Literature Review

Cognitive decline in middle age may not result from β-amyloid deposition, according to a study published online ahead of print March 16 in JAMA Neurology. Declines in memory and hippocampal volume occur at earlier ages than abnormal amyloid PET does, which implies that these outcomes “must have some mechanistic independence from β-amyloid accumulation,” said Clifford R. Jack, Jr., MD, Professor of Radiology at Mayo Clinic in Rochester, Minnesota.

From age 70 onward, median amyloid PET accumulation is greater in cognitively normal individuals with the APOE ε4 allele, compared with people without the allele. In addition, abnormal amyloid PET may appear at an earlier age among APOE ε4 carriers, compared with noncarriers. The study results also indicate that male gender, but not APOE ε4, is associated with worse memory and adjusted hippocampal volume among cognitively normal individuals.

A Population Between Ages 30 and 95
Dr. Jack and colleagues conducted a cross-sectional observational study from March 2006 to October 2014 to compare the effects of age, sex, and APOE ε4 on memory, brain structure (ie, adjusted hippocampal volume), and amyloid PET in cognitively normal people. The researchers studied 1,246 participants from two cohorts. The first cohort was a random sample of 1,209 participants (ages 50 to 95) who were enrolled in the Mayo Clinic Study of Aging (MCSA). The second group included 37 self-selected volunteers (ages 30 to 49). All participants underwent identical PET, MRI, and memory testing protocols, including the Auditory Verbal Learning Test.

The study population’s median age was 72, and approximately 53% of subjects were male. About 27% of participants had the APOE ε4 allele, and the population’s median hippocampal volume at baseline was 7.5 cm³.

Memory Was Worse Among Men
Median memory performance declined for all patients from age 30 through the 90s. The decline after age 70 was steeper for men with APOE ε4 and for women. Memory was worse among men than among women overall, especially after age 40. APOE ε4 status was not associated with a difference in memory, but APOE ε4 carriers tended to have worse memory after age 80 than noncarriers.

For all participants, adjusted hippocampal volume decreased gradually from age 30 to the mid 60s, and the decrease became more acute after that point. Overall, adjusted hippocampal volume was lower in men than in women, especially after age 60. Within each gender, APOE ε4 was not associated with a difference in adjusted hippocampal volume.

The researchers observed a slight upward trend in median amyloid PET from age 30 through the 90s among APOE ε4 noncarriers. APOE ε4 carriers had a slight upward trend in median amyloid PET until age 70, followed by a steeper increase. The ages at which 10% of the population was amyloid PET positive were 57 for APOE ε4 carriers and 64 for noncarriers. The investigators saw no significant difference in amyloid PET by gender.

Data May Represent Typical Aging
“Overall age-dependent trends in our data are largely consistent with prior studies that show progressive declines in memory and brain volumes with age,” said Dr. Jack. The finding that memory and adjusted hippocampal volume worsen continuously from age 30—before obviously abnormal amyloid PET appears—contradicts the theory that subclinical declines in brain structure and cognitive function in middle age result from underlying β-amyloid deposition. The data instead imply that these declines “are a fundamental characteristic of typical aging,” said Dr. Jack.

“Reasonable candidates for non-Alzheimer’s disease processes associated with structural and functional decline in middle age are cerebrovascular disease and its risk factors, including primary age-related tauopathy, brain aging in the absence of any specific pathophysiologic process, or combinations of these [processes],” he added.

The study’s limitations included the small sample size of people between ages 30 and 49, and the non-population-based nature of this sample. The “obvious inflection points” in plots of memory, adjusted hippocampal volume, and amyloid PET versus age, however, appear well within the age range of 50 to the 90s of the MCSA cohort, not between the younger group and the MCSA cohort, said the authors. Another limitation is that cross-sectional studies tend to confound age effects with birth-cohort effects, but “cohort effects are unavoidable when examining age-dependent trends covering a range of 60 years.”

What Causes Memory Decline?
Dr. Jack and his colleagues “present new information that challenges the notion that amyloid accumulation explains memory performance across the entire age range,” said Charles DeCarli, MD, Director of the Alzheimer’s Disease Center at the University of California, Davis Health System in Sacramento, in an accompanying editorial. “This work does not only address the likely highly significant impact of cerebral amyloid accumulation on dementia risk, but also extends current knowledge relating to the impact of the aging process across the spectrum of ages 30 to 95 to brain structure, amyloid accumulation, and memory performance among cognitively normal individuals.”

Although vascular risk factors such as diabetes and hypertension “likely contribute to some of the cognitive impairments known to occur with normal aging, they do not fully overlap with the findings reported by Jack et al,” said Dr. DeCarli. Genetic differences such as gender and APOE ε4 status also may play a role.

Additional genetic and animal research may reveal specific cell types and cortical networks that change dramatically during the first 50 years of life. Understanding these early processes will help neurologists identify ways to maintain cognitive health and resist dementia. “Such work requires the necessary motivation found by seminal work, such as that of Jack et al, which tell us where and when to investigate these processes,” said Dr. DeCarli. “Establishing what is normal creates avenues for new research, increasing the likelihood of discovering novel therapeutics for late-life disease states, which is a laudable goal indeed,” he concluded.

