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Dementia linked to increased mortality risk in adults with Down syndrome
Adults with Down syndrome and dementia had a risk of death five times higher than those without dementia, according to results of a recent prospective study.
More than 70% of the individuals with Down syndrome who died over the course of follow-up had a clinical diagnosis of dementia in this longitudinal study of community dwelling participants, many of whom had factors associated with dementia such as the apolipoprotein E (APOE) genotype.
The findings of this study support an “urgent need” for clinical trials of treatment that might delay or prevent dementia in individuals with Down syndrome, said the investigators, led by Rosalyn Hithersay, MSc, of the department of forensic and neurodevelopmental sciences in the Institute of Psychiatry, Psychology, and Neuroscience at King’s College London (United Kingdom).
“We hope that our findings can improve clinical care by identifying factors associated with increased risk for dementia and mortality risk in this population, suggesting the potentially beneficial effects of existing medication options and helping clinicians provide prognostic information for their patients,” the authors wrote in JAMA Neurology.
The risk of dementia in individuals with Down syndrome has grown to “exceptional” levels, alongside a dramatic increase in life expectancy in these patients, from just 10 years of age some 50 years ago, to nearly 64 years today, investigators said.
Although other research has confirmed that dementia is frequently recorded as a contributory factor in Down syndrome deaths in recent years, this latest study provides crude mortality rates and exploratory analyses of factors that may modify mortality and dementia risk, according to the researchers.
Their study included 211 individuals with Down syndrome who were aged at least 36 years at study entry and followed for a total of 503.92 person-years, the investigators reported.
A total of 27 individuals died during follow-up, with a median age at death of 57 years; of those individuals, 19 (70.37%) had a clinical diagnosis of dementia, according to the report.
The crude mortality rate for individuals with dementia was nearly 1,192 deaths per 10,000 person-years, compared with 232 deaths per 10,000 person-years for those with no dementia diagnosis, the investigators found.
Further analysis showed that factors independently associated with mortality in those with a dementia diagnosis included APOE genotype, dementia medication status, early-onset epilepsy, and presence of two or more comorbid conditions.
In a combined model, APOE genotype was significantly associated with mortality risk, they added.
Among the eight individuals with Down syndrome who died without a dementia diagnosis, one reportedly had early signs of cognitive decline, and two had late-onset epilepsy.
Late-onset epilepsy, identified in seven individuals (4.8%) with no dementia diagnosis in this study, was the only factor associated with mortality in individuals without dementia, conferring a 10-fold increase in risk of that outcome, according to the analysis.
“This raises the question of whether seizures can begin in the absence of other features of dementia in individuals with Down syndrome or whether these seven individuals had significant AD pathology and neurological symptoms but had yet to receive a formal dementia diagnosis,” the researchers wrote in a discussion of results.
The authors reported no conflict of interest disclosures related to the study. Their research was supported by UK National Institute for Health Research networks and participating National Health Services trusts, as well as a Wellcome Trust Strategic Award to the London Down Syndrome Consortium.
SOURCE: Hithersay R et al. JAMA Neurol. 2018 Nov 19. doi: 10.1001/jamaneurol.2018.3616
Although this prospective longitudinal study has a limited sample size and short follow-up, the finding that dementia is the proximate cause of death in approximately 70% of individuals with Down syndrome was “astonishing,” Michael S. Rafii, MD, PhD, and Stephanie L. Santoro, MD, wrote in an editorial.
Mortality rates among individuals with Down syndrome were five times higher in those with dementia as compared with those without dementia in this study, with a median age at death of 57 years (see article).
“By comparison, in the general population, dementia of any subtype is listed in only 18% of death certificates for those older than 65 years, with mortality rates being slightly less than twofold higher in those with dementia than those without,” Dr. Rafiii and Dr. Santoro wrote in their editorial.
Results of the study imply that most older individuals with Down syndrome will have dementia at the time of death, which suggests that these individuals and their families have a “greater need” to plan for a life stage that includes dementia, the authors said.
Physicians and health care systems could consider screening for dementia and epilepsy as part of their standard care practices for older adults with Down syndrome based on these study results, they added.
“Although consensus guidelines and screening tools have been published for the evaluation and management of dementia in Down syndrome, it remains unclear if there has been widespread implementation of these,” the authors said.
Dr. Rafii is with the Alzheimer’s Therapeutic Research Institute at the University of Southern California, San Diego. Coauthor Dr. Santoro is with the Down Syndrome Program at Massachusetts General Hospital and with Harvard Medical School, both in Boston. The authors reported no conflict of interest disclosures related to their editorial, which appears in JAMA Neurology .
Although this prospective longitudinal study has a limited sample size and short follow-up, the finding that dementia is the proximate cause of death in approximately 70% of individuals with Down syndrome was “astonishing,” Michael S. Rafii, MD, PhD, and Stephanie L. Santoro, MD, wrote in an editorial.
Mortality rates among individuals with Down syndrome were five times higher in those with dementia as compared with those without dementia in this study, with a median age at death of 57 years (see article).
“By comparison, in the general population, dementia of any subtype is listed in only 18% of death certificates for those older than 65 years, with mortality rates being slightly less than twofold higher in those with dementia than those without,” Dr. Rafiii and Dr. Santoro wrote in their editorial.
Results of the study imply that most older individuals with Down syndrome will have dementia at the time of death, which suggests that these individuals and their families have a “greater need” to plan for a life stage that includes dementia, the authors said.
Physicians and health care systems could consider screening for dementia and epilepsy as part of their standard care practices for older adults with Down syndrome based on these study results, they added.
“Although consensus guidelines and screening tools have been published for the evaluation and management of dementia in Down syndrome, it remains unclear if there has been widespread implementation of these,” the authors said.
Dr. Rafii is with the Alzheimer’s Therapeutic Research Institute at the University of Southern California, San Diego. Coauthor Dr. Santoro is with the Down Syndrome Program at Massachusetts General Hospital and with Harvard Medical School, both in Boston. The authors reported no conflict of interest disclosures related to their editorial, which appears in JAMA Neurology .
Although this prospective longitudinal study has a limited sample size and short follow-up, the finding that dementia is the proximate cause of death in approximately 70% of individuals with Down syndrome was “astonishing,” Michael S. Rafii, MD, PhD, and Stephanie L. Santoro, MD, wrote in an editorial.
Mortality rates among individuals with Down syndrome were five times higher in those with dementia as compared with those without dementia in this study, with a median age at death of 57 years (see article).
“By comparison, in the general population, dementia of any subtype is listed in only 18% of death certificates for those older than 65 years, with mortality rates being slightly less than twofold higher in those with dementia than those without,” Dr. Rafiii and Dr. Santoro wrote in their editorial.
Results of the study imply that most older individuals with Down syndrome will have dementia at the time of death, which suggests that these individuals and their families have a “greater need” to plan for a life stage that includes dementia, the authors said.
Physicians and health care systems could consider screening for dementia and epilepsy as part of their standard care practices for older adults with Down syndrome based on these study results, they added.
“Although consensus guidelines and screening tools have been published for the evaluation and management of dementia in Down syndrome, it remains unclear if there has been widespread implementation of these,” the authors said.
Dr. Rafii is with the Alzheimer’s Therapeutic Research Institute at the University of Southern California, San Diego. Coauthor Dr. Santoro is with the Down Syndrome Program at Massachusetts General Hospital and with Harvard Medical School, both in Boston. The authors reported no conflict of interest disclosures related to their editorial, which appears in JAMA Neurology .
Adults with Down syndrome and dementia had a risk of death five times higher than those without dementia, according to results of a recent prospective study.
More than 70% of the individuals with Down syndrome who died over the course of follow-up had a clinical diagnosis of dementia in this longitudinal study of community dwelling participants, many of whom had factors associated with dementia such as the apolipoprotein E (APOE) genotype.
The findings of this study support an “urgent need” for clinical trials of treatment that might delay or prevent dementia in individuals with Down syndrome, said the investigators, led by Rosalyn Hithersay, MSc, of the department of forensic and neurodevelopmental sciences in the Institute of Psychiatry, Psychology, and Neuroscience at King’s College London (United Kingdom).
“We hope that our findings can improve clinical care by identifying factors associated with increased risk for dementia and mortality risk in this population, suggesting the potentially beneficial effects of existing medication options and helping clinicians provide prognostic information for their patients,” the authors wrote in JAMA Neurology.
The risk of dementia in individuals with Down syndrome has grown to “exceptional” levels, alongside a dramatic increase in life expectancy in these patients, from just 10 years of age some 50 years ago, to nearly 64 years today, investigators said.
Although other research has confirmed that dementia is frequently recorded as a contributory factor in Down syndrome deaths in recent years, this latest study provides crude mortality rates and exploratory analyses of factors that may modify mortality and dementia risk, according to the researchers.
Their study included 211 individuals with Down syndrome who were aged at least 36 years at study entry and followed for a total of 503.92 person-years, the investigators reported.
A total of 27 individuals died during follow-up, with a median age at death of 57 years; of those individuals, 19 (70.37%) had a clinical diagnosis of dementia, according to the report.
The crude mortality rate for individuals with dementia was nearly 1,192 deaths per 10,000 person-years, compared with 232 deaths per 10,000 person-years for those with no dementia diagnosis, the investigators found.
Further analysis showed that factors independently associated with mortality in those with a dementia diagnosis included APOE genotype, dementia medication status, early-onset epilepsy, and presence of two or more comorbid conditions.
In a combined model, APOE genotype was significantly associated with mortality risk, they added.
Among the eight individuals with Down syndrome who died without a dementia diagnosis, one reportedly had early signs of cognitive decline, and two had late-onset epilepsy.
Late-onset epilepsy, identified in seven individuals (4.8%) with no dementia diagnosis in this study, was the only factor associated with mortality in individuals without dementia, conferring a 10-fold increase in risk of that outcome, according to the analysis.
“This raises the question of whether seizures can begin in the absence of other features of dementia in individuals with Down syndrome or whether these seven individuals had significant AD pathology and neurological symptoms but had yet to receive a formal dementia diagnosis,” the researchers wrote in a discussion of results.
The authors reported no conflict of interest disclosures related to the study. Their research was supported by UK National Institute for Health Research networks and participating National Health Services trusts, as well as a Wellcome Trust Strategic Award to the London Down Syndrome Consortium.
SOURCE: Hithersay R et al. JAMA Neurol. 2018 Nov 19. doi: 10.1001/jamaneurol.2018.3616
Adults with Down syndrome and dementia had a risk of death five times higher than those without dementia, according to results of a recent prospective study.
More than 70% of the individuals with Down syndrome who died over the course of follow-up had a clinical diagnosis of dementia in this longitudinal study of community dwelling participants, many of whom had factors associated with dementia such as the apolipoprotein E (APOE) genotype.
The findings of this study support an “urgent need” for clinical trials of treatment that might delay or prevent dementia in individuals with Down syndrome, said the investigators, led by Rosalyn Hithersay, MSc, of the department of forensic and neurodevelopmental sciences in the Institute of Psychiatry, Psychology, and Neuroscience at King’s College London (United Kingdom).
“We hope that our findings can improve clinical care by identifying factors associated with increased risk for dementia and mortality risk in this population, suggesting the potentially beneficial effects of existing medication options and helping clinicians provide prognostic information for their patients,” the authors wrote in JAMA Neurology.
The risk of dementia in individuals with Down syndrome has grown to “exceptional” levels, alongside a dramatic increase in life expectancy in these patients, from just 10 years of age some 50 years ago, to nearly 64 years today, investigators said.
Although other research has confirmed that dementia is frequently recorded as a contributory factor in Down syndrome deaths in recent years, this latest study provides crude mortality rates and exploratory analyses of factors that may modify mortality and dementia risk, according to the researchers.
Their study included 211 individuals with Down syndrome who were aged at least 36 years at study entry and followed for a total of 503.92 person-years, the investigators reported.
A total of 27 individuals died during follow-up, with a median age at death of 57 years; of those individuals, 19 (70.37%) had a clinical diagnosis of dementia, according to the report.
The crude mortality rate for individuals with dementia was nearly 1,192 deaths per 10,000 person-years, compared with 232 deaths per 10,000 person-years for those with no dementia diagnosis, the investigators found.
Further analysis showed that factors independently associated with mortality in those with a dementia diagnosis included APOE genotype, dementia medication status, early-onset epilepsy, and presence of two or more comorbid conditions.
In a combined model, APOE genotype was significantly associated with mortality risk, they added.
Among the eight individuals with Down syndrome who died without a dementia diagnosis, one reportedly had early signs of cognitive decline, and two had late-onset epilepsy.
Late-onset epilepsy, identified in seven individuals (4.8%) with no dementia diagnosis in this study, was the only factor associated with mortality in individuals without dementia, conferring a 10-fold increase in risk of that outcome, according to the analysis.
“This raises the question of whether seizures can begin in the absence of other features of dementia in individuals with Down syndrome or whether these seven individuals had significant AD pathology and neurological symptoms but had yet to receive a formal dementia diagnosis,” the researchers wrote in a discussion of results.
The authors reported no conflict of interest disclosures related to the study. Their research was supported by UK National Institute for Health Research networks and participating National Health Services trusts, as well as a Wellcome Trust Strategic Award to the London Down Syndrome Consortium.
SOURCE: Hithersay R et al. JAMA Neurol. 2018 Nov 19. doi: 10.1001/jamaneurol.2018.3616
FROM JAMA NEUROLOGY
Key clinical point: Adults with Down syndrome and dementia had a risk of death five times higher than those without dementia.
Major finding: The crude mortality rate for individuals with dementia versus those without dementia, respectively, was approximately 1,192 and 232 deaths per 10,000 person-years.
Study details: A prospective longitudinal study of 211 community-dwelling adults with Down syndrome in the United Kingdom.
Disclosures: Study authors reported no conflict of interest disclosures. The research was supported by National Institute for Health Research networks and participating National Health Services trusts, and a Wellcome Trust Strategic Award.
Source: Hithersay R et al. JAMA Neurol. 2018 Nov 19.
New HHS physical activity guidelines break fresh ground
CHICAGO – The newly released comprehensive second edition of the federal physical activity guidelines have a lofty goal.
Adm. Brett P. Giroir, MD, declared in introducing the recommendations at the American Heart Association scientific sessions.
“Physical activity is one of the most effective preventive health interventions available, and we need more emphasis on prevention as we transition to a value-based reimbursement structure that rewards better health maintenance and avoids chronic conditions,” added Adm. Giroir, assistant secretary for health at the U.S. Department of Health & Human Services.
Although the agency opted to unveil the new guidelines before an audience of cardiologists at the AHA scientific sessions, the report includes sections relevant for a wide range of medical specialists, including primary care physicians, pediatricians, psychiatrists, neurologists, endocrinologists, and geriatricians.
Before launching into a description of what’s new in the second edition, Adm. Giroir set the stage with blunt talk about the nation’s poor state of physical fitness.
“Inactivity causes 10% of premature mortality in the United States. That means if we can just get 25% of inactive people to be active and meet the recommendations, almost 75,000 deaths per year would be prevented in the United States. And on an even larger scale worldwide, if 25% of those same people who are inactive started moving and met the guidelines, more than 1.3 million deaths would be prevented,” according to Adm. Giroir.
At present, only 26% of men, 19% of women, and 20% of teenagers meet the physical activity recommendations.
Failure to meet the federal aerobic physical activity recommendations accounts for an estimated nearly $117 billion in annual health care costs. And it poses a national security threat, too: Nearly one-third of all 17- to 24-year-olds are disqualified from military service because of obesity. Even more eye-opening, he continued, is that fully 71% of all 17- to 24-year-olds are ineligible for military service because of obesity, lack of physical fitness, lack of education, or substance use.
The actual recommendations contained in the second edition of the Physical Activity Guidelines for Americans remain unchanged from those in the first, issued a decade earlier. That is, in order to gain substantial health benefits, adults and adolescents should engage in at least 150-300 min/week of moderate intensity aerobic physical activity or 75-150 min/week of vigorous intensity aerobic activity. Plus they should do muscle-strengthening exercises such as weight lifting or push-ups at moderate or greater intensity at least 2 days/week.
Asked why the guidelines are sticking with time-based physical activity recommendations in an era when popular smartwatches and other mobile devices can readily spit out number of steps walked, calories burned, and heart-rate data, cardiologist William E. Kraus, MD, one of the 17 members of the scientific advisory committee who reviewed and graded the scientific evidence on physical activity, sedentary behavior, and health, answered. He said the group’s careful review concluded that “there’s just not enough evidence at this time to make a recommendation” with regard to mobile device–based measurements of physical activity and their relationship with health benefits.
“We’re hoping to spur more research in this area, so that the next time we make recommendations, that can be incorporated,” added Dr. Kraus, a professor of medicine and cardiologist at Duke University, Durham, N.C., as well as president-elect of the American College of Sports Medicine.
What’s new in the guidelines
“This edition tells us that it’s easier to meet the recommendations in the physical activity guidelines,” according to Adm. Giroir. “The new guidelines demonstrate, based on the best science, everyone can dramatically improve their health just by moving: anytime, anywhere, and by any means that gets you active.” He broke the guidelines down as follows:
- We have new evidence about the risks of sedentary behavior, and new evidence that any amount – any amount – of moderate to vigorous physical activity, like walking, dancing, line dancing if you’re from Texas, and household chores is beneficial,” Adm. Giroir observed.
- While the first edition of the federal guidelines cited strong evidence that physical activity reduces the risk of two types of cancer, breast and colon, the intervening decade has brought forth strong evidence of a protective effect against an additional six types of cancer: bladder, endometrial, kidney, stomach, esophageal, and lung cancer.
- The guidelines formulate for the first time physical activity standards for children aged 3-5 years. The recommended target is at least 3 hr/day of varied physical activity, consistent with existing guidelines in Australia Canada, and the United Kingdom.
