Commenting on the findings, Rebecca Edelmayer, PhD, director of scientific engagement for the Alzheimer’s Association, said that the longitudinal study adds to the growing body of research showing that “what is good for the heart is also good for the brain.”
“This is still a relatively small study, and larger studies have been published that show similar results,” said Dr. Edelmayer, who was not involved with the research.
She noted that results of the large SPRINT-MIND trial, published last year in JAMA and reported by Medscape Medical News, “provided the strongest evidence to date about reducing risk of mild cognitive impairment through the management of high blood pressure.”
The Alzheimer’s Association has provided seed funding for SPRINT-MIND 2.0, a 2-year extension of the study to evaluate whether intensive blood pressure management reduces risk for all-cause dementia.
Support for the current study was provided by the National Institutes of Health, the National Heart, Lung, and Blood Institute, the University of Alabama at Birmingham, Northwestern University, the University of Minnesota, and the Kaiser Foundation Research Institute. Drs. Sorond and Edelmayer have reported no relevant financial relationships.
This article first appeared on Medscape.com.
, new research suggests. New findings from the Coronary Artery Risk Development in Young Adults (CARDIA) study show that individuals who had better cardiovascular health in their 20s scored higher on tests of thinking and memory 30 years later than their peers who had poorer cardiovascular health as young adults.
“We have learned that midlife vascular risk factors, rather than risk factors in older age, are particularly associated with cognition in older age,” study author Farzaneh Sorond, MD, PhD, Northwestern University Feinberg School of Medicine, Chicago, Illinois, told Medscape Medical News
“Our findings from the CARDIA study expand this knowledge and show that vascular health during young adulthood, rather than midlife, is also specifically associated with brain vascular health and cognitive function” in later life, Dr. Sorond said.
“These results indicate that people need to pay close attention to their health even in their early 20s,” she added in a statement.
The findings were released February 26 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage.
Early prevention key
The analysis examined data from 189 participants (45% women, 45% black) in the CARDIA study who were followed for 30 years. The mean age at baseline was 24 years.
Vascular risk factors were assessed eight times during the 30-year study period. A cardiovascular health score (range, 0 – 10) was calculated on the basis of smoking status, body mass index, blood pressure, total cholesterol level, and fasting glucose level.
At the final assessment, which was conducted 30 years after baseline, dynamic cerebral autoregulation was calculated as the transfer function phase of the spontaneous oscillations in blood pressure and flow velocity in the middle cerebral artery using transcranial Doppler ultrasound.
Cognition was assessed using a series of standard neuropsychological tests. Multivariate linear regression models were used to assess the association of heart health at each visit with cerebral autoregulation and cognition.
Results showed that the participants with better cardiovascular health at the beginning of the study were more likely to have higher cognitive test scores 30 years later in comparison with those with worse cardiovascular health.
For example, on a test of attention skills in which scores ranged from 7 to 103, each point higher on the cardiovascular health score was associated with a 2.2-point higher score in attention skills. These results held up after adjustment for other factors that could affect cognitive test scores, such as education level.
Better cardiovascular health at baseline and at 7 years was also associated with significantly better dynamic cerebral autoregulation.
“Our findings suggest that the earlier vascular risk factors are modified and addressed, the more likely that they will impact brain health across life span,” Dr. Sorond said.
“Moreover, these findings underscore the importance of primordial prevention and addressing the significant knowledge gap that currently exist in this domain,” she added.
Good for the heart, good for the brain
Commenting on the findings, Rebecca Edelmayer, PhD, director of scientific engagement for the Alzheimer’s Association, said that the longitudinal study adds to the growing body of research showing that “what is good for the heart is also good for the brain.”
“This is still a relatively small study, and larger studies have been published that show similar results,” said Dr. Edelmayer, who was not involved with the research.
She noted that results of the large SPRINT-MIND trial, published last year in JAMA and reported by Medscape Medical News, “provided the strongest evidence to date about reducing risk of mild cognitive impairment through the management of high blood pressure.”
The Alzheimer’s Association has provided seed funding for SPRINT-MIND 2.0, a 2-year extension of the study to evaluate whether intensive blood pressure management reduces risk for all-cause dementia.
Support for the current study was provided by the National Institutes of Health, the National Heart, Lung, and Blood Institute, the University of Alabama at Birmingham, Northwestern University, the University of Minnesota, and the Kaiser Foundation Research Institute. Drs. Sorond and Edelmayer have reported no relevant financial relationships.
This article first appeared on Medscape.com.
New gene variants linked to tau deposits in Alzheimer’s disease
Investigator Vijay Ramanan, MD, PhD, behavioral neurology fellow, Mayo Clinic, Rochester, Minnesota, noted that this is the first genome-wide study of tau positron-emission tomography (PET) and that it identifies variations in DNA profiles associated with tau load in the brain.
“These early results represent an important step to better understanding why some individuals have a greater susceptibility to tau accumulation while others are more resistant,” Dr. Ramanan told Medscape Medical News.
“As we learn more about that process, the longer-term hope would be to use that information to better predict who may become symptomatic from the disease and to develop targets for treatment based on those individualized profiles,” he added.
The findings were released March 9 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage.
Genome-wide associations
The researchers assessed genetic profile and regional tau-PET data for 754 participants (mean age, 72.4 years; 54.6% men; 87% cognitively unimpaired) in the Mayo Clinic Study of Aging.
They found that individuals with novel genetic variants on chromosomes 1 and 5 had a higher amount of tau in their brains, compared with their counterparts who had more typical gene sequences in those regions.
The genetic variants were found in 2% to 3% of the group, and those individuals had about 10% higher tau levels than patients who did not have the variants.
Specifically, investigators identified genome-wide significant associations with higher tau for rs76752255 in protein phosphatase 2 regulatory subunit B (PPP2R2B), an enzyme of the PPP2R2B gene on chromosome 5, and for rs115862481 in an intergenic region on chromosome 1. Each minor allele had a stronger association in amyloid-positive than in amyloid-negative individuals.
In addition, three single-nucleotide polymorphisms (SNPs) within microtubule-associated protein tau (MAPT) genes displayed nominal associations to tau burden. These included rs3785883, which previously was found to be associated with higher levels of cerebrospinal fluid tau in an independent cohort.
However, no associations with tau burden were identified for the SNPs defining apolipoprotein E (APOE) e4 or for genotyped SNPs previously associated with Alzheimer’s disease in large case-control studies.
“The fact that these variants are new, coupled with the lack of strong signal for tau in APOE, reinforces the concept that Alzheimer’s disease is complex and that across patients, different sets of genes may be involved in entering into the Alzheimer’s disease pathway versus modifying its course or symptomatic expression,” Dr. Ramanan said.
“Lots of exciting work is ongoing to try to disentangle those issues, and this study is a valuable step on that path,” he added.
Dr. Ramanan said there is a great need for a better understanding of the factors that influence tau deposition, particularly since the burden and location of tau buildup in the brain are closely related to cognitive symptoms of Alzheimer’s disease.
He noted that the approach of “imaging genetics”—using brain scans that capture disease biomarkers and connecting those with data on the genome to improve knowledge about risk and treatment targeting—has been growing. However, only recently has it become possible to apply that framework to tau.
Dr, Ramanan emphasized that replication studies and functional characterization of these novel genetic findings are needed.
“Distant” clinical implications
Commenting on the study, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, said that there is currently “a fair amount of this kind of work going on” in assessing polygenetic risk in Alzheimer’s disease. This includes examining APOE as well as “a whole bunch of other genes” associated with the disease.
“Far and away, the APOE genetic association with Alzheimer’s disease risk is the most powerful one. In and of themselves, none of these other risk genes cause Alzheimer’s disease, they only contribute to risk,” Dr. Fillit noted.
“This study found some new genes that were associated with susceptibility to tau deposition, but at the end of the day, they are just associations. They don’t prove causality,” he added.
“It’s interesting, but really hard to know what to conclude from it; and the clinical implications, I think, are rather distant,” Dr. Fillit concluded.
The study was supported by the National Institutes of Health; the Gerald and Henrietta Rauenhorst Foundation; the Alexander Family Alzheimer’s Disease Research Professorship of Mayo Clinic; the Mayo Foundation for Medical Education and Research; a Liston Award; the Elsie and Marvin Dekelboum Family Foundation; the Schuler Foundation; and Avid Radiopharmaceuticals, which supplied the imaging agent used by researchers to detect tau in the brain. Ramanan and Fillit have reported no relevant financial relationships.
This article first appeared on Medscape.com.
Investigator Vijay Ramanan, MD, PhD, behavioral neurology fellow, Mayo Clinic, Rochester, Minnesota, noted that this is the first genome-wide study of tau positron-emission tomography (PET) and that it identifies variations in DNA profiles associated with tau load in the brain.
“These early results represent an important step to better understanding why some individuals have a greater susceptibility to tau accumulation while others are more resistant,” Dr. Ramanan told Medscape Medical News.
“As we learn more about that process, the longer-term hope would be to use that information to better predict who may become symptomatic from the disease and to develop targets for treatment based on those individualized profiles,” he added.
The findings were released March 9 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage.
Genome-wide associations
The researchers assessed genetic profile and regional tau-PET data for 754 participants (mean age, 72.4 years; 54.6% men; 87% cognitively unimpaired) in the Mayo Clinic Study of Aging.
They found that individuals with novel genetic variants on chromosomes 1 and 5 had a higher amount of tau in their brains, compared with their counterparts who had more typical gene sequences in those regions.
The genetic variants were found in 2% to 3% of the group, and those individuals had about 10% higher tau levels than patients who did not have the variants.
Specifically, investigators identified genome-wide significant associations with higher tau for rs76752255 in protein phosphatase 2 regulatory subunit B (PPP2R2B), an enzyme of the PPP2R2B gene on chromosome 5, and for rs115862481 in an intergenic region on chromosome 1. Each minor allele had a stronger association in amyloid-positive than in amyloid-negative individuals.
In addition, three single-nucleotide polymorphisms (SNPs) within microtubule-associated protein tau (MAPT) genes displayed nominal associations to tau burden. These included rs3785883, which previously was found to be associated with higher levels of cerebrospinal fluid tau in an independent cohort.
However, no associations with tau burden were identified for the SNPs defining apolipoprotein E (APOE) e4 or for genotyped SNPs previously associated with Alzheimer’s disease in large case-control studies.
“The fact that these variants are new, coupled with the lack of strong signal for tau in APOE, reinforces the concept that Alzheimer’s disease is complex and that across patients, different sets of genes may be involved in entering into the Alzheimer’s disease pathway versus modifying its course or symptomatic expression,” Dr. Ramanan said.
“Lots of exciting work is ongoing to try to disentangle those issues, and this study is a valuable step on that path,” he added.
Dr. Ramanan said there is a great need for a better understanding of the factors that influence tau deposition, particularly since the burden and location of tau buildup in the brain are closely related to cognitive symptoms of Alzheimer’s disease.
He noted that the approach of “imaging genetics”—using brain scans that capture disease biomarkers and connecting those with data on the genome to improve knowledge about risk and treatment targeting—has been growing. However, only recently has it become possible to apply that framework to tau.
Dr, Ramanan emphasized that replication studies and functional characterization of these novel genetic findings are needed.
“Distant” clinical implications
Commenting on the study, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, said that there is currently “a fair amount of this kind of work going on” in assessing polygenetic risk in Alzheimer’s disease. This includes examining APOE as well as “a whole bunch of other genes” associated with the disease.
“Far and away, the APOE genetic association with Alzheimer’s disease risk is the most powerful one. In and of themselves, none of these other risk genes cause Alzheimer’s disease, they only contribute to risk,” Dr. Fillit noted.
“This study found some new genes that were associated with susceptibility to tau deposition, but at the end of the day, they are just associations. They don’t prove causality,” he added.
“It’s interesting, but really hard to know what to conclude from it; and the clinical implications, I think, are rather distant,” Dr. Fillit concluded.
The study was supported by the National Institutes of Health; the Gerald and Henrietta Rauenhorst Foundation; the Alexander Family Alzheimer’s Disease Research Professorship of Mayo Clinic; the Mayo Foundation for Medical Education and Research; a Liston Award; the Elsie and Marvin Dekelboum Family Foundation; the Schuler Foundation; and Avid Radiopharmaceuticals, which supplied the imaging agent used by researchers to detect tau in the brain. Ramanan and Fillit have reported no relevant financial relationships.
This article first appeared on Medscape.com.
Investigator Vijay Ramanan, MD, PhD, behavioral neurology fellow, Mayo Clinic, Rochester, Minnesota, noted that this is the first genome-wide study of tau positron-emission tomography (PET) and that it identifies variations in DNA profiles associated with tau load in the brain.
“These early results represent an important step to better understanding why some individuals have a greater susceptibility to tau accumulation while others are more resistant,” Dr. Ramanan told Medscape Medical News.
“As we learn more about that process, the longer-term hope would be to use that information to better predict who may become symptomatic from the disease and to develop targets for treatment based on those individualized profiles,” he added.
The findings were released March 9 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage.
Genome-wide associations
The researchers assessed genetic profile and regional tau-PET data for 754 participants (mean age, 72.4 years; 54.6% men; 87% cognitively unimpaired) in the Mayo Clinic Study of Aging.
They found that individuals with novel genetic variants on chromosomes 1 and 5 had a higher amount of tau in their brains, compared with their counterparts who had more typical gene sequences in those regions.
The genetic variants were found in 2% to 3% of the group, and those individuals had about 10% higher tau levels than patients who did not have the variants.
Specifically, investigators identified genome-wide significant associations with higher tau for rs76752255 in protein phosphatase 2 regulatory subunit B (PPP2R2B), an enzyme of the PPP2R2B gene on chromosome 5, and for rs115862481 in an intergenic region on chromosome 1. Each minor allele had a stronger association in amyloid-positive than in amyloid-negative individuals.
In addition, three single-nucleotide polymorphisms (SNPs) within microtubule-associated protein tau (MAPT) genes displayed nominal associations to tau burden. These included rs3785883, which previously was found to be associated with higher levels of cerebrospinal fluid tau in an independent cohort.
However, no associations with tau burden were identified for the SNPs defining apolipoprotein E (APOE) e4 or for genotyped SNPs previously associated with Alzheimer’s disease in large case-control studies.
“The fact that these variants are new, coupled with the lack of strong signal for tau in APOE, reinforces the concept that Alzheimer’s disease is complex and that across patients, different sets of genes may be involved in entering into the Alzheimer’s disease pathway versus modifying its course or symptomatic expression,” Dr. Ramanan said.
“Lots of exciting work is ongoing to try to disentangle those issues, and this study is a valuable step on that path,” he added.
Dr. Ramanan said there is a great need for a better understanding of the factors that influence tau deposition, particularly since the burden and location of tau buildup in the brain are closely related to cognitive symptoms of Alzheimer’s disease.
He noted that the approach of “imaging genetics”—using brain scans that capture disease biomarkers and connecting those with data on the genome to improve knowledge about risk and treatment targeting—has been growing. However, only recently has it become possible to apply that framework to tau.
Dr, Ramanan emphasized that replication studies and functional characterization of these novel genetic findings are needed.
“Distant” clinical implications
Commenting on the study, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, said that there is currently “a fair amount of this kind of work going on” in assessing polygenetic risk in Alzheimer’s disease. This includes examining APOE as well as “a whole bunch of other genes” associated with the disease.
“Far and away, the APOE genetic association with Alzheimer’s disease risk is the most powerful one. In and of themselves, none of these other risk genes cause Alzheimer’s disease, they only contribute to risk,” Dr. Fillit noted.
“This study found some new genes that were associated with susceptibility to tau deposition, but at the end of the day, they are just associations. They don’t prove causality,” he added.
“It’s interesting, but really hard to know what to conclude from it; and the clinical implications, I think, are rather distant,” Dr. Fillit concluded.
The study was supported by the National Institutes of Health; the Gerald and Henrietta Rauenhorst Foundation; the Alexander Family Alzheimer’s Disease Research Professorship of Mayo Clinic; the Mayo Foundation for Medical Education and Research; a Liston Award; the Elsie and Marvin Dekelboum Family Foundation; the Schuler Foundation; and Avid Radiopharmaceuticals, which supplied the imaging agent used by researchers to detect tau in the brain. Ramanan and Fillit have reported no relevant financial relationships.
This article first appeared on Medscape.com.
Klotho allele lowers APOE4-associated risk of Alzheimer’s
Cognitively normal carriers of the apolipoprotein E epsilon-4 (APOE4) allele aged 60 years and older who also showed heterozygosity for the Klotho-VS allele had a significantly reduced risk of developing Alzheimer’s disease, according to data from 22 research groups including more than 20,000 adults.