—Erik Greb

Cognitive decline in middle age may not result from β-amyloid deposition, according to a study published online ahead of print March 16 in JAMA Neurology. Declines in memory and hippocampal volume occur at earlier ages than abnormal amyloid PET does, which implies that these outcomes “must have some mechanistic independence from β-amyloid accumulation,” said Clifford R. Jack, Jr., MD, Professor of Radiology at Mayo Clinic in Rochester, Minnesota.

From age 70 onward, median amyloid PET accumulation is greater in cognitively normal individuals with the APOE ε4 allele, compared with people without the allele. In addition, abnormal amyloid PET may appear at an earlier age among APOE ε4 carriers, compared with noncarriers. The study results also indicate that male gender, but not APOE ε4, is associated with worse memory and adjusted hippocampal volume among cognitively normal individuals.

A Population Between Ages 30 and 95
Dr. Jack and colleagues conducted a cross-sectional observational study from March 2006 to October 2014 to compare the effects of age, sex, and APOE ε4 on memory, brain structure (ie, adjusted hippocampal volume), and amyloid PET in cognitively normal people. The researchers studied 1,246 participants from two cohorts. The first cohort was a random sample of 1,209 participants (ages 50 to 95) who were enrolled in the Mayo Clinic Study of Aging (MCSA). The second group included 37 self-selected volunteers (ages 30 to 49). All participants underwent identical PET, MRI, and memory testing protocols, including the Auditory Verbal Learning Test.

The study population’s median age was 72, and approximately 53% of subjects were male. About 27% of participants had the APOE ε4 allele, and the population’s median hippocampal volume at baseline was 7.5 cm³.

Memory Was Worse Among Men
Median memory performance declined for all patients from age 30 through the 90s. The decline after age 70 was steeper for men with APOE ε4 and for women. Memory was worse among men than among women overall, especially after age 40. APOE ε4 status was not associated with a difference in memory, but APOE ε4 carriers tended to have worse memory after age 80 than noncarriers.

For all participants, adjusted hippocampal volume decreased gradually from age 30 to the mid 60s, and the decrease became more acute after that point. Overall, adjusted hippocampal volume was lower in men than in women, especially after age 60. Within each gender, APOE ε4 was not associated with a difference in adjusted hippocampal volume.

The researchers observed a slight upward trend in median amyloid PET from age 30 through the 90s among APOE ε4 noncarriers. APOE ε4 carriers had a slight upward trend in median amyloid PET until age 70, followed by a steeper increase. The ages at which 10% of the population was amyloid PET positive were 57 for APOE ε4 carriers and 64 for noncarriers. The investigators saw no significant difference in amyloid PET by gender.

Data May Represent Typical Aging
“Overall age-dependent trends in our data are largely consistent with prior studies that show progressive declines in memory and brain volumes with age,” said Dr. Jack. The finding that memory and adjusted hippocampal volume worsen continuously from age 30—before obviously abnormal amyloid PET appears—contradicts the theory that subclinical declines in brain structure and cognitive function in middle age result from underlying β-amyloid deposition. The data instead imply that these declines “are a fundamental characteristic of typical aging,” said Dr. Jack.

“Reasonable candidates for non-Alzheimer’s disease processes associated with structural and functional decline in middle age are cerebrovascular disease and its risk factors, including primary age-related tauopathy, brain aging in the absence of any specific pathophysiologic process, or combinations of these [processes],” he added.

The study’s limitations included the small sample size of people between ages 30 and 49, and the non-population-based nature of this sample. The “obvious inflection points” in plots of memory, adjusted hippocampal volume, and amyloid PET versus age, however, appear well within the age range of 50 to the 90s of the MCSA cohort, not between the younger group and the MCSA cohort, said the authors. Another limitation is that cross-sectional studies tend to confound age effects with birth-cohort effects, but “cohort effects are unavoidable when examining age-dependent trends covering a range of 60 years.”

What Causes Memory Decline?
Dr. Jack and his colleagues “present new information that challenges the notion that amyloid accumulation explains memory performance across the entire age range,” said Charles DeCarli, MD, Director of the Alzheimer’s Disease Center at the University of California, Davis Health System in Sacramento, in an accompanying editorial. “This work does not only address the likely highly significant impact of cerebral amyloid accumulation on dementia risk, but also extends current knowledge relating to the impact of the aging process across the spectrum of ages 30 to 95 to brain structure, amyloid accumulation, and memory performance among cognitively normal individuals.”

Although vascular risk factors such as diabetes and hypertension “likely contribute to some of the cognitive impairments known to occur with normal aging, they do not fully overlap with the findings reported by Jack et al,” said Dr. DeCarli. Genetic differences such as gender and APOE ε4 status also may play a role.

Additional genetic and animal research may reveal specific cell types and cortical networks that change dramatically during the first 50 years of life. Understanding these early processes will help neurologists identify ways to maintain cognitive health and resist dementia. “Such work requires the necessary motivation found by seminal work, such as that of Jack et al, which tell us where and when to investigate these processes,” said Dr. DeCarli. “Establishing what is normal creates avenues for new research, increasing the likelihood of discovering novel therapeutics for late-life disease states, which is a laudable goal indeed,” he concluded.

—Erik Greb

Cognitive decline in middle age may not result from β-amyloid deposition, according to a study published online ahead of print March 16 in JAMA Neurology. Declines in memory and hippocampal volume occur at earlier ages than abnormal amyloid PET does, which implies that these outcomes “must have some mechanistic independence from β-amyloid accumulation,” said Clifford R. Jack, Jr., MD, Professor of Radiology at Mayo Clinic in Rochester, Minnesota.