- Updated recommendations for children aged 6-17 years call for an hour or more/day of moderate- or vigorous-intensity physical activity on a daily basis, with that activity level falling within the vigorous category on at least 3 days/week. Plus, it recommends bone- and muscle-strengthening activity on at least 3 days.
- The pediatric guidelines are linked to a planned HHS national strategy to expand children’s participation in youth sports as part of an effort to curb childhood obesity, rates of which have more than tripled since the 1970s.
“We’ll soon announce funding opportunities for communities to increase participation in sports among children and teens through participation in affordable programs with trained coaches,” said Dr. Giroir, a pediatrician.
The new guidelines endorse what is called “the comprehensive school physical activity model.”
“I strongly believe our schools should take action to implement this approach. There is a lot of interest right now to affect change in the schools across our country. Part of the answer, I think, is to provide kids with high-quality physical education, but I think we recognize that alone will not be enough.” The comprehensive school activity model calls for not only enriching school PE programs but also incorporating active transport to school, classroom activity, active learning, and after school programs – activity in all settings during the school day. “I’m very hopeful that this model, which is endorsed in the guidelines document, will be widely adopted by schools in this country over the next decade,” Dr. Giroir said.
The first edition declared that only bouts of physical activity of at least 10 minutes duration should count toward meeting the guidelines. That requirement is gone in the second edition. It was an impediment to being active, and upon close examination it wasn’t based on scientific evidence. That means taking the stairs instead of the escalator or parking farther away from the store count toward the weekly physical activity goal, Dr. Kraus said.
“It makes it easier to achieve the guidelines and to encourage Americans to move more and sit less just by making a better choice at many times during the day,” observed Dr. Giroir, a four-star admiral in the U.S. Public Health Service Commissioned Corps.
The latest guidelines contain up-to-date information on the benefits of regular physical activity in terms of brain health, including reduced risk of developing Alzheimer’s disease, and improved cognition, including performance on academic achievement tests and measures of executive function, memory, and processing speed, in preadolescent children as well as older adults. Solid evidence also is cited for improved cognition in patients with MS, dementia, ADHD, and Parkinson’s disease.
The guidelines provide new recommendations for physical activity for women during pregnancy and post partum.
A section of the guidelines is devoted to proven evidence-based strategies to promote physical activity at the individual, small group, and community level.
Physicians now have a resource to aid them in prescribing an individualized physical activity prescription for their patients with existing health conditions, including osteoarthritis, type 2 diabetes, cancer survivors, and physical disabilities.
The new physical activity guidelines and related resources for health care professionals are available at the Health.gov website.
SOURCE: Giroir BP. AHA Scientific Sessions, Session ME.05.
CHICAGO – The newly released comprehensive second edition of the federal physical activity guidelines have a lofty goal.
Adm. Brett P. Giroir, MD, declared in introducing the recommendations at the American Heart Association scientific sessions.
“Physical activity is one of the most effective preventive health interventions available, and we need more emphasis on prevention as we transition to a value-based reimbursement structure that rewards better health maintenance and avoids chronic conditions,” added Adm. Giroir, assistant secretary for health at the U.S. Department of Health & Human Services.
Although the agency opted to unveil the new guidelines before an audience of cardiologists at the AHA scientific sessions, the report includes sections relevant for a wide range of medical specialists, including primary care physicians, pediatricians, psychiatrists, neurologists, endocrinologists, and geriatricians.
Before launching into a description of what’s new in the second edition, Adm. Giroir set the stage with blunt talk about the nation’s poor state of physical fitness.
“Inactivity causes 10% of premature mortality in the United States. That means if we can just get 25% of inactive people to be active and meet the recommendations, almost 75,000 deaths per year would be prevented in the United States. And on an even larger scale worldwide, if 25% of those same people who are inactive started moving and met the guidelines, more than 1.3 million deaths would be prevented,” according to Adm. Giroir.
At present, only 26% of men, 19% of women, and 20% of teenagers meet the physical activity recommendations.
Failure to meet the federal aerobic physical activity recommendations accounts for an estimated nearly $117 billion in annual health care costs. And it poses a national security threat, too: Nearly one-third of all 17- to 24-year-olds are disqualified from military service because of obesity. Even more eye-opening, he continued, is that fully 71% of all 17- to 24-year-olds are ineligible for military service because of obesity, lack of physical fitness, lack of education, or substance use.
The actual recommendations contained in the second edition of the Physical Activity Guidelines for Americans remain unchanged from those in the first, issued a decade earlier. That is, in order to gain substantial health benefits, adults and adolescents should engage in at least 150-300 min/week of moderate intensity aerobic physical activity or 75-150 min/week of vigorous intensity aerobic activity. Plus they should do muscle-strengthening exercises such as weight lifting or push-ups at moderate or greater intensity at least 2 days/week.
Asked why the guidelines are sticking with time-based physical activity recommendations in an era when popular smartwatches and other mobile devices can readily spit out number of steps walked, calories burned, and heart-rate data, cardiologist William E. Kraus, MD, one of the 17 members of the scientific advisory committee who reviewed and graded the scientific evidence on physical activity, sedentary behavior, and health, answered. He said the group’s careful review concluded that “there’s just not enough evidence at this time to make a recommendation” with regard to mobile device–based measurements of physical activity and their relationship with health benefits.
“We’re hoping to spur more research in this area, so that the next time we make recommendations, that can be incorporated,” added Dr. Kraus, a professor of medicine and cardiologist at Duke University, Durham, N.C., as well as president-elect of the American College of Sports Medicine.
What’s new in the guidelines
“This edition tells us that it’s easier to meet the recommendations in the physical activity guidelines,” according to Adm. Giroir. “The new guidelines demonstrate, based on the best science, everyone can dramatically improve their health just by moving: anytime, anywhere, and by any means that gets you active.” He broke the guidelines down as follows:
- We have new evidence about the risks of sedentary behavior, and new evidence that any amount – any amount – of moderate to vigorous physical activity, like walking, dancing, line dancing if you’re from Texas, and household chores is beneficial,” Adm. Giroir observed.
- While the first edition of the federal guidelines cited strong evidence that physical activity reduces the risk of two types of cancer, breast and colon, the intervening decade has brought forth strong evidence of a protective effect against an additional six types of cancer: bladder, endometrial, kidney, stomach, esophageal, and lung cancer.
- The guidelines formulate for the first time physical activity standards for children aged 3-5 years. The recommended target is at least 3 hr/day of varied physical activity, consistent with existing guidelines in Australia Canada, and the United Kingdom.
- Updated recommendations for children aged 6-17 years call for an hour or more/day of moderate- or vigorous-intensity physical activity on a daily basis, with that activity level falling within the vigorous category on at least 3 days/week. Plus, it recommends bone- and muscle-strengthening activity on at least 3 days.
- The pediatric guidelines are linked to a planned HHS national strategy to expand children’s participation in youth sports as part of an effort to curb childhood obesity, rates of which have more than tripled since the 1970s.
“We’ll soon announce funding opportunities for communities to increase participation in sports among children and teens through participation in affordable programs with trained coaches,” said Dr. Giroir, a pediatrician.
The new guidelines endorse what is called “the comprehensive school physical activity model.”
“I strongly believe our schools should take action to implement this approach. There is a lot of interest right now to affect change in the schools across our country. Part of the answer, I think, is to provide kids with high-quality physical education, but I think we recognize that alone will not be enough.” The comprehensive school activity model calls for not only enriching school PE programs but also incorporating active transport to school, classroom activity, active learning, and after school programs – activity in all settings during the school day. “I’m very hopeful that this model, which is endorsed in the guidelines document, will be widely adopted by schools in this country over the next decade,” Dr. Giroir said.
The first edition declared that only bouts of physical activity of at least 10 minutes duration should count toward meeting the guidelines. That requirement is gone in the second edition. It was an impediment to being active, and upon close examination it wasn’t based on scientific evidence. That means taking the stairs instead of the escalator or parking farther away from the store count toward the weekly physical activity goal, Dr. Kraus said.
“It makes it easier to achieve the guidelines and to encourage Americans to move more and sit less just by making a better choice at many times during the day,” observed Dr. Giroir, a four-star admiral in the U.S. Public Health Service Commissioned Corps.
The latest guidelines contain up-to-date information on the benefits of regular physical activity in terms of brain health, including reduced risk of developing Alzheimer’s disease, and improved cognition, including performance on academic achievement tests and measures of executive function, memory, and processing speed, in preadolescent children as well as older adults. Solid evidence also is cited for improved cognition in patients with MS, dementia, ADHD, and Parkinson’s disease.
The guidelines provide new recommendations for physical activity for women during pregnancy and post partum.
A section of the guidelines is devoted to proven evidence-based strategies to promote physical activity at the individual, small group, and community level.
Physicians now have a resource to aid them in prescribing an individualized physical activity prescription for their patients with existing health conditions, including osteoarthritis, type 2 diabetes, cancer survivors, and physical disabilities.
The new physical activity guidelines and related resources for health care professionals are available at the Health.gov website.
SOURCE: Giroir BP. AHA Scientific Sessions, Session ME.05.
CHICAGO – The newly released comprehensive second edition of the federal physical activity guidelines have a lofty goal.
Adm. Brett P. Giroir, MD, declared in introducing the recommendations at the American Heart Association scientific sessions.
“Physical activity is one of the most effective preventive health interventions available, and we need more emphasis on prevention as we transition to a value-based reimbursement structure that rewards better health maintenance and avoids chronic conditions,” added Adm. Giroir, assistant secretary for health at the U.S. Department of Health & Human Services.
Although the agency opted to unveil the new guidelines before an audience of cardiologists at the AHA scientific sessions, the report includes sections relevant for a wide range of medical specialists, including primary care physicians, pediatricians, psychiatrists, neurologists, endocrinologists, and geriatricians.
Before launching into a description of what’s new in the second edition, Adm. Giroir set the stage with blunt talk about the nation’s poor state of physical fitness.
“Inactivity causes 10% of premature mortality in the United States. That means if we can just get 25% of inactive people to be active and meet the recommendations, almost 75,000 deaths per year would be prevented in the United States. And on an even larger scale worldwide, if 25% of those same people who are inactive started moving and met the guidelines, more than 1.3 million deaths would be prevented,” according to Adm. Giroir.
At present, only 26% of men, 19% of women, and 20% of teenagers meet the physical activity recommendations.
Failure to meet the federal aerobic physical activity recommendations accounts for an estimated nearly $117 billion in annual health care costs. And it poses a national security threat, too: Nearly one-third of all 17- to 24-year-olds are disqualified from military service because of obesity. Even more eye-opening, he continued, is that fully 71% of all 17- to 24-year-olds are ineligible for military service because of obesity, lack of physical fitness, lack of education, or substance use.
The actual recommendations contained in the second edition of the Physical Activity Guidelines for Americans remain unchanged from those in the first, issued a decade earlier. That is, in order to gain substantial health benefits, adults and adolescents should engage in at least 150-300 min/week of moderate intensity aerobic physical activity or 75-150 min/week of vigorous intensity aerobic activity. Plus they should do muscle-strengthening exercises such as weight lifting or push-ups at moderate or greater intensity at least 2 days/week.
Asked why the guidelines are sticking with time-based physical activity recommendations in an era when popular smartwatches and other mobile devices can readily spit out number of steps walked, calories burned, and heart-rate data, cardiologist William E. Kraus, MD, one of the 17 members of the scientific advisory committee who reviewed and graded the scientific evidence on physical activity, sedentary behavior, and health, answered. He said the group’s careful review concluded that “there’s just not enough evidence at this time to make a recommendation” with regard to mobile device–based measurements of physical activity and their relationship with health benefits.
“We’re hoping to spur more research in this area, so that the next time we make recommendations, that can be incorporated,” added Dr. Kraus, a professor of medicine and cardiologist at Duke University, Durham, N.C., as well as president-elect of the American College of Sports Medicine.
What’s new in the guidelines
“This edition tells us that it’s easier to meet the recommendations in the physical activity guidelines,” according to Adm. Giroir. “The new guidelines demonstrate, based on the best science, everyone can dramatically improve their health just by moving: anytime, anywhere, and by any means that gets you active.” He broke the guidelines down as follows:
- We have new evidence about the risks of sedentary behavior, and new evidence that any amount – any amount – of moderate to vigorous physical activity, like walking, dancing, line dancing if you’re from Texas, and household chores is beneficial,” Adm. Giroir observed.
- While the first edition of the federal guidelines cited strong evidence that physical activity reduces the risk of two types of cancer, breast and colon, the intervening decade has brought forth strong evidence of a protective effect against an additional six types of cancer: bladder, endometrial, kidney, stomach, esophageal, and lung cancer.
- The guidelines formulate for the first time physical activity standards for children aged 3-5 years. The recommended target is at least 3 hr/day of varied physical activity, consistent with existing guidelines in Australia Canada, and the United Kingdom.
- Updated recommendations for children aged 6-17 years call for an hour or more/day of moderate- or vigorous-intensity physical activity on a daily basis, with that activity level falling within the vigorous category on at least 3 days/week. Plus, it recommends bone- and muscle-strengthening activity on at least 3 days.
- The pediatric guidelines are linked to a planned HHS national strategy to expand children’s participation in youth sports as part of an effort to curb childhood obesity, rates of which have more than tripled since the 1970s.
“We’ll soon announce funding opportunities for communities to increase participation in sports among children and teens through participation in affordable programs with trained coaches,” said Dr. Giroir, a pediatrician.
The new guidelines endorse what is called “the comprehensive school physical activity model.”
“I strongly believe our schools should take action to implement this approach. There is a lot of interest right now to affect change in the schools across our country. Part of the answer, I think, is to provide kids with high-quality physical education, but I think we recognize that alone will not be enough.” The comprehensive school activity model calls for not only enriching school PE programs but also incorporating active transport to school, classroom activity, active learning, and after school programs – activity in all settings during the school day. “I’m very hopeful that this model, which is endorsed in the guidelines document, will be widely adopted by schools in this country over the next decade,” Dr. Giroir said.
The first edition declared that only bouts of physical activity of at least 10 minutes duration should count toward meeting the guidelines. That requirement is gone in the second edition. It was an impediment to being active, and upon close examination it wasn’t based on scientific evidence. That means taking the stairs instead of the escalator or parking farther away from the store count toward the weekly physical activity goal, Dr. Kraus said.
“It makes it easier to achieve the guidelines and to encourage Americans to move more and sit less just by making a better choice at many times during the day,” observed Dr. Giroir, a four-star admiral in the U.S. Public Health Service Commissioned Corps.
The latest guidelines contain up-to-date information on the benefits of regular physical activity in terms of brain health, including reduced risk of developing Alzheimer’s disease, and improved cognition, including performance on academic achievement tests and measures of executive function, memory, and processing speed, in preadolescent children as well as older adults. Solid evidence also is cited for improved cognition in patients with MS, dementia, ADHD, and Parkinson’s disease.
The guidelines provide new recommendations for physical activity for women during pregnancy and post partum.
A section of the guidelines is devoted to proven evidence-based strategies to promote physical activity at the individual, small group, and community level.
Physicians now have a resource to aid them in prescribing an individualized physical activity prescription for their patients with existing health conditions, including osteoarthritis, type 2 diabetes, cancer survivors, and physical disabilities.
The new physical activity guidelines and related resources for health care professionals are available at the Health.gov website.
SOURCE: Giroir BP. AHA Scientific Sessions, Session ME.05.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Robin Williams’ widow recounts ‘terror’ of late husband’s Lewy body dementia
ATLANTA –
“With our medical team’s care, for the next 10 months we chased symptoms, but they were so elusive,” Mr. Williams’ widow, Susan Schneider Williams, said during a keynote address at the annual meeting of the American Neurological Association. “One hallmark of LBD is that symptoms appear and disappear randomly. The game whack-a-mole comes to mind. As soon as you think you are about to figure out a symptom, it disappears, and another one pops up.”
Mr. Williams’ medical team included one general physician, one neurologist, one motor specialist, two psychiatrists, one hypnotherapist, one physical trainer, and assorted alternative specialists. “We had been celebrating our second wedding anniversary when Robin started having gut discomfort,” Ms. Williams recalled. “He was tested for diverticulitis [but] the results came back negative. The pain eventually subsided but what was alarming was Robin’s reaction to it. He had a sudden and sustained spike in fear and anxiety unlike anything I’d seen before. By that point, we’d been by each other’s side long enough that I knew his normal baseline moods, fears, and anxieties. This was totally out of character, and I wondered privately: ‘Is my husband a hypochondriac?’ What I know now is that he was exhibiting a notable hallmark of LBD: new onset anxiety, sustained.” Lewy body disease is characterized by more than 40 symptoms, she continued, “and Robin experienced nearly all of them. He was particularly debilitated by fear, anxiety, delusions, paranoia, and as I came to find out later, hallucinations.”
The medical team continued running all sorts of tests, but everything kept came back negative, except for a very high cortisol count. By the late spring of 2014, however, Mr. Williams was diagnosed with Parkinson’s disease. “I was relieved to find out we finally had an answer, but I could tell, Robin was not buying it,” said Ms. Williams, who is a California-based fine artist, author, and brain health advocate. “The motor specialist said it was early and mild and that he’d be feeling better once he adjusted to the medications, [that] he had another 10 good years.”
In an attempt to treat the Parkinson’s and what was assumed to be depression, his care plan involved adjusting Parkinson’s medications, combined with an antidepressant. His physician also recommended a visit to the Dan Anderson Renewal Center in Minnesota, “for enhanced 12-step work to augment his sobriety,” Ms. Williams said. “The hope was this might help with fear and anxiety. Robin was clean and sober for 8 continuous years when he passed. I watched how he gained spiritually in so many ways from all the work he’d been doing, but his brain biology was going in the exact opposite direction. He tried desperately to join the parts of his heart, mind, and spirit, but his brain was pulling him apart. I felt like I was watching my husband disintegrate before my eyes, and there was nothing anyone could do about it. There came a day when we were getting ready to go to one of our dear friend’s birthday party. I came and saw Robin as he lay on our bed, imprisoned by fear and anxiety. Through tears, he pleaded, ‘I just want to reboot my brain!’ I promised him, ‘I know, honey. I swear we’re going to get to the bottom of this.’ ”
The couple was about a week away from choosing which neurocognitive testing facility to go to for further evaluation when Mr. Williams took his own life in his Paradise Cay, Calif., home on Aug. 11, 2014. “Robin was exhausted from the terror coming from his brain,” Ms. Williams said. “He took [his own life] before it could take any more of him.”