The transmembrane protein known as klotho (KL) is part of a functional haplotype known as KL-VS. “Specifically, heterozygosity for KL-VS (KL-VSHET+ status) has been shown to increase serum levels of KL and exert protective effects on healthy aging and longevity when compared with individuals who are homozygotes for the major or minor alleles (KL-VSHET−),” wrote Michael E. Belloy, PhD, of Stanford (Calif.) University and colleagues. However, the possible role of KL-VS in protecting against neurodegenerative disorders such as Alzheimer’s disease (AD) remains unclear, they said.
In a study published in JAMA Neurology, the researchers reviewed data from 20,928 participants in case-control studies, as well as 3,008 participants in conversion studies, 556 in amyloid-beta (a-beta) cerebrospinal fluid regression analyses, and 251 in brain amyloid PET regression analyses. The participants were aged 60-80 years, and of non-Hispanic northern European ancestry and were identified as cognitively normal or having mild cognitive impairment (MCI) or AD.
Overall, individuals with the APOE4 allele who were cognitively normal and heterozygous for KL-VS had a significantly reduced risk for developing AD (odds ratio, 0.75).
In addition, cognitively normal carriers of APOE4 with KL-VS heterozygosity had significantly lower risk of developing either MCI or AD (hazard ratio, 0.64). Also, those persons with APOE4 and positive KL-VS heterozygosity had higher a-beta in cerebrospinal fluid (P = .03) and lower a-beta on PET scans (P = .04). However, no association with cognitive outcomes were noted among APOE4 noncarriers, the researchers noted.
“This suggests that KL-VS interacts with aspects of AD pathology that are more pronounced in those who carry APOE4, such as a-beta accumulation during the presymptomatic phases of the disease,” they said.
The study findings were limited by the variable age and diagnoses across the multiple cohorts, but strengthened by the meta- and mega-analyses and sensitivity analyses that yielded consistent results, the researchers noted.
“Our work paves the way for biological validation studies to elucidate the molecular pathways by which KL-VS and APOE interact,” they said.
“The specificity of KL-VS benefits on AD in individuals who carry APOE4 is striking and suggests a yet-unstudied interaction between biological pathways of the klotho and APOE4 proteins,” wrote Dena B. Dubal, MD, and Jennifer S. Yokoyama, PhD, of the University of California, San Francisco, in an accompanying editorial. Despite limitations, the study findings have implications for clinical neurology, as well as clinical and translational research, they said.
“For personalized genomics, KL-VS status should integrate into knowledge that both lifestyle and genetics can negate or at least mitigate harmful influences of APOE4,” they noted. “In light of this, we might consider an individual’s KLOTHO genotype when counseling individuals who carry APOE4 about their prognosis for AD. In clinical trials using APOE4 for trial enrichment, further selection of individuals who carry APOE4 without KL-VS could define a population more likely to convert to AD and thus increase detection of a therapeutic benefit. In translational research, understanding how klotho itself or its biological pathways may counter APOE4 could lead to monumental progress in the future treatment of AD,” they added.
“Applying our growing knowledge of klotho to APOE4 and AD could ultimately pave the path to novel therapeutics for individuals who carry APOE4,” they concluded.
The study was supported by the Iqbal Farrukh & Asad Jamal Center for Cognitive Health in Aging, the South Palm Beach County Foundation, and the National Institutes of Health. The researchers had no financial conflicts to disclose. Dr. Dubal disclosed holding a patent for Methods for Improving Cognition that includes klotho, as well as consulting for Unity Biotechnology and receiving research funding from the National Institutes of Health, the American Federation for Aging Research, Glenn Medical Foundation, Unity Biotechnology, and other philanthropic support for translational research. Dr. Yokoyama disclosed research funding from the National Institutes of Health, the Department of Defense, and other foundations and philanthropic donors.
SOURCE: Belloy ME et al. JAMA Neurol. 2020 Apr 13. doi: 10.1001/jamaneurol.2020.0414.
Cognitively normal carriers of the apolipoprotein E epsilon-4 (APOE4) allele aged 60 years and older who also showed heterozygosity for the Klotho-VS allele had a significantly reduced risk of developing Alzheimer’s disease, according to data from 22 research groups including more than 20,000 adults.
The transmembrane protein known as klotho (KL) is part of a functional haplotype known as KL-VS. “Specifically, heterozygosity for KL-VS (KL-VSHET+ status) has been shown to increase serum levels of KL and exert protective effects on healthy aging and longevity when compared with individuals who are homozygotes for the major or minor alleles (KL-VSHET−),” wrote Michael E. Belloy, PhD, of Stanford (Calif.) University and colleagues. However, the possible role of KL-VS in protecting against neurodegenerative disorders such as Alzheimer’s disease (AD) remains unclear, they said.
In a study published in JAMA Neurology, the researchers reviewed data from 20,928 participants in case-control studies, as well as 3,008 participants in conversion studies, 556 in amyloid-beta (a-beta) cerebrospinal fluid regression analyses, and 251 in brain amyloid PET regression analyses. The participants were aged 60-80 years, and of non-Hispanic northern European ancestry and were identified as cognitively normal or having mild cognitive impairment (MCI) or AD.
Overall, individuals with the APOE4 allele who were cognitively normal and heterozygous for KL-VS had a significantly reduced risk for developing AD (odds ratio, 0.75).
In addition, cognitively normal carriers of APOE4 with KL-VS heterozygosity had significantly lower risk of developing either MCI or AD (hazard ratio, 0.64). Also, those persons with APOE4 and positive KL-VS heterozygosity had higher a-beta in cerebrospinal fluid (P = .03) and lower a-beta on PET scans (P = .04). However, no association with cognitive outcomes were noted among APOE4 noncarriers, the researchers noted.
“This suggests that KL-VS interacts with aspects of AD pathology that are more pronounced in those who carry APOE4, such as a-beta accumulation during the presymptomatic phases of the disease,” they said.
The study findings were limited by the variable age and diagnoses across the multiple cohorts, but strengthened by the meta- and mega-analyses and sensitivity analyses that yielded consistent results, the researchers noted.
“Our work paves the way for biological validation studies to elucidate the molecular pathways by which KL-VS and APOE interact,” they said.
“The specificity of KL-VS benefits on AD in individuals who carry APOE4 is striking and suggests a yet-unstudied interaction between biological pathways of the klotho and APOE4 proteins,” wrote Dena B. Dubal, MD, and Jennifer S. Yokoyama, PhD, of the University of California, San Francisco, in an accompanying editorial. Despite limitations, the study findings have implications for clinical neurology, as well as clinical and translational research, they said.
“For personalized genomics, KL-VS status should integrate into knowledge that both lifestyle and genetics can negate or at least mitigate harmful influences of APOE4,” they noted. “In light of this, we might consider an individual’s KLOTHO genotype when counseling individuals who carry APOE4 about their prognosis for AD. In clinical trials using APOE4 for trial enrichment, further selection of individuals who carry APOE4 without KL-VS could define a population more likely to convert to AD and thus increase detection of a therapeutic benefit. In translational research, understanding how klotho itself or its biological pathways may counter APOE4 could lead to monumental progress in the future treatment of AD,” they added.
“Applying our growing knowledge of klotho to APOE4 and AD could ultimately pave the path to novel therapeutics for individuals who carry APOE4,” they concluded.
The study was supported by the Iqbal Farrukh & Asad Jamal Center for Cognitive Health in Aging, the South Palm Beach County Foundation, and the National Institutes of Health. The researchers had no financial conflicts to disclose. Dr. Dubal disclosed holding a patent for Methods for Improving Cognition that includes klotho, as well as consulting for Unity Biotechnology and receiving research funding from the National Institutes of Health, the American Federation for Aging Research, Glenn Medical Foundation, Unity Biotechnology, and other philanthropic support for translational research. Dr. Yokoyama disclosed research funding from the National Institutes of Health, the Department of Defense, and other foundations and philanthropic donors.
SOURCE: Belloy ME et al. JAMA Neurol. 2020 Apr 13. doi: 10.1001/jamaneurol.2020.0414.
Cognitively normal carriers of the apolipoprotein E epsilon-4 (APOE4) allele aged 60 years and older who also showed heterozygosity for the Klotho-VS allele had a significantly reduced risk of developing Alzheimer’s disease, according to data from 22 research groups including more than 20,000 adults.
The transmembrane protein known as klotho (KL) is part of a functional haplotype known as KL-VS. “Specifically, heterozygosity for KL-VS (KL-VSHET+ status) has been shown to increase serum levels of KL and exert protective effects on healthy aging and longevity when compared with individuals who are homozygotes for the major or minor alleles (KL-VSHET−),” wrote Michael E. Belloy, PhD, of Stanford (Calif.) University and colleagues. However, the possible role of KL-VS in protecting against neurodegenerative disorders such as Alzheimer’s disease (AD) remains unclear, they said.
In a study published in JAMA Neurology, the researchers reviewed data from 20,928 participants in case-control studies, as well as 3,008 participants in conversion studies, 556 in amyloid-beta (a-beta) cerebrospinal fluid regression analyses, and 251 in brain amyloid PET regression analyses. The participants were aged 60-80 years, and of non-Hispanic northern European ancestry and were identified as cognitively normal or having mild cognitive impairment (MCI) or AD.
Overall, individuals with the APOE4 allele who were cognitively normal and heterozygous for KL-VS had a significantly reduced risk for developing AD (odds ratio, 0.75).
In addition, cognitively normal carriers of APOE4 with KL-VS heterozygosity had significantly lower risk of developing either MCI or AD (hazard ratio, 0.64). Also, those persons with APOE4 and positive KL-VS heterozygosity had higher a-beta in cerebrospinal fluid (P = .03) and lower a-beta on PET scans (P = .04). However, no association with cognitive outcomes were noted among APOE4 noncarriers, the researchers noted.
“This suggests that KL-VS interacts with aspects of AD pathology that are more pronounced in those who carry APOE4, such as a-beta accumulation during the presymptomatic phases of the disease,” they said.
The study findings were limited by the variable age and diagnoses across the multiple cohorts, but strengthened by the meta- and mega-analyses and sensitivity analyses that yielded consistent results, the researchers noted.
“Our work paves the way for biological validation studies to elucidate the molecular pathways by which KL-VS and APOE interact,” they said.
“The specificity of KL-VS benefits on AD in individuals who carry APOE4 is striking and suggests a yet-unstudied interaction between biological pathways of the klotho and APOE4 proteins,” wrote Dena B. Dubal, MD, and Jennifer S. Yokoyama, PhD, of the University of California, San Francisco, in an accompanying editorial. Despite limitations, the study findings have implications for clinical neurology, as well as clinical and translational research, they said.
“For personalized genomics, KL-VS status should integrate into knowledge that both lifestyle and genetics can negate or at least mitigate harmful influences of APOE4,” they noted. “In light of this, we might consider an individual’s KLOTHO genotype when counseling individuals who carry APOE4 about their prognosis for AD. In clinical trials using APOE4 for trial enrichment, further selection of individuals who carry APOE4 without KL-VS could define a population more likely to convert to AD and thus increase detection of a therapeutic benefit. In translational research, understanding how klotho itself or its biological pathways may counter APOE4 could lead to monumental progress in the future treatment of AD,” they added.
“Applying our growing knowledge of klotho to APOE4 and AD could ultimately pave the path to novel therapeutics for individuals who carry APOE4,” they concluded.
The study was supported by the Iqbal Farrukh & Asad Jamal Center for Cognitive Health in Aging, the South Palm Beach County Foundation, and the National Institutes of Health. The researchers had no financial conflicts to disclose. Dr. Dubal disclosed holding a patent for Methods for Improving Cognition that includes klotho, as well as consulting for Unity Biotechnology and receiving research funding from the National Institutes of Health, the American Federation for Aging Research, Glenn Medical Foundation, Unity Biotechnology, and other philanthropic support for translational research. Dr. Yokoyama disclosed research funding from the National Institutes of Health, the Department of Defense, and other foundations and philanthropic donors.
SOURCE: Belloy ME et al. JAMA Neurol. 2020 Apr 13. doi: 10.1001/jamaneurol.2020.0414.
FROM JAMA NEUROLOGY
Amid coronavirus concerns, researchers urge mental health interventions for patients with dementia
according to a letter published online ahead of print March 30 in Lancet. Consistent with recommendations from Alzheimer’s Disease International and other dementia experts, teams that include mental health professionals, social workers, nursing home administrators, and volunteers should collaborate to provide mental health care for people with dementia. Experts in dementia should lead each team and support team members from other disciplines, wrote Huali Wang, MD, chair of clinical research at Peking University Institute of Mental Health in Beijing, and colleagues.
Interventions could be administered through telehealth, said the authors. Teams led by mental health professionals could use electronic media to provide self-help guidance for reducing stress, such as relaxation or meditation exercise. These teams also could use telephone hotlines to support behavioral management, and psychological counselors could provide online consultations for caregivers in nursing homes or in the community. “We encourage people who have a parent with dementia to have more frequent contact or spend more time with their parent, or to take on some of the caregiving duties so as to give the carer some respite time,” wrote Dr. Wang and colleagues.
Many local authorities are banning visits to nursing home residents to reduce the latter’s risk of COVID-19 infection. As a consequence, these elderly people are becoming more isolated, and anxiety is increasing among nursing home staffs.
In China, five organizations, including the Chinese Society of Geriatric Psychiatry and Alzheimer’s Disease Chinese, responded to the COVID-19 outbreak by publishing recommendations for providing mental health and psychosocial support. Groups of providers from various disciplines offered free counseling services for people with dementia and their caregivers. “These approaches minimized the complex impact of both COVID-19 outbreak and dementia,” wrote the authors.
“China has contained the epidemic, and business is starting to return to normal,” they continued. “We believe that learning lessons from China would empower the world to tackle the COVID-19 pandemic, with little risk of compromising the quality of life of people living with dementia and their carers.”
Dr. Wang has received lecture fees from Eisai China and Lundbeck China. She owns the copyright for the neuropsychiatric symptoms individualized management system. Her coauthors reported serving as advisory board members and receiving fees from companies such as Biogen, Novartis, and Genentech.
SOURCE: Wang H et al. Lancet. 2020 Mar 30. doi: 10.1016/S0140-6736(20)30755-8.
according to a letter published online ahead of print March 30 in Lancet. Consistent with recommendations from Alzheimer’s Disease International and other dementia experts, teams that include mental health professionals, social workers, nursing home administrators, and volunteers should collaborate to provide mental health care for people with dementia. Experts in dementia should lead each team and support team members from other disciplines, wrote Huali Wang, MD, chair of clinical research at Peking University Institute of Mental Health in Beijing, and colleagues.
Interventions could be administered through telehealth, said the authors. Teams led by mental health professionals could use electronic media to provide self-help guidance for reducing stress, such as relaxation or meditation exercise. These teams also could use telephone hotlines to support behavioral management, and psychological counselors could provide online consultations for caregivers in nursing homes or in the community. “We encourage people who have a parent with dementia to have more frequent contact or spend more time with their parent, or to take on some of the caregiving duties so as to give the carer some respite time,” wrote Dr. Wang and colleagues.
Many local authorities are banning visits to nursing home residents to reduce the latter’s risk of COVID-19 infection. As a consequence, these elderly people are becoming more isolated, and anxiety is increasing among nursing home staffs.
In China, five organizations, including the Chinese Society of Geriatric Psychiatry and Alzheimer’s Disease Chinese, responded to the COVID-19 outbreak by publishing recommendations for providing mental health and psychosocial support. Groups of providers from various disciplines offered free counseling services for people with dementia and their caregivers. “These approaches minimized the complex impact of both COVID-19 outbreak and dementia,” wrote the authors.
“China has contained the epidemic, and business is starting to return to normal,” they continued. “We believe that learning lessons from China would empower the world to tackle the COVID-19 pandemic, with little risk of compromising the quality of life of people living with dementia and their carers.”
Dr. Wang has received lecture fees from Eisai China and Lundbeck China. She owns the copyright for the neuropsychiatric symptoms individualized management system. Her coauthors reported serving as advisory board members and receiving fees from companies such as Biogen, Novartis, and Genentech.
SOURCE: Wang H et al. Lancet. 2020 Mar 30. doi: 10.1016/S0140-6736(20)30755-8.
according to a letter published online ahead of print March 30 in Lancet. Consistent with recommendations from Alzheimer’s Disease International and other dementia experts, teams that include mental health professionals, social workers, nursing home administrators, and volunteers should collaborate to provide mental health care for people with dementia. Experts in dementia should lead each team and support team members from other disciplines, wrote Huali Wang, MD, chair of clinical research at Peking University Institute of Mental Health in Beijing, and colleagues.
Interventions could be administered through telehealth, said the authors. Teams led by mental health professionals could use electronic media to provide self-help guidance for reducing stress, such as relaxation or meditation exercise. These teams also could use telephone hotlines to support behavioral management, and psychological counselors could provide online consultations for caregivers in nursing homes or in the community. “We encourage people who have a parent with dementia to have more frequent contact or spend more time with their parent, or to take on some of the caregiving duties so as to give the carer some respite time,” wrote Dr. Wang and colleagues.