From age 70 onward, median amyloid PET accumulation is greater in cognitively normal individuals with the APOE ε4 allele, compared with people without the allele. In addition, abnormal amyloid PET may appear at an earlier age among APOE ε4 carriers, compared with noncarriers. The study results also indicate that male gender, but not APOE ε4, is associated with worse memory and adjusted hippocampal volume among cognitively normal individuals.

A Population Between Ages 30 and 95
Dr. Jack and colleagues conducted a cross-sectional observational study from March 2006 to October 2014 to compare the effects of age, sex, and APOE ε4 on memory, brain structure (ie, adjusted hippocampal volume), and amyloid PET in cognitively normal people. The researchers studied 1,246 participants from two cohorts. The first cohort was a random sample of 1,209 participants (ages 50 to 95) who were enrolled in the Mayo Clinic Study of Aging (MCSA). The second group included 37 self-selected volunteers (ages 30 to 49). All participants underwent identical PET, MRI, and memory testing protocols, including the Auditory Verbal Learning Test.

The study population’s median age was 72, and approximately 53% of subjects were male. About 27% of participants had the APOE ε4 allele, and the population’s median hippocampal volume at baseline was 7.5 cm³.

Memory Was Worse Among Men
Median memory performance declined for all patients from age 30 through the 90s. The decline after age 70 was steeper for men with APOE ε4 and for women. Memory was worse among men than among women overall, especially after age 40. APOE ε4 status was not associated with a difference in memory, but APOE ε4 carriers tended to have worse memory after age 80 than noncarriers.

For all participants, adjusted hippocampal volume decreased gradually from age 30 to the mid 60s, and the decrease became more acute after that point. Overall, adjusted hippocampal volume was lower in men than in women, especially after age 60. Within each gender, APOE ε4 was not associated with a difference in adjusted hippocampal volume.

The researchers observed a slight upward trend in median amyloid PET from age 30 through the 90s among APOE ε4 noncarriers. APOE ε4 carriers had a slight upward trend in median amyloid PET until age 70, followed by a steeper increase. The ages at which 10% of the population was amyloid PET positive were 57 for APOE ε4 carriers and 64 for noncarriers. The investigators saw no significant difference in amyloid PET by gender.

Data May Represent Typical Aging
“Overall age-dependent trends in our data are largely consistent with prior studies that show progressive declines in memory and brain volumes with age,” said Dr. Jack. The finding that memory and adjusted hippocampal volume worsen continuously from age 30—before obviously abnormal amyloid PET appears—contradicts the theory that subclinical declines in brain structure and cognitive function in middle age result from underlying β-amyloid deposition. The data instead imply that these declines “are a fundamental characteristic of typical aging,” said Dr. Jack.

“Reasonable candidates for non-Alzheimer’s disease processes associated with structural and functional decline in middle age are cerebrovascular disease and its risk factors, including primary age-related tauopathy, brain aging in the absence of any specific pathophysiologic process, or combinations of these [processes],” he added.

The study’s limitations included the small sample size of people between ages 30 and 49, and the non-population-based nature of this sample. The “obvious inflection points” in plots of memory, adjusted hippocampal volume, and amyloid PET versus age, however, appear well within the age range of 50 to the 90s of the MCSA cohort, not between the younger group and the MCSA cohort, said the authors. Another limitation is that cross-sectional studies tend to confound age effects with birth-cohort effects, but “cohort effects are unavoidable when examining age-dependent trends covering a range of 60 years.”

What Causes Memory Decline?
Dr. Jack and his colleagues “present new information that challenges the notion that amyloid accumulation explains memory performance across the entire age range,” said Charles DeCarli, MD, Director of the Alzheimer’s Disease Center at the University of California, Davis Health System in Sacramento, in an accompanying editorial. “This work does not only address the likely highly significant impact of cerebral amyloid accumulation on dementia risk, but also extends current knowledge relating to the impact of the aging process across the spectrum of ages 30 to 95 to brain structure, amyloid accumulation, and memory performance among cognitively normal individuals.”

Although vascular risk factors such as diabetes and hypertension “likely contribute to some of the cognitive impairments known to occur with normal aging, they do not fully overlap with the findings reported by Jack et al,” said Dr. DeCarli. Genetic differences such as gender and APOE ε4 status also may play a role.

Additional genetic and animal research may reveal specific cell types and cortical networks that change dramatically during the first 50 years of life. Understanding these early processes will help neurologists identify ways to maintain cognitive health and resist dementia. “Such work requires the necessary motivation found by seminal work, such as that of Jack et al, which tell us where and when to investigate these processes,” said Dr. DeCarli. “Establishing what is normal creates avenues for new research, increasing the likelihood of discovering novel therapeutics for late-life disease states, which is a laudable goal indeed,” he concluded.

—Erik Greb

While millions of prescriptions per year are written for drugs to calm the behavior of people with Alzheimer’s disease and other types of dementia, nonpharmacologic approaches may work better and carry far fewer risks, according to a report published online ahead of print March 2 in BMJ.

Nonpharmacologic approaches should be the first choice for common symptoms such as irritability, agitation, depression, anxiety, sleep problems, aggression, apathy, and delusions in patients with dementia, according to the authors. The best evidence supports nonpharmacologic approaches that focus on training caregivers—whether they are spouses, adult children, or staff in nursing homes and assisted living facilities—to perform behavioral and environmental interventions.