About 3 months later, the underlying cause of death was revealed: diffuse Lewy body dementia, “one of the worst cases they’d ever seen,” she said. “Because Robin’s disease pathway was extreme and unfolded the way it did, it highlights quite strikingly this disease spectrum. He had a perfusion of Lewy bodies, the essential underlying shared biology between Parkinson’s and Lewy body disease, scattered throughout his entire brain and brain stem.” She added that her husband’s prior history of depression from earlier in life “added to the challenge of getting a proper diagnosis. That single symptom of depression was being treated as its own illness, rather than part of the larger neurocognitive disease. It seems that one of the biggest challenges to getting an accurate diagnosis is that LBD symptoms have tremendous crossover with normal human psychology and behavior, mood, cognition and sleep issues. All of us experience fear, stress, anxiety, paranoia, trouble sleeping, mild depression, and other issues from time to time. We would hardly be human if we didn’t. The challenge of LBD is seeing the giant constellation that it is, rather than just a few of its stars.”
In early 2016, Ms. Williams received the “Commitment to Cures Award” from American Brain Foundation, honoring work she’s done raising awareness for Lewy body disease since her husband’s death. “The day I accepted that award and told our story to a room full of neurologists, my path was forever changed,” she said. “The ABF’s mission of connecting donors to researchers and curing brain disease was an alignment with my mission and hope.” She currently serves as vice chair of the ABF’s board of directors.
“From my own research and from the myriad of letters and information that has come to me, I have distilled what I think are the top three overlooked ideas in this disease space,” Ms. Williams said. “1. Diagnosis: The norm seems to be misdiagnosis, switched diagnosis, or no diagnosis at all. 2. Symptoms: They are being treated independently, apart from the neurological disorder. 3. Suicides: If more autopsies were done, more suicides would be attributed to this disease.”
She concluded her address by reflecting on the impact of her husband’s death has had in bringing an international spotlight to LBD. “When I meet individuals who have lost someone they loved to LBD, I see the pain in their eyes, but I hear the determination in their voice as they chart their own course toward making a difference,” Ms. Williams said. “I have been blessed to learn over and over again that I am not alone. I believe that Robin’s death in this battle against these diseases holds a profound purpose. There was tremendous power in what he suffered, and I saw that power up close. I’m here doing all that I can to see that power transformed into something good.”
ATLANTA –
“With our medical team’s care, for the next 10 months we chased symptoms, but they were so elusive,” Mr. Williams’ widow, Susan Schneider Williams, said during a keynote address at the annual meeting of the American Neurological Association. “One hallmark of LBD is that symptoms appear and disappear randomly. The game whack-a-mole comes to mind. As soon as you think you are about to figure out a symptom, it disappears, and another one pops up.”
Mr. Williams’ medical team included one general physician, one neurologist, one motor specialist, two psychiatrists, one hypnotherapist, one physical trainer, and assorted alternative specialists. “We had been celebrating our second wedding anniversary when Robin started having gut discomfort,” Ms. Williams recalled. “He was tested for diverticulitis [but] the results came back negative. The pain eventually subsided but what was alarming was Robin’s reaction to it. He had a sudden and sustained spike in fear and anxiety unlike anything I’d seen before. By that point, we’d been by each other’s side long enough that I knew his normal baseline moods, fears, and anxieties. This was totally out of character, and I wondered privately: ‘Is my husband a hypochondriac?’ What I know now is that he was exhibiting a notable hallmark of LBD: new onset anxiety, sustained.” Lewy body disease is characterized by more than 40 symptoms, she continued, “and Robin experienced nearly all of them. He was particularly debilitated by fear, anxiety, delusions, paranoia, and as I came to find out later, hallucinations.”
The medical team continued running all sorts of tests, but everything kept came back negative, except for a very high cortisol count. By the late spring of 2014, however, Mr. Williams was diagnosed with Parkinson’s disease. “I was relieved to find out we finally had an answer, but I could tell, Robin was not buying it,” said Ms. Williams, who is a California-based fine artist, author, and brain health advocate. “The motor specialist said it was early and mild and that he’d be feeling better once he adjusted to the medications, [that] he had another 10 good years.”
In an attempt to treat the Parkinson’s and what was assumed to be depression, his care plan involved adjusting Parkinson’s medications, combined with an antidepressant. His physician also recommended a visit to the Dan Anderson Renewal Center in Minnesota, “for enhanced 12-step work to augment his sobriety,” Ms. Williams said. “The hope was this might help with fear and anxiety. Robin was clean and sober for 8 continuous years when he passed. I watched how he gained spiritually in so many ways from all the work he’d been doing, but his brain biology was going in the exact opposite direction. He tried desperately to join the parts of his heart, mind, and spirit, but his brain was pulling him apart. I felt like I was watching my husband disintegrate before my eyes, and there was nothing anyone could do about it. There came a day when we were getting ready to go to one of our dear friend’s birthday party. I came and saw Robin as he lay on our bed, imprisoned by fear and anxiety. Through tears, he pleaded, ‘I just want to reboot my brain!’ I promised him, ‘I know, honey. I swear we’re going to get to the bottom of this.’ ”
The couple was about a week away from choosing which neurocognitive testing facility to go to for further evaluation when Mr. Williams took his own life in his Paradise Cay, Calif., home on Aug. 11, 2014. “Robin was exhausted from the terror coming from his brain,” Ms. Williams said. “He took [his own life] before it could take any more of him.”
About 3 months later, the underlying cause of death was revealed: diffuse Lewy body dementia, “one of the worst cases they’d ever seen,” she said. “Because Robin’s disease pathway was extreme and unfolded the way it did, it highlights quite strikingly this disease spectrum. He had a perfusion of Lewy bodies, the essential underlying shared biology between Parkinson’s and Lewy body disease, scattered throughout his entire brain and brain stem.” She added that her husband’s prior history of depression from earlier in life “added to the challenge of getting a proper diagnosis. That single symptom of depression was being treated as its own illness, rather than part of the larger neurocognitive disease. It seems that one of the biggest challenges to getting an accurate diagnosis is that LBD symptoms have tremendous crossover with normal human psychology and behavior, mood, cognition and sleep issues. All of us experience fear, stress, anxiety, paranoia, trouble sleeping, mild depression, and other issues from time to time. We would hardly be human if we didn’t. The challenge of LBD is seeing the giant constellation that it is, rather than just a few of its stars.”
In early 2016, Ms. Williams received the “Commitment to Cures Award” from American Brain Foundation, honoring work she’s done raising awareness for Lewy body disease since her husband’s death. “The day I accepted that award and told our story to a room full of neurologists, my path was forever changed,” she said. “The ABF’s mission of connecting donors to researchers and curing brain disease was an alignment with my mission and hope.” She currently serves as vice chair of the ABF’s board of directors.
“From my own research and from the myriad of letters and information that has come to me, I have distilled what I think are the top three overlooked ideas in this disease space,” Ms. Williams said. “1. Diagnosis: The norm seems to be misdiagnosis, switched diagnosis, or no diagnosis at all. 2. Symptoms: They are being treated independently, apart from the neurological disorder. 3. Suicides: If more autopsies were done, more suicides would be attributed to this disease.”
She concluded her address by reflecting on the impact of her husband’s death has had in bringing an international spotlight to LBD. “When I meet individuals who have lost someone they loved to LBD, I see the pain in their eyes, but I hear the determination in their voice as they chart their own course toward making a difference,” Ms. Williams said. “I have been blessed to learn over and over again that I am not alone. I believe that Robin’s death in this battle against these diseases holds a profound purpose. There was tremendous power in what he suffered, and I saw that power up close. I’m here doing all that I can to see that power transformed into something good.”
ATLANTA –
“With our medical team’s care, for the next 10 months we chased symptoms, but they were so elusive,” Mr. Williams’ widow, Susan Schneider Williams, said during a keynote address at the annual meeting of the American Neurological Association. “One hallmark of LBD is that symptoms appear and disappear randomly. The game whack-a-mole comes to mind. As soon as you think you are about to figure out a symptom, it disappears, and another one pops up.”
Mr. Williams’ medical team included one general physician, one neurologist, one motor specialist, two psychiatrists, one hypnotherapist, one physical trainer, and assorted alternative specialists. “We had been celebrating our second wedding anniversary when Robin started having gut discomfort,” Ms. Williams recalled. “He was tested for diverticulitis [but] the results came back negative. The pain eventually subsided but what was alarming was Robin’s reaction to it. He had a sudden and sustained spike in fear and anxiety unlike anything I’d seen before. By that point, we’d been by each other’s side long enough that I knew his normal baseline moods, fears, and anxieties. This was totally out of character, and I wondered privately: ‘Is my husband a hypochondriac?’ What I know now is that he was exhibiting a notable hallmark of LBD: new onset anxiety, sustained.” Lewy body disease is characterized by more than 40 symptoms, she continued, “and Robin experienced nearly all of them. He was particularly debilitated by fear, anxiety, delusions, paranoia, and as I came to find out later, hallucinations.”
The medical team continued running all sorts of tests, but everything kept came back negative, except for a very high cortisol count. By the late spring of 2014, however, Mr. Williams was diagnosed with Parkinson’s disease. “I was relieved to find out we finally had an answer, but I could tell, Robin was not buying it,” said Ms. Williams, who is a California-based fine artist, author, and brain health advocate. “The motor specialist said it was early and mild and that he’d be feeling better once he adjusted to the medications, [that] he had another 10 good years.”
In an attempt to treat the Parkinson’s and what was assumed to be depression, his care plan involved adjusting Parkinson’s medications, combined with an antidepressant. His physician also recommended a visit to the Dan Anderson Renewal Center in Minnesota, “for enhanced 12-step work to augment his sobriety,” Ms. Williams said. “The hope was this might help with fear and anxiety. Robin was clean and sober for 8 continuous years when he passed. I watched how he gained spiritually in so many ways from all the work he’d been doing, but his brain biology was going in the exact opposite direction. He tried desperately to join the parts of his heart, mind, and spirit, but his brain was pulling him apart. I felt like I was watching my husband disintegrate before my eyes, and there was nothing anyone could do about it. There came a day when we were getting ready to go to one of our dear friend’s birthday party. I came and saw Robin as he lay on our bed, imprisoned by fear and anxiety. Through tears, he pleaded, ‘I just want to reboot my brain!’ I promised him, ‘I know, honey. I swear we’re going to get to the bottom of this.’ ”
The couple was about a week away from choosing which neurocognitive testing facility to go to for further evaluation when Mr. Williams took his own life in his Paradise Cay, Calif., home on Aug. 11, 2014. “Robin was exhausted from the terror coming from his brain,” Ms. Williams said. “He took [his own life] before it could take any more of him.”
About 3 months later, the underlying cause of death was revealed: diffuse Lewy body dementia, “one of the worst cases they’d ever seen,” she said. “Because Robin’s disease pathway was extreme and unfolded the way it did, it highlights quite strikingly this disease spectrum. He had a perfusion of Lewy bodies, the essential underlying shared biology between Parkinson’s and Lewy body disease, scattered throughout his entire brain and brain stem.” She added that her husband’s prior history of depression from earlier in life “added to the challenge of getting a proper diagnosis. That single symptom of depression was being treated as its own illness, rather than part of the larger neurocognitive disease. It seems that one of the biggest challenges to getting an accurate diagnosis is that LBD symptoms have tremendous crossover with normal human psychology and behavior, mood, cognition and sleep issues. All of us experience fear, stress, anxiety, paranoia, trouble sleeping, mild depression, and other issues from time to time. We would hardly be human if we didn’t. The challenge of LBD is seeing the giant constellation that it is, rather than just a few of its stars.”
In early 2016, Ms. Williams received the “Commitment to Cures Award” from American Brain Foundation, honoring work she’s done raising awareness for Lewy body disease since her husband’s death. “The day I accepted that award and told our story to a room full of neurologists, my path was forever changed,” she said. “The ABF’s mission of connecting donors to researchers and curing brain disease was an alignment with my mission and hope.” She currently serves as vice chair of the ABF’s board of directors.
“From my own research and from the myriad of letters and information that has come to me, I have distilled what I think are the top three overlooked ideas in this disease space,” Ms. Williams said. “1. Diagnosis: The norm seems to be misdiagnosis, switched diagnosis, or no diagnosis at all. 2. Symptoms: They are being treated independently, apart from the neurological disorder. 3. Suicides: If more autopsies were done, more suicides would be attributed to this disease.”
She concluded her address by reflecting on the impact of her husband’s death has had in bringing an international spotlight to LBD. “When I meet individuals who have lost someone they loved to LBD, I see the pain in their eyes, but I hear the determination in their voice as they chart their own course toward making a difference,” Ms. Williams said. “I have been blessed to learn over and over again that I am not alone. I believe that Robin’s death in this battle against these diseases holds a profound purpose. There was tremendous power in what he suffered, and I saw that power up close. I’m here doing all that I can to see that power transformed into something good.”
REPORTING FROM ANA 2018
Cognitive and Behavioral Problems Increase With ALS Disease Stage
Data raise the question of whether cognitive and behavioral change should be included in ALS diagnostic criteria.
Cognitive deficits and behavioral symptoms that are specific to amyotrophic lateral sclerosis (ALS) occur more frequently as the disease progresses, according to research published online ahead of print September 12 in Neurology. Few patients are free of neuropsychologic impairment when they reach the final stage of the disease. It might be appropriate to include cognitive and behavioral change in the diagnostic criteria and future staging systems for ALS, said the authors.
In 2013, Elamin et al suggested that cognitive change in ALS may be associated with indirect measures of disease progression, such as total score on the ALS Functional Rating Scale-Revised. Christopher Crockford, PhD, a researcher at the University of Edinburgh, and colleagues sought to determine whether the cognitive and behavioral symptoms in ALS were more prevalent at more advanced stages of disease. 
The Role of Letter Fluency Impairment
They conducted a multicenter, cross-sectional, observational study that included 161 patients from Edinburgh, Dublin, and London with possible, probable, or definite ALS, according to revised El Escorial diagnostic criteria. The researchers also recruited 80 healthy, matched controls. Through interviews, Dr. Crockford and colleagues elicited demographic and clinical data. They measured participants’ clinical staging with the King’s Clinical Staging System and neuropsychologic status with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS).
The investigators did not observe significant differences between the patient and control groups in background variables. Approximately 67% of patients with ALS were male, compared with 60% of controls. Mean age at testing was approximately 61 in both groups. Among patients with ALS, 40 were in Stage 1, 45 were in Stage 2, 22 were in Stage 3, and 54 were in Stage 4.
Compared with controls, patients with ALS had significantly worse cognitive performance on all domains of the ECAS except visuospatial functioning. Dr. Crockford’s group found a significant cross-sectional effect across disease stages for ALS-specific functions (eg, executive, language, and letter fluency) and ECAS total score. They did not find a similar effect for ALS-nonspecific functions (eg, memory and visuospatial). In addition, rates of ALS-specific impairment and behavioral change increased with increasing disease stage.
Letter fluency impairment may explain the relationship between cognitive function and disease stage, said the authors. They observed higher rates of all behavioral problems in later King’s stages. Bulbar signs were significantly related to ALS-specific scores, ECAS total score, and behavioral scores. Site of onset was not related to these scores, however.
Intervention programs to alleviate the effect of patients’ neuropsychologic impairment on caregivers may be appropriate, said the authors. “Furthermore, clinicians should be cognizant of current neuropsychologic status when prescribing life-prolonging interventions to patients and implement support structures for those with a neuropsychologic impairment,” they added.
Informing Patients and Caregivers
Although Dr. Crockford and colleagues focused on the behavioral and cognitive effects of ALS, the disease may affect mental health as well, said Paul Wicks, PhD, Vice President of Innovation at PatientsLikeMe in Cambridge, Massachusetts, and Steven M. Albert, PhD, Professor and Chair of Behavioral and Community Health Sciences at the University of Pittsburgh, in an accompanying editorial. The data show that the rates of major depression and depressed mood increase with increasing disease stage.
Drs. Wicks and Albert cited a survey in which 90% of patients and caregivers reported that their doctors had not told them that cognitive or psychologic symptoms can arise in ALS. “In our experience, colleagues report keeping the information from patients in order to spare them further distress,” they said. Yet most respondents to this survey reported that they would have liked to have been informed about these symptoms.
“Educating patients and caregivers that cognitive change is a part of ALS should be no different from similar discussions to be had in multiple sclerosis, Parkinson disease, and a range of other conditions,” said Drs. Wicks and Albert. “Keeping the truth from patients and caregivers is not protective; it is paternalistic, and it is time to stop. Only by facing up to the hard truth that one of the most dreaded conditions in medicine is even worse than we previously acknowledged can we take stock, marshal our resources, and make renewed plans to defeat our common enemy.”
Suggested Reading
Crockford C, Newton J, Lonergan K, et al. ALS-specific cognitive and behavior changes associated with advancing disease stage in ALS. Neurology. 2018 Sep 12 [Epub ahead of print].
Wicks P, Albert SM. It’s time to stop saying “the mind is unaffected” in ALS. Neurology. 2018 Sep 12 [Epub ahead of print].
Data raise the question of whether cognitive and behavioral change should be included in ALS diagnostic criteria.
Data raise the question of whether cognitive and behavioral change should be included in ALS diagnostic criteria.
Cognitive deficits and behavioral symptoms that are specific to amyotrophic lateral sclerosis (ALS) occur more frequently as the disease progresses, according to research published online ahead of print September 12 in Neurology. Few patients are free of neuropsychologic impairment when they reach the final stage of the disease. It might be appropriate to include cognitive and behavioral change in the diagnostic criteria and future staging systems for ALS, said the authors.