Many local authorities are banning visits to nursing home residents to reduce the latter’s risk of COVID-19 infection. As a consequence, these elderly people are becoming more isolated, and anxiety is increasing among nursing home staffs.
In China, five organizations, including the Chinese Society of Geriatric Psychiatry and Alzheimer’s Disease Chinese, responded to the COVID-19 outbreak by publishing recommendations for providing mental health and psychosocial support. Groups of providers from various disciplines offered free counseling services for people with dementia and their caregivers. “These approaches minimized the complex impact of both COVID-19 outbreak and dementia,” wrote the authors.
“China has contained the epidemic, and business is starting to return to normal,” they continued. “We believe that learning lessons from China would empower the world to tackle the COVID-19 pandemic, with little risk of compromising the quality of life of people living with dementia and their carers.”
Dr. Wang has received lecture fees from Eisai China and Lundbeck China. She owns the copyright for the neuropsychiatric symptoms individualized management system. Her coauthors reported serving as advisory board members and receiving fees from companies such as Biogen, Novartis, and Genentech.
SOURCE: Wang H et al. Lancet. 2020 Mar 30. doi: 10.1016/S0140-6736(20)30755-8.
REPORTING FROM THE LANCET
Cardiovascular disease is implicated in link between air pollution and dementia
Virtually all of the association between air pollution and dementia seemed to occur through the presence or the development of cardiovascular disease, which suggests a need to optimize treatment of concurrent cardiovascular disease and risk-factor control in older adults at higher risk for dementia and living in polluted urban areas, said lead author Giulia Grande, MD, a researcher at the Aging Research Center, Karolinska Institutet and Stockholm University, in Solna, Sweden.
In the longitudinal, population-based cohort study, investigators studied 2,927 randomly selected residents in a district of Stockholm who were aged 60 years or older (mean, 74.1 years), lived at home or in institutions, and were free of dementia at baseline (March 2001 through August 2004).
The investigators assessed the participants’ exposure to two major air pollutants – particulate matter ≤2.5 mcm and nitrogen oxide – yearly starting in 1990, from outdoor levels at their residential addresses. Both pollutants are generated by road traffic, among other sources.
Results reported in JAMA Neurology showed that, with a mean follow-up of 6.01 years, 12.4% of the older adults received a dementia diagnosis.
Dementia risk increased with the level of air pollutants at their residential address in the past, with strongest associations seen for exposure in the preceding 5 years: The hazard ratio (HR) for dementia was 1.54 for an interquartile range difference of 0.88 mcg/m3 in particulate matter ≤2.5 mcm and 1.14 for an interquartile range difference of 8.35 mcg/m3 in nitrogen oxide during that time period.
Of note, the study cohort lived in an area having “comparatively good ambient air quality” in which restrictions on air pollution have increased in recent decades, Dr. Grande and coinvestigators noted. “Interestingly, the higher limit reported herein is not only below the current European limit for fine particulate matter but also below the US standard. In other words, we were able to establish harmful effects at levels below current standards,” they wrote.
In analyses of effect modification, the elevation of risk related to particulate matter ≤2.5 mcm exposure and nitrogen oxide exposure was significantly greater among older adults who had heart failure (HRs, 1.93 and 1.43, respectively). Risk was marginally greater among those with ischemic heart disease (HRs, 1.67 and 1.36, respectively).
Analyses of potential mediators showed that preceding stroke accounted for the largest share of all dementia cases related to particulate matter ≤2.5 mcm exposure, at 49.4%.
The stronger association for exposure in the past 5 years is noteworthy for the big picture, they added. “From a policy point of view, this result is encouraging because it might imply that reducing air pollutant levels today could yield better outcomes already in the shorter term, reinforcing the need for appropriately set air quality standards,” they said.
Dr. Grande disclosed no relevant conflicts of interest. The study was funded by the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K); the Swedish Ministry of Health and Social Affairs; the participating County Councils and Municipalities; the Swedish Research Council; funding for doctoral education from the Karolinska Institutet; and the Swedish Research Council for Health, Working Life and Welfare.
SOURCE: Grande G et al. JAMA Neurol. 2020. doi:10.1001/jamaneurol.2019.4914.
Virtually all of the association between air pollution and dementia seemed to occur through the presence or the development of cardiovascular disease, which suggests a need to optimize treatment of concurrent cardiovascular disease and risk-factor control in older adults at higher risk for dementia and living in polluted urban areas, said lead author Giulia Grande, MD, a researcher at the Aging Research Center, Karolinska Institutet and Stockholm University, in Solna, Sweden.
In the longitudinal, population-based cohort study, investigators studied 2,927 randomly selected residents in a district of Stockholm who were aged 60 years or older (mean, 74.1 years), lived at home or in institutions, and were free of dementia at baseline (March 2001 through August 2004).
The investigators assessed the participants’ exposure to two major air pollutants – particulate matter ≤2.5 mcm and nitrogen oxide – yearly starting in 1990, from outdoor levels at their residential addresses. Both pollutants are generated by road traffic, among other sources.
Results reported in JAMA Neurology showed that, with a mean follow-up of 6.01 years, 12.4% of the older adults received a dementia diagnosis.
Dementia risk increased with the level of air pollutants at their residential address in the past, with strongest associations seen for exposure in the preceding 5 years: The hazard ratio (HR) for dementia was 1.54 for an interquartile range difference of 0.88 mcg/m3 in particulate matter ≤2.5 mcm and 1.14 for an interquartile range difference of 8.35 mcg/m3 in nitrogen oxide during that time period.
Of note, the study cohort lived in an area having “comparatively good ambient air quality” in which restrictions on air pollution have increased in recent decades, Dr. Grande and coinvestigators noted. “Interestingly, the higher limit reported herein is not only below the current European limit for fine particulate matter but also below the US standard. In other words, we were able to establish harmful effects at levels below current standards,” they wrote.
In analyses of effect modification, the elevation of risk related to particulate matter ≤2.5 mcm exposure and nitrogen oxide exposure was significantly greater among older adults who had heart failure (HRs, 1.93 and 1.43, respectively). Risk was marginally greater among those with ischemic heart disease (HRs, 1.67 and 1.36, respectively).
Analyses of potential mediators showed that preceding stroke accounted for the largest share of all dementia cases related to particulate matter ≤2.5 mcm exposure, at 49.4%.
The stronger association for exposure in the past 5 years is noteworthy for the big picture, they added. “From a policy point of view, this result is encouraging because it might imply that reducing air pollutant levels today could yield better outcomes already in the shorter term, reinforcing the need for appropriately set air quality standards,” they said.
Dr. Grande disclosed no relevant conflicts of interest. The study was funded by the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K); the Swedish Ministry of Health and Social Affairs; the participating County Councils and Municipalities; the Swedish Research Council; funding for doctoral education from the Karolinska Institutet; and the Swedish Research Council for Health, Working Life and Welfare.
SOURCE: Grande G et al. JAMA Neurol. 2020. doi:10.1001/jamaneurol.2019.4914.
Virtually all of the association between air pollution and dementia seemed to occur through the presence or the development of cardiovascular disease, which suggests a need to optimize treatment of concurrent cardiovascular disease and risk-factor control in older adults at higher risk for dementia and living in polluted urban areas, said lead author Giulia Grande, MD, a researcher at the Aging Research Center, Karolinska Institutet and Stockholm University, in Solna, Sweden.
In the longitudinal, population-based cohort study, investigators studied 2,927 randomly selected residents in a district of Stockholm who were aged 60 years or older (mean, 74.1 years), lived at home or in institutions, and were free of dementia at baseline (March 2001 through August 2004).
The investigators assessed the participants’ exposure to two major air pollutants – particulate matter ≤2.5 mcm and nitrogen oxide – yearly starting in 1990, from outdoor levels at their residential addresses. Both pollutants are generated by road traffic, among other sources.
Results reported in JAMA Neurology showed that, with a mean follow-up of 6.01 years, 12.4% of the older adults received a dementia diagnosis.
Dementia risk increased with the level of air pollutants at their residential address in the past, with strongest associations seen for exposure in the preceding 5 years: The hazard ratio (HR) for dementia was 1.54 for an interquartile range difference of 0.88 mcg/m3 in particulate matter ≤2.5 mcm and 1.14 for an interquartile range difference of 8.35 mcg/m3 in nitrogen oxide during that time period.
Of note, the study cohort lived in an area having “comparatively good ambient air quality” in which restrictions on air pollution have increased in recent decades, Dr. Grande and coinvestigators noted. “Interestingly, the higher limit reported herein is not only below the current European limit for fine particulate matter but also below the US standard. In other words, we were able to establish harmful effects at levels below current standards,” they wrote.
In analyses of effect modification, the elevation of risk related to particulate matter ≤2.5 mcm exposure and nitrogen oxide exposure was significantly greater among older adults who had heart failure (HRs, 1.93 and 1.43, respectively). Risk was marginally greater among those with ischemic heart disease (HRs, 1.67 and 1.36, respectively).
Analyses of potential mediators showed that preceding stroke accounted for the largest share of all dementia cases related to particulate matter ≤2.5 mcm exposure, at 49.4%.
The stronger association for exposure in the past 5 years is noteworthy for the big picture, they added. “From a policy point of view, this result is encouraging because it might imply that reducing air pollutant levels today could yield better outcomes already in the shorter term, reinforcing the need for appropriately set air quality standards,” they said.
Dr. Grande disclosed no relevant conflicts of interest. The study was funded by the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K); the Swedish Ministry of Health and Social Affairs; the participating County Councils and Municipalities; the Swedish Research Council; funding for doctoral education from the Karolinska Institutet; and the Swedish Research Council for Health, Working Life and Welfare.
SOURCE: Grande G et al. JAMA Neurol. 2020. doi:10.1001/jamaneurol.2019.4914.
FROM JAMA NEUROLOGY
Sleep-disordered breathing linked with Alzheimer’s disease biomarkers in cognitively normal older adults
investigators have found.
Among 127 adults enrolled in a randomized clinical trial of interventions to promote mental well-being in older adults, those with sleep-disordered breathing had significantly greater amyloid burden and gray-matter volume, as well as increased perfusion and metabolism in parietal-occipital regions, reported Claire André, PhD, from the French Institute of Health and Medical Research (INSERM) unit in Caen, and colleagues.
“Our findings highlight the need to treat sleep disorders in the older population, even in the absence of cognitive or behavioral manifestations,” they wrote in a study published in JAMA Neurology.
Previous studies of the possible association between sleep-disordered breathing and dementia risk have shown conflicting or inconsistent results, the authors noted.
“These discrepancies may be explained by the characteristics of patients with sleep-disordered breathing (e.g., recruited from sleep clinics versus from the community, differences in age and disease duration), the scoring criteria of respiratory events, sample sizes, or the lack of controls for possibly biasing covariates,” they wrote.
To see whether they could clear up the confusion, the investigators conducted a retrospective analysis of 127 patients who were enrolled in the Age-Well randomized, controlled trial of the Medit-Ageing European project. The participants were community-dwelling adults (mean age, 69.1 years; 63% women), who were enrolled in the trial and underwent evaluation from 2016 to 2018 at the Cyceron Cancer Center in Caen.
The participants, all of whom were cognitively unimpaired at baseline, underwent neuropsychological assessment, polysomnography, MRI, plus florbetapir- and fluorodeoxyglucose-labeled PET.
The investigators defined sleep-disordered breathing as 15 apnea-hypopnea index events per hour or higher, and compared results between those with sleep-disordered breathing and those without for each imaging modality.
Participants with sleep-disordered breathing has significantly greater amyloid burden (P = .04), gray-matter volume (P = .04), perfusion (P = .04), and metabolism (P = .001), primarily overlapping the posterior cingulate cortex and precuneus, areas known to be significantly involved in Alzheimer’s disease.
When the investigators looked for behavioral and cognitive correlates of sleep-disordered breathing severity with associated brain changes, however, they found no associations with either cognitive performance, self-reported cognitive or sleep difficulties, or symptoms of daytime sleepiness.
“Importantly, to the best of our knowledge, our results show in vivo for the first time that greater amyloid burden colocalizes with greater gray-matter volume, perfusion, and metabolism in older participants with sleep-disordered breathing who are cognitively unimpaired. We believe that these overlapping patterns reinforce the likelihood of common underlying mechanisms,” they wrote.
The Age-Well randomized clinical trial is part of the Medit-Ageing project and is funded through the European Union’s Horizon 2020 Research and Innovation Program, INSERM, and Fondation d’ Entreprise MMA des Entrepreneurs du Futur. Dr. André reported no conflicts of interest to disclose.
SOURCE: André C et al. JAMA Neurol. 2020 Mar 23. doi: 10.1001/jamaneurol.2020.0311.
investigators have found.
Among 127 adults enrolled in a randomized clinical trial of interventions to promote mental well-being in older adults, those with sleep-disordered breathing had significantly greater amyloid burden and gray-matter volume, as well as increased perfusion and metabolism in parietal-occipital regions, reported Claire André, PhD, from the French Institute of Health and Medical Research (INSERM) unit in Caen, and colleagues.
“Our findings highlight the need to treat sleep disorders in the older population, even in the absence of cognitive or behavioral manifestations,” they wrote in a study published in JAMA Neurology.
Previous studies of the possible association between sleep-disordered breathing and dementia risk have shown conflicting or inconsistent results, the authors noted.
“These discrepancies may be explained by the characteristics of patients with sleep-disordered breathing (e.g., recruited from sleep clinics versus from the community, differences in age and disease duration), the scoring criteria of respiratory events, sample sizes, or the lack of controls for possibly biasing covariates,” they wrote.
To see whether they could clear up the confusion, the investigators conducted a retrospective analysis of 127 patients who were enrolled in the Age-Well randomized, controlled trial of the Medit-Ageing European project. The participants were community-dwelling adults (mean age, 69.1 years; 63% women), who were enrolled in the trial and underwent evaluation from 2016 to 2018 at the Cyceron Cancer Center in Caen.
The participants, all of whom were cognitively unimpaired at baseline, underwent neuropsychological assessment, polysomnography, MRI, plus florbetapir- and fluorodeoxyglucose-labeled PET.
The investigators defined sleep-disordered breathing as 15 apnea-hypopnea index events per hour or higher, and compared results between those with sleep-disordered breathing and those without for each imaging modality.
Participants with sleep-disordered breathing has significantly greater amyloid burden (P = .04), gray-matter volume (P = .04), perfusion (P = .04), and metabolism (P = .001), primarily overlapping the posterior cingulate cortex and precuneus, areas known to be significantly involved in Alzheimer’s disease.
When the investigators looked for behavioral and cognitive correlates of sleep-disordered breathing severity with associated brain changes, however, they found no associations with either cognitive performance, self-reported cognitive or sleep difficulties, or symptoms of daytime sleepiness.
“Importantly, to the best of our knowledge, our results show in vivo for the first time that greater amyloid burden colocalizes with greater gray-matter volume, perfusion, and metabolism in older participants with sleep-disordered breathing who are cognitively unimpaired. We believe that these overlapping patterns reinforce the likelihood of common underlying mechanisms,” they wrote.
The Age-Well randomized clinical trial is part of the Medit-Ageing project and is funded through the European Union’s Horizon 2020 Research and Innovation Program, INSERM, and Fondation d’ Entreprise MMA des Entrepreneurs du Futur. Dr. André reported no conflicts of interest to disclose.
SOURCE: André C et al. JAMA Neurol. 2020 Mar 23. doi: 10.1001/jamaneurol.2020.0311.
investigators have found.
Among 127 adults enrolled in a randomized clinical trial of interventions to promote mental well-being in older adults, those with sleep-disordered breathing had significantly greater amyloid burden and gray-matter volume, as well as increased perfusion and metabolism in parietal-occipital regions, reported Claire André, PhD, from the French Institute of Health and Medical Research (INSERM) unit in Caen, and colleagues.
“Our findings highlight the need to treat sleep disorders in the older population, even in the absence of cognitive or behavioral manifestations,” they wrote in a study published in JAMA Neurology.
Previous studies of the possible association between sleep-disordered breathing and dementia risk have shown conflicting or inconsistent results, the authors noted.
“These discrepancies may be explained by the characteristics of patients with sleep-disordered breathing (e.g., recruited from sleep clinics versus from the community, differences in age and disease duration), the scoring criteria of respiratory events, sample sizes, or the lack of controls for possibly biasing covariates,” they wrote.
To see whether they could clear up the confusion, the investigators conducted a retrospective analysis of 127 patients who were enrolled in the Age-Well randomized, controlled trial of the Medit-Ageing European project. The participants were community-dwelling adults (mean age, 69.1 years; 63% women), who were enrolled in the trial and underwent evaluation from 2016 to 2018 at the Cyceron Cancer Center in Caen.
The participants, all of whom were cognitively unimpaired at baseline, underwent neuropsychological assessment, polysomnography, MRI, plus florbetapir- and fluorodeoxyglucose-labeled PET.