Evidence-Based Recommendations
Researchers from the University of Michigan Medical School in Ann Arbor and Johns Hopkins University in Baltimore reviewed two decades’ worth of research to reach their conclusions about drugs like antipsychotics and antidepressants and nonpharmacologic approaches that help caregivers address behavioral problems in patients with dementia. Their report describes their findings, along with a framework that doctors and caregivers can use to take advantage of current medical understanding. The Describe, Investigate, Create, and Evaluate (DICE) framework enables physicians to tailor approaches to individual patients and to changing symptoms.

“The evidence for nonpharmaceutical approaches to the behavior problems often seen in dementia is better than the evidence for antipsychotics, and far better than [that] for other classes of medication,” said lead author Helen C. Kales, MD, Head of the University of Michigan Program for Positive Aging at the University of Michigan Health System and an investigator at the VA Center for Clinical Management Research in Ann Arbor. “The issue and the challenge is that our health care system has not incentivized training in alternatives to drug use, and there is little to no reimbursement for caregiver-based methods.”

Corroborating Evidence From Government Report
A US Government Accountability Office (GAO) report published the same day as the BMJ paper addressed the overuse of antipsychotic medication for the behavior problems often seen in dementia. It found that one-third of older adults with dementia who had long-term nursing home stays in 2012 were prescribed an antipsychotic, and that about 14% of older adults with dementia outside nursing homes were prescribed an antipsychotic that same year.

The GAO called on the federal government to reduce the use of these drugs by expanding its outreach and educational efforts. Specifically, the office asked the government to reduce antipsychotic drug use among older adults with dementia who reside outside of nursing homes.

Dr. Kales, however, cautioned that penalizing doctors for prescribing antipsychotic drugs to these patients could backfire if caregiver-based nonpharmacologic approaches are not encouraged. She, Laura N. Gitlin, PhD, Director of the Center for Innovative Care in Aging at Johns Hopkins University, and Constantine Lyketsos, MD, Elizabeth Plank Althouse Professor and Chair of Psychiatry at Johns Hopkins Bayview in Baltimore, noted in their BMJ paper that “there needs to be a shift of resources from paying for psychoactive drugs and emergency room and hospital stays to adopting a more proactive approach.”

Complementary Approaches
“Drugs still have their place,” the authors noted, “especially for the management of acute situations where the safety of the person with dementia or family caregiver may be at risk.” For instance, antidepressants make sense for patients with dementia and severe depression, and antipsychotic drugs should be used when patients have psychosis or aggression that could lead them to harm themselves or others. But these uses should be closely monitored and ended as soon as possible.

The authors laid out five first-line nonpharmacologic approaches based on their review of the medical evidence. The following approaches have been shown to help reduce behavior problems:

• Provide education for the caregiver.

• Enhance effective communication between the caregiver and the person with dementia.

• Create meaningful activities for the person with dementia.

• Simplify tasks and establish structured routines for the person with dementia.

• Ensure safety and simplify and enhance the the patient’s environment, whether it be the home or the nursing or assisted living setting.

Many “hidden” medical issues in patients with dementia (eg, urinary tract infection and other infections, constipation, dehydration, and pain) can lead to behavioral problems, as can drug interactions, the authors noted. Physicians should assess and address these problems wherever possible.

Drs. Kales, Gitlin, and Lyketsos are working with the University of Michigan’s Center for Health Communications Research to begin a clinical trial in spring 2015 that will test the DICE approach through a computer-based tool for caregivers called the We- CareAdvisor. The tool will help families identify tips and resources in a single computer interface to address behavioral symptoms. The tips are designed to avoid or mitigate the effects of possible triggers for common behavioral symptoms such as pacing, repetitive questioning, restlessness, or shadowing.

For instance, decluttering the environment, using music or simple activities that help to engage a person with dementia, or using a calm voice instead of being confrontational, could help greatly to reduce behavioral symptoms, Dr. Kales said. Making sure that caregivers get breaks from their responsibilities and take care of themselves, especially in the home, can help them avoid burnout and taking their frustration out on patients.

“Behavior-based strategies may take longer [to work] than prescriptions,” acknowledged Dr. Kales. “But if you teach people the principles behind DICE, the approach becomes more natural and part of one’s routine. It can be empowering for caregivers or nursing home staff.”

More research on new drug options and the best ways to assess and address behavioral symptoms is needed, the authors noted. In the meantime, the evidence to date favors nonpharmacologic approaches to these symptoms in most cases, they concluded.

While millions of prescriptions per year are written for drugs to calm the behavior of people with Alzheimer’s disease and other types of dementia, nonpharmacologic approaches may work better and carry far fewer risks, according to a report published online ahead of print March 2 in BMJ.

Nonpharmacologic approaches should be the first choice for common symptoms such as irritability, agitation, depression, anxiety, sleep problems, aggression, apathy, and delusions in patients with dementia, according to the authors. The best evidence supports nonpharmacologic approaches that focus on training caregivers—whether they are spouses, adult children, or staff in nursing homes and assisted living facilities—to perform behavioral and environmental interventions.