In 2013, Elamin et al suggested that cognitive change in ALS may be associated with indirect measures of disease progression, such as total score on the ALS Functional Rating Scale-Revised. Christopher Crockford, PhD, a researcher at the University of Edinburgh, and colleagues sought to determine whether the cognitive and behavioral symptoms in ALS were more prevalent at more advanced stages of disease.
The Role of Letter Fluency Impairment
They conducted a multicenter, cross-sectional, observational study that included 161 patients from Edinburgh, Dublin, and London with possible, probable, or definite ALS, according to revised El Escorial diagnostic criteria. The researchers also recruited 80 healthy, matched controls. Through interviews, Dr. Crockford and colleagues elicited demographic and clinical data. They measured participants’ clinical staging with the King’s Clinical Staging System and neuropsychologic status with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS).
The investigators did not observe significant differences between the patient and control groups in background variables. Approximately 67% of patients with ALS were male, compared with 60% of controls. Mean age at testing was approximately 61 in both groups. Among patients with ALS, 40 were in Stage 1, 45 were in Stage 2, 22 were in Stage 3, and 54 were in Stage 4.
Compared with controls, patients with ALS had significantly worse cognitive performance on all domains of the ECAS except visuospatial functioning. Dr. Crockford’s group found a significant cross-sectional effect across disease stages for ALS-specific functions (eg, executive, language, and letter fluency) and ECAS total score. They did not find a similar effect for ALS-nonspecific functions (eg, memory and visuospatial). In addition, rates of ALS-specific impairment and behavioral change increased with increasing disease stage.
Letter fluency impairment may explain the relationship between cognitive function and disease stage, said the authors. They observed higher rates of all behavioral problems in later King’s stages. Bulbar signs were significantly related to ALS-specific scores, ECAS total score, and behavioral scores. Site of onset was not related to these scores, however.
Intervention programs to alleviate the effect of patients’ neuropsychologic impairment on caregivers may be appropriate, said the authors. “Furthermore, clinicians should be cognizant of current neuropsychologic status when prescribing life-prolonging interventions to patients and implement support structures for those with a neuropsychologic impairment,” they added.
Informing Patients and Caregivers
Although Dr. Crockford and colleagues focused on the behavioral and cognitive effects of ALS, the disease may affect mental health as well, said Paul Wicks, PhD, Vice President of Innovation at PatientsLikeMe in Cambridge, Massachusetts, and Steven M. Albert, PhD, Professor and Chair of Behavioral and Community Health Sciences at the University of Pittsburgh, in an accompanying editorial. The data show that the rates of major depression and depressed mood increase with increasing disease stage.
Drs. Wicks and Albert cited a survey in which 90% of patients and caregivers reported that their doctors had not told them that cognitive or psychologic symptoms can arise in ALS. “In our experience, colleagues report keeping the information from patients in order to spare them further distress,” they said. Yet most respondents to this survey reported that they would have liked to have been informed about these symptoms.
“Educating patients and caregivers that cognitive change is a part of ALS should be no different from similar discussions to be had in multiple sclerosis, Parkinson disease, and a range of other conditions,” said Drs. Wicks and Albert. “Keeping the truth from patients and caregivers is not protective; it is paternalistic, and it is time to stop. Only by facing up to the hard truth that one of the most dreaded conditions in medicine is even worse than we previously acknowledged can we take stock, marshal our resources, and make renewed plans to defeat our common enemy.”
Suggested Reading
Crockford C, Newton J, Lonergan K, et al. ALS-specific cognitive and behavior changes associated with advancing disease stage in ALS. Neurology. 2018 Sep 12 [Epub ahead of print].
Wicks P, Albert SM. It’s time to stop saying “the mind is unaffected” in ALS. Neurology. 2018 Sep 12 [Epub ahead of print].
Cognitive deficits and behavioral symptoms that are specific to amyotrophic lateral sclerosis (ALS) occur more frequently as the disease progresses, according to research published online ahead of print September 12 in Neurology. Few patients are free of neuropsychologic impairment when they reach the final stage of the disease. It might be appropriate to include cognitive and behavioral change in the diagnostic criteria and future staging systems for ALS, said the authors.
In 2013, Elamin et al suggested that cognitive change in ALS may be associated with indirect measures of disease progression, such as total score on the ALS Functional Rating Scale-Revised. Christopher Crockford, PhD, a researcher at the University of Edinburgh, and colleagues sought to determine whether the cognitive and behavioral symptoms in ALS were more prevalent at more advanced stages of disease.
The Role of Letter Fluency Impairment
They conducted a multicenter, cross-sectional, observational study that included 161 patients from Edinburgh, Dublin, and London with possible, probable, or definite ALS, according to revised El Escorial diagnostic criteria. The researchers also recruited 80 healthy, matched controls. Through interviews, Dr. Crockford and colleagues elicited demographic and clinical data. They measured participants’ clinical staging with the King’s Clinical Staging System and neuropsychologic status with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS).
The investigators did not observe significant differences between the patient and control groups in background variables. Approximately 67% of patients with ALS were male, compared with 60% of controls. Mean age at testing was approximately 61 in both groups. Among patients with ALS, 40 were in Stage 1, 45 were in Stage 2, 22 were in Stage 3, and 54 were in Stage 4.
Compared with controls, patients with ALS had significantly worse cognitive performance on all domains of the ECAS except visuospatial functioning. Dr. Crockford’s group found a significant cross-sectional effect across disease stages for ALS-specific functions (eg, executive, language, and letter fluency) and ECAS total score. They did not find a similar effect for ALS-nonspecific functions (eg, memory and visuospatial). In addition, rates of ALS-specific impairment and behavioral change increased with increasing disease stage.
Letter fluency impairment may explain the relationship between cognitive function and disease stage, said the authors. They observed higher rates of all behavioral problems in later King’s stages. Bulbar signs were significantly related to ALS-specific scores, ECAS total score, and behavioral scores. Site of onset was not related to these scores, however.
Intervention programs to alleviate the effect of patients’ neuropsychologic impairment on caregivers may be appropriate, said the authors. “Furthermore, clinicians should be cognizant of current neuropsychologic status when prescribing life-prolonging interventions to patients and implement support structures for those with a neuropsychologic impairment,” they added.
Informing Patients and Caregivers
Although Dr. Crockford and colleagues focused on the behavioral and cognitive effects of ALS, the disease may affect mental health as well, said Paul Wicks, PhD, Vice President of Innovation at PatientsLikeMe in Cambridge, Massachusetts, and Steven M. Albert, PhD, Professor and Chair of Behavioral and Community Health Sciences at the University of Pittsburgh, in an accompanying editorial. The data show that the rates of major depression and depressed mood increase with increasing disease stage.
Drs. Wicks and Albert cited a survey in which 90% of patients and caregivers reported that their doctors had not told them that cognitive or psychologic symptoms can arise in ALS. “In our experience, colleagues report keeping the information from patients in order to spare them further distress,” they said. Yet most respondents to this survey reported that they would have liked to have been informed about these symptoms.
“Educating patients and caregivers that cognitive change is a part of ALS should be no different from similar discussions to be had in multiple sclerosis, Parkinson disease, and a range of other conditions,” said Drs. Wicks and Albert. “Keeping the truth from patients and caregivers is not protective; it is paternalistic, and it is time to stop. Only by facing up to the hard truth that one of the most dreaded conditions in medicine is even worse than we previously acknowledged can we take stock, marshal our resources, and make renewed plans to defeat our common enemy.”
Suggested Reading
Crockford C, Newton J, Lonergan K, et al. ALS-specific cognitive and behavior changes associated with advancing disease stage in ALS. Neurology. 2018 Sep 12 [Epub ahead of print].
Wicks P, Albert SM. It’s time to stop saying “the mind is unaffected” in ALS. Neurology. 2018 Sep 12 [Epub ahead of print].
High Systemic Inflammation at Midlife Portends Cognitive Changes in Later Life
Systemic inflammation may have an early pathogenic role in the cognitive decline that occurs before older adulthood.
ATLANTA—Individuals with higher levels of systemic inflammation during midlife experience greater rates of cognitive decline over the subsequent 20-year period, according to results from a long-term analysis presented at the 143rd Annual Meeting of the American Neurological Association.
“There is considerable evidence suggesting that abnormal immune functioning and inflammation may influence cognitive functioning and promote dementia,” said lead study author Keenan Walker, PhD, a clinical neuropsychology postdoctoral fellow at the Johns Hopkins University School of Medicine in Baltimore. “For example, several studies have found higher levels of inflammatory markers in the blood and CSF of patients with dementia, compared to nondemented individuals of a comparable age. What is less clear, however, is whether inflammation actually promotes cognitive decline or occurs simply as a result of the brain changes underlying dementia.”
To help answer this question, Dr. Walker and his colleagues evaluated blood biomarkers of inflammation in 12,727 middle-aged participants during visits one and two of the Atherosclerosis Risk in Communities (ARIC) study, a prospective epidemiologic analysis conducted in four US communities and funded by the National Heart, Lung, and Blood Institute. Visit 1 occurred between 1987 and 1989, and Visit 2 took place between 1990 and 1992. The researchers related these markers to cognitive change over the subsequent decades. Specifically, they used four biomarkers (ie, fibrinogen, white blood cell count, von Willebrand factor, and Factor VIII) to create an inflammation composite score at Visit 1 and measured C-reactive protein (CRP) at Visit 2. Next, they used measures of memory, executive function, and language to assess cognition over three visits spanning 20 years.
The average age of study participants at the first cognitive assessment was 57, 56% were women, and 21% were black. After controlling for differences in demographic variables, vascular risk factors, and comorbidities, the researchers observed that each standard deviation (SD) increase in the midlife inflammation composite score was associated with an additional 20-year global cognitive decline of –0.035 SD. They found a similar association between each SD higher midlife CRP level and additional 20-year decline in global cognition (–0.038 SD). In addition, study participants with a midlife inflammation composite score in the top quartile had a 7.6% steeper decline in global cognition, compared with participants in the lowest quartile. A similar association was observed for CRP.
“We were surprised at what we found when we looked at inflammation’s effect on individual cognitive domains,” said Dr. Walker. “Specifically, we found that inflammation was associated with declines in memory, but not declines in other domains, such as executive function or language. One possible interpretation for these findings is that inflammation may selectively influence brain regions such as the hippocampus that are necessary for memory consolidation and are also most vulnerable to Alzheimer’s disease.” He added that the current findings “provide support for the idea that systemic inflammation may have an early pathogenic role in the cognitive decline that occurs in the decades leading up to older adulthood.”
Dr. Walker acknowledged certain limitations of the study, including the attrition of participants because of deaths and dropouts over the 20-year follow-up period. “Because high levels of inflammation and comorbid disease are related to death and risk of study dropout, the sample of participants who completed the entirety of the study may represent a group that is healthier overall than the general population,” he said. “However, we took several steps to reduce any potential attrition bias using advanced statistical techniques.”
—Doug Brunk
Systemic inflammation may have an early pathogenic role in the cognitive decline that occurs before older adulthood.
Systemic inflammation may have an early pathogenic role in the cognitive decline that occurs before older adulthood.
ATLANTA—Individuals with higher levels of systemic inflammation during midlife experience greater rates of cognitive decline over the subsequent 20-year period, according to results from a long-term analysis presented at the 143rd Annual Meeting of the American Neurological Association.
“There is considerable evidence suggesting that abnormal immune functioning and inflammation may influence cognitive functioning and promote dementia,” said lead study author Keenan Walker, PhD, a clinical neuropsychology postdoctoral fellow at the Johns Hopkins University School of Medicine in Baltimore. “For example, several studies have found higher levels of inflammatory markers in the blood and CSF of patients with dementia, compared to nondemented individuals of a comparable age. What is less clear, however, is whether inflammation actually promotes cognitive decline or occurs simply as a result of the brain changes underlying dementia.”
To help answer this question, Dr. Walker and his colleagues evaluated blood biomarkers of inflammation in 12,727 middle-aged participants during visits one and two of the Atherosclerosis Risk in Communities (ARIC) study, a prospective epidemiologic analysis conducted in four US communities and funded by the National Heart, Lung, and Blood Institute. Visit 1 occurred between 1987 and 1989, and Visit 2 took place between 1990 and 1992. The researchers related these markers to cognitive change over the subsequent decades. Specifically, they used four biomarkers (ie, fibrinogen, white blood cell count, von Willebrand factor, and Factor VIII) to create an inflammation composite score at Visit 1 and measured C-reactive protein (CRP) at Visit 2. Next, they used measures of memory, executive function, and language to assess cognition over three visits spanning 20 years.
The average age of study participants at the first cognitive assessment was 57, 56% were women, and 21% were black. After controlling for differences in demographic variables, vascular risk factors, and comorbidities, the researchers observed that each standard deviation (SD) increase in the midlife inflammation composite score was associated with an additional 20-year global cognitive decline of –0.035 SD. They found a similar association between each SD higher midlife CRP level and additional 20-year decline in global cognition (–0.038 SD). In addition, study participants with a midlife inflammation composite score in the top quartile had a 7.6% steeper decline in global cognition, compared with participants in the lowest quartile. A similar association was observed for CRP.
“We were surprised at what we found when we looked at inflammation’s effect on individual cognitive domains,” said Dr. Walker. “Specifically, we found that inflammation was associated with declines in memory, but not declines in other domains, such as executive function or language. One possible interpretation for these findings is that inflammation may selectively influence brain regions such as the hippocampus that are necessary for memory consolidation and are also most vulnerable to Alzheimer’s disease.” He added that the current findings “provide support for the idea that systemic inflammation may have an early pathogenic role in the cognitive decline that occurs in the decades leading up to older adulthood.”
Dr. Walker acknowledged certain limitations of the study, including the attrition of participants because of deaths and dropouts over the 20-year follow-up period. “Because high levels of inflammation and comorbid disease are related to death and risk of study dropout, the sample of participants who completed the entirety of the study may represent a group that is healthier overall than the general population,” he said. “However, we took several steps to reduce any potential attrition bias using advanced statistical techniques.”
—Doug Brunk
ATLANTA—Individuals with higher levels of systemic inflammation during midlife experience greater rates of cognitive decline over the subsequent 20-year period, according to results from a long-term analysis presented at the 143rd Annual Meeting of the American Neurological Association.
“There is considerable evidence suggesting that abnormal immune functioning and inflammation may influence cognitive functioning and promote dementia,” said lead study author Keenan Walker, PhD, a clinical neuropsychology postdoctoral fellow at the Johns Hopkins University School of Medicine in Baltimore. “For example, several studies have found higher levels of inflammatory markers in the blood and CSF of patients with dementia, compared to nondemented individuals of a comparable age. What is less clear, however, is whether inflammation actually promotes cognitive decline or occurs simply as a result of the brain changes underlying dementia.”
To help answer this question, Dr. Walker and his colleagues evaluated blood biomarkers of inflammation in 12,727 middle-aged participants during visits one and two of the Atherosclerosis Risk in Communities (ARIC) study, a prospective epidemiologic analysis conducted in four US communities and funded by the National Heart, Lung, and Blood Institute. Visit 1 occurred between 1987 and 1989, and Visit 2 took place between 1990 and 1992. The researchers related these markers to cognitive change over the subsequent decades. Specifically, they used four biomarkers (ie, fibrinogen, white blood cell count, von Willebrand factor, and Factor VIII) to create an inflammation composite score at Visit 1 and measured C-reactive protein (CRP) at Visit 2. Next, they used measures of memory, executive function, and language to assess cognition over three visits spanning 20 years.
The average age of study participants at the first cognitive assessment was 57, 56% were women, and 21% were black. After controlling for differences in demographic variables, vascular risk factors, and comorbidities, the researchers observed that each standard deviation (SD) increase in the midlife inflammation composite score was associated with an additional 20-year global cognitive decline of –0.035 SD. They found a similar association between each SD higher midlife CRP level and additional 20-year decline in global cognition (–0.038 SD). In addition, study participants with a midlife inflammation composite score in the top quartile had a 7.6% steeper decline in global cognition, compared with participants in the lowest quartile. A similar association was observed for CRP.
“We were surprised at what we found when we looked at inflammation’s effect on individual cognitive domains,” said Dr. Walker. “Specifically, we found that inflammation was associated with declines in memory, but not declines in other domains, such as executive function or language. One possible interpretation for these findings is that inflammation may selectively influence brain regions such as the hippocampus that are necessary for memory consolidation and are also most vulnerable to Alzheimer’s disease.” He added that the current findings “provide support for the idea that systemic inflammation may have an early pathogenic role in the cognitive decline that occurs in the decades leading up to older adulthood.”
Dr. Walker acknowledged certain limitations of the study, including the attrition of participants because of deaths and dropouts over the 20-year follow-up period. “Because high levels of inflammation and comorbid disease are related to death and risk of study dropout, the sample of participants who completed the entirety of the study may represent a group that is healthier overall than the general population,” he said. “However, we took several steps to reduce any potential attrition bias using advanced statistical techniques.”
—Doug Brunk
Management of Lewy body dementia remains complex
ATLANTA – In the not-so-distant past, neurologists viewed dementia with Lewy bodies as a disorder primarily of the brain, but it turned out to be far more complex than that.
At the annual meeting of the American Neurological Association, Bradley F. Boeve, MD, described dementia with Lewy bodies (DLB) as a systemic neurologic disorder affecting the brain, including brain stem, spinal cord, and peripheral nervous system, especially the autonomic nervous system. “This leads to the complex array of clinical manifestations, which are quite different from patient to patient cross-sectionally and longitudinally,” said Dr. Boeve, the Little Family Foundation Professor of Lewy Body Dementia in the department of neurology at the Mayo Clinic, Rochester, Minn.