The investigators defined sleep-disordered breathing as 15 apnea-hypopnea index events per hour or higher, and compared results between those with sleep-disordered breathing and those without for each imaging modality.
Participants with sleep-disordered breathing has significantly greater amyloid burden (P = .04), gray-matter volume (P = .04), perfusion (P = .04), and metabolism (P = .001), primarily overlapping the posterior cingulate cortex and precuneus, areas known to be significantly involved in Alzheimer’s disease.
When the investigators looked for behavioral and cognitive correlates of sleep-disordered breathing severity with associated brain changes, however, they found no associations with either cognitive performance, self-reported cognitive or sleep difficulties, or symptoms of daytime sleepiness.
“Importantly, to the best of our knowledge, our results show in vivo for the first time that greater amyloid burden colocalizes with greater gray-matter volume, perfusion, and metabolism in older participants with sleep-disordered breathing who are cognitively unimpaired. We believe that these overlapping patterns reinforce the likelihood of common underlying mechanisms,” they wrote.
The Age-Well randomized clinical trial is part of the Medit-Ageing project and is funded through the European Union’s Horizon 2020 Research and Innovation Program, INSERM, and Fondation d’ Entreprise MMA des Entrepreneurs du Futur. Dr. André reported no conflicts of interest to disclose.
SOURCE: André C et al. JAMA Neurol. 2020 Mar 23. doi: 10.1001/jamaneurol.2020.0311.
FROM JAMA NEUROLOGY
Expert says progress in gut-brain research requires an open mind
A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.
Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.
Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.
“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”
For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.
At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.
For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.
Dr. Cryan likened this process to an “artificial fecal transplant.”
“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”
While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.
“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.
He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.
“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”
In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.
“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”
According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.
Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.
“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”
In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.
In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.
“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”
To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.
“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.
Dr. Cryan concluded his presentation on an optimistic note.
“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”
Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.
A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.
Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.
Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.
“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”
For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.
At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.
For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.
Dr. Cryan likened this process to an “artificial fecal transplant.”
“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”
While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.
“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.
He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.
“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”
In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.
“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”
According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.
Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.
“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”
In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.
In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.
“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”
To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.
“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.
Dr. Cryan concluded his presentation on an optimistic note.
“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”
Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.
A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.
Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.
Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.
“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”
For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.
At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.
For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.
Dr. Cryan likened this process to an “artificial fecal transplant.”
“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”
While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.
“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.
He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.
“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”
In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.
“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”
According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.
Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.
“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”
In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.
In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.
“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”
To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.
“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.
Dr. Cryan concluded his presentation on an optimistic note.
“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”
Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.
FROM GMFH 2020
Scientific community ‘shocked’ by loss of MIND diet pioneer
Martha Clare Morris, ScD, a pioneer in research linking nutrition to brain health and a creator of the breakthrough MIND diet, has died of cancer at the age of 64.
Morris was a professor in the Department of Internal Medicine, assistant provost of community research, and director of the Rush Institute for Healthy Aging at Rush University, in Chicago, Illinois. She was also a director of the internal medicine department’s Section of Community Epidemiology.
Long-time friend and colleague Julie A. Schneider, MD, the Deborah R. and Edgar D. Jannotta Presidential Professor of Pathology and Neurological Sciences, Rush University Medical Center, described Morris as creative, passionate, and adventurous.
Her death was “a shock” to the scientific community, Schneider told Medscape Medical News.
“It’s a tragic loss in so many ways,” said Schneider, who is also associate director of the Rush Alzheimer’s Disease Center. She was a very well-respected nutritional epidemiologist and was passionate about her work; she had just so much unwavering commitment to it.
Diet, said Schneider, is “notoriously a hard thing to study” because “it’s so intertwined with lifestyle” and other factors that create “barriers” to conducting such research.
But Morris had a unique and creative talent for filtering out what might be the individual contribution of a particular modifiable risk factor, said Heather Snyder, PhD, vice president of medical and scientific relations, Alzheimer’s Association, who also knew Morris both personally and professionally.
“Humble” trailblazer
Morris’s pioneering research examined the connection between nutrition and the prevention of cognitive decline. Taking results from this research, she developed the MIND diet – a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension – along with colleagues at both Rush and Harvard Universities.
The MIND diet – an acronym for Mediterranean-DASH Intervention for Neurodegenerative Delay – emphasizes brain-healthy foods, including leafy green vegetables, nuts, berries, chicken, fish, whole grains, beans, olive oil, and moderate amounts of red wine. The diet limits consumption of red meat, butter, margarine, and processed foods.
In 2015, Morris published her initial findings on the MIND diet in Alzheimer’s and Dementia. Reported by Medscape Medical News at that time, the study showed that the diet protected cardiovascular health and slowed cognitive decline in older individuals.
The excitement around the findings inspired Morris to write “Diet for the Mind,” which was published in 2017. The book summarizes the benefits of the MIND diet and includes brain-healthy recipes created by her daughter Laura, who is a chef. Despite many accolades, Morris was “humble” about this project, said Schneider.
“This was not about publicity and trying to get a book out; she wanted to see if this diet really was going to change people’s lives. She wanted to bring it into the community,” she said.
Proud legacy
Since 2017, Morris had led a large clinical trial of the effectiveness of the MIND diet in preventing cognitive decline. The first study of its kind, the trial received a $14.5 million grant from the National Institutes of Health (NIH). Results of this study are expected in 2021.
The MIND diet was ranked among the top 10 diets for five consecutive years in US News and World Report.
Morris’s nutrition-related research went beyond diets and examined the impact of individual nutrients. One of her studies, published in 2018 and reported by Medscape Medical News, suggested that the presence of folate, phylloquinone, and lutein – nutrients found in relatively large amounts in green leafy vegetables – may account for why consuming a daily serving of these vegetables slows cognitive decline.
One of the most recent studies from Morris’ group, published in January 2020 and reported by Medscape Medical News at that time, provided the first evidence that dietary flavonols, which are found in many fruits and vegetables, are associated with a significantly reduced risk for dementia.
What Morris did so well was to “look at the big picture” and “think about commonalities that cross nutritional components” of diets such as MIND, DASH, the Mediterranean diet, and the Nordic diet, which is similar to the Mediterranean diet but highlights local foods such as fish from Nordic regions, Snyder told Medscape Medical News.
Morris was instrumental in getting the Alzheimer’s Association’s US POINTER (US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk) study off the ground. The 2-year clinical trial is testing whether combining a healthy diet with exercise, cognitive and social stimulation, and the management of cardiovascular conditions protects cognitive function in older adults who are at increased risk for cognitive decline.
This study will be part of her legacy, said Snyder.
“She will be remembered for her perseverance to get us to a place where we can be looking at nutrition as a modifiable risk factor and now testing it in trials that she helped to set up,” she said.
Even before her involvement with US POINTER, Morris had long been an active volunteer for the Alzheimer’s Association, said Snyder.
“She contributed significant time and expertise as we looked at the state of the evidence around nutrition and other lifestyle and behavioral interventions.”
We’ll ‘always have Paris’
While Morris was “truly passionate” about diet and health “both professionally and personally,” she also had a fun side, said Schneider. She remembers she and Morris had a chance meeting in Paris, where they spent an entire day going to museums and restaurants and just talking about life and their travels. To the end, they joked they would “always have Paris,” said Schneider.
She was also a loyal friend. Morris threw a baby shower when Schneider was pregnant, organizing every detail, despite her extremely busy schedule.
Family was another of Morris’s passions. Snyder recalls Morris’s face lighting up when she talked about her children and grandchildren. She also remembers her friend’s zest for life. “She had an energy that was contagious.”
Morris also loved the outdoors and was a keen adventurer. She once trained for weeks before a long bike trip with her daughter and would take a helicopter to access remote backcountry on hiking excursions.
“She wanted to try everything,” said Schneider.
An author or contributor to more than 80 articles in peer-reviewed journals, Morris also served two terms (from 2011 to 2013) as chair of the NIH’s Neurological, Aging and Musculoskeletal Epidemiology Study Section.
She left behind multiple grants for various studies. One unique study, said Schneider, investigated the relationship between iron and other metals in the brain and the neuropathology of Alzheimer disease.
“She was really in the prime of her career,” noted Schneider. “She had so much left to give and to offer, so this is tremendously sad.”
According to news reports, Morris (nee Chinn) grew up in Homewood, Illinois, and earned bachelor’s and master’s degrees in sociology from the University of Iowa in Iowa City, where she met her husband, James Morris. The two married in 1978 and had three children.
Morris completed a doctorate in epidemiology at the Harvard School of Public Health. James died in 2012, also from cancer. Morris passed away peacefully at her home on February 15.
Martha Clare Morris, ScD, a pioneer in research linking nutrition to brain health and a creator of the breakthrough MIND diet, has died of cancer at the age of 64.
Morris was a professor in the Department of Internal Medicine, assistant provost of community research, and director of the Rush Institute for Healthy Aging at Rush University, in Chicago, Illinois. She was also a director of the internal medicine department’s Section of Community Epidemiology.
Long-time friend and colleague Julie A. Schneider, MD, the Deborah R. and Edgar D. Jannotta Presidential Professor of Pathology and Neurological Sciences, Rush University Medical Center, described Morris as creative, passionate, and adventurous.
Her death was “a shock” to the scientific community, Schneider told Medscape Medical News.
“It’s a tragic loss in so many ways,” said Schneider, who is also associate director of the Rush Alzheimer’s Disease Center. She was a very well-respected nutritional epidemiologist and was passionate about her work; she had just so much unwavering commitment to it.
Diet, said Schneider, is “notoriously a hard thing to study” because “it’s so intertwined with lifestyle” and other factors that create “barriers” to conducting such research.
But Morris had a unique and creative talent for filtering out what might be the individual contribution of a particular modifiable risk factor, said Heather Snyder, PhD, vice president of medical and scientific relations, Alzheimer’s Association, who also knew Morris both personally and professionally.
“Humble” trailblazer
Morris’s pioneering research examined the connection between nutrition and the prevention of cognitive decline. Taking results from this research, she developed the MIND diet – a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension – along with colleagues at both Rush and Harvard Universities.
The MIND diet – an acronym for Mediterranean-DASH Intervention for Neurodegenerative Delay – emphasizes brain-healthy foods, including leafy green vegetables, nuts, berries, chicken, fish, whole grains, beans, olive oil, and moderate amounts of red wine. The diet limits consumption of red meat, butter, margarine, and processed foods.
In 2015, Morris published her initial findings on the MIND diet in Alzheimer’s and Dementia. Reported by Medscape Medical News at that time, the study showed that the diet protected cardiovascular health and slowed cognitive decline in older individuals.
The excitement around the findings inspired Morris to write “Diet for the Mind,” which was published in 2017. The book summarizes the benefits of the MIND diet and includes brain-healthy recipes created by her daughter Laura, who is a chef. Despite many accolades, Morris was “humble” about this project, said Schneider.
“This was not about publicity and trying to get a book out; she wanted to see if this diet really was going to change people’s lives. She wanted to bring it into the community,” she said.
Proud legacy
Since 2017, Morris had led a large clinical trial of the effectiveness of the MIND diet in preventing cognitive decline. The first study of its kind, the trial received a $14.5 million grant from the National Institutes of Health (NIH). Results of this study are expected in 2021.
The MIND diet was ranked among the top 10 diets for five consecutive years in US News and World Report.
Morris’s nutrition-related research went beyond diets and examined the impact of individual nutrients. One of her studies, published in 2018 and reported by Medscape Medical News, suggested that the presence of folate, phylloquinone, and lutein – nutrients found in relatively large amounts in green leafy vegetables – may account for why consuming a daily serving of these vegetables slows cognitive decline.
One of the most recent studies from Morris’ group, published in January 2020 and reported by Medscape Medical News at that time, provided the first evidence that dietary flavonols, which are found in many fruits and vegetables, are associated with a significantly reduced risk for dementia.
What Morris did so well was to “look at the big picture” and “think about commonalities that cross nutritional components” of diets such as MIND, DASH, the Mediterranean diet, and the Nordic diet, which is similar to the Mediterranean diet but highlights local foods such as fish from Nordic regions, Snyder told Medscape Medical News.
Morris was instrumental in getting the Alzheimer’s Association’s US POINTER (US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk) study off the ground. The 2-year clinical trial is testing whether combining a healthy diet with exercise, cognitive and social stimulation, and the management of cardiovascular conditions protects cognitive function in older adults who are at increased risk for cognitive decline.
This study will be part of her legacy, said Snyder.
“She will be remembered for her perseverance to get us to a place where we can be looking at nutrition as a modifiable risk factor and now testing it in trials that she helped to set up,” she said.
Even before her involvement with US POINTER, Morris had long been an active volunteer for the Alzheimer’s Association, said Snyder.
“She contributed significant time and expertise as we looked at the state of the evidence around nutrition and other lifestyle and behavioral interventions.”
We’ll ‘always have Paris’
While Morris was “truly passionate” about diet and health “both professionally and personally,” she also had a fun side, said Schneider. She remembers she and Morris had a chance meeting in Paris, where they spent an entire day going to museums and restaurants and just talking about life and their travels. To the end, they joked they would “always have Paris,” said Schneider.
She was also a loyal friend. Morris threw a baby shower when Schneider was pregnant, organizing every detail, despite her extremely busy schedule.
Family was another of Morris’s passions. Snyder recalls Morris’s face lighting up when she talked about her children and grandchildren. She also remembers her friend’s zest for life. “She had an energy that was contagious.”
Morris also loved the outdoors and was a keen adventurer. She once trained for weeks before a long bike trip with her daughter and would take a helicopter to access remote backcountry on hiking excursions.
“She wanted to try everything,” said Schneider.
An author or contributor to more than 80 articles in peer-reviewed journals, Morris also served two terms (from 2011 to 2013) as chair of the NIH’s Neurological, Aging and Musculoskeletal Epidemiology Study Section.
She left behind multiple grants for various studies. One unique study, said Schneider, investigated the relationship between iron and other metals in the brain and the neuropathology of Alzheimer disease.
“She was really in the prime of her career,” noted Schneider. “She had so much left to give and to offer, so this is tremendously sad.”
According to news reports, Morris (nee Chinn) grew up in Homewood, Illinois, and earned bachelor’s and master’s degrees in sociology from the University of Iowa in Iowa City, where she met her husband, James Morris. The two married in 1978 and had three children.
Morris completed a doctorate in epidemiology at the Harvard School of Public Health. James died in 2012, also from cancer. Morris passed away peacefully at her home on February 15.
Martha Clare Morris, ScD, a pioneer in research linking nutrition to brain health and a creator of the breakthrough MIND diet, has died of cancer at the age of 64.
Morris was a professor in the Department of Internal Medicine, assistant provost of community research, and director of the Rush Institute for Healthy Aging at Rush University, in Chicago, Illinois. She was also a director of the internal medicine department’s Section of Community Epidemiology.
Long-time friend and colleague Julie A. Schneider, MD, the Deborah R. and Edgar D. Jannotta Presidential Professor of Pathology and Neurological Sciences, Rush University Medical Center, described Morris as creative, passionate, and adventurous.
Her death was “a shock” to the scientific community, Schneider told Medscape Medical News.
“It’s a tragic loss in so many ways,” said Schneider, who is also associate director of the Rush Alzheimer’s Disease Center. She was a very well-respected nutritional epidemiologist and was passionate about her work; she had just so much unwavering commitment to it.
Diet, said Schneider, is “notoriously a hard thing to study” because “it’s so intertwined with lifestyle” and other factors that create “barriers” to conducting such research.
But Morris had a unique and creative talent for filtering out what might be the individual contribution of a particular modifiable risk factor, said Heather Snyder, PhD, vice president of medical and scientific relations, Alzheimer’s Association, who also knew Morris both personally and professionally.
“Humble” trailblazer
Morris’s pioneering research examined the connection between nutrition and the prevention of cognitive decline. Taking results from this research, she developed the MIND diet – a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension – along with colleagues at both Rush and Harvard Universities.
The MIND diet – an acronym for Mediterranean-DASH Intervention for Neurodegenerative Delay – emphasizes brain-healthy foods, including leafy green vegetables, nuts, berries, chicken, fish, whole grains, beans, olive oil, and moderate amounts of red wine. The diet limits consumption of red meat, butter, margarine, and processed foods.
In 2015, Morris published her initial findings on the MIND diet in Alzheimer’s and Dementia. Reported by Medscape Medical News at that time, the study showed that the diet protected cardiovascular health and slowed cognitive decline in older individuals.
The excitement around the findings inspired Morris to write “Diet for the Mind,” which was published in 2017. The book summarizes the benefits of the MIND diet and includes brain-healthy recipes created by her daughter Laura, who is a chef. Despite many accolades, Morris was “humble” about this project, said Schneider.
“This was not about publicity and trying to get a book out; she wanted to see if this diet really was going to change people’s lives. She wanted to bring it into the community,” she said.