Evidence-Based Recommendations
Researchers from the University of Michigan Medical School in Ann Arbor and Johns Hopkins University in Baltimore reviewed two decades’ worth of research to reach their conclusions about drugs like antipsychotics and antidepressants and nonpharmacologic approaches that help caregivers address behavioral problems in patients with dementia. Their report describes their findings, along with a framework that doctors and caregivers can use to take advantage of current medical understanding. The Describe, Investigate, Create, and Evaluate (DICE) framework enables physicians to tailor approaches to individual patients and to changing symptoms.

“The evidence for nonpharmaceutical approaches to the behavior problems often seen in dementia is better than the evidence for antipsychotics, and far better than [that] for other classes of medication,” said lead author Helen C. Kales, MD, Head of the University of Michigan Program for Positive Aging at the University of Michigan Health System and an investigator at the VA Center for Clinical Management Research in Ann Arbor. “The issue and the challenge is that our health care system has not incentivized training in alternatives to drug use, and there is little to no reimbursement for caregiver-based methods.”

Corroborating Evidence From Government Report
A US Government Accountability Office (GAO) report published the same day as the BMJ paper addressed the overuse of antipsychotic medication for the behavior problems often seen in dementia. It found that one-third of older adults with dementia who had long-term nursing home stays in 2012 were prescribed an antipsychotic, and that about 14% of older adults with dementia outside nursing homes were prescribed an antipsychotic that same year.

The GAO called on the federal government to reduce the use of these drugs by expanding its outreach and educational efforts. Specifically, the office asked the government to reduce antipsychotic drug use among older adults with dementia who reside outside of nursing homes.

Dr. Kales, however, cautioned that penalizing doctors for prescribing antipsychotic drugs to these patients could backfire if caregiver-based nonpharmacologic approaches are not encouraged. She, Laura N. Gitlin, PhD, Director of the Center for Innovative Care in Aging at Johns Hopkins University, and Constantine Lyketsos, MD, Elizabeth Plank Althouse Professor and Chair of Psychiatry at Johns Hopkins Bayview in Baltimore, noted in their BMJ paper that “there needs to be a shift of resources from paying for psychoactive drugs and emergency room and hospital stays to adopting a more proactive approach.”

Complementary Approaches
“Drugs still have their place,” the authors noted, “especially for the management of acute situations where the safety of the person with dementia or family caregiver may be at risk.” For instance, antidepressants make sense for patients with dementia and severe depression, and antipsychotic drugs should be used when patients have psychosis or aggression that could lead them to harm themselves or others. But these uses should be closely monitored and ended as soon as possible.

The authors laid out five first-line nonpharmacologic approaches based on their review of the medical evidence. The following approaches have been shown to help reduce behavior problems:

• Provide education for the caregiver.

• Enhance effective communication between the caregiver and the person with dementia.

• Create meaningful activities for the person with dementia.

• Simplify tasks and establish structured routines for the person with dementia.

• Ensure safety and simplify and enhance the the patient’s environment, whether it be the home or the nursing or assisted living setting.

Many “hidden” medical issues in patients with dementia (eg, urinary tract infection and other infections, constipation, dehydration, and pain) can lead to behavioral problems, as can drug interactions, the authors noted. Physicians should assess and address these problems wherever possible.

Drs. Kales, Gitlin, and Lyketsos are working with the University of Michigan’s Center for Health Communications Research to begin a clinical trial in spring 2015 that will test the DICE approach through a computer-based tool for caregivers called the We- CareAdvisor. The tool will help families identify tips and resources in a single computer interface to address behavioral symptoms. The tips are designed to avoid or mitigate the effects of possible triggers for common behavioral symptoms such as pacing, repetitive questioning, restlessness, or shadowing.

For instance, decluttering the environment, using music or simple activities that help to engage a person with dementia, or using a calm voice instead of being confrontational, could help greatly to reduce behavioral symptoms, Dr. Kales said. Making sure that caregivers get breaks from their responsibilities and take care of themselves, especially in the home, can help them avoid burnout and taking their frustration out on patients.

“Behavior-based strategies may take longer [to work] than prescriptions,” acknowledged Dr. Kales. “But if you teach people the principles behind DICE, the approach becomes more natural and part of one’s routine. It can be empowering for caregivers or nursing home staff.”

More research on new drug options and the best ways to assess and address behavioral symptoms is needed, the authors noted. In the meantime, the evidence to date favors nonpharmacologic approaches to these symptoms in most cases, they concluded.

While millions of prescriptions per year are written for drugs to calm the behavior of people with Alzheimer’s disease and other types of dementia, nonpharmacologic approaches may work better and carry far fewer risks, according to a report published online ahead of print March 2 in BMJ.

Nonpharmacologic approaches should be the first choice for common symptoms such as irritability, agitation, depression, anxiety, sleep problems, aggression, apathy, and delusions in patients with dementia, according to the authors. The best evidence supports nonpharmacologic approaches that focus on training caregivers—whether they are spouses, adult children, or staff in nursing homes and assisted living facilities—to perform behavioral and environmental interventions.

Evidence-Based Recommendations
Researchers from the University of Michigan Medical School in Ann Arbor and Johns Hopkins University in Baltimore reviewed two decades’ worth of research to reach their conclusions about drugs like antipsychotics and antidepressants and nonpharmacologic approaches that help caregivers address behavioral problems in patients with dementia. Their report describes their findings, along with a framework that doctors and caregivers can use to take advantage of current medical understanding. The Describe, Investigate, Create, and Evaluate (DICE) framework enables physicians to tailor approaches to individual patients and to changing symptoms.