, he said. The four core clinical features are Parkinsonism unrelated to medications; recurrent, fully-formed visual hallucinations; fluctuations in cognition and/or arousal; and rapid eye movement (REM) sleep behavior disorder. “This is the most predictive of all four features,” Dr. Boeve said. He described REM sleep behavior disorder as a parasomnia manifested by the tendency to repeatedly “act out one’s dreams.” The dreams tend to contain a chasing/attacking theme, and behaviors mirror dream content. Injuries to the patient and bed partner can occur.
Typically, patients will present with REM sleep behavior disorder in their 50s and 60s, and sometimes in their 30s and 40s, “decades before cognitive changes begin,” he said. “This is usually followed by Parkinsonism and visual hallucinations. That’s the prototypical DLB [case], but there are many examples where this is not followed. Prominent neuropsychiatric features can also begin before any cognitive changes.”
Neuropsychological features of DLB often include impairment of executive functions and visuospatial functions. “Early in the course of Alzheimer’s disease, typically performance on memory measures – especially delayed recall – are down and the other measures are borderline or mildly impaired,” Dr. Boeve noted. “By contrast, in DLB, attention, executive function, and visuospatial measures are down, but memory is often pretty good. What’s remarkable is that in the office setting, when you take a history the person often says, ‘I’m very forgetful,’ yet in the testing environment people tend to rise to the occasion pretty well.”
Imaging isn’t always helpful in establishing a diagnosis of DLB. MRI scans, for example, “can look pretty normal, including the hippocampi,” he said. “This is really the norm in DLB and it seems to be a disconnect. The person can have significant symptoms yet their MRI scan can be pretty normal.”
In Alzheimer’s disease, 18F-fluorodeoxyglucose-PET (FDG-PET) shows temporal, parietal, and frontal hypometabolism, sparing of the sensory-motor strip and sparing of the primary occipital cortex, while in DLB, FDG-PET shows marked deficits in the occipital regions with relative sparing of the frontal and temporal lobes. Another key neuroimaging sign of DLB is the posterior cingulate island sign, which is characterized by sparing of the posterior cingulate cortex relative to the precuneus plus cuneus on FDG-PET.
In 2017, the Dementia with Lewy Bodies Consortium published updated recommendations on the diagnosis and management of the disease (Neurology. 2017;89[1]:88-100). In its consensus report, the consortium defines probable DLB as dementia plus two or more clinical features or one core clinical feature plus one or more indicative biomarker. These biomarkers include reduced dopamine transport uptake in basal ganglia by SPECT or PET; abnormal (low uptake) meta-iodobenzylguanidine (MIBG) myocardial scintigraphy, and/or polysomnographic confirmation of REM sleep without atonia.
“Neuropathologically, limbic with or without neocortical Lewy bodies and Lewy neurites are the defining characteristics of pathologically-proven DLB,” added Dr. Boeve, a member of the DLB consortium. “The classic DLB phenotype can occur in limbic-predominant DLB. Lewy bodies in the neocortex are not necessary to cause a dementia syndrome.”
He characterized management of DLB as “very complicated. Consider symptoms as they relate to cognitive impairment, neuropsychiatric features, motor features, sleep disorders, and autonomic dysfunction.” He often asks the patient/family to prioritize the three most troublesome issues they seek to change, and develops a plan based on their input.
There is no Food and Drug Administration–approved medication for DLB, but the standard of care is an acetylcholinesterase inhibitor such as donepezil. “There is evidence that memantine can provide a modest benefit,” Dr. Boeve said. “Hypersomnia is quite prominent in DLB and worthy of assessing and treating.” Clinicians must weigh the pros and cons of pharmacotherapy with each patient. “For example, in the atypical neuroleptic class [of drugs], there may be a benefit to the hallucinations and delusions in DLB but hypersomnia can worsen,” he said. “Selecting agents is challenging but worth the effort.”
Survival is lower and more rapid with DLB, compared with Alzheimer’s. Most people pass away from primary DLB-related features or failure to thrive. The second most common is pneumonia or aspiration. Median survival was 4 years after diagnosis in one study, and end-of life discussions occurred in less than half of all patients. “This is a frustrating reminder that we as clinicians are not very good at discussing important topics such as end-of-life care with patients and their families,” Dr. Boeve said. Resources that he recommends for education and support include the Lewy Body Dementia Association and The Lewy Body Society.
At the 2016 Alzheimer’s Disease-Related Dementias Summit, clinicians formed a list of DLB research priorities (Neurology 2017;89[23]:2381-91). Among them were recommendations to “initiate clinical trials in diverse populations using therapies that address symptoms that have the greatest effect on patient function and caregiver burden” and “identify novel common and rare genetic variants, epigenetic changes, and environmental influences that affect the risk for and clinical features of” the disease.
Meanwhile, several research protocols are under way, including the development of a DLB module by the U.S. Alzheimer’s Research Disease Centers and a number of DLB-focused projects from the National Institute of Neurological Disorders and Stroke (NINDS) Parkinson’s Disease Biomarkers Program. In addition, the Lewy Body Dementia Association Research Centers of Excellence program is focused on optimizing clinical care and setting up the infrastructure for clinical trials, while the North American Prodromal Synucleinopathy Consortium is conducting longitudinal studies in those with REM sleep behavior disorder.
Dr. Boeve disclosed that he has been an investigator for clinical trials sponsored by GE Healthcare, Axovant, and Biogen. He is a member of the scientific advisory board for the Tau Consortium and has received research support from the National Institute on Aging, the NINDS, the Mangurian Foundation, and the Little Family Foundation.
ATLANTA – In the not-so-distant past, neurologists viewed dementia with Lewy bodies as a disorder primarily of the brain, but it turned out to be far more complex than that.
At the annual meeting of the American Neurological Association, Bradley F. Boeve, MD, described dementia with Lewy bodies (DLB) as a systemic neurologic disorder affecting the brain, including brain stem, spinal cord, and peripheral nervous system, especially the autonomic nervous system. “This leads to the complex array of clinical manifestations, which are quite different from patient to patient cross-sectionally and longitudinally,” said Dr. Boeve, the Little Family Foundation Professor of Lewy Body Dementia in the department of neurology at the Mayo Clinic, Rochester, Minn.
, he said. The four core clinical features are Parkinsonism unrelated to medications; recurrent, fully-formed visual hallucinations; fluctuations in cognition and/or arousal; and rapid eye movement (REM) sleep behavior disorder. “This is the most predictive of all four features,” Dr. Boeve said. He described REM sleep behavior disorder as a parasomnia manifested by the tendency to repeatedly “act out one’s dreams.” The dreams tend to contain a chasing/attacking theme, and behaviors mirror dream content. Injuries to the patient and bed partner can occur.
Typically, patients will present with REM sleep behavior disorder in their 50s and 60s, and sometimes in their 30s and 40s, “decades before cognitive changes begin,” he said. “This is usually followed by Parkinsonism and visual hallucinations. That’s the prototypical DLB [case], but there are many examples where this is not followed. Prominent neuropsychiatric features can also begin before any cognitive changes.”
Neuropsychological features of DLB often include impairment of executive functions and visuospatial functions. “Early in the course of Alzheimer’s disease, typically performance on memory measures – especially delayed recall – are down and the other measures are borderline or mildly impaired,” Dr. Boeve noted. “By contrast, in DLB, attention, executive function, and visuospatial measures are down, but memory is often pretty good. What’s remarkable is that in the office setting, when you take a history the person often says, ‘I’m very forgetful,’ yet in the testing environment people tend to rise to the occasion pretty well.”
Imaging isn’t always helpful in establishing a diagnosis of DLB. MRI scans, for example, “can look pretty normal, including the hippocampi,” he said. “This is really the norm in DLB and it seems to be a disconnect. The person can have significant symptoms yet their MRI scan can be pretty normal.”
In Alzheimer’s disease, 18F-fluorodeoxyglucose-PET (FDG-PET) shows temporal, parietal, and frontal hypometabolism, sparing of the sensory-motor strip and sparing of the primary occipital cortex, while in DLB, FDG-PET shows marked deficits in the occipital regions with relative sparing of the frontal and temporal lobes. Another key neuroimaging sign of DLB is the posterior cingulate island sign, which is characterized by sparing of the posterior cingulate cortex relative to the precuneus plus cuneus on FDG-PET.
In 2017, the Dementia with Lewy Bodies Consortium published updated recommendations on the diagnosis and management of the disease (Neurology. 2017;89[1]:88-100). In its consensus report, the consortium defines probable DLB as dementia plus two or more clinical features or one core clinical feature plus one or more indicative biomarker. These biomarkers include reduced dopamine transport uptake in basal ganglia by SPECT or PET; abnormal (low uptake) meta-iodobenzylguanidine (MIBG) myocardial scintigraphy, and/or polysomnographic confirmation of REM sleep without atonia.
“Neuropathologically, limbic with or without neocortical Lewy bodies and Lewy neurites are the defining characteristics of pathologically-proven DLB,” added Dr. Boeve, a member of the DLB consortium. “The classic DLB phenotype can occur in limbic-predominant DLB. Lewy bodies in the neocortex are not necessary to cause a dementia syndrome.”
He characterized management of DLB as “very complicated. Consider symptoms as they relate to cognitive impairment, neuropsychiatric features, motor features, sleep disorders, and autonomic dysfunction.” He often asks the patient/family to prioritize the three most troublesome issues they seek to change, and develops a plan based on their input.
There is no Food and Drug Administration–approved medication for DLB, but the standard of care is an acetylcholinesterase inhibitor such as donepezil. “There is evidence that memantine can provide a modest benefit,” Dr. Boeve said. “Hypersomnia is quite prominent in DLB and worthy of assessing and treating.” Clinicians must weigh the pros and cons of pharmacotherapy with each patient. “For example, in the atypical neuroleptic class [of drugs], there may be a benefit to the hallucinations and delusions in DLB but hypersomnia can worsen,” he said. “Selecting agents is challenging but worth the effort.”
Survival is lower and more rapid with DLB, compared with Alzheimer’s. Most people pass away from primary DLB-related features or failure to thrive. The second most common is pneumonia or aspiration. Median survival was 4 years after diagnosis in one study, and end-of life discussions occurred in less than half of all patients. “This is a frustrating reminder that we as clinicians are not very good at discussing important topics such as end-of-life care with patients and their families,” Dr. Boeve said. Resources that he recommends for education and support include the Lewy Body Dementia Association and The Lewy Body Society.
At the 2016 Alzheimer’s Disease-Related Dementias Summit, clinicians formed a list of DLB research priorities (Neurology 2017;89[23]:2381-91). Among them were recommendations to “initiate clinical trials in diverse populations using therapies that address symptoms that have the greatest effect on patient function and caregiver burden” and “identify novel common and rare genetic variants, epigenetic changes, and environmental influences that affect the risk for and clinical features of” the disease.
Meanwhile, several research protocols are under way, including the development of a DLB module by the U.S. Alzheimer’s Research Disease Centers and a number of DLB-focused projects from the National Institute of Neurological Disorders and Stroke (NINDS) Parkinson’s Disease Biomarkers Program. In addition, the Lewy Body Dementia Association Research Centers of Excellence program is focused on optimizing clinical care and setting up the infrastructure for clinical trials, while the North American Prodromal Synucleinopathy Consortium is conducting longitudinal studies in those with REM sleep behavior disorder.
Dr. Boeve disclosed that he has been an investigator for clinical trials sponsored by GE Healthcare, Axovant, and Biogen. He is a member of the scientific advisory board for the Tau Consortium and has received research support from the National Institute on Aging, the NINDS, the Mangurian Foundation, and the Little Family Foundation.
ATLANTA – In the not-so-distant past, neurologists viewed dementia with Lewy bodies as a disorder primarily of the brain, but it turned out to be far more complex than that.
At the annual meeting of the American Neurological Association, Bradley F. Boeve, MD, described dementia with Lewy bodies (DLB) as a systemic neurologic disorder affecting the brain, including brain stem, spinal cord, and peripheral nervous system, especially the autonomic nervous system. “This leads to the complex array of clinical manifestations, which are quite different from patient to patient cross-sectionally and longitudinally,” said Dr. Boeve, the Little Family Foundation Professor of Lewy Body Dementia in the department of neurology at the Mayo Clinic, Rochester, Minn.
, he said. The four core clinical features are Parkinsonism unrelated to medications; recurrent, fully-formed visual hallucinations; fluctuations in cognition and/or arousal; and rapid eye movement (REM) sleep behavior disorder. “This is the most predictive of all four features,” Dr. Boeve said. He described REM sleep behavior disorder as a parasomnia manifested by the tendency to repeatedly “act out one’s dreams.” The dreams tend to contain a chasing/attacking theme, and behaviors mirror dream content. Injuries to the patient and bed partner can occur.
Typically, patients will present with REM sleep behavior disorder in their 50s and 60s, and sometimes in their 30s and 40s, “decades before cognitive changes begin,” he said. “This is usually followed by Parkinsonism and visual hallucinations. That’s the prototypical DLB [case], but there are many examples where this is not followed. Prominent neuropsychiatric features can also begin before any cognitive changes.”
Neuropsychological features of DLB often include impairment of executive functions and visuospatial functions. “Early in the course of Alzheimer’s disease, typically performance on memory measures – especially delayed recall – are down and the other measures are borderline or mildly impaired,” Dr. Boeve noted. “By contrast, in DLB, attention, executive function, and visuospatial measures are down, but memory is often pretty good. What’s remarkable is that in the office setting, when you take a history the person often says, ‘I’m very forgetful,’ yet in the testing environment people tend to rise to the occasion pretty well.”
Imaging isn’t always helpful in establishing a diagnosis of DLB. MRI scans, for example, “can look pretty normal, including the hippocampi,” he said. “This is really the norm in DLB and it seems to be a disconnect. The person can have significant symptoms yet their MRI scan can be pretty normal.”
In Alzheimer’s disease, 18F-fluorodeoxyglucose-PET (FDG-PET) shows temporal, parietal, and frontal hypometabolism, sparing of the sensory-motor strip and sparing of the primary occipital cortex, while in DLB, FDG-PET shows marked deficits in the occipital regions with relative sparing of the frontal and temporal lobes. Another key neuroimaging sign of DLB is the posterior cingulate island sign, which is characterized by sparing of the posterior cingulate cortex relative to the precuneus plus cuneus on FDG-PET.
In 2017, the Dementia with Lewy Bodies Consortium published updated recommendations on the diagnosis and management of the disease (Neurology. 2017;89[1]:88-100). In its consensus report, the consortium defines probable DLB as dementia plus two or more clinical features or one core clinical feature plus one or more indicative biomarker. These biomarkers include reduced dopamine transport uptake in basal ganglia by SPECT or PET; abnormal (low uptake) meta-iodobenzylguanidine (MIBG) myocardial scintigraphy, and/or polysomnographic confirmation of REM sleep without atonia.
“Neuropathologically, limbic with or without neocortical Lewy bodies and Lewy neurites are the defining characteristics of pathologically-proven DLB,” added Dr. Boeve, a member of the DLB consortium. “The classic DLB phenotype can occur in limbic-predominant DLB. Lewy bodies in the neocortex are not necessary to cause a dementia syndrome.”
He characterized management of DLB as “very complicated. Consider symptoms as they relate to cognitive impairment, neuropsychiatric features, motor features, sleep disorders, and autonomic dysfunction.” He often asks the patient/family to prioritize the three most troublesome issues they seek to change, and develops a plan based on their input.
There is no Food and Drug Administration–approved medication for DLB, but the standard of care is an acetylcholinesterase inhibitor such as donepezil. “There is evidence that memantine can provide a modest benefit,” Dr. Boeve said. “Hypersomnia is quite prominent in DLB and worthy of assessing and treating.” Clinicians must weigh the pros and cons of pharmacotherapy with each patient. “For example, in the atypical neuroleptic class [of drugs], there may be a benefit to the hallucinations and delusions in DLB but hypersomnia can worsen,” he said. “Selecting agents is challenging but worth the effort.”
Survival is lower and more rapid with DLB, compared with Alzheimer’s. Most people pass away from primary DLB-related features or failure to thrive. The second most common is pneumonia or aspiration. Median survival was 4 years after diagnosis in one study, and end-of life discussions occurred in less than half of all patients. “This is a frustrating reminder that we as clinicians are not very good at discussing important topics such as end-of-life care with patients and their families,” Dr. Boeve said. Resources that he recommends for education and support include the Lewy Body Dementia Association and The Lewy Body Society.
At the 2016 Alzheimer’s Disease-Related Dementias Summit, clinicians formed a list of DLB research priorities (Neurology 2017;89[23]:2381-91). Among them were recommendations to “initiate clinical trials in diverse populations using therapies that address symptoms that have the greatest effect on patient function and caregiver burden” and “identify novel common and rare genetic variants, epigenetic changes, and environmental influences that affect the risk for and clinical features of” the disease.
Meanwhile, several research protocols are under way, including the development of a DLB module by the U.S. Alzheimer’s Research Disease Centers and a number of DLB-focused projects from the National Institute of Neurological Disorders and Stroke (NINDS) Parkinson’s Disease Biomarkers Program. In addition, the Lewy Body Dementia Association Research Centers of Excellence program is focused on optimizing clinical care and setting up the infrastructure for clinical trials, while the North American Prodromal Synucleinopathy Consortium is conducting longitudinal studies in those with REM sleep behavior disorder.
Dr. Boeve disclosed that he has been an investigator for clinical trials sponsored by GE Healthcare, Axovant, and Biogen. He is a member of the scientific advisory board for the Tau Consortium and has received research support from the National Institute on Aging, the NINDS, the Mangurian Foundation, and the Little Family Foundation.
EXPERT ANALYSIS FROM ANA 2018
Researchers Develop Guidelines for Evaluating Cognitive and Behavioral Syndromes in Adults
A care partner almost always should be involved in the evaluation, the guidelines advise.