Proud legacy
Since 2017, Morris had led a large clinical trial of the effectiveness of the MIND diet in preventing cognitive decline. The first study of its kind, the trial received a $14.5 million grant from the National Institutes of Health (NIH). Results of this study are expected in 2021.
The MIND diet was ranked among the top 10 diets for five consecutive years in US News and World Report.
Morris’s nutrition-related research went beyond diets and examined the impact of individual nutrients. One of her studies, published in 2018 and reported by Medscape Medical News, suggested that the presence of folate, phylloquinone, and lutein – nutrients found in relatively large amounts in green leafy vegetables – may account for why consuming a daily serving of these vegetables slows cognitive decline.
One of the most recent studies from Morris’ group, published in January 2020 and reported by Medscape Medical News at that time, provided the first evidence that dietary flavonols, which are found in many fruits and vegetables, are associated with a significantly reduced risk for dementia.
What Morris did so well was to “look at the big picture” and “think about commonalities that cross nutritional components” of diets such as MIND, DASH, the Mediterranean diet, and the Nordic diet, which is similar to the Mediterranean diet but highlights local foods such as fish from Nordic regions, Snyder told Medscape Medical News.
Morris was instrumental in getting the Alzheimer’s Association’s US POINTER (US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk) study off the ground. The 2-year clinical trial is testing whether combining a healthy diet with exercise, cognitive and social stimulation, and the management of cardiovascular conditions protects cognitive function in older adults who are at increased risk for cognitive decline.
This study will be part of her legacy, said Snyder.
“She will be remembered for her perseverance to get us to a place where we can be looking at nutrition as a modifiable risk factor and now testing it in trials that she helped to set up,” she said.
Even before her involvement with US POINTER, Morris had long been an active volunteer for the Alzheimer’s Association, said Snyder.
“She contributed significant time and expertise as we looked at the state of the evidence around nutrition and other lifestyle and behavioral interventions.”
We’ll ‘always have Paris’
While Morris was “truly passionate” about diet and health “both professionally and personally,” she also had a fun side, said Schneider. She remembers she and Morris had a chance meeting in Paris, where they spent an entire day going to museums and restaurants and just talking about life and their travels. To the end, they joked they would “always have Paris,” said Schneider.
She was also a loyal friend. Morris threw a baby shower when Schneider was pregnant, organizing every detail, despite her extremely busy schedule.
Family was another of Morris’s passions. Snyder recalls Morris’s face lighting up when she talked about her children and grandchildren. She also remembers her friend’s zest for life. “She had an energy that was contagious.”
Morris also loved the outdoors and was a keen adventurer. She once trained for weeks before a long bike trip with her daughter and would take a helicopter to access remote backcountry on hiking excursions.
“She wanted to try everything,” said Schneider.
An author or contributor to more than 80 articles in peer-reviewed journals, Morris also served two terms (from 2011 to 2013) as chair of the NIH’s Neurological, Aging and Musculoskeletal Epidemiology Study Section.
She left behind multiple grants for various studies. One unique study, said Schneider, investigated the relationship between iron and other metals in the brain and the neuropathology of Alzheimer disease.
“She was really in the prime of her career,” noted Schneider. “She had so much left to give and to offer, so this is tremendously sad.”
According to news reports, Morris (nee Chinn) grew up in Homewood, Illinois, and earned bachelor’s and master’s degrees in sociology from the University of Iowa in Iowa City, where she met her husband, James Morris. The two married in 1978 and had three children.
Morris completed a doctorate in epidemiology at the Harvard School of Public Health. James died in 2012, also from cancer. Morris passed away peacefully at her home on February 15.
Depression, or something else?
CASE Suicidal behavior, severe headaches
Ms. A, age 60, presents to the emergency department (ED) with depression, suicidal behavior, and 3 days of severe headaches. Neurology is consulted and an MRI is ordered, which shows a 3.0-cm mass lesion in the left temporal lobe with associated vasogenic edema that is suspicious for metastatic disease (Figure).
Ms. A is admitted to the hospital for further workup of her brain lesion. She is started on IV dexamethasone, 10 mg every 6 hours, a glucocorticosteroid, for brain edema, and levetiracetam, 500 mg twice a day, for seizure prophylaxis.
Upon admission, in addition to oncology and neurosurgery, psychiatry is also consulted to evaluate Ms. A for depression and suicidality.
EVALUATION Mood changes and poor judgment
Ms. A has a psychiatric history of depression and alcohol use disorder but says she has not consumed any alcohol in years. Her medical history includes hypertension, diabetes, and stage 4 non-small–cell lung cancer, for which she received surgery and adjuvant chemoradiotherapy 1 year ago.
On initial intake, Ms. A reports that in addition to the headaches, she has also been experiencing worsening depression and suicidal behavior. For the past 2 months, she has had a severely depressed mood, with notable anhedonia, poor appetite, insomnia, low energy, and decreased concentration. The changes in her mental health were triggered by her mother’s death. Three days prior to admission, the patient planned to overdose on antihypertensive pills, but her suicide attempt was interrupted when her family called. She denies any current suicidal ideation, intent, or plan.
According to her family, Ms. A has been increasingly irritable and her personality has changed in the past month. She also has been repeatedly sorting through her neighbors’ garbage.
Ms. A’s current psychiatric medications are duloxetine, 30 mg/d; quetiapine, 50 mg every night at bedtime; and buspirone, 10 mg/d. However, it is unclear if she is consistently taking these medications.
Continue to: On mental status examination...
On mental status examination, Ms. A is calm and she has no abnormal movements. She says she is depressed. Her affect is reactive and labile. She is alert and oriented to person, place, and time. Her attention, registration, and recall are intact. Her executive function is not tested. However, Ms. A’s insight and judgment seem poor.
To address Ms. A’s worsening depression, the psychiatry team increases her duloxetine from 30 to 60 mg/d, and she continues quetiapine, 50 mg every night at bedtime, for mood lability. Buspirone is not continued because she was not taking a therapeutic dosage in the community.
Within 4 days, Ms. A shows improvement in sleep, appetite, and mood. She has no further suicidal ideation.
[polldaddy:10511743]
The authors’ observations
Ms. A had a recurrence of what was presumed to be major depressive disorder (MDD) in the context of her mother’s death. However, she also exhibited irritability, mood lability, and impulsivity, all of which could be part of her depression, or a separate problem related to her brain tumor. Because Ms. A had never displayed bizarre behavior before the past few weeks, it is likely that her CNS lesion was directly affecting her personality and possibly underlying her planned suicide attempt.
Fifty to 80% of patients with CNS tumors, either primary or metastatic, present with psychiatric symptoms.1 Table 11-3 lists common psychiatric symptoms of brain tumors. Unfortunately, there is little reliable evidence that directly correlates tumor location with specific psychiatric symptoms. A 2010 meta-analysis found a statistically significant link between anorexia nervosa and hypothalamic tumors.1 However, for other brain regions, there is only an increased likelihood that any given tumor location will produce psychiatric symptoms.1,4 For instance, compared to patients with tumors in other locations, those with temporal lobe tumors are more likely to present with mood disorders, personality changes, and memory problems.1 In contrast, patients with frontal lobe tumors have an increased likelihood of psychosis, mood disorders, and personality changes.1 Patients with tumors in the pituitary region often present with anxiety.1
Continue to: When considering treatment options...
When considering treatment options for Ms. A, alcohol withdrawal was unlikely given the remote history of alcohol use, low alcohol blood level, and lack of evidence of unstable vital signs or tremor. Although she might have benefited from inpatient psychiatric treatment, this needed to wait until there was a definitive treatment plan for her brain tumor. Finally, although a paraneoplastic syndrome, such as limbic encephalitis, could be causing her psychiatric symptoms, this scenario is less likely with non-small–cell lung cancer.
Although uncommon, CNS tumors can present with psychiatric symptoms as the only manifestation. This is more likely when a patient exhibits new-onset or atypical symptoms, or fails to respond to standard psychiatric treatment.4 Case reports have described patients with brain tumors being misdiagnosed as having a primary psychiatric condition, which delays treatment of their CNS cancer.2 Additionally, frontal and limbic tumors are more likely to present with psychiatric manifestations; up to 90% of patients exhibit altered mental status or personality changes, as did Ms. A.1,4 Clearly, it is easier to identify patients with psychiatric symptoms resulting from a brain tumor when they also present with focal neurologic deficits or systemic symptoms, such as headache or nausea and vomiting. Ms. A presented with severe headaches, which is what led to her early imaging and prompt diagnosis.
Numerous proposed mechanisms might account for the psychiatric symptoms that occur during the course of a brain tumor, including direct injury to neuronal cells, secretion of hormones or other tumor-derived substances, and peri-ictal phenomena.3
TREATMENT Tumor is removed, but memory is impaired
Ms. A is scheduled for craniotomy and surgical resection of the frontal mass. Prior to surgery, Ms. A shows interest in improving her health, cooperates with staff, and seeks her daughter’s input on treatment. One week after admission, Ms. A has her mass resected, which is confirmed on biopsy to be a lung metastasis. Post-surgery, Ms. A receives codeine, 30 mg every 6 hours as needed, for pain; she continues dexamethasone, 4 mg IV every 6 hours, for brain edema and levetiracetam, 500 mg twice a day, for seizure prophylaxis.
On Day 2 after surgery, Ms. A attempts to elope. When she is approached by a psychiatrist on the treatment team, she does not recognize him. Although her long-term memory seems intact, she is unable to remember the details of recent events, including her medical and surgical treatments.
[polldaddy:10511745]
Continue to: The authors' observations
The authors’ observations
Ms. A’s memory impairment may be secondary to a surgically acquired neurocognitive deficit. In the United States, brain metastases represent a significant public health issue, affecting >100,000 patients per year.5 Metastatic lesions are the most common brain tumors. Lung cancer, breast cancer, and melanoma are the leading solid tumors to spread to the CNS.5 In cases of single brain metastasis, similar to Ms. A’s solitary left temporal lobe lesion, surgical resection plays a critical role in treatment. It provides histological confirmation of metastatic disease and can relieve mass effect if present. Studies have shown that combined surgical resection with radiation improves survival relative to patients who undergo radiation therapy alone.6,7
However, the benefits of surgical resection need to be balanced with preservation of neurologic function. Emerging evidence suggests that a majority of patients have surgically-acquired cognitive deficits due to damage of normal surrounding tissues, and these deficits are associated with reduced quality of life.8,9 Further, a study examining glioma surgical resections found that patients with left temporal lobe tumors exhibit more frequent and severe neurocognitive decline than patients with right temporal lobe tumors, especially in domains such as verbal memory.8 Ms. A’s memory impairment was persistent during her postoperative course, which suggests that it was not just an immediate post-surgical phenomenon, but a longer-lasting cognitive change directly related to the resection.
It is also possible that Ms. A had a prior neurocognitive disorder that manifested to a greater degree as a result of the CNS tumor. Ms. A might have had early-onset Alzheimer’s disease, although her intact memory before surgery makes this less likely. Alternatively, she could have had vascular dementia, especially given her long-standing hypertension and diabetes. This might have been missed in the initial evaluation because executive function was not tested. However, the relatively abrupt onset of memory problems after surgery suggests that she had no underlying neurocognitive disorder.
Ms. A’s presumed episode of MDD might also explain her memory changes. Major depressive disorder is increasingly common among geriatric patients, affecting approximately 5% of community-dwelling older adults.10 Its incidence increases with medical comorbidities, as suggested by depression rates of 5% to 10% in the primary care setting vs 37% in patients after critical-care hospitalizations.10 Late-life depression (LLD) occurs in adults age ≥60. Unlike depression in younger patients, LLD is more likely to be associated with cognitive impairment, specifically impairment of executive function and memory.11 The incidence of cognitive impairment in LLD is higher in patients with a history of depression, such as Ms. A.11,12 However, in general, patients who are depressed have memory complaints out of proportion to the clinical findings, and they show poor effort on cognitive testing. Ms. A exhibited neither of these, which makes it less likely that LLD was the exclusive cause of her memory loss.13 Table 214 outlines the management of cognitive deficits in a patient with a brain tumor.
EVALUATION Increasingly agitated and paranoid
After the tumor resection, Ms. A becomes increasingly irritable, uncooperative, and agitated. She repeatedly demands to be discharged. She insists she is fine and refuses medications and further laboratory workup. She becomes paranoid about the nursing staff and believes they are trying to kill her.
Continue to: On psychiatric re-evaluation...
On psychiatric re-evaluation, Ms. A demonstrates pressured speech, perseveration about going home, paranoid delusions, and anger at her family and physicians.
[polldaddy:10511747]
The authors’ observations
Ms. A’s refusal of medications and agitation may be explained by postoperative delirium, a surgical complication that is increasingly common among geriatric patients and is associated with poor clinical outcomes. Delirium is characterized by an acute onset and fluctuating course of symptoms that include inattention, motoric hypo- or hyperactivity, inappropriate behavior, emotional lability, cognitive dysfunction, and psychotic symptoms.15 Risk factors that contribute to postoperative delirium include older age, alcohol use, and poor baseline functional and cognitive status.16 The pathophysiology of delirium is not fully understood, but accumulating evidence suggests that different sets of interacting biologic factors (ie, neurotransmitters and inflammation) contribute to a disruption of large-scale neuronal networks in the brain, resulting in cognitive dysfunction.15 Patients who develop postoperative delirium are more likely to develop long-term cognitive dysfunction and have an increased risk of dementia.16
Another potential source of Ms. A’s agitation is steroid use. Ms. A received IV dexamethasone, 8 to 16 mg/d, around the time of her surgery. Steroids are commonly used to treat brain tumors, particularly when there is vasogenic edema. Steroid psychosis is a term loosely used to describe a wide range of psychiatric symptoms induced by corticosteroids that includes, but is not limited to, depression, mania, psychosis, delirium, and cognitive impairment.17 Steroid-induced psychiatric adverse effects occur in 5% to 18% of patients receiving corticosteroids and often happen early in treatment, although they can occur at any point.18 Corticosteroids influence brain activity via glucocorticoid and mineralocorticoid receptors. These receptors are widely distributed throughout the brain and affect neurotransmitter systems, such as the serotonergic system, that are associated with changes in mood, behavior, and cognition.17 While the adverse psychiatric manifestations of steroid use vary, higher dosages are associated with an increased risk of psychiatric complications; mania is more prevalent early in the course of treatment, and depression is more common with long-term use.17,19 Table 317,18 outlines the evidence-based treatment of corticosteroid-induced adverse psychiatric effects.
Although there are no clinical guidelines or FDA-approved medications for treating steroid-induced psychiatric adverse events, these are best managed by tapering and discontinuing steroids when possible and simultaneously using psychotropic medications to treat psychiatric symptoms. Case reports and limited evidence-based literature have demonstrated that steroid-induced mania responds to mood stabilizers or antipsychotics, while depression can be managed with antidepressants or lithium.17
Additionally, patients with CNS tumors are at risk for seizures and often are prescribed antiepileptics. Because it is easy to administer and does not need to be titrated, levetiracetam is a commonly used agent. However, levetiracetam can cause psychiatric adverse effects, including behavior changes and frank psychosis.20
Continue to: Finally, Ms. A's altered mental status...
Finally, Ms. A’s altered mental status could have been related to opioid intoxication. Opioids are used to manage postsurgical pain, and studies have shown these medications can be a precipitating factor for delirium in geriatric patients.21
TREATMENT Medication adjustments
At the request of the psychiatry team, levetiracetam is discontinued due to its potential for psychiatric adverse effects. The neurosurgery team replaces it with valproic acid, 500 mg every 12 hours. Ms. A is also tapered off steroids fairly rapidly because of the potential for steroid-induced psychiatric adverse effects. Her quetiapine is titrated from 50 to 150 mg every night at bedtime, and duloxetine is discontinued.
OUTCOME Agitation improves dramatically
Ms. A’s new medication regimen dramatically improves her agitation, which allows Ms. A, her family, and the medical team to work together to establish treatment goals. Ms. A ultimately returns home with the assistance of her family. She continues to have memory issues, but with improved emotion regulation. Several months later, Ms. A is readmitted to the hospital because her cancer has progressed despite treatment.
Bottom Line
Brain tumors may present with various psychiatric manifestations that can change during the course of the patient’s treatment. A comprehensive psychiatric evaluation should parse out the interplay between direct effects of the tumor and any adverse effects that are the result of medical and/or surgical interventions to determine the cause of psychiatric symptoms and their appropriate management.
Related Resource
Madhusoodanan S, Ting MB, Farah T, et al. Psychiatric aspects of brain tumors: a review. World J Psychiatry. 2015;5(3):273-285.