“The evidence for nonpharmaceutical approaches to the behavior problems often seen in dementia is better than the evidence for antipsychotics, and far better than [that] for other classes of medication,” said lead author Helen C. Kales, MD, Head of the University of Michigan Program for Positive Aging at the University of Michigan Health System and an investigator at the VA Center for Clinical Management Research in Ann Arbor. “The issue and the challenge is that our health care system has not incentivized training in alternatives to drug use, and there is little to no reimbursement for caregiver-based methods.”

Corroborating Evidence From Government Report
A US Government Accountability Office (GAO) report published the same day as the BMJ paper addressed the overuse of antipsychotic medication for the behavior problems often seen in dementia. It found that one-third of older adults with dementia who had long-term nursing home stays in 2012 were prescribed an antipsychotic, and that about 14% of older adults with dementia outside nursing homes were prescribed an antipsychotic that same year.

The GAO called on the federal government to reduce the use of these drugs by expanding its outreach and educational efforts. Specifically, the office asked the government to reduce antipsychotic drug use among older adults with dementia who reside outside of nursing homes.

Dr. Kales, however, cautioned that penalizing doctors for prescribing antipsychotic drugs to these patients could backfire if caregiver-based nonpharmacologic approaches are not encouraged. She, Laura N. Gitlin, PhD, Director of the Center for Innovative Care in Aging at Johns Hopkins University, and Constantine Lyketsos, MD, Elizabeth Plank Althouse Professor and Chair of Psychiatry at Johns Hopkins Bayview in Baltimore, noted in their BMJ paper that “there needs to be a shift of resources from paying for psychoactive drugs and emergency room and hospital stays to adopting a more proactive approach.”

Complementary Approaches
“Drugs still have their place,” the authors noted, “especially for the management of acute situations where the safety of the person with dementia or family caregiver may be at risk.” For instance, antidepressants make sense for patients with dementia and severe depression, and antipsychotic drugs should be used when patients have psychosis or aggression that could lead them to harm themselves or others. But these uses should be closely monitored and ended as soon as possible.

The authors laid out five first-line nonpharmacologic approaches based on their review of the medical evidence. The following approaches have been shown to help reduce behavior problems:

• Provide education for the caregiver.

• Enhance effective communication between the caregiver and the person with dementia.

• Create meaningful activities for the person with dementia.

• Simplify tasks and establish structured routines for the person with dementia.

• Ensure safety and simplify and enhance the the patient’s environment, whether it be the home or the nursing or assisted living setting.

Many “hidden” medical issues in patients with dementia (eg, urinary tract infection and other infections, constipation, dehydration, and pain) can lead to behavioral problems, as can drug interactions, the authors noted. Physicians should assess and address these problems wherever possible.

Drs. Kales, Gitlin, and Lyketsos are working with the University of Michigan’s Center for Health Communications Research to begin a clinical trial in spring 2015 that will test the DICE approach through a computer-based tool for caregivers called the We- CareAdvisor. The tool will help families identify tips and resources in a single computer interface to address behavioral symptoms. The tips are designed to avoid or mitigate the effects of possible triggers for common behavioral symptoms such as pacing, repetitive questioning, restlessness, or shadowing.

For instance, decluttering the environment, using music or simple activities that help to engage a person with dementia, or using a calm voice instead of being confrontational, could help greatly to reduce behavioral symptoms, Dr. Kales said. Making sure that caregivers get breaks from their responsibilities and take care of themselves, especially in the home, can help them avoid burnout and taking their frustration out on patients.

“Behavior-based strategies may take longer [to work] than prescriptions,” acknowledged Dr. Kales. “But if you teach people the principles behind DICE, the approach becomes more natural and part of one’s routine. It can be empowering for caregivers or nursing home staff.”

More research on new drug options and the best ways to assess and address behavioral symptoms is needed, the authors noted. In the meantime, the evidence to date favors nonpharmacologic approaches to these symptoms in most cases, they concluded.

Researchers have identified a genetic variation that significantly increases women’s risk of developing multiple sclerosis (MS). The variant, a single nucleotide polymorphism (SNP) in the gene serine-threonine-kinase 11 (STK11), occurs approximately 1.7 times more often in women with MS than in women without the disease, according to a study published February 18 in ASN Neuro.

Researchers zeroed in on the STK11 SNP after a woman told study coordinator and lead author Anne I. Boullerne, PhD, Research Assistant Professor of Anesthesiology at the University of Illinois at Chicago, that she and her four siblings all had MS or clinically isolated syndrome. The five siblings—four sisters, including twins, and a brother—were between ages 23 and 26.

The woman, who was participating in another medical study at the university, also described a prevalence of diseases associated with Peutz–Jeghers syndrome, a rare genetic disease caused by mutations in the STK11 gene, on her mother’s side of the family. The syndrome is characterized by an increased risk for certain cancers, including breast, ovary, and colon cancers.

Gene Tied to Loss of Myelin in Mice
A literature search by senior author Douglas L. Feinstein, PhD, Professor of Anesthesiology at the University of Illinois at Chicago and Research Biologist at the Jesse Brown VA Medical Center, uncovered an article that described how mice with a disabled STK11 gene had a higher incidence of loss of myelin from the nerves of the CNS, a defining characteristic of MS.