CHICAGO—An Alzheimer’s Association workgroup has developed 20 recommendations for the clinical evaluation of patients with cognitive or behavioral complaints. All middle-aged or older individuals who report or whose care partner or clinician reports cognitive, behavioral, or functional changes should undergo a timely evaluation, the guidelines advise. A care partner almost always should be involved the evaluation, according to the guidelines.
The recommendations cover the recognition and evaluation of symptoms, selection of brain imaging and other tests, and communication with and support of affected individuals and their caregivers. 
Alireza Atri, MD, PhD, cochair of the workgroup, presented the recommendations at AAIC 2018. The authors plan to finalize and publish the guidelines in 2018.
“Until now, we have not had highly specific and multispecialty US national guidelines that can inform the diagnostic process across all care settings and that provide standards meant to improve patient autonomy, care, and outcomes,” said Dr. Atri, Director of the Banner Sun Health Research Institute in Sun City, Arizona, and Lecturer in Neurology at the Center for Brain/Mind Medicine at Brigham and Women’s Hospital and Harvard Medical School in Boston.
Cognitive Behavioral Syndromes
The clinical practice guidelines recognize a broad category of cognitive behavioral syndromes marked by memory and thinking symptoms as well as changes in sleep, anxiety, personality, and relationships.
The Alzheimer’s Association in 2017 convened a Diagnostic Evaluation Clinical Practice Guideline workgroup to develop evidence-based guidelines. The group includes experts in medical, neuropsychologic, and nursing specialties. The members conducted a systematic review of the literature and made recommendations using a modified Delphi consensus process. They graded the recommendations as “A” (must be done; will improve outcomes in almost all cases), “B” (should be done), and “C” (may be done).
The recommendations emphasize obtaining a history from not only the patient, but also from someone who knows the patient well to establish the presence and characteristics of any substantial changes and to categorize the cognitive behavioral syndrome.
Other recommendations for evaluating patients with cognitive behavioral syndromes include the following:
- For patients with atypical or rapidly progressive cognitive behavioral symptoms, the clinician should expedite an evaluation and strongly consider referral to a specialist. (Level A)
- The evaluation process should use tiers of assessments and tests based on a patient’s presentation, risk factors, and profile. (Level A)
- The clinician should involve an informant to obtain reliable information about changes in cognition, activities of daily living, mood and other neuropsychiatric symptoms, and sensory and motor function. Use of structured instruments for assessing these domains is helpful. (Level A)
- Clinicians should use validated tools to assess cognition. (Level A)
- When office-based cognitive assessment is not sufficiently informative (eg, when interpretation of results is uncertain due to a complex clinical profile or confounding demographic characteristics), neuropsychologic evaluation is recommended. (Level A)
- The clinician should obtain MRI as a first-tier approach to aid in establishing etiology. If MRI is not available or is contraindicated, CT should be obtained. (Level B)
- If etiology remains uncertain after interpretation of structural imaging, a dementia specialist can obtain molecular imaging with FDG-PET to improve diagnostic accuracy. (Level B)
- In cases with continued diagnostic uncertainty, a dementia specialist can obtain CSF according to appropriate use criteria for analysis of aβ42 amyloid and tau/p-tau profiles to evaluate for Alzheimer’s disease pathology. (Level C)
- If diagnostic uncertainty remains after obtaining structural imaging and FDG-PET, and CSF aβ and tau/p-tau profiles are unavailable or uninterpretable, the dementia specialist can obtain an amyloid PET scan according to the appropriate use criteria. (Level C)
- In a patient with an established cognitive behavioral syndrome and a likely autosomal dominant family history, the dementia specialist should consider whether genetic testing is warranted. A genetic counselor should be involved throughout the process. (Level A)
A Tool for Medical Professionals
According to the workgroup, a timely and accurate diagnosis of Alzheimer’s disease and related dementias increases patient autonomy when he or she is most able to participate in goals of treatment and life and care decisions. It also allows for early intervention to maximize support opportunities and treatment outcomes.
“These new guidelines will provide an important new tool for medical professionals to more accurately diagnose Alzheimer’s [disease] and other dementias. As a result, people will get the right care and appropriate treatments; families will get the right support and be able to plan for the future,” said James Hendrix, PhD, Alzheimer’s Association Director of Global Science Initiatives and a member of the workgroup. “Too often, cognitive and behavioral symptoms due to Alzheimer’s disease and other dementias are unrecognized or attributed to something else.”
“The guidelines can empower patients, families, and clinicians to expect that symptoms will be evaluated in a patient-centered, structured, and collaborative manner,” Dr. Atri said. “In addition, they help to ensure that, regardless of the specific diagnosis, the results are communicated in a timely and compassionate way to help patients and families live the best lives possible.”
A care partner almost always should be involved in the evaluation, the guidelines advise.
A care partner almost always should be involved in the evaluation, the guidelines advise.
CHICAGO—An Alzheimer’s Association workgroup has developed 20 recommendations for the clinical evaluation of patients with cognitive or behavioral complaints. All middle-aged or older individuals who report or whose care partner or clinician reports cognitive, behavioral, or functional changes should undergo a timely evaluation, the guidelines advise. A care partner almost always should be involved the evaluation, according to the guidelines.
The recommendations cover the recognition and evaluation of symptoms, selection of brain imaging and other tests, and communication with and support of affected individuals and their caregivers.
Alireza Atri, MD, PhD, cochair of the workgroup, presented the recommendations at AAIC 2018. The authors plan to finalize and publish the guidelines in 2018.
“Until now, we have not had highly specific and multispecialty US national guidelines that can inform the diagnostic process across all care settings and that provide standards meant to improve patient autonomy, care, and outcomes,” said Dr. Atri, Director of the Banner Sun Health Research Institute in Sun City, Arizona, and Lecturer in Neurology at the Center for Brain/Mind Medicine at Brigham and Women’s Hospital and Harvard Medical School in Boston.
Cognitive Behavioral Syndromes
The clinical practice guidelines recognize a broad category of cognitive behavioral syndromes marked by memory and thinking symptoms as well as changes in sleep, anxiety, personality, and relationships.
The Alzheimer’s Association in 2017 convened a Diagnostic Evaluation Clinical Practice Guideline workgroup to develop evidence-based guidelines. The group includes experts in medical, neuropsychologic, and nursing specialties. The members conducted a systematic review of the literature and made recommendations using a modified Delphi consensus process. They graded the recommendations as “A” (must be done; will improve outcomes in almost all cases), “B” (should be done), and “C” (may be done).
The recommendations emphasize obtaining a history from not only the patient, but also from someone who knows the patient well to establish the presence and characteristics of any substantial changes and to categorize the cognitive behavioral syndrome.
Other recommendations for evaluating patients with cognitive behavioral syndromes include the following:
- For patients with atypical or rapidly progressive cognitive behavioral symptoms, the clinician should expedite an evaluation and strongly consider referral to a specialist. (Level A)
- The evaluation process should use tiers of assessments and tests based on a patient’s presentation, risk factors, and profile. (Level A)
- The clinician should involve an informant to obtain reliable information about changes in cognition, activities of daily living, mood and other neuropsychiatric symptoms, and sensory and motor function. Use of structured instruments for assessing these domains is helpful. (Level A)
- Clinicians should use validated tools to assess cognition. (Level A)
- When office-based cognitive assessment is not sufficiently informative (eg, when interpretation of results is uncertain due to a complex clinical profile or confounding demographic characteristics), neuropsychologic evaluation is recommended. (Level A)
- The clinician should obtain MRI as a first-tier approach to aid in establishing etiology. If MRI is not available or is contraindicated, CT should be obtained. (Level B)
- If etiology remains uncertain after interpretation of structural imaging, a dementia specialist can obtain molecular imaging with FDG-PET to improve diagnostic accuracy. (Level B)
- In cases with continued diagnostic uncertainty, a dementia specialist can obtain CSF according to appropriate use criteria for analysis of aβ42 amyloid and tau/p-tau profiles to evaluate for Alzheimer’s disease pathology. (Level C)
- If diagnostic uncertainty remains after obtaining structural imaging and FDG-PET, and CSF aβ and tau/p-tau profiles are unavailable or uninterpretable, the dementia specialist can obtain an amyloid PET scan according to the appropriate use criteria. (Level C)
- In a patient with an established cognitive behavioral syndrome and a likely autosomal dominant family history, the dementia specialist should consider whether genetic testing is warranted. A genetic counselor should be involved throughout the process. (Level A)
A Tool for Medical Professionals
According to the workgroup, a timely and accurate diagnosis of Alzheimer’s disease and related dementias increases patient autonomy when he or she is most able to participate in goals of treatment and life and care decisions. It also allows for early intervention to maximize support opportunities and treatment outcomes.
“These new guidelines will provide an important new tool for medical professionals to more accurately diagnose Alzheimer’s [disease] and other dementias. As a result, people will get the right care and appropriate treatments; families will get the right support and be able to plan for the future,” said James Hendrix, PhD, Alzheimer’s Association Director of Global Science Initiatives and a member of the workgroup. “Too often, cognitive and behavioral symptoms due to Alzheimer’s disease and other dementias are unrecognized or attributed to something else.”
“The guidelines can empower patients, families, and clinicians to expect that symptoms will be evaluated in a patient-centered, structured, and collaborative manner,” Dr. Atri said. “In addition, they help to ensure that, regardless of the specific diagnosis, the results are communicated in a timely and compassionate way to help patients and families live the best lives possible.”
CHICAGO—An Alzheimer’s Association workgroup has developed 20 recommendations for the clinical evaluation of patients with cognitive or behavioral complaints. All middle-aged or older individuals who report or whose care partner or clinician reports cognitive, behavioral, or functional changes should undergo a timely evaluation, the guidelines advise. A care partner almost always should be involved the evaluation, according to the guidelines.
The recommendations cover the recognition and evaluation of symptoms, selection of brain imaging and other tests, and communication with and support of affected individuals and their caregivers.
Alireza Atri, MD, PhD, cochair of the workgroup, presented the recommendations at AAIC 2018. The authors plan to finalize and publish the guidelines in 2018.
“Until now, we have not had highly specific and multispecialty US national guidelines that can inform the diagnostic process across all care settings and that provide standards meant to improve patient autonomy, care, and outcomes,” said Dr. Atri, Director of the Banner Sun Health Research Institute in Sun City, Arizona, and Lecturer in Neurology at the Center for Brain/Mind Medicine at Brigham and Women’s Hospital and Harvard Medical School in Boston.
Cognitive Behavioral Syndromes
The clinical practice guidelines recognize a broad category of cognitive behavioral syndromes marked by memory and thinking symptoms as well as changes in sleep, anxiety, personality, and relationships.
The Alzheimer’s Association in 2017 convened a Diagnostic Evaluation Clinical Practice Guideline workgroup to develop evidence-based guidelines. The group includes experts in medical, neuropsychologic, and nursing specialties. The members conducted a systematic review of the literature and made recommendations using a modified Delphi consensus process. They graded the recommendations as “A” (must be done; will improve outcomes in almost all cases), “B” (should be done), and “C” (may be done).
The recommendations emphasize obtaining a history from not only the patient, but also from someone who knows the patient well to establish the presence and characteristics of any substantial changes and to categorize the cognitive behavioral syndrome.
Other recommendations for evaluating patients with cognitive behavioral syndromes include the following:
- For patients with atypical or rapidly progressive cognitive behavioral symptoms, the clinician should expedite an evaluation and strongly consider referral to a specialist. (Level A)
- The evaluation process should use tiers of assessments and tests based on a patient’s presentation, risk factors, and profile. (Level A)
- The clinician should involve an informant to obtain reliable information about changes in cognition, activities of daily living, mood and other neuropsychiatric symptoms, and sensory and motor function. Use of structured instruments for assessing these domains is helpful. (Level A)
- Clinicians should use validated tools to assess cognition. (Level A)
- When office-based cognitive assessment is not sufficiently informative (eg, when interpretation of results is uncertain due to a complex clinical profile or confounding demographic characteristics), neuropsychologic evaluation is recommended. (Level A)
- The clinician should obtain MRI as a first-tier approach to aid in establishing etiology. If MRI is not available or is contraindicated, CT should be obtained. (Level B)
- If etiology remains uncertain after interpretation of structural imaging, a dementia specialist can obtain molecular imaging with FDG-PET to improve diagnostic accuracy. (Level B)
- In cases with continued diagnostic uncertainty, a dementia specialist can obtain CSF according to appropriate use criteria for analysis of aβ42 amyloid and tau/p-tau profiles to evaluate for Alzheimer’s disease pathology. (Level C)
- If diagnostic uncertainty remains after obtaining structural imaging and FDG-PET, and CSF aβ and tau/p-tau profiles are unavailable or uninterpretable, the dementia specialist can obtain an amyloid PET scan according to the appropriate use criteria. (Level C)
- In a patient with an established cognitive behavioral syndrome and a likely autosomal dominant family history, the dementia specialist should consider whether genetic testing is warranted. A genetic counselor should be involved throughout the process. (Level A)
A Tool for Medical Professionals
According to the workgroup, a timely and accurate diagnosis of Alzheimer’s disease and related dementias increases patient autonomy when he or she is most able to participate in goals of treatment and life and care decisions. It also allows for early intervention to maximize support opportunities and treatment outcomes.
“These new guidelines will provide an important new tool for medical professionals to more accurately diagnose Alzheimer’s [disease] and other dementias. As a result, people will get the right care and appropriate treatments; families will get the right support and be able to plan for the future,” said James Hendrix, PhD, Alzheimer’s Association Director of Global Science Initiatives and a member of the workgroup. “Too often, cognitive and behavioral symptoms due to Alzheimer’s disease and other dementias are unrecognized or attributed to something else.”
“The guidelines can empower patients, families, and clinicians to expect that symptoms will be evaluated in a patient-centered, structured, and collaborative manner,” Dr. Atri said. “In addition, they help to ensure that, regardless of the specific diagnosis, the results are communicated in a timely and compassionate way to help patients and families live the best lives possible.”
BAN2401 subanalyses attempt to ease concerns over study design and findings
BARCELONA – Alzheimer’s disease genetic risk status didn’t influence positive findings of the investigational monoclonal antibody, BAN2401, in a post hoc analysis of a phase 2 study’s secondary endpoint, Eisai said in a report released during the Clinical Trials on Alzheimer’s Disease conference.
In fact, according to the new analysis, the positive data presented last summer probably underestimated the molecule’s benefit to homozygous carriers of the apolipoprotein E epsilon-4 (APOE4), Chad Swanson, PhD, said at the meeting.
The new data cut was based on a small fraction of the 856 patients with early Alzheimer’s disease (AD) who were enrolled in Study 201: 10 APOE4 carriers and 69 noncarriers who completed 18 months on infusions of BAN2401 at 10 mg/kg biweekly, the only beneficial dose. The subanalysis determined that carriers benefited much more than did noncarriers on the three clinical measures, said Dr. Swanson, senior director of neurology clinical research at Eisai, and the study’s director:
- The Alzheimer’s Disease Composite Score (ADCOMS), a new measure of subtle cognitive changes in early disease: Carriers, 63% less decline than placebo vs. 7% less in noncarriers.
- Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog): Carriers, 84% less decline than placebo vs. 43% less in noncarriers.
- Clinical Dementia Rating-Sum of Boxes (CDR-SB): Carriers, 60% less decline than placebo vs. a 7% worsening in noncarriers.
To strengthen the power of the analysis, Dr. Swanson pooled data from the entire 18 months of both the 10 mg/kg biweekly and the next-highest dose (10 mg/kg monthly). This increased the numbers to 273 carriers and 141 noncarriers who had at least one exposure to the antibody.
He said this corrected the APOE4 imbalance and showed a 25% slowing of ADCOMS decline in carriers, a 6% slowing in noncarriers, and a 21% slowing overall, relative to placebo.
The somewhat counterintuitive findings took even copresenter Jeffrey L. Cummings, MD, by surprise.
“I would have hypothesized a greater effect in noncarriers than carriers, but that’s the great thing about data – they challenge our assumptions,” said Dr. Cummings, director of the Center for Neurodegeneration and Translational Neuroscience and director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas and a consultant for both Eisai and Biogen, the company’s BAN2401 developmental partner. He postulated that APOE4-driven differences in plaque composition could have contributed to the observed benefit. “I think this also points to a very interesting biology that we don’t yet know. The plaque compactness is different, the distribution of diffuse plaques is different. This will bear a lot of additional analysis.”
Study 201 randomized patients with early Alzheimer’s to up to 18 months of treatment with placebo or infusions of BAN2401 at 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, or 10 mg/kg biweekly. It had two unusual design features. First, patents were allocated to treatment arms by a Bayesian algorithm. The computer program examined results after every 50 enrollees and then allocated new subjects to what were, at that point, the most effective two doses. Additionally, the 18-month study was designed with a potential 12-month exit point, if computer modeling showed that it had at least an 80% probability of reaching at least a 25% cognitive benefit. In December, Eisai announced that the study hit just a 64% probability, missing the primary endpoint. But because Eisai felt the numbers were moving in the right direction, it continued with the additional 6 months of treatment, as allowed for in the study design, and then reanalyzed results with conventional statistics.
Thus, the successes reported at the Alzheimer’s Association International Conference in July and reanalyzed at CTAD, were secondary cognitive and functional outcomes.
Partway through the trial, a European regulatory body became alarmed at the rate of amyloid-related imaging abnormalities (ARIA) in the APOE4 carriers and excluded them from the highest-dose group. This meant that carriers comprised about 70%-80% of every unsuccessful treatment arm but just 29% of the successful one. The unbalanced randomization caused July’s skepticism. The CTAD subanalysis didn’t entirely alleviate it, and several acclaimed Alzheimer’s researchers gave it voice.
“You showed no difference in placebo rates of decline, but an increased benefit in the E4 carriers, which was really interesting,” said Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston. “One difference in the E4 carriers was their rate of ARIA and how long they stayed in the study. How did you account for these issues in this analysis?”
“We didn’t specifically look at that kind of question,” Dr. Swanson said. “I think we feel that we actually see effects in both carriers and noncarriers, and we are still exploring the data and will keep looking through them to see what we can find.”