Drug Brand Names
Aripiprazole • Abilify
Buspirone • Buspar
Chlorpromazine • Thorazine
Codeine • Codeine systemic
Dexamethasone • Decadron
Duloxetine • Cymbalta
Haloperidol • Haldol
Levetiracetam • Keppra
Lorazepam • Ativan
Lithium • Eskalith, Lithobid
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Valproic acid • Depakene
1. Madhusoodanan S, Opler MG, Moise D, et al. Brain tumor location and psychiatric symptoms: is there any association? A meta-analysis of published case studies. Expert Rev Neurother. 2010;10(10):1529-1536.
2. Bunevicius A, Deltuva VP, Deltuviene D, et al. Brain lesions manifesting as psychiatric disorders: eight cases. CNS Spectr. 2008;13(11):950-958.
3. Pearl ML, Talgat G, Valea FA, et al. Psychiatric symptoms due to brain metastases. Med Update Psychiatr. 1998;3(4):91-94.
4. Madhusoodanan S, Danan D, Moise D. Psychiatric manifestations of brain tumors: diagnostic implications. Expert Rev Neurother. 2007;7(4):343-349.
5. Ferguson SD, Wagner KM, Prabhu SS, et al. Neurosurgical management of brain metastases. Clin Exp Metastasis. 2017;34(6-7):377-389.
6. Husain ZA, Regine WF, Kwok Y, et al. Brain metastases: contemporary management and future directions. Eur J Clin Med Oncol. 2011;3(3):38-45.
7. Vecht CJ, Haaxmareiche H, Noordijk EM, et al. Treatment of single brain metastasis - radiotherapy alone or combined with neurosurgery. Ann Neurol. 1993;33(6):583-590.
8. Barry RL, Byun NE, Tantawy MN, et al. In vivo neuroimaging and behavioral correlates in a rat model of chemotherapy-induced cognitive dysfunction. Brain Imaging Behav. 2018;12(1):87-95.
9. Wu AS, Witgert ME, Lang FF, et al. Neurocognitive function before and after surgery for insular gliomas. J Neurosurg. 2011;115(6):1115-1125.
10. Taylor WD. Depression in the elderly. N Engl J Med. 2014;371(13):1228-1236.
11. Liguori C, Pierantozzi M, Chiaravalloti A, et al. When cognitive decline and depression coexist in the elderly: CSF biomarkers analysis can differentiate Alzheimer’s disease from late-life depression. Front Aging Neurosci. 2018;10:38.
12. Luijendijk HJ, van den Berg JF, Dekker MJHJ, et al. Incidence and recurrence of late-life depression. Arch Gen Psychiatry. 2008;65(12):1394-1401.
13. Potter GG, Steffens DC. Contribution of depression to cognitive impairment and dementia in older adults. Neurologist. 2007;13(3):105-117.
14. Taphoorn MJB, Klein M. Cognitive deficits in adult patients with brain tumours. Lancet Neurol. 2004;3(3):159-168.
15. Inouye SK, Westendorp RGJ, Saczynski JS. Delirium in elderly people. Lancet. 2014;383(9920):911-922.
16. Sprung J, Roberts RO, Weingarten TN, et al. Postoperative delirium in elderly patients is associated with subsequent cognitive impairment. Br J Anaesth. 2017;119(2):316-323.
17. Kusljic S, Manias E, Gogos A. Corticosteroid-induced psychiatric disturbances: it is time for pharmacists to take notice. Res Soc Adm Pharm. 2016;12(2):355-360.
18. Cerullo MA. Corticosteroid-induced mania: prepare for the unpredictable. Current Psychiatry. 2006;5(6):43-50.
19. Dubovsky AN, Arvikar S, Stern TA, et al. Steroid psychosis revisited. Psychosomatics. 2012;53(2):103-115.
20. Habets JGV, Leentjens AFG, Schijns OEMG. Serious and reversible levetiracetam-induced psychiatric symptoms after resection of frontal low-grade glioma: two case histories. Br J Neurosurg. 2017;31(4):471-473.
21
CASE Suicidal behavior, severe headaches
Ms. A, age 60, presents to the emergency department (ED) with depression, suicidal behavior, and 3 days of severe headaches. Neurology is consulted and an MRI is ordered, which shows a 3.0-cm mass lesion in the left temporal lobe with associated vasogenic edema that is suspicious for metastatic disease (Figure).
Ms. A is admitted to the hospital for further workup of her brain lesion. She is started on IV dexamethasone, 10 mg every 6 hours, a glucocorticosteroid, for brain edema, and levetiracetam, 500 mg twice a day, for seizure prophylaxis.
Upon admission, in addition to oncology and neurosurgery, psychiatry is also consulted to evaluate Ms. A for depression and suicidality.
EVALUATION Mood changes and poor judgment
Ms. A has a psychiatric history of depression and alcohol use disorder but says she has not consumed any alcohol in years. Her medical history includes hypertension, diabetes, and stage 4 non-small–cell lung cancer, for which she received surgery and adjuvant chemoradiotherapy 1 year ago.
On initial intake, Ms. A reports that in addition to the headaches, she has also been experiencing worsening depression and suicidal behavior. For the past 2 months, she has had a severely depressed mood, with notable anhedonia, poor appetite, insomnia, low energy, and decreased concentration. The changes in her mental health were triggered by her mother’s death. Three days prior to admission, the patient planned to overdose on antihypertensive pills, but her suicide attempt was interrupted when her family called. She denies any current suicidal ideation, intent, or plan.
According to her family, Ms. A has been increasingly irritable and her personality has changed in the past month. She also has been repeatedly sorting through her neighbors’ garbage.
Ms. A’s current psychiatric medications are duloxetine, 30 mg/d; quetiapine, 50 mg every night at bedtime; and buspirone, 10 mg/d. However, it is unclear if she is consistently taking these medications.
Continue to: On mental status examination...
On mental status examination, Ms. A is calm and she has no abnormal movements. She says she is depressed. Her affect is reactive and labile. She is alert and oriented to person, place, and time. Her attention, registration, and recall are intact. Her executive function is not tested. However, Ms. A’s insight and judgment seem poor.
To address Ms. A’s worsening depression, the psychiatry team increases her duloxetine from 30 to 60 mg/d, and she continues quetiapine, 50 mg every night at bedtime, for mood lability. Buspirone is not continued because she was not taking a therapeutic dosage in the community.
Within 4 days, Ms. A shows improvement in sleep, appetite, and mood. She has no further suicidal ideation.
[polldaddy:10511743]
The authors’ observations
Ms. A had a recurrence of what was presumed to be major depressive disorder (MDD) in the context of her mother’s death. However, she also exhibited irritability, mood lability, and impulsivity, all of which could be part of her depression, or a separate problem related to her brain tumor. Because Ms. A had never displayed bizarre behavior before the past few weeks, it is likely that her CNS lesion was directly affecting her personality and possibly underlying her planned suicide attempt.
Fifty to 80% of patients with CNS tumors, either primary or metastatic, present with psychiatric symptoms.1 Table 11-3 lists common psychiatric symptoms of brain tumors. Unfortunately, there is little reliable evidence that directly correlates tumor location with specific psychiatric symptoms. A 2010 meta-analysis found a statistically significant link between anorexia nervosa and hypothalamic tumors.1 However, for other brain regions, there is only an increased likelihood that any given tumor location will produce psychiatric symptoms.1,4 For instance, compared to patients with tumors in other locations, those with temporal lobe tumors are more likely to present with mood disorders, personality changes, and memory problems.1 In contrast, patients with frontal lobe tumors have an increased likelihood of psychosis, mood disorders, and personality changes.1 Patients with tumors in the pituitary region often present with anxiety.1
Continue to: When considering treatment options...
When considering treatment options for Ms. A, alcohol withdrawal was unlikely given the remote history of alcohol use, low alcohol blood level, and lack of evidence of unstable vital signs or tremor. Although she might have benefited from inpatient psychiatric treatment, this needed to wait until there was a definitive treatment plan for her brain tumor. Finally, although a paraneoplastic syndrome, such as limbic encephalitis, could be causing her psychiatric symptoms, this scenario is less likely with non-small–cell lung cancer.
Although uncommon, CNS tumors can present with psychiatric symptoms as the only manifestation. This is more likely when a patient exhibits new-onset or atypical symptoms, or fails to respond to standard psychiatric treatment.4 Case reports have described patients with brain tumors being misdiagnosed as having a primary psychiatric condition, which delays treatment of their CNS cancer.2 Additionally, frontal and limbic tumors are more likely to present with psychiatric manifestations; up to 90% of patients exhibit altered mental status or personality changes, as did Ms. A.1,4 Clearly, it is easier to identify patients with psychiatric symptoms resulting from a brain tumor when they also present with focal neurologic deficits or systemic symptoms, such as headache or nausea and vomiting. Ms. A presented with severe headaches, which is what led to her early imaging and prompt diagnosis.
Numerous proposed mechanisms might account for the psychiatric symptoms that occur during the course of a brain tumor, including direct injury to neuronal cells, secretion of hormones or other tumor-derived substances, and peri-ictal phenomena.3
TREATMENT Tumor is removed, but memory is impaired
Ms. A is scheduled for craniotomy and surgical resection of the frontal mass. Prior to surgery, Ms. A shows interest in improving her health, cooperates with staff, and seeks her daughter’s input on treatment. One week after admission, Ms. A has her mass resected, which is confirmed on biopsy to be a lung metastasis. Post-surgery, Ms. A receives codeine, 30 mg every 6 hours as needed, for pain; she continues dexamethasone, 4 mg IV every 6 hours, for brain edema and levetiracetam, 500 mg twice a day, for seizure prophylaxis.
On Day 2 after surgery, Ms. A attempts to elope. When she is approached by a psychiatrist on the treatment team, she does not recognize him. Although her long-term memory seems intact, she is unable to remember the details of recent events, including her medical and surgical treatments.
[polldaddy:10511745]
Continue to: The authors' observations
The authors’ observations
Ms. A’s memory impairment may be secondary to a surgically acquired neurocognitive deficit. In the United States, brain metastases represent a significant public health issue, affecting >100,000 patients per year.5 Metastatic lesions are the most common brain tumors. Lung cancer, breast cancer, and melanoma are the leading solid tumors to spread to the CNS.5 In cases of single brain metastasis, similar to Ms. A’s solitary left temporal lobe lesion, surgical resection plays a critical role in treatment. It provides histological confirmation of metastatic disease and can relieve mass effect if present. Studies have shown that combined surgical resection with radiation improves survival relative to patients who undergo radiation therapy alone.6,7
However, the benefits of surgical resection need to be balanced with preservation of neurologic function. Emerging evidence suggests that a majority of patients have surgically-acquired cognitive deficits due to damage of normal surrounding tissues, and these deficits are associated with reduced quality of life.8,9 Further, a study examining glioma surgical resections found that patients with left temporal lobe tumors exhibit more frequent and severe neurocognitive decline than patients with right temporal lobe tumors, especially in domains such as verbal memory.8 Ms. A’s memory impairment was persistent during her postoperative course, which suggests that it was not just an immediate post-surgical phenomenon, but a longer-lasting cognitive change directly related to the resection.
It is also possible that Ms. A had a prior neurocognitive disorder that manifested to a greater degree as a result of the CNS tumor. Ms. A might have had early-onset Alzheimer’s disease, although her intact memory before surgery makes this less likely. Alternatively, she could have had vascular dementia, especially given her long-standing hypertension and diabetes. This might have been missed in the initial evaluation because executive function was not tested. However, the relatively abrupt onset of memory problems after surgery suggests that she had no underlying neurocognitive disorder.
Ms. A’s presumed episode of MDD might also explain her memory changes. Major depressive disorder is increasingly common among geriatric patients, affecting approximately 5% of community-dwelling older adults.10 Its incidence increases with medical comorbidities, as suggested by depression rates of 5% to 10% in the primary care setting vs 37% in patients after critical-care hospitalizations.10 Late-life depression (LLD) occurs in adults age ≥60. Unlike depression in younger patients, LLD is more likely to be associated with cognitive impairment, specifically impairment of executive function and memory.11 The incidence of cognitive impairment in LLD is higher in patients with a history of depression, such as Ms. A.11,12 However, in general, patients who are depressed have memory complaints out of proportion to the clinical findings, and they show poor effort on cognitive testing. Ms. A exhibited neither of these, which makes it less likely that LLD was the exclusive cause of her memory loss.13 Table 214 outlines the management of cognitive deficits in a patient with a brain tumor.
EVALUATION Increasingly agitated and paranoid
After the tumor resection, Ms. A becomes increasingly irritable, uncooperative, and agitated. She repeatedly demands to be discharged. She insists she is fine and refuses medications and further laboratory workup. She becomes paranoid about the nursing staff and believes they are trying to kill her.
Continue to: On psychiatric re-evaluation...
On psychiatric re-evaluation, Ms. A demonstrates pressured speech, perseveration about going home, paranoid delusions, and anger at her family and physicians.
[polldaddy:10511747]
The authors’ observations
Ms. A’s refusal of medications and agitation may be explained by postoperative delirium, a surgical complication that is increasingly common among geriatric patients and is associated with poor clinical outcomes. Delirium is characterized by an acute onset and fluctuating course of symptoms that include inattention, motoric hypo- or hyperactivity, inappropriate behavior, emotional lability, cognitive dysfunction, and psychotic symptoms.15 Risk factors that contribute to postoperative delirium include older age, alcohol use, and poor baseline functional and cognitive status.16 The pathophysiology of delirium is not fully understood, but accumulating evidence suggests that different sets of interacting biologic factors (ie, neurotransmitters and inflammation) contribute to a disruption of large-scale neuronal networks in the brain, resulting in cognitive dysfunction.15 Patients who develop postoperative delirium are more likely to develop long-term cognitive dysfunction and have an increased risk of dementia.16
Another potential source of Ms. A’s agitation is steroid use. Ms. A received IV dexamethasone, 8 to 16 mg/d, around the time of her surgery. Steroids are commonly used to treat brain tumors, particularly when there is vasogenic edema. Steroid psychosis is a term loosely used to describe a wide range of psychiatric symptoms induced by corticosteroids that includes, but is not limited to, depression, mania, psychosis, delirium, and cognitive impairment.17 Steroid-induced psychiatric adverse effects occur in 5% to 18% of patients receiving corticosteroids and often happen early in treatment, although they can occur at any point.18 Corticosteroids influence brain activity via glucocorticoid and mineralocorticoid receptors. These receptors are widely distributed throughout the brain and affect neurotransmitter systems, such as the serotonergic system, that are associated with changes in mood, behavior, and cognition.17 While the adverse psychiatric manifestations of steroid use vary, higher dosages are associated with an increased risk of psychiatric complications; mania is more prevalent early in the course of treatment, and depression is more common with long-term use.17,19 Table 317,18 outlines the evidence-based treatment of corticosteroid-induced adverse psychiatric effects.
Although there are no clinical guidelines or FDA-approved medications for treating steroid-induced psychiatric adverse events, these are best managed by tapering and discontinuing steroids when possible and simultaneously using psychotropic medications to treat psychiatric symptoms. Case reports and limited evidence-based literature have demonstrated that steroid-induced mania responds to mood stabilizers or antipsychotics, while depression can be managed with antidepressants or lithium.17
Additionally, patients with CNS tumors are at risk for seizures and often are prescribed antiepileptics. Because it is easy to administer and does not need to be titrated, levetiracetam is a commonly used agent. However, levetiracetam can cause psychiatric adverse effects, including behavior changes and frank psychosis.20
Continue to: Finally, Ms. A's altered mental status...
Finally, Ms. A’s altered mental status could have been related to opioid intoxication. Opioids are used to manage postsurgical pain, and studies have shown these medications can be a precipitating factor for delirium in geriatric patients.21
TREATMENT Medication adjustments
At the request of the psychiatry team, levetiracetam is discontinued due to its potential for psychiatric adverse effects. The neurosurgery team replaces it with valproic acid, 500 mg every 12 hours. Ms. A is also tapered off steroids fairly rapidly because of the potential for steroid-induced psychiatric adverse effects. Her quetiapine is titrated from 50 to 150 mg every night at bedtime, and duloxetine is discontinued.
OUTCOME Agitation improves dramatically
Ms. A’s new medication regimen dramatically improves her agitation, which allows Ms. A, her family, and the medical team to work together to establish treatment goals. Ms. A ultimately returns home with the assistance of her family. She continues to have memory issues, but with improved emotion regulation. Several months later, Ms. A is readmitted to the hospital because her cancer has progressed despite treatment.
Bottom Line
Brain tumors may present with various psychiatric manifestations that can change during the course of the patient’s treatment. A comprehensive psychiatric evaluation should parse out the interplay between direct effects of the tumor and any adverse effects that are the result of medical and/or surgical interventions to determine the cause of psychiatric symptoms and their appropriate management.
Related Resource
Madhusoodanan S, Ting MB, Farah T, et al. Psychiatric aspects of brain tumors: a review. World J Psychiatry. 2015;5(3):273-285.