The woman consented to a complete DNA sequencing of her genome, and Dr. Boullerne examined the STK11 gene, where she discovered the SNP. Dr. Boullerne then obtained consent to sequence the genomes of two of the woman’s sisters and found that they carried the same SNP. Researchers do not know whether the other two siblings have the same variation.

The authors then screened DNA samples from approximately 1,400 people, including 754 people with MS. They found that the SNP was 1.66 times as prevalent in women with MS as in women without the disease. That makes the variant “one of the strongest genetic risk factors for MS discovered to date,” Dr. Feinstein said.

Researchers compared DNA samples from 654 patients with relapsing-remitting MS (RRMS), 100 patients with primary progressive MS (PPMS), and 661 controls.

While the STK11 SNP is present in about 7% of the general population, the variant was present in approximately 11% of the women with MS. In men, the risk of RRMS was only modestly increased by the STK11 SNP, and none of the male patients with PPMS had the variant.

Variant Associated With Reduced Disease Severity
The STK11 SNP was not associated with disease duration or onset. However, it was significantly associated with reduced disease severity, with the lowest MS severity scores in patients who also harbored the HLA-DRB1*1501 allele, the strongest known genetic risk factor for MS.

The researchers plan to continue looking for other genetic risk factors for MS among the five siblings and possibly their parents. Dr. Boullerne found no published studies that identified five siblings with MS. Identifying the five siblings with MS and suspected MS is an opportunity to pinpoint genes related to the disease, she said.

“I was immediately interested in the possibility of a genetic study of the family because all five siblings—an entire generation—are affected by MS, and so we could have a very good chance of discovering key genes related to inheritance of the disease,” Dr. Boullerne said.

Researchers also will investigate the function of the STK11 gene in the laboratory, which could reveal molecular pathways involved in MS. Their findings raise the possibility that cells harboring the STK11 SNP could be targeted by drugs that increase metabolic stress.

Rarity of Cases Has Limited Analyses
Genetic factors are known to influence the risk of developing MS, but the rarity of multigenerational cases of MS, or families with four or more affected members, has limited further analyses, said the authors.

Several studies have identified the HLA-DRB1*1501 allele as a variant associated with increased risk, with an odds ratio of approximately 3 across various ethnic groups.

The STK11 SNP had odds ratios for females of 1.63 in RRMS, 1.88 in PPMS, and 1.66 for both MS forms.

The different ratios for women with RRMS and PPMS could result from the different group sizes used in the study (ie, 56 female patients with PPMS, compared with 396 female patients with RRMS) or because of differences in the development and evolution of PPMS and RRMS, said the authors.

—Jake Remaly

Researchers have identified a genetic variation that significantly increases women’s risk of developing multiple sclerosis (MS). The variant, a single nucleotide polymorphism (SNP) in the gene serine-threonine-kinase 11 (STK11), occurs approximately 1.7 times more often in women with MS than in women without the disease, according to a study published February 18 in ASN Neuro.

Researchers zeroed in on the STK11 SNP after a woman told study coordinator and lead author Anne I. Boullerne, PhD, Research Assistant Professor of Anesthesiology at the University of Illinois at Chicago, that she and her four siblings all had MS or clinically isolated syndrome. The five siblings—four sisters, including twins, and a brother—were between ages 23 and 26.

The woman, who was participating in another medical study at the university, also described a prevalence of diseases associated with Peutz–Jeghers syndrome, a rare genetic disease caused by mutations in the STK11 gene, on her mother’s side of the family. The syndrome is characterized by an increased risk for certain cancers, including breast, ovary, and colon cancers.

Gene Tied to Loss of Myelin in Mice
A literature search by senior author Douglas L. Feinstein, PhD, Professor of Anesthesiology at the University of Illinois at Chicago and Research Biologist at the Jesse Brown VA Medical Center, uncovered an article that described how mice with a disabled STK11 gene had a higher incidence of loss of myelin from the nerves of the CNS, a defining characteristic of MS.

The woman consented to a complete DNA sequencing of her genome, and Dr. Boullerne examined the STK11 gene, where she discovered the SNP. Dr. Boullerne then obtained consent to sequence the genomes of two of the woman’s sisters and found that they carried the same SNP. Researchers do not know whether the other two siblings have the same variation.

The authors then screened DNA samples from approximately 1,400 people, including 754 people with MS. They found that the SNP was 1.66 times as prevalent in women with MS as in women without the disease. That makes the variant “one of the strongest genetic risk factors for MS discovered to date,” Dr. Feinstein said.

Researchers compared DNA samples from 654 patients with relapsing-remitting MS (RRMS), 100 patients with primary progressive MS (PPMS), and 661 controls.

While the STK11 SNP is present in about 7% of the general population, the variant was present in approximately 11% of the women with MS. In men, the risk of RRMS was only modestly increased by the STK11 SNP, and none of the male patients with PPMS had the variant.

Variant Associated With Reduced Disease Severity
The STK11 SNP was not associated with disease duration or onset. However, it was significantly associated with reduced disease severity, with the lowest MS severity scores in patients who also harbored the HLA-DRB1*1501 allele, the strongest known genetic risk factor for MS.

The researchers plan to continue looking for other genetic risk factors for MS among the five siblings and possibly their parents. Dr. Boullerne found no published studies that identified five siblings with MS. Identifying the five siblings with MS and suspected MS is an opportunity to pinpoint genes related to the disease, she said.