Gil Rabinovici, MD, also expressed some reservations.
“I agree that the post hoc analyses are encouraging, but I wouldn’t say they alleviate the concern when you have such a dramatic imbalance in a core feature of this disease, like APOE4 between the placebo and the high-dose group,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. “The people on this panel know far more than I do of the pitfalls of these kinds of analyses. We really need to see true randomization to put this issue to rest.”
Biomarkers support subanalysis finding
Dr. Swanson also presented new cerebrospinal fluid biomarker data showing changes in phosphorylated tau, neurogranin, and neurofilament light chain that support the overall 47% slowing of cognitive decline reported last summer. The 10 mg/kg biweekly and monthly groups were again combined to increase the sample size, but it remained quite small, with full data on 16 in the placebo group and 23 in the active group:
- Neurogranin, a synaptic protein that is a marker of neuronal damage, decreased by a median 58 pg/mL (11%), compared with a 13.5-pg/mL increase in the placebo group.
- Phosphorylated tau, a marker of tau pathology in the brain, decreased by a median 12 pg/mL (13%), compared with no change in the placebo group.
- Neurofilament light chain, a neuronal structural scaffold protein that is a marker of axonal degeneration, increased by a median 75 pg/mL in the active group, compared with a 156-pg/mL increase in the placebo group – a 48% difference.
The positive biomarker data bolstered the subanalysis to some extent, researchers felt. But in the end, Study 201 is just a first step for BAN2401, said Laurie Ryan, PhD, chief of the dementias of aging branch in the division of neuroscience at the National Institute on Aging.
“Today’s presentation gave us a new look at the trial data from the summer,” Dr. Ryan said in an interview. “The new analysis supports the findings previously released but is still preliminary. Nothing is definitive in a phase 2 study, so while it appears to suggest a potential positive, beneficial result, it needs further testing.”
Eisai has made its subanalysis presentation slides publicly available.
Dr. Swanson is an employee of Eisai. Dr. Cummings is a consultant for Eisai and Biogen. Dr. Sperling has consulted for numerous pharmaceutical companies. Dr. Rabinovici and Dr. Ryan have no disclosures.
SOURCE: Swanson C et al. CTAD, Symposium 3.
BARCELONA – Alzheimer’s disease genetic risk status didn’t influence positive findings of the investigational monoclonal antibody, BAN2401, in a post hoc analysis of a phase 2 study’s secondary endpoint, Eisai said in a report released during the Clinical Trials on Alzheimer’s Disease conference.
In fact, according to the new analysis, the positive data presented last summer probably underestimated the molecule’s benefit to homozygous carriers of the apolipoprotein E epsilon-4 (APOE4), Chad Swanson, PhD, said at the meeting.
The new data cut was based on a small fraction of the 856 patients with early Alzheimer’s disease (AD) who were enrolled in Study 201: 10 APOE4 carriers and 69 noncarriers who completed 18 months on infusions of BAN2401 at 10 mg/kg biweekly, the only beneficial dose. The subanalysis determined that carriers benefited much more than did noncarriers on the three clinical measures, said Dr. Swanson, senior director of neurology clinical research at Eisai, and the study’s director:
- The Alzheimer’s Disease Composite Score (ADCOMS), a new measure of subtle cognitive changes in early disease: Carriers, 63% less decline than placebo vs. 7% less in noncarriers.
- Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog): Carriers, 84% less decline than placebo vs. 43% less in noncarriers.
- Clinical Dementia Rating-Sum of Boxes (CDR-SB): Carriers, 60% less decline than placebo vs. a 7% worsening in noncarriers.
To strengthen the power of the analysis, Dr. Swanson pooled data from the entire 18 months of both the 10 mg/kg biweekly and the next-highest dose (10 mg/kg monthly). This increased the numbers to 273 carriers and 141 noncarriers who had at least one exposure to the antibody.
He said this corrected the APOE4 imbalance and showed a 25% slowing of ADCOMS decline in carriers, a 6% slowing in noncarriers, and a 21% slowing overall, relative to placebo.
The somewhat counterintuitive findings took even copresenter Jeffrey L. Cummings, MD, by surprise.
“I would have hypothesized a greater effect in noncarriers than carriers, but that’s the great thing about data – they challenge our assumptions,” said Dr. Cummings, director of the Center for Neurodegeneration and Translational Neuroscience and director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas and a consultant for both Eisai and Biogen, the company’s BAN2401 developmental partner. He postulated that APOE4-driven differences in plaque composition could have contributed to the observed benefit. “I think this also points to a very interesting biology that we don’t yet know. The plaque compactness is different, the distribution of diffuse plaques is different. This will bear a lot of additional analysis.”
Study 201 randomized patients with early Alzheimer’s to up to 18 months of treatment with placebo or infusions of BAN2401 at 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, or 10 mg/kg biweekly. It had two unusual design features. First, patents were allocated to treatment arms by a Bayesian algorithm. The computer program examined results after every 50 enrollees and then allocated new subjects to what were, at that point, the most effective two doses. Additionally, the 18-month study was designed with a potential 12-month exit point, if computer modeling showed that it had at least an 80% probability of reaching at least a 25% cognitive benefit. In December, Eisai announced that the study hit just a 64% probability, missing the primary endpoint. But because Eisai felt the numbers were moving in the right direction, it continued with the additional 6 months of treatment, as allowed for in the study design, and then reanalyzed results with conventional statistics.
Thus, the successes reported at the Alzheimer’s Association International Conference in July and reanalyzed at CTAD, were secondary cognitive and functional outcomes.
Partway through the trial, a European regulatory body became alarmed at the rate of amyloid-related imaging abnormalities (ARIA) in the APOE4 carriers and excluded them from the highest-dose group. This meant that carriers comprised about 70%-80% of every unsuccessful treatment arm but just 29% of the successful one. The unbalanced randomization caused July’s skepticism. The CTAD subanalysis didn’t entirely alleviate it, and several acclaimed Alzheimer’s researchers gave it voice.
“You showed no difference in placebo rates of decline, but an increased benefit in the E4 carriers, which was really interesting,” said Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston. “One difference in the E4 carriers was their rate of ARIA and how long they stayed in the study. How did you account for these issues in this analysis?”
“We didn’t specifically look at that kind of question,” Dr. Swanson said. “I think we feel that we actually see effects in both carriers and noncarriers, and we are still exploring the data and will keep looking through them to see what we can find.”
Gil Rabinovici, MD, also expressed some reservations.
“I agree that the post hoc analyses are encouraging, but I wouldn’t say they alleviate the concern when you have such a dramatic imbalance in a core feature of this disease, like APOE4 between the placebo and the high-dose group,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. “The people on this panel know far more than I do of the pitfalls of these kinds of analyses. We really need to see true randomization to put this issue to rest.”
Biomarkers support subanalysis finding
Dr. Swanson also presented new cerebrospinal fluid biomarker data showing changes in phosphorylated tau, neurogranin, and neurofilament light chain that support the overall 47% slowing of cognitive decline reported last summer. The 10 mg/kg biweekly and monthly groups were again combined to increase the sample size, but it remained quite small, with full data on 16 in the placebo group and 23 in the active group:
- Neurogranin, a synaptic protein that is a marker of neuronal damage, decreased by a median 58 pg/mL (11%), compared with a 13.5-pg/mL increase in the placebo group.
- Phosphorylated tau, a marker of tau pathology in the brain, decreased by a median 12 pg/mL (13%), compared with no change in the placebo group.
- Neurofilament light chain, a neuronal structural scaffold protein that is a marker of axonal degeneration, increased by a median 75 pg/mL in the active group, compared with a 156-pg/mL increase in the placebo group – a 48% difference.
The positive biomarker data bolstered the subanalysis to some extent, researchers felt. But in the end, Study 201 is just a first step for BAN2401, said Laurie Ryan, PhD, chief of the dementias of aging branch in the division of neuroscience at the National Institute on Aging.
“Today’s presentation gave us a new look at the trial data from the summer,” Dr. Ryan said in an interview. “The new analysis supports the findings previously released but is still preliminary. Nothing is definitive in a phase 2 study, so while it appears to suggest a potential positive, beneficial result, it needs further testing.”
Eisai has made its subanalysis presentation slides publicly available.
Dr. Swanson is an employee of Eisai. Dr. Cummings is a consultant for Eisai and Biogen. Dr. Sperling has consulted for numerous pharmaceutical companies. Dr. Rabinovici and Dr. Ryan have no disclosures.
SOURCE: Swanson C et al. CTAD, Symposium 3.
BARCELONA – Alzheimer’s disease genetic risk status didn’t influence positive findings of the investigational monoclonal antibody, BAN2401, in a post hoc analysis of a phase 2 study’s secondary endpoint, Eisai said in a report released during the Clinical Trials on Alzheimer’s Disease conference.
In fact, according to the new analysis, the positive data presented last summer probably underestimated the molecule’s benefit to homozygous carriers of the apolipoprotein E epsilon-4 (APOE4), Chad Swanson, PhD, said at the meeting.
The new data cut was based on a small fraction of the 856 patients with early Alzheimer’s disease (AD) who were enrolled in Study 201: 10 APOE4 carriers and 69 noncarriers who completed 18 months on infusions of BAN2401 at 10 mg/kg biweekly, the only beneficial dose. The subanalysis determined that carriers benefited much more than did noncarriers on the three clinical measures, said Dr. Swanson, senior director of neurology clinical research at Eisai, and the study’s director:
- The Alzheimer’s Disease Composite Score (ADCOMS), a new measure of subtle cognitive changes in early disease: Carriers, 63% less decline than placebo vs. 7% less in noncarriers.
- Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog): Carriers, 84% less decline than placebo vs. 43% less in noncarriers.
- Clinical Dementia Rating-Sum of Boxes (CDR-SB): Carriers, 60% less decline than placebo vs. a 7% worsening in noncarriers.
To strengthen the power of the analysis, Dr. Swanson pooled data from the entire 18 months of both the 10 mg/kg biweekly and the next-highest dose (10 mg/kg monthly). This increased the numbers to 273 carriers and 141 noncarriers who had at least one exposure to the antibody.
He said this corrected the APOE4 imbalance and showed a 25% slowing of ADCOMS decline in carriers, a 6% slowing in noncarriers, and a 21% slowing overall, relative to placebo.
The somewhat counterintuitive findings took even copresenter Jeffrey L. Cummings, MD, by surprise.
“I would have hypothesized a greater effect in noncarriers than carriers, but that’s the great thing about data – they challenge our assumptions,” said Dr. Cummings, director of the Center for Neurodegeneration and Translational Neuroscience and director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas and a consultant for both Eisai and Biogen, the company’s BAN2401 developmental partner. He postulated that APOE4-driven differences in plaque composition could have contributed to the observed benefit. “I think this also points to a very interesting biology that we don’t yet know. The plaque compactness is different, the distribution of diffuse plaques is different. This will bear a lot of additional analysis.”
Study 201 randomized patients with early Alzheimer’s to up to 18 months of treatment with placebo or infusions of BAN2401 at 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, or 10 mg/kg biweekly. It had two unusual design features. First, patents were allocated to treatment arms by a Bayesian algorithm. The computer program examined results after every 50 enrollees and then allocated new subjects to what were, at that point, the most effective two doses. Additionally, the 18-month study was designed with a potential 12-month exit point, if computer modeling showed that it had at least an 80% probability of reaching at least a 25% cognitive benefit. In December, Eisai announced that the study hit just a 64% probability, missing the primary endpoint. But because Eisai felt the numbers were moving in the right direction, it continued with the additional 6 months of treatment, as allowed for in the study design, and then reanalyzed results with conventional statistics.
Thus, the successes reported at the Alzheimer’s Association International Conference in July and reanalyzed at CTAD, were secondary cognitive and functional outcomes.
Partway through the trial, a European regulatory body became alarmed at the rate of amyloid-related imaging abnormalities (ARIA) in the APOE4 carriers and excluded them from the highest-dose group. This meant that carriers comprised about 70%-80% of every unsuccessful treatment arm but just 29% of the successful one. The unbalanced randomization caused July’s skepticism. The CTAD subanalysis didn’t entirely alleviate it, and several acclaimed Alzheimer’s researchers gave it voice.
“You showed no difference in placebo rates of decline, but an increased benefit in the E4 carriers, which was really interesting,” said Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston. “One difference in the E4 carriers was their rate of ARIA and how long they stayed in the study. How did you account for these issues in this analysis?”
“We didn’t specifically look at that kind of question,” Dr. Swanson said. “I think we feel that we actually see effects in both carriers and noncarriers, and we are still exploring the data and will keep looking through them to see what we can find.”
Gil Rabinovici, MD, also expressed some reservations.
“I agree that the post hoc analyses are encouraging, but I wouldn’t say they alleviate the concern when you have such a dramatic imbalance in a core feature of this disease, like APOE4 between the placebo and the high-dose group,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. “The people on this panel know far more than I do of the pitfalls of these kinds of analyses. We really need to see true randomization to put this issue to rest.”
Biomarkers support subanalysis finding
Dr. Swanson also presented new cerebrospinal fluid biomarker data showing changes in phosphorylated tau, neurogranin, and neurofilament light chain that support the overall 47% slowing of cognitive decline reported last summer. The 10 mg/kg biweekly and monthly groups were again combined to increase the sample size, but it remained quite small, with full data on 16 in the placebo group and 23 in the active group:
- Neurogranin, a synaptic protein that is a marker of neuronal damage, decreased by a median 58 pg/mL (11%), compared with a 13.5-pg/mL increase in the placebo group.
- Phosphorylated tau, a marker of tau pathology in the brain, decreased by a median 12 pg/mL (13%), compared with no change in the placebo group.
- Neurofilament light chain, a neuronal structural scaffold protein that is a marker of axonal degeneration, increased by a median 75 pg/mL in the active group, compared with a 156-pg/mL increase in the placebo group – a 48% difference.
The positive biomarker data bolstered the subanalysis to some extent, researchers felt. But in the end, Study 201 is just a first step for BAN2401, said Laurie Ryan, PhD, chief of the dementias of aging branch in the division of neuroscience at the National Institute on Aging.
“Today’s presentation gave us a new look at the trial data from the summer,” Dr. Ryan said in an interview. “The new analysis supports the findings previously released but is still preliminary. Nothing is definitive in a phase 2 study, so while it appears to suggest a potential positive, beneficial result, it needs further testing.”
Eisai has made its subanalysis presentation slides publicly available.
Dr. Swanson is an employee of Eisai. Dr. Cummings is a consultant for Eisai and Biogen. Dr. Sperling has consulted for numerous pharmaceutical companies. Dr. Rabinovici and Dr. Ryan have no disclosures.
SOURCE: Swanson C et al. CTAD, Symposium 3.
REPORTING FROM CTAD
Acute kidney injury linked to later dementia
SAN DIEGO –
That’s according to a new study offering more evidence of a link between kidney disease and neurological problems.
“Clinicians should know that AKI is associated with poor long-term outcomes,” said lead author Jessica B. Kendrick MD, associate professor of medicine at the University of Colorado, Aurora. “We need to identify ways to prevent these long-term consequences.”
The findings were presented at Kidney Week 2018, sponsored by the American Society of Nephrology.
According to Dr. Kendrick, the acute neurological effects of AKI are well known. But no previous studies have examined the potential long-term cerebrovascular complications of AKI.
For the new study, Dr. Kendrick and her colleagues retrospectively analyzed 2,082 hospitalized patients in Utah from 1999 to 2009: 1,041 who completely recovered from AKI by discharge, and 1,041 who did not have AKI.
The average age was 61 years, and the average baseline creatinine was 0.9 ± 0.2 mg/dL. Over a median follow-up of 6 years, 97 patients developed dementia.
Those with AKI were more likely to develop dementia compared with the control group: 7% vs. 2% (hazard ratio, 3.4; 95% confidence interval, 2.14-5.40).
Other studies have linked kidney disease to cognitive impairment.
“There are a lot of theories as to why this is,” nephrologist Daniel Weiner, MD, of Tufts University, Boston, said in an interview. “It is most likely that the presence of kidney disease identifies individuals with a high burden of vascular disease, and that vascular disease, particularly of the small blood vessels, is an important contributor to cognitive impairment and dementia.”
That appears to be most notable in people who have protein in their urine, Dr. Weiner added. “The presence of protein in the urine identifies a severe enough process to affect the blood vessels in the kidney, and there is no reason to think that blood vessels elsewhere in the body, including in the brain, are not similarly affected.”
As for the current study, Dr. Weiner said it could support the vascular disease theory.
“People with vulnerable kidneys to acute injury also have vulnerable brains to acute injury,” he said. “People who get AKI usually have susceptibility to perfusion-related kidney injury. In other words, the small blood vessels that supply the kidney are unable to compensate to maintain sufficient blood flow during a time of low blood pressure or other systemic illness.”
That vulnerability “suggests to me that small blood vessels elsewhere in the body are less likely to be able to respond to challenges like low blood pressure,” Dr. Weiner explained. “If this occurs in the brain, it leads to microvascular disease and greater abnormal white-matter burden. This change in the brain anatomy is highly correlated with cognitive impairment.”
How can physicians put these finding to use? “These patients may require more monitoring,” Dr. Kendrick said. “For example, patients with AKI and complete recovery may not have any follow-up with a nephrologist, and perhaps they should.”
Moving forward, she said, “we are examining the association of AKI with cognitive dysfunction in different patient populations.” Researchers also are planning studies to better understand the mechanisms that are at work, she said.
The National Heart, Lung, and Blood Institute funded the study. The study authors had no disclosures.
SOURCE: Kendrick JB et al. Kidney Week 2018. Abstract TH-OR116.
SAN DIEGO –
That’s according to a new study offering more evidence of a link between kidney disease and neurological problems.
“Clinicians should know that AKI is associated with poor long-term outcomes,” said lead author Jessica B. Kendrick MD, associate professor of medicine at the University of Colorado, Aurora. “We need to identify ways to prevent these long-term consequences.”