Drug Brand Names
Aripiprazole • Abilify
Buspirone • Buspar
Chlorpromazine • Thorazine
Codeine • Codeine systemic
Dexamethasone • Decadron
Duloxetine • Cymbalta
Haloperidol • Haldol
Levetiracetam • Keppra
Lorazepam • Ativan
Lithium • Eskalith, Lithobid
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Valproic acid • Depakene
CASE Suicidal behavior, severe headaches
Ms. A, age 60, presents to the emergency department (ED) with depression, suicidal behavior, and 3 days of severe headaches. Neurology is consulted and an MRI is ordered, which shows a 3.0-cm mass lesion in the left temporal lobe with associated vasogenic edema that is suspicious for metastatic disease (Figure).
Ms. A is admitted to the hospital for further workup of her brain lesion. She is started on IV dexamethasone, 10 mg every 6 hours, a glucocorticosteroid, for brain edema, and levetiracetam, 500 mg twice a day, for seizure prophylaxis.
Upon admission, in addition to oncology and neurosurgery, psychiatry is also consulted to evaluate Ms. A for depression and suicidality.
EVALUATION Mood changes and poor judgment
Ms. A has a psychiatric history of depression and alcohol use disorder but says she has not consumed any alcohol in years. Her medical history includes hypertension, diabetes, and stage 4 non-small–cell lung cancer, for which she received surgery and adjuvant chemoradiotherapy 1 year ago.
On initial intake, Ms. A reports that in addition to the headaches, she has also been experiencing worsening depression and suicidal behavior. For the past 2 months, she has had a severely depressed mood, with notable anhedonia, poor appetite, insomnia, low energy, and decreased concentration. The changes in her mental health were triggered by her mother’s death. Three days prior to admission, the patient planned to overdose on antihypertensive pills, but her suicide attempt was interrupted when her family called. She denies any current suicidal ideation, intent, or plan.
According to her family, Ms. A has been increasingly irritable and her personality has changed in the past month. She also has been repeatedly sorting through her neighbors’ garbage.
Ms. A’s current psychiatric medications are duloxetine, 30 mg/d; quetiapine, 50 mg every night at bedtime; and buspirone, 10 mg/d. However, it is unclear if she is consistently taking these medications.
Continue to: On mental status examination...
On mental status examination, Ms. A is calm and she has no abnormal movements. She says she is depressed. Her affect is reactive and labile. She is alert and oriented to person, place, and time. Her attention, registration, and recall are intact. Her executive function is not tested. However, Ms. A’s insight and judgment seem poor.
To address Ms. A’s worsening depression, the psychiatry team increases her duloxetine from 30 to 60 mg/d, and she continues quetiapine, 50 mg every night at bedtime, for mood lability. Buspirone is not continued because she was not taking a therapeutic dosage in the community.
Within 4 days, Ms. A shows improvement in sleep, appetite, and mood. She has no further suicidal ideation.
[polldaddy:10511743]
The authors’ observations
Ms. A had a recurrence of what was presumed to be major depressive disorder (MDD) in the context of her mother’s death. However, she also exhibited irritability, mood lability, and impulsivity, all of which could be part of her depression, or a separate problem related to her brain tumor. Because Ms. A had never displayed bizarre behavior before the past few weeks, it is likely that her CNS lesion was directly affecting her personality and possibly underlying her planned suicide attempt.
Fifty to 80% of patients with CNS tumors, either primary or metastatic, present with psychiatric symptoms.1 Table 11-3 lists common psychiatric symptoms of brain tumors. Unfortunately, there is little reliable evidence that directly correlates tumor location with specific psychiatric symptoms. A 2010 meta-analysis found a statistically significant link between anorexia nervosa and hypothalamic tumors.1 However, for other brain regions, there is only an increased likelihood that any given tumor location will produce psychiatric symptoms.1,4 For instance, compared to patients with tumors in other locations, those with temporal lobe tumors are more likely to present with mood disorders, personality changes, and memory problems.1 In contrast, patients with frontal lobe tumors have an increased likelihood of psychosis, mood disorders, and personality changes.1 Patients with tumors in the pituitary region often present with anxiety.1
Continue to: When considering treatment options...
When considering treatment options for Ms. A, alcohol withdrawal was unlikely given the remote history of alcohol use, low alcohol blood level, and lack of evidence of unstable vital signs or tremor. Although she might have benefited from inpatient psychiatric treatment, this needed to wait until there was a definitive treatment plan for her brain tumor. Finally, although a paraneoplastic syndrome, such as limbic encephalitis, could be causing her psychiatric symptoms, this scenario is less likely with non-small–cell lung cancer.
Although uncommon, CNS tumors can present with psychiatric symptoms as the only manifestation. This is more likely when a patient exhibits new-onset or atypical symptoms, or fails to respond to standard psychiatric treatment.4 Case reports have described patients with brain tumors being misdiagnosed as having a primary psychiatric condition, which delays treatment of their CNS cancer.2 Additionally, frontal and limbic tumors are more likely to present with psychiatric manifestations; up to 90% of patients exhibit altered mental status or personality changes, as did Ms. A.1,4 Clearly, it is easier to identify patients with psychiatric symptoms resulting from a brain tumor when they also present with focal neurologic deficits or systemic symptoms, such as headache or nausea and vomiting. Ms. A presented with severe headaches, which is what led to her early imaging and prompt diagnosis.
Numerous proposed mechanisms might account for the psychiatric symptoms that occur during the course of a brain tumor, including direct injury to neuronal cells, secretion of hormones or other tumor-derived substances, and peri-ictal phenomena.3
TREATMENT Tumor is removed, but memory is impaired
Ms. A is scheduled for craniotomy and surgical resection of the frontal mass. Prior to surgery, Ms. A shows interest in improving her health, cooperates with staff, and seeks her daughter’s input on treatment. One week after admission, Ms. A has her mass resected, which is confirmed on biopsy to be a lung metastasis. Post-surgery, Ms. A receives codeine, 30 mg every 6 hours as needed, for pain; she continues dexamethasone, 4 mg IV every 6 hours, for brain edema and levetiracetam, 500 mg twice a day, for seizure prophylaxis.
On Day 2 after surgery, Ms. A attempts to elope. When she is approached by a psychiatrist on the treatment team, she does not recognize him. Although her long-term memory seems intact, she is unable to remember the details of recent events, including her medical and surgical treatments.
[polldaddy:10511745]
Continue to: The authors' observations
The authors’ observations
Ms. A’s memory impairment may be secondary to a surgically acquired neurocognitive deficit. In the United States, brain metastases represent a significant public health issue, affecting >100,000 patients per year.5 Metastatic lesions are the most common brain tumors. Lung cancer, breast cancer, and melanoma are the leading solid tumors to spread to the CNS.5 In cases of single brain metastasis, similar to Ms. A’s solitary left temporal lobe lesion, surgical resection plays a critical role in treatment. It provides histological confirmation of metastatic disease and can relieve mass effect if present. Studies have shown that combined surgical resection with radiation improves survival relative to patients who undergo radiation therapy alone.6,7
However, the benefits of surgical resection need to be balanced with preservation of neurologic function. Emerging evidence suggests that a majority of patients have surgically-acquired cognitive deficits due to damage of normal surrounding tissues, and these deficits are associated with reduced quality of life.8,9 Further, a study examining glioma surgical resections found that patients with left temporal lobe tumors exhibit more frequent and severe neurocognitive decline than patients with right temporal lobe tumors, especially in domains such as verbal memory.8 Ms. A’s memory impairment was persistent during her postoperative course, which suggests that it was not just an immediate post-surgical phenomenon, but a longer-lasting cognitive change directly related to the resection.
It is also possible that Ms. A had a prior neurocognitive disorder that manifested to a greater degree as a result of the CNS tumor. Ms. A might have had early-onset Alzheimer’s disease, although her intact memory before surgery makes this less likely. Alternatively, she could have had vascular dementia, especially given her long-standing hypertension and diabetes. This might have been missed in the initial evaluation because executive function was not tested. However, the relatively abrupt onset of memory problems after surgery suggests that she had no underlying neurocognitive disorder.
Ms. A’s presumed episode of MDD might also explain her memory changes. Major depressive disorder is increasingly common among geriatric patients, affecting approximately 5% of community-dwelling older adults.10 Its incidence increases with medical comorbidities, as suggested by depression rates of 5% to 10% in the primary care setting vs 37% in patients after critical-care hospitalizations.10 Late-life depression (LLD) occurs in adults age ≥60. Unlike depression in younger patients, LLD is more likely to be associated with cognitive impairment, specifically impairment of executive function and memory.11 The incidence of cognitive impairment in LLD is higher in patients with a history of depression, such as Ms. A.11,12 However, in general, patients who are depressed have memory complaints out of proportion to the clinical findings, and they show poor effort on cognitive testing. Ms. A exhibited neither of these, which makes it less likely that LLD was the exclusive cause of her memory loss.13 Table 214 outlines the management of cognitive deficits in a patient with a brain tumor.
EVALUATION Increasingly agitated and paranoid
After the tumor resection, Ms. A becomes increasingly irritable, uncooperative, and agitated. She repeatedly demands to be discharged. She insists she is fine and refuses medications and further laboratory workup. She becomes paranoid about the nursing staff and believes they are trying to kill her.
Continue to: On psychiatric re-evaluation...
On psychiatric re-evaluation, Ms. A demonstrates pressured speech, perseveration about going home, paranoid delusions, and anger at her family and physicians.
[polldaddy:10511747]
The authors’ observations
Ms. A’s refusal of medications and agitation may be explained by postoperative delirium, a surgical complication that is increasingly common among geriatric patients and is associated with poor clinical outcomes. Delirium is characterized by an acute onset and fluctuating course of symptoms that include inattention, motoric hypo- or hyperactivity, inappropriate behavior, emotional lability, cognitive dysfunction, and psychotic symptoms.15 Risk factors that contribute to postoperative delirium include older age, alcohol use, and poor baseline functional and cognitive status.16 The pathophysiology of delirium is not fully understood, but accumulating evidence suggests that different sets of interacting biologic factors (ie, neurotransmitters and inflammation) contribute to a disruption of large-scale neuronal networks in the brain, resulting in cognitive dysfunction.15 Patients who develop postoperative delirium are more likely to develop long-term cognitive dysfunction and have an increased risk of dementia.16
Another potential source of Ms. A’s agitation is steroid use. Ms. A received IV dexamethasone, 8 to 16 mg/d, around the time of her surgery. Steroids are commonly used to treat brain tumors, particularly when there is vasogenic edema. Steroid psychosis is a term loosely used to describe a wide range of psychiatric symptoms induced by corticosteroids that includes, but is not limited to, depression, mania, psychosis, delirium, and cognitive impairment.17 Steroid-induced psychiatric adverse effects occur in 5% to 18% of patients receiving corticosteroids and often happen early in treatment, although they can occur at any point.18 Corticosteroids influence brain activity via glucocorticoid and mineralocorticoid receptors. These receptors are widely distributed throughout the brain and affect neurotransmitter systems, such as the serotonergic system, that are associated with changes in mood, behavior, and cognition.17 While the adverse psychiatric manifestations of steroid use vary, higher dosages are associated with an increased risk of psychiatric complications; mania is more prevalent early in the course of treatment, and depression is more common with long-term use.17,19 Table 317,18 outlines the evidence-based treatment of corticosteroid-induced adverse psychiatric effects.
Although there are no clinical guidelines or FDA-approved medications for treating steroid-induced psychiatric adverse events, these are best managed by tapering and discontinuing steroids when possible and simultaneously using psychotropic medications to treat psychiatric symptoms. Case reports and limited evidence-based literature have demonstrated that steroid-induced mania responds to mood stabilizers or antipsychotics, while depression can be managed with antidepressants or lithium.17
Additionally, patients with CNS tumors are at risk for seizures and often are prescribed antiepileptics. Because it is easy to administer and does not need to be titrated, levetiracetam is a commonly used agent. However, levetiracetam can cause psychiatric adverse effects, including behavior changes and frank psychosis.20
Continue to: Finally, Ms. A's altered mental status...
Finally, Ms. A’s altered mental status could have been related to opioid intoxication. Opioids are used to manage postsurgical pain, and studies have shown these medications can be a precipitating factor for delirium in geriatric patients.21
TREATMENT Medication adjustments
At the request of the psychiatry team, levetiracetam is discontinued due to its potential for psychiatric adverse effects. The neurosurgery team replaces it with valproic acid, 500 mg every 12 hours. Ms. A is also tapered off steroids fairly rapidly because of the potential for steroid-induced psychiatric adverse effects. Her quetiapine is titrated from 50 to 150 mg every night at bedtime, and duloxetine is discontinued.
OUTCOME Agitation improves dramatically
Ms. A’s new medication regimen dramatically improves her agitation, which allows Ms. A, her family, and the medical team to work together to establish treatment goals. Ms. A ultimately returns home with the assistance of her family. She continues to have memory issues, but with improved emotion regulation. Several months later, Ms. A is readmitted to the hospital because her cancer has progressed despite treatment.
Bottom Line
Brain tumors may present with various psychiatric manifestations that can change during the course of the patient’s treatment. A comprehensive psychiatric evaluation should parse out the interplay between direct effects of the tumor and any adverse effects that are the result of medical and/or surgical interventions to determine the cause of psychiatric symptoms and their appropriate management.
Related Resource
Madhusoodanan S, Ting MB, Farah T, et al. Psychiatric aspects of brain tumors: a review. World J Psychiatry. 2015;5(3):273-285.
Drug Brand Names
Aripiprazole • Abilify
Buspirone • Buspar
Chlorpromazine • Thorazine
Codeine • Codeine systemic
Dexamethasone • Decadron
Duloxetine • Cymbalta
Haloperidol • Haldol
Levetiracetam • Keppra
Lorazepam • Ativan
Lithium • Eskalith, Lithobid
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Valproic acid • Depakene
1. Madhusoodanan S, Opler MG, Moise D, et al. Brain tumor location and psychiatric symptoms: is there any association? A meta-analysis of published case studies. Expert Rev Neurother. 2010;10(10):1529-1536.
2. Bunevicius A, Deltuva VP, Deltuviene D, et al. Brain lesions manifesting as psychiatric disorders: eight cases. CNS Spectr. 2008;13(11):950-958.
3. Pearl ML, Talgat G, Valea FA, et al. Psychiatric symptoms due to brain metastases. Med Update Psychiatr. 1998;3(4):91-94.
4. Madhusoodanan S, Danan D, Moise D. Psychiatric manifestations of brain tumors: diagnostic implications. Expert Rev Neurother. 2007;7(4):343-349.
5. Ferguson SD, Wagner KM, Prabhu SS, et al. Neurosurgical management of brain metastases. Clin Exp Metastasis. 2017;34(6-7):377-389.
6. Husain ZA, Regine WF, Kwok Y, et al. Brain metastases: contemporary management and future directions. Eur J Clin Med Oncol. 2011;3(3):38-45.
7. Vecht CJ, Haaxmareiche H, Noordijk EM, et al. Treatment of single brain metastasis - radiotherapy alone or combined with neurosurgery. Ann Neurol. 1993;33(6):583-590.
8. Barry RL, Byun NE, Tantawy MN, et al. In vivo neuroimaging and behavioral correlates in a rat model of chemotherapy-induced cognitive dysfunction. Brain Imaging Behav. 2018;12(1):87-95.
9. Wu AS, Witgert ME, Lang FF, et al. Neurocognitive function before and after surgery for insular gliomas. J Neurosurg. 2011;115(6):1115-1125.
10. Taylor WD. Depression in the elderly. N Engl J Med. 2014;371(13):1228-1236.
11. Liguori C, Pierantozzi M, Chiaravalloti A, et al. When cognitive decline and depression coexist in the elderly: CSF biomarkers analysis can differentiate Alzheimer’s disease from late-life depression. Front Aging Neurosci. 2018;10:38.
12. Luijendijk HJ, van den Berg JF, Dekker MJHJ, et al. Incidence and recurrence of late-life depression. Arch Gen Psychiatry. 2008;65(12):1394-1401.
13. Potter GG, Steffens DC. Contribution of depression to cognitive impairment and dementia in older adults. Neurologist. 2007;13(3):105-117.
14. Taphoorn MJB, Klein M. Cognitive deficits in adult patients with brain tumours. Lancet Neurol. 2004;3(3):159-168.
15. Inouye SK, Westendorp RGJ, Saczynski JS. Delirium in elderly people. Lancet. 2014;383(9920):911-922.
16. Sprung J, Roberts RO, Weingarten TN, et al. Postoperative delirium in elderly patients is associated with subsequent cognitive impairment. Br J Anaesth. 2017;119(2):316-323.
17. Kusljic S, Manias E, Gogos A. Corticosteroid-induced psychiatric disturbances: it is time for pharmacists to take notice. Res Soc Adm Pharm. 2016;12(2):355-360.