The findings were presented at Kidney Week 2018, sponsored by the American Society of Nephrology.
According to Dr. Kendrick, the acute neurological effects of AKI are well known. But no previous studies have examined the potential long-term cerebrovascular complications of AKI.
For the new study, Dr. Kendrick and her colleagues retrospectively analyzed 2,082 hospitalized patients in Utah from 1999 to 2009: 1,041 who completely recovered from AKI by discharge, and 1,041 who did not have AKI.
The average age was 61 years, and the average baseline creatinine was 0.9 ± 0.2 mg/dL. Over a median follow-up of 6 years, 97 patients developed dementia.
Those with AKI were more likely to develop dementia compared with the control group: 7% vs. 2% (hazard ratio, 3.4; 95% confidence interval, 2.14-5.40).
Other studies have linked kidney disease to cognitive impairment.
“There are a lot of theories as to why this is,” nephrologist Daniel Weiner, MD, of Tufts University, Boston, said in an interview. “It is most likely that the presence of kidney disease identifies individuals with a high burden of vascular disease, and that vascular disease, particularly of the small blood vessels, is an important contributor to cognitive impairment and dementia.”
That appears to be most notable in people who have protein in their urine, Dr. Weiner added. “The presence of protein in the urine identifies a severe enough process to affect the blood vessels in the kidney, and there is no reason to think that blood vessels elsewhere in the body, including in the brain, are not similarly affected.”
As for the current study, Dr. Weiner said it could support the vascular disease theory.
“People with vulnerable kidneys to acute injury also have vulnerable brains to acute injury,” he said. “People who get AKI usually have susceptibility to perfusion-related kidney injury. In other words, the small blood vessels that supply the kidney are unable to compensate to maintain sufficient blood flow during a time of low blood pressure or other systemic illness.”
That vulnerability “suggests to me that small blood vessels elsewhere in the body are less likely to be able to respond to challenges like low blood pressure,” Dr. Weiner explained. “If this occurs in the brain, it leads to microvascular disease and greater abnormal white-matter burden. This change in the brain anatomy is highly correlated with cognitive impairment.”
How can physicians put these finding to use? “These patients may require more monitoring,” Dr. Kendrick said. “For example, patients with AKI and complete recovery may not have any follow-up with a nephrologist, and perhaps they should.”
Moving forward, she said, “we are examining the association of AKI with cognitive dysfunction in different patient populations.” Researchers also are planning studies to better understand the mechanisms that are at work, she said.
The National Heart, Lung, and Blood Institute funded the study. The study authors had no disclosures.
SOURCE: Kendrick JB et al. Kidney Week 2018. Abstract TH-OR116.
SAN DIEGO –
That’s according to a new study offering more evidence of a link between kidney disease and neurological problems.
“Clinicians should know that AKI is associated with poor long-term outcomes,” said lead author Jessica B. Kendrick MD, associate professor of medicine at the University of Colorado, Aurora. “We need to identify ways to prevent these long-term consequences.”
The findings were presented at Kidney Week 2018, sponsored by the American Society of Nephrology.
According to Dr. Kendrick, the acute neurological effects of AKI are well known. But no previous studies have examined the potential long-term cerebrovascular complications of AKI.
For the new study, Dr. Kendrick and her colleagues retrospectively analyzed 2,082 hospitalized patients in Utah from 1999 to 2009: 1,041 who completely recovered from AKI by discharge, and 1,041 who did not have AKI.
The average age was 61 years, and the average baseline creatinine was 0.9 ± 0.2 mg/dL. Over a median follow-up of 6 years, 97 patients developed dementia.
Those with AKI were more likely to develop dementia compared with the control group: 7% vs. 2% (hazard ratio, 3.4; 95% confidence interval, 2.14-5.40).
Other studies have linked kidney disease to cognitive impairment.
“There are a lot of theories as to why this is,” nephrologist Daniel Weiner, MD, of Tufts University, Boston, said in an interview. “It is most likely that the presence of kidney disease identifies individuals with a high burden of vascular disease, and that vascular disease, particularly of the small blood vessels, is an important contributor to cognitive impairment and dementia.”
That appears to be most notable in people who have protein in their urine, Dr. Weiner added. “The presence of protein in the urine identifies a severe enough process to affect the blood vessels in the kidney, and there is no reason to think that blood vessels elsewhere in the body, including in the brain, are not similarly affected.”
As for the current study, Dr. Weiner said it could support the vascular disease theory.
“People with vulnerable kidneys to acute injury also have vulnerable brains to acute injury,” he said. “People who get AKI usually have susceptibility to perfusion-related kidney injury. In other words, the small blood vessels that supply the kidney are unable to compensate to maintain sufficient blood flow during a time of low blood pressure or other systemic illness.”
That vulnerability “suggests to me that small blood vessels elsewhere in the body are less likely to be able to respond to challenges like low blood pressure,” Dr. Weiner explained. “If this occurs in the brain, it leads to microvascular disease and greater abnormal white-matter burden. This change in the brain anatomy is highly correlated with cognitive impairment.”
How can physicians put these finding to use? “These patients may require more monitoring,” Dr. Kendrick said. “For example, patients with AKI and complete recovery may not have any follow-up with a nephrologist, and perhaps they should.”
Moving forward, she said, “we are examining the association of AKI with cognitive dysfunction in different patient populations.” Researchers also are planning studies to better understand the mechanisms that are at work, she said.
The National Heart, Lung, and Blood Institute funded the study. The study authors had no disclosures.
SOURCE: Kendrick JB et al. Kidney Week 2018. Abstract TH-OR116.
REPORTING FROM KIDNEY WEEK 2018
Key clinical point: Patients with acute kidney injury seem to face a much higher risk of dementia.
Major finding: Hospitalized patients with AKI were 3.4 times more likely to develop dementia within a median of 6 years, compared with other hospitalized patients.
Study details: A retrospective study of 2,082 propensity-matched hospitalized patients, 1,041 who had AKI and fully recovered, and 1,041 who did not have AKI.
Disclosures: The National Heart, Lung, and Blood Institute funded the study. The authors had no disclosures.
Source: Kendrick JB et al. Kidney Week 2018. Abstract No. TH-OR116.
Antipsychotic drugs failed to shorten ICU delirium
The antipsychotic medications in patients in intensive care, new research has found.
In a paper published in the New England Journal of Medicine, researchers reported the results of a randomized, double-blind, placebo-controlled trial in 566 patients with acute respiratory failure or shock and hypoactive or hyperactive delirium. Participants were randomized either to a maximum of 20 mg IV haloperidol daily, maximum 40 mg ziprasidone daily, or placebo.
At the end of the 14-day intervention period, the placebo group had a median of 8.5 days alive without delirium or coma, the haloperidol group had a median of 7.9 days, and the ziprasidone group had a median of 8.7 days. The difference between groups was not statistically significant.
There were also no significant differences between the three groups in the secondary end point of duration of delirium and coma, 30-day and 90-day survival, time to freedom from mechanical ventilation, ICU discharge, ICU readmission, or hospital discharge.
Timothy D. Girard, MD, from the department of critical care at the University of Pittsburgh, and his coauthors wrote that their findings echoed those of two previous placebo-controlled trials in smaller numbers of ICU patients.
“One possible reason that we found no evidence that the use of haloperidol or ziprasidone resulted in a fewer days with delirium or coma than placebo is that the mechanism of brain dysfunction that is considered to be targeted by antipsychotic medications – increased dopamine signaling – may not play a major role in the pathogenesis of delirium during critical illness,” they wrote.
“In the current trial, approximately 90% of the patients received one or more doses of sedatives or analgesics, and the doses of sedatives and offtrial antipsychotic medications and the durations of exposures to those agents were similar in all trial groups,” the authors added.
Most of the patients in the trial had hypotensive delirium, which made it difficult to assess the effects of antipsychotics on hypertensive delirium.
The authors also commented that the patients enrolled were a mixed group, so their findings did not rule out the possibility that certain subgroups of patients – such as nonintubated patients with hyperactive delirium, those with alcohol withdrawal, or with other delirium phenotypes – may still benefit from antipsychotics.
Patients treated with ziprasidone were more likely to experience prolongation of the corrected QT interval. Two patients in the haloperidol group developed torsades de pointes but neither had received haloperidol in the 4 days preceding the onset of the arrhythmia.
One patient in each group – including the placebo group – experienced extrapyramidal symptoms and had treatment withheld. One patient in the haloperidol group also had the trial drug withheld because of suspected neuroleptic malignant syndrome, but this was later ruled out, and one patient had haloperidol withheld because of dystonia.
The dose of haloperidol used in the study was considered high, the authors said, but they left open the possibility that even higher doses might help. However, they also noted that doses of 25 mg and above were known to have adverse effects on cognition, which is why they chose the 20-mg dosage.
The study was supported by the National Institutes of Health and the Department of Veterans Affairs Geriatric Research Education and Clinical Center. Most authors declared support from the NIH or VA during the course of the study. Four authors also reported fees and grants from private industry outside the context of the study.
SOURCE: Girard TD et al. N Engl J Med.2018 Oct 22. doi: 10.1056/NEJMoa1808217.
In a comment published with this study, Thomas P. Bleck, MD, of the department of neurologic sciences at Rush Medical College, Chicago, wrote, “A change in mental status in a patient in intensive care can be one of the most vexing problems. In the past 2 decades, the idea has arisen that antipsychotic drugs – and particularly dopamine antagonists, which ameliorate thought disorders in psychotic patients – could help patients with disordered thinking in other contexts, such as the intensive care unit. However, yet another trial has now called this idea into question.”
He noted that, in the study group, a bolus of placebo was just as effective as a bolus of active medication, which may be because of the majority of patients having hypoactive delirium, which the active drugs may not impact.
“I would still consider using dopamine agonists in patients at imminent risk of injurious behaviors but have less confidence in their benefits than I once had,” Dr. Bleck wrote.
Dr. Bleck did not report any conflicts of interest.
In a comment published with this study, Thomas P. Bleck, MD, of the department of neurologic sciences at Rush Medical College, Chicago, wrote, “A change in mental status in a patient in intensive care can be one of the most vexing problems. In the past 2 decades, the idea has arisen that antipsychotic drugs – and particularly dopamine antagonists, which ameliorate thought disorders in psychotic patients – could help patients with disordered thinking in other contexts, such as the intensive care unit. However, yet another trial has now called this idea into question.”
He noted that, in the study group, a bolus of placebo was just as effective as a bolus of active medication, which may be because of the majority of patients having hypoactive delirium, which the active drugs may not impact.
“I would still consider using dopamine agonists in patients at imminent risk of injurious behaviors but have less confidence in their benefits than I once had,” Dr. Bleck wrote.
Dr. Bleck did not report any conflicts of interest.
In a comment published with this study, Thomas P. Bleck, MD, of the department of neurologic sciences at Rush Medical College, Chicago, wrote, “A change in mental status in a patient in intensive care can be one of the most vexing problems. In the past 2 decades, the idea has arisen that antipsychotic drugs – and particularly dopamine antagonists, which ameliorate thought disorders in psychotic patients – could help patients with disordered thinking in other contexts, such as the intensive care unit. However, yet another trial has now called this idea into question.”
He noted that, in the study group, a bolus of placebo was just as effective as a bolus of active medication, which may be because of the majority of patients having hypoactive delirium, which the active drugs may not impact.
“I would still consider using dopamine agonists in patients at imminent risk of injurious behaviors but have less confidence in their benefits than I once had,” Dr. Bleck wrote.
Dr. Bleck did not report any conflicts of interest.
The antipsychotic medications in patients in intensive care, new research has found.
In a paper published in the New England Journal of Medicine, researchers reported the results of a randomized, double-blind, placebo-controlled trial in 566 patients with acute respiratory failure or shock and hypoactive or hyperactive delirium. Participants were randomized either to a maximum of 20 mg IV haloperidol daily, maximum 40 mg ziprasidone daily, or placebo.
At the end of the 14-day intervention period, the placebo group had a median of 8.5 days alive without delirium or coma, the haloperidol group had a median of 7.9 days, and the ziprasidone group had a median of 8.7 days. The difference between groups was not statistically significant.
There were also no significant differences between the three groups in the secondary end point of duration of delirium and coma, 30-day and 90-day survival, time to freedom from mechanical ventilation, ICU discharge, ICU readmission, or hospital discharge.
Timothy D. Girard, MD, from the department of critical care at the University of Pittsburgh, and his coauthors wrote that their findings echoed those of two previous placebo-controlled trials in smaller numbers of ICU patients.
“One possible reason that we found no evidence that the use of haloperidol or ziprasidone resulted in a fewer days with delirium or coma than placebo is that the mechanism of brain dysfunction that is considered to be targeted by antipsychotic medications – increased dopamine signaling – may not play a major role in the pathogenesis of delirium during critical illness,” they wrote.
“In the current trial, approximately 90% of the patients received one or more doses of sedatives or analgesics, and the doses of sedatives and offtrial antipsychotic medications and the durations of exposures to those agents were similar in all trial groups,” the authors added.
Most of the patients in the trial had hypotensive delirium, which made it difficult to assess the effects of antipsychotics on hypertensive delirium.
The authors also commented that the patients enrolled were a mixed group, so their findings did not rule out the possibility that certain subgroups of patients – such as nonintubated patients with hyperactive delirium, those with alcohol withdrawal, or with other delirium phenotypes – may still benefit from antipsychotics.
Patients treated with ziprasidone were more likely to experience prolongation of the corrected QT interval. Two patients in the haloperidol group developed torsades de pointes but neither had received haloperidol in the 4 days preceding the onset of the arrhythmia.
One patient in each group – including the placebo group – experienced extrapyramidal symptoms and had treatment withheld. One patient in the haloperidol group also had the trial drug withheld because of suspected neuroleptic malignant syndrome, but this was later ruled out, and one patient had haloperidol withheld because of dystonia.
The dose of haloperidol used in the study was considered high, the authors said, but they left open the possibility that even higher doses might help. However, they also noted that doses of 25 mg and above were known to have adverse effects on cognition, which is why they chose the 20-mg dosage.
The study was supported by the National Institutes of Health and the Department of Veterans Affairs Geriatric Research Education and Clinical Center. Most authors declared support from the NIH or VA during the course of the study. Four authors also reported fees and grants from private industry outside the context of the study.
SOURCE: Girard TD et al. N Engl J Med.2018 Oct 22. doi: 10.1056/NEJMoa1808217.
The antipsychotic medications in patients in intensive care, new research has found.
In a paper published in the New England Journal of Medicine, researchers reported the results of a randomized, double-blind, placebo-controlled trial in 566 patients with acute respiratory failure or shock and hypoactive or hyperactive delirium. Participants were randomized either to a maximum of 20 mg IV haloperidol daily, maximum 40 mg ziprasidone daily, or placebo.
At the end of the 14-day intervention period, the placebo group had a median of 8.5 days alive without delirium or coma, the haloperidol group had a median of 7.9 days, and the ziprasidone group had a median of 8.7 days. The difference between groups was not statistically significant.
There were also no significant differences between the three groups in the secondary end point of duration of delirium and coma, 30-day and 90-day survival, time to freedom from mechanical ventilation, ICU discharge, ICU readmission, or hospital discharge.
Timothy D. Girard, MD, from the department of critical care at the University of Pittsburgh, and his coauthors wrote that their findings echoed those of two previous placebo-controlled trials in smaller numbers of ICU patients.
“One possible reason that we found no evidence that the use of haloperidol or ziprasidone resulted in a fewer days with delirium or coma than placebo is that the mechanism of brain dysfunction that is considered to be targeted by antipsychotic medications – increased dopamine signaling – may not play a major role in the pathogenesis of delirium during critical illness,” they wrote.
“In the current trial, approximately 90% of the patients received one or more doses of sedatives or analgesics, and the doses of sedatives and offtrial antipsychotic medications and the durations of exposures to those agents were similar in all trial groups,” the authors added.
Most of the patients in the trial had hypotensive delirium, which made it difficult to assess the effects of antipsychotics on hypertensive delirium.
The authors also commented that the patients enrolled were a mixed group, so their findings did not rule out the possibility that certain subgroups of patients – such as nonintubated patients with hyperactive delirium, those with alcohol withdrawal, or with other delirium phenotypes – may still benefit from antipsychotics.
Patients treated with ziprasidone were more likely to experience prolongation of the corrected QT interval. Two patients in the haloperidol group developed torsades de pointes but neither had received haloperidol in the 4 days preceding the onset of the arrhythmia.
One patient in each group – including the placebo group – experienced extrapyramidal symptoms and had treatment withheld. One patient in the haloperidol group also had the trial drug withheld because of suspected neuroleptic malignant syndrome, but this was later ruled out, and one patient had haloperidol withheld because of dystonia.
The dose of haloperidol used in the study was considered high, the authors said, but they left open the possibility that even higher doses might help. However, they also noted that doses of 25 mg and above were known to have adverse effects on cognition, which is why they chose the 20-mg dosage.
The study was supported by the National Institutes of Health and the Department of Veterans Affairs Geriatric Research Education and Clinical Center. Most authors declared support from the NIH or VA during the course of the study. Four authors also reported fees and grants from private industry outside the context of the study.
SOURCE: Girard TD et al. N Engl J Med.2018 Oct 22. doi: 10.1056/NEJMoa1808217.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Antipsychotics do not reduce the duration or incidence of delirium in intensive care.
Major finding: Patients treated with antipsychotics showed similar median days without delirium or coma, compared with those treated with placebo.
Study details: A randomized, double-blind, placebo-controlled trial in 566 intensive care patients.
Disclosures: The study was supported by the National Institutes of Health and the Department of Veterans Affairs Geriatric Research Education and Clinical Center. Most authors were supported by the NIH or VA during the course of the study. Four authors also reported fees and grants from private industry outside the context of the study.
Source: Girard TD et al. N Engl J Med. 2018 Oct 22. doi: 10.1056/NEJMoa1808217.