18. Cerullo MA. Corticosteroid-induced mania: prepare for the unpredictable. Current Psychiatry. 2006;5(6):43-50.
19. Dubovsky AN, Arvikar S, Stern TA, et al. Steroid psychosis revisited. Psychosomatics. 2012;53(2):103-115.
20. Habets JGV, Leentjens AFG, Schijns OEMG. Serious and reversible levetiracetam-induced psychiatric symptoms after resection of frontal low-grade glioma: two case histories. Br J Neurosurg. 2017;31(4):471-473.
21
1. Madhusoodanan S, Opler MG, Moise D, et al. Brain tumor location and psychiatric symptoms: is there any association? A meta-analysis of published case studies. Expert Rev Neurother. 2010;10(10):1529-1536.
2. Bunevicius A, Deltuva VP, Deltuviene D, et al. Brain lesions manifesting as psychiatric disorders: eight cases. CNS Spectr. 2008;13(11):950-958.
3. Pearl ML, Talgat G, Valea FA, et al. Psychiatric symptoms due to brain metastases. Med Update Psychiatr. 1998;3(4):91-94.
4. Madhusoodanan S, Danan D, Moise D. Psychiatric manifestations of brain tumors: diagnostic implications. Expert Rev Neurother. 2007;7(4):343-349.
5. Ferguson SD, Wagner KM, Prabhu SS, et al. Neurosurgical management of brain metastases. Clin Exp Metastasis. 2017;34(6-7):377-389.
6. Husain ZA, Regine WF, Kwok Y, et al. Brain metastases: contemporary management and future directions. Eur J Clin Med Oncol. 2011;3(3):38-45.
7. Vecht CJ, Haaxmareiche H, Noordijk EM, et al. Treatment of single brain metastasis - radiotherapy alone or combined with neurosurgery. Ann Neurol. 1993;33(6):583-590.
8. Barry RL, Byun NE, Tantawy MN, et al. In vivo neuroimaging and behavioral correlates in a rat model of chemotherapy-induced cognitive dysfunction. Brain Imaging Behav. 2018;12(1):87-95.
9. Wu AS, Witgert ME, Lang FF, et al. Neurocognitive function before and after surgery for insular gliomas. J Neurosurg. 2011;115(6):1115-1125.
10. Taylor WD. Depression in the elderly. N Engl J Med. 2014;371(13):1228-1236.
11. Liguori C, Pierantozzi M, Chiaravalloti A, et al. When cognitive decline and depression coexist in the elderly: CSF biomarkers analysis can differentiate Alzheimer’s disease from late-life depression. Front Aging Neurosci. 2018;10:38.
12. Luijendijk HJ, van den Berg JF, Dekker MJHJ, et al. Incidence and recurrence of late-life depression. Arch Gen Psychiatry. 2008;65(12):1394-1401.
13. Potter GG, Steffens DC. Contribution of depression to cognitive impairment and dementia in older adults. Neurologist. 2007;13(3):105-117.
14. Taphoorn MJB, Klein M. Cognitive deficits in adult patients with brain tumours. Lancet Neurol. 2004;3(3):159-168.
15. Inouye SK, Westendorp RGJ, Saczynski JS. Delirium in elderly people. Lancet. 2014;383(9920):911-922.
16. Sprung J, Roberts RO, Weingarten TN, et al. Postoperative delirium in elderly patients is associated with subsequent cognitive impairment. Br J Anaesth. 2017;119(2):316-323.
17. Kusljic S, Manias E, Gogos A. Corticosteroid-induced psychiatric disturbances: it is time for pharmacists to take notice. Res Soc Adm Pharm. 2016;12(2):355-360.
18. Cerullo MA. Corticosteroid-induced mania: prepare for the unpredictable. Current Psychiatry. 2006;5(6):43-50.
19. Dubovsky AN, Arvikar S, Stern TA, et al. Steroid psychosis revisited. Psychosomatics. 2012;53(2):103-115.
20. Habets JGV, Leentjens AFG, Schijns OEMG. Serious and reversible levetiracetam-induced psychiatric symptoms after resection of frontal low-grade glioma: two case histories. Br J Neurosurg. 2017;31(4):471-473.
21
USPSTF again deems evidence insufficient to recommend cognitive impairment screening in older adults
The U.S. Preventive Services Task Force has deemed the current evidence “insufficient” to make a recommendation in regard to screening for cognitive impairment in adults aged 65 years or older.
“More research is needed on the effect of screening and early detection of cognitive impairment on important patient, caregiver, and societal outcomes, including decision making, advance planning, and caregiver outcomes,” wrote lead author Douglas K. Owens, MD, of Stanford (Calif.) University and fellow members of the task force. The statement was published in JAMA.
To update a 2014 recommendation from the USPSTF, which also found insufficient evidence to properly assess cognitive screening’s benefits and harms, the task force commissioned a systematic review of studies applicable to community-dwelling older adults who are not exhibiting signs or symptoms of cognitive impairment. For their statement, “cognitive impairment” is defined as mild cognitive impairment and mild to moderate dementia.
Ultimately, they determined several factors that limited the overall evidence, including the short duration of most trials and the heterogenous nature of interventions and inconsistencies in outcomes reported. Any evidence that suggested improvements was mostly applicable to patients with moderate dementia, meaning “its applicability to a screen-detected population is uncertain.”
Updating 2014 recommendations
Their statement was based on an evidence report, also published in JAMA, in which a team of researchers reviewed 287 studies that included more than 285,000 older adults; 92 of the studies were newly identified, while the other 195 were carried forward from the 2014 recommendation’s review. The researchers sought the answers to five key questions, carrying over the framework from the previous review.
“Despite the accumulation of new data, the conclusions for these key questions are essentially unchanged from the prior review,” wrote lead author Carrie D. Patnode, PhD, of the Kaiser Permanente Center for Health Research in Portland, Ore., and coauthors.
Of the questions – which concerned the accuracy of screening instruments; the harms of screening; the harms of interventions; and if screening or interventions improved decision making or outcomes for the patient, family/caregiver, or society – moderate evidence was found to support the accuracy of the instruments, treatment with acetylcholinesterase inhibitors and memantine for patients with moderate dementia, and psychoeducation interventions for caregivers of patients with moderate dementia. At the same time, there was moderate evidence of adverse effects from acetylcholinesterase inhibitors and memantine in patients with moderate dementia.
“I think, eventually, there will be sufficient evidence to justify screening, once we have what I call a tiered approach,” Marwan Sabbagh, MD, of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, said in an interview. “The very near future will include blood tests for Alzheimer’s, or PET scans, or genetics, or something else. Right now, the cognitive screens lack the specificity and sensitivity, and the secondary screening infrastructure that would improve the accuracy doesn’t exist yet.
“I think this is a ‘not now,’ ” he added, “but I wouldn’t say ‘not ever.’ ”
Dr. Patnode and coauthors noted specific limitations in the evidence, including a lack of studies on how screening for and treating cognitive impairment affects decision making. In addition, details like quality of life and institutionalization were inconsistently reported, and “consistent and standardized reporting of results according to meaningful thresholds of clinical significance” would have been valuable across all measures.
Clinical implications
The implications of this report’s conclusions are substantial, especially as the rising prevalence of mild cognitive impairment and dementia becomes a worldwide concern, wrote Ronald C. Petersen, PhD, MD, of the Mayo Clinic in Rochester, Minn., and Kristine Yaffe, MD, of the University of California, San Francisco, in an accompanying editorial.
Though the data does not explicitly support screening, Dr. Petersen and Dr. Yaffe noted that it still may have benefits. An estimated 10% of cognitive impairment is caused by at least somewhat reversible causes, and screening could also be used to improve care in medical problems that are worsened by cognitive impairment. To find the true value of these efforts, they wrote, researchers need to design and execute additional clinical trials that “answer many of the important questions surrounding screening and treatment of cognitive impairment.”
“The absence of evidence for benefit may lead to inaction,” they added, noting that clinicians screening should still consider the value of screening on a case-by-case basis in order to keep up with the impact of new disease-modifying therapies for certain neurodegenerative diseases.
All members of the USPSTF received travel reimbursement and an honorarium for participating in meetings. One member reported receiving grants and personal fees from Healthwise. The study was funded by the Department of Health & Human Services. One of the authors reported receiving grants from the National Institutes of Health and the Food and Drug Administration. Dr. Petersen and Dr. Yaffe reported consulting for, and receiving funding from, various pharmaceutical companies, foundations, and government organizations.
SOURCES: Owens DK et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2020.0435; Patnode CD et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2019.22258.
The U.S. Preventive Services Task Force has deemed the current evidence “insufficient” to make a recommendation in regard to screening for cognitive impairment in adults aged 65 years or older.
“More research is needed on the effect of screening and early detection of cognitive impairment on important patient, caregiver, and societal outcomes, including decision making, advance planning, and caregiver outcomes,” wrote lead author Douglas K. Owens, MD, of Stanford (Calif.) University and fellow members of the task force. The statement was published in JAMA.
To update a 2014 recommendation from the USPSTF, which also found insufficient evidence to properly assess cognitive screening’s benefits and harms, the task force commissioned a systematic review of studies applicable to community-dwelling older adults who are not exhibiting signs or symptoms of cognitive impairment. For their statement, “cognitive impairment” is defined as mild cognitive impairment and mild to moderate dementia.
Ultimately, they determined several factors that limited the overall evidence, including the short duration of most trials and the heterogenous nature of interventions and inconsistencies in outcomes reported. Any evidence that suggested improvements was mostly applicable to patients with moderate dementia, meaning “its applicability to a screen-detected population is uncertain.”
Updating 2014 recommendations
Their statement was based on an evidence report, also published in JAMA, in which a team of researchers reviewed 287 studies that included more than 285,000 older adults; 92 of the studies were newly identified, while the other 195 were carried forward from the 2014 recommendation’s review. The researchers sought the answers to five key questions, carrying over the framework from the previous review.
“Despite the accumulation of new data, the conclusions for these key questions are essentially unchanged from the prior review,” wrote lead author Carrie D. Patnode, PhD, of the Kaiser Permanente Center for Health Research in Portland, Ore., and coauthors.
Of the questions – which concerned the accuracy of screening instruments; the harms of screening; the harms of interventions; and if screening or interventions improved decision making or outcomes for the patient, family/caregiver, or society – moderate evidence was found to support the accuracy of the instruments, treatment with acetylcholinesterase inhibitors and memantine for patients with moderate dementia, and psychoeducation interventions for caregivers of patients with moderate dementia. At the same time, there was moderate evidence of adverse effects from acetylcholinesterase inhibitors and memantine in patients with moderate dementia.
“I think, eventually, there will be sufficient evidence to justify screening, once we have what I call a tiered approach,” Marwan Sabbagh, MD, of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, said in an interview. “The very near future will include blood tests for Alzheimer’s, or PET scans, or genetics, or something else. Right now, the cognitive screens lack the specificity and sensitivity, and the secondary screening infrastructure that would improve the accuracy doesn’t exist yet.
“I think this is a ‘not now,’ ” he added, “but I wouldn’t say ‘not ever.’ ”
Dr. Patnode and coauthors noted specific limitations in the evidence, including a lack of studies on how screening for and treating cognitive impairment affects decision making. In addition, details like quality of life and institutionalization were inconsistently reported, and “consistent and standardized reporting of results according to meaningful thresholds of clinical significance” would have been valuable across all measures.
Clinical implications
The implications of this report’s conclusions are substantial, especially as the rising prevalence of mild cognitive impairment and dementia becomes a worldwide concern, wrote Ronald C. Petersen, PhD, MD, of the Mayo Clinic in Rochester, Minn., and Kristine Yaffe, MD, of the University of California, San Francisco, in an accompanying editorial.
Though the data does not explicitly support screening, Dr. Petersen and Dr. Yaffe noted that it still may have benefits. An estimated 10% of cognitive impairment is caused by at least somewhat reversible causes, and screening could also be used to improve care in medical problems that are worsened by cognitive impairment. To find the true value of these efforts, they wrote, researchers need to design and execute additional clinical trials that “answer many of the important questions surrounding screening and treatment of cognitive impairment.”
“The absence of evidence for benefit may lead to inaction,” they added, noting that clinicians screening should still consider the value of screening on a case-by-case basis in order to keep up with the impact of new disease-modifying therapies for certain neurodegenerative diseases.
All members of the USPSTF received travel reimbursement and an honorarium for participating in meetings. One member reported receiving grants and personal fees from Healthwise. The study was funded by the Department of Health & Human Services. One of the authors reported receiving grants from the National Institutes of Health and the Food and Drug Administration. Dr. Petersen and Dr. Yaffe reported consulting for, and receiving funding from, various pharmaceutical companies, foundations, and government organizations.
SOURCES: Owens DK et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2020.0435; Patnode CD et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2019.22258.
The U.S. Preventive Services Task Force has deemed the current evidence “insufficient” to make a recommendation in regard to screening for cognitive impairment in adults aged 65 years or older.
“More research is needed on the effect of screening and early detection of cognitive impairment on important patient, caregiver, and societal outcomes, including decision making, advance planning, and caregiver outcomes,” wrote lead author Douglas K. Owens, MD, of Stanford (Calif.) University and fellow members of the task force. The statement was published in JAMA.
To update a 2014 recommendation from the USPSTF, which also found insufficient evidence to properly assess cognitive screening’s benefits and harms, the task force commissioned a systematic review of studies applicable to community-dwelling older adults who are not exhibiting signs or symptoms of cognitive impairment. For their statement, “cognitive impairment” is defined as mild cognitive impairment and mild to moderate dementia.
Ultimately, they determined several factors that limited the overall evidence, including the short duration of most trials and the heterogenous nature of interventions and inconsistencies in outcomes reported. Any evidence that suggested improvements was mostly applicable to patients with moderate dementia, meaning “its applicability to a screen-detected population is uncertain.”
Updating 2014 recommendations
Their statement was based on an evidence report, also published in JAMA, in which a team of researchers reviewed 287 studies that included more than 285,000 older adults; 92 of the studies were newly identified, while the other 195 were carried forward from the 2014 recommendation’s review. The researchers sought the answers to five key questions, carrying over the framework from the previous review.
“Despite the accumulation of new data, the conclusions for these key questions are essentially unchanged from the prior review,” wrote lead author Carrie D. Patnode, PhD, of the Kaiser Permanente Center for Health Research in Portland, Ore., and coauthors.
Of the questions – which concerned the accuracy of screening instruments; the harms of screening; the harms of interventions; and if screening or interventions improved decision making or outcomes for the patient, family/caregiver, or society – moderate evidence was found to support the accuracy of the instruments, treatment with acetylcholinesterase inhibitors and memantine for patients with moderate dementia, and psychoeducation interventions for caregivers of patients with moderate dementia. At the same time, there was moderate evidence of adverse effects from acetylcholinesterase inhibitors and memantine in patients with moderate dementia.
“I think, eventually, there will be sufficient evidence to justify screening, once we have what I call a tiered approach,” Marwan Sabbagh, MD, of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, said in an interview. “The very near future will include blood tests for Alzheimer’s, or PET scans, or genetics, or something else. Right now, the cognitive screens lack the specificity and sensitivity, and the secondary screening infrastructure that would improve the accuracy doesn’t exist yet.
“I think this is a ‘not now,’ ” he added, “but I wouldn’t say ‘not ever.’ ”
Dr. Patnode and coauthors noted specific limitations in the evidence, including a lack of studies on how screening for and treating cognitive impairment affects decision making. In addition, details like quality of life and institutionalization were inconsistently reported, and “consistent and standardized reporting of results according to meaningful thresholds of clinical significance” would have been valuable across all measures.
Clinical implications
The implications of this report’s conclusions are substantial, especially as the rising prevalence of mild cognitive impairment and dementia becomes a worldwide concern, wrote Ronald C. Petersen, PhD, MD, of the Mayo Clinic in Rochester, Minn., and Kristine Yaffe, MD, of the University of California, San Francisco, in an accompanying editorial.
Though the data does not explicitly support screening, Dr. Petersen and Dr. Yaffe noted that it still may have benefits. An estimated 10% of cognitive impairment is caused by at least somewhat reversible causes, and screening could also be used to improve care in medical problems that are worsened by cognitive impairment. To find the true value of these efforts, they wrote, researchers need to design and execute additional clinical trials that “answer many of the important questions surrounding screening and treatment of cognitive impairment.”
“The absence of evidence for benefit may lead to inaction,” they added, noting that clinicians screening should still consider the value of screening on a case-by-case basis in order to keep up with the impact of new disease-modifying therapies for certain neurodegenerative diseases.
All members of the USPSTF received travel reimbursement and an honorarium for participating in meetings. One member reported receiving grants and personal fees from Healthwise. The study was funded by the Department of Health & Human Services. One of the authors reported receiving grants from the National Institutes of Health and the Food and Drug Administration. Dr. Petersen and Dr. Yaffe reported consulting for, and receiving funding from, various pharmaceutical companies, foundations, and government organizations.
SOURCES: Owens DK et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2020.0435; Patnode CD et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2019.22258.
FROM JAMA