“I was immediately interested in the possibility of a genetic study of the family because all five siblings—an entire generation—are affected by MS, and so we could have a very good chance of discovering key genes related to inheritance of the disease,” Dr. Boullerne said.

Researchers also will investigate the function of the STK11 gene in the laboratory, which could reveal molecular pathways involved in MS. Their findings raise the possibility that cells harboring the STK11 SNP could be targeted by drugs that increase metabolic stress.

Rarity of Cases Has Limited Analyses
Genetic factors are known to influence the risk of developing MS, but the rarity of multigenerational cases of MS, or families with four or more affected members, has limited further analyses, said the authors.

Several studies have identified the HLA-DRB1*1501 allele as a variant associated with increased risk, with an odds ratio of approximately 3 across various ethnic groups.

The STK11 SNP had odds ratios for females of 1.63 in RRMS, 1.88 in PPMS, and 1.66 for both MS forms.

The different ratios for women with RRMS and PPMS could result from the different group sizes used in the study (ie, 56 female patients with PPMS, compared with 396 female patients with RRMS) or because of differences in the development and evolution of PPMS and RRMS, said the authors.

—Jake Remaly

Researchers have identified a genetic variation that significantly increases women’s risk of developing multiple sclerosis (MS). The variant, a single nucleotide polymorphism (SNP) in the gene serine-threonine-kinase 11 (STK11), occurs approximately 1.7 times more often in women with MS than in women without the disease, according to a study published February 18 in ASN Neuro.

Researchers zeroed in on the STK11 SNP after a woman told study coordinator and lead author Anne I. Boullerne, PhD, Research Assistant Professor of Anesthesiology at the University of Illinois at Chicago, that she and her four siblings all had MS or clinically isolated syndrome. The five siblings—four sisters, including twins, and a brother—were between ages 23 and 26.

The woman, who was participating in another medical study at the university, also described a prevalence of diseases associated with Peutz–Jeghers syndrome, a rare genetic disease caused by mutations in the STK11 gene, on her mother’s side of the family. The syndrome is characterized by an increased risk for certain cancers, including breast, ovary, and colon cancers.

Gene Tied to Loss of Myelin in Mice
A literature search by senior author Douglas L. Feinstein, PhD, Professor of Anesthesiology at the University of Illinois at Chicago and Research Biologist at the Jesse Brown VA Medical Center, uncovered an article that described how mice with a disabled STK11 gene had a higher incidence of loss of myelin from the nerves of the CNS, a defining characteristic of MS.

The woman consented to a complete DNA sequencing of her genome, and Dr. Boullerne examined the STK11 gene, where she discovered the SNP. Dr. Boullerne then obtained consent to sequence the genomes of two of the woman’s sisters and found that they carried the same SNP. Researchers do not know whether the other two siblings have the same variation.

The authors then screened DNA samples from approximately 1,400 people, including 754 people with MS. They found that the SNP was 1.66 times as prevalent in women with MS as in women without the disease. That makes the variant “one of the strongest genetic risk factors for MS discovered to date,” Dr. Feinstein said.

Researchers compared DNA samples from 654 patients with relapsing-remitting MS (RRMS), 100 patients with primary progressive MS (PPMS), and 661 controls.

While the STK11 SNP is present in about 7% of the general population, the variant was present in approximately 11% of the women with MS. In men, the risk of RRMS was only modestly increased by the STK11 SNP, and none of the male patients with PPMS had the variant.

Variant Associated With Reduced Disease Severity
The STK11 SNP was not associated with disease duration or onset. However, it was significantly associated with reduced disease severity, with the lowest MS severity scores in patients who also harbored the HLA-DRB1*1501 allele, the strongest known genetic risk factor for MS.

The researchers plan to continue looking for other genetic risk factors for MS among the five siblings and possibly their parents. Dr. Boullerne found no published studies that identified five siblings with MS. Identifying the five siblings with MS and suspected MS is an opportunity to pinpoint genes related to the disease, she said.

“I was immediately interested in the possibility of a genetic study of the family because all five siblings—an entire generation—are affected by MS, and so we could have a very good chance of discovering key genes related to inheritance of the disease,” Dr. Boullerne said.

Researchers also will investigate the function of the STK11 gene in the laboratory, which could reveal molecular pathways involved in MS. Their findings raise the possibility that cells harboring the STK11 SNP could be targeted by drugs that increase metabolic stress.

Rarity of Cases Has Limited Analyses
Genetic factors are known to influence the risk of developing MS, but the rarity of multigenerational cases of MS, or families with four or more affected members, has limited further analyses, said the authors.

Several studies have identified the HLA-DRB1*1501 allele as a variant associated with increased risk, with an odds ratio of approximately 3 across various ethnic groups.

The STK11 SNP had odds ratios for females of 1.63 in RRMS, 1.88 in PPMS, and 1.66 for both MS forms.

The different ratios for women with RRMS and PPMS could result from the different group sizes used in the study (ie, 56 female patients with PPMS, compared with 396 female patients with RRMS) or because of differences in the development and evolution of PPMS and RRMS, said the authors.

—Jake Remaly

Among patients with Parkinson’s disease, probable REM sleep behavior disorder (RBD) is associated with longer disease duration and more severe symptoms, according to research published March 3 in Neurology. In addition, patients with Parkinson’s disease and probable RBD may have elevated levels of α-synuclein and inflammatory factors, including nitric oxide and interleukin 1β, in CSF, compared with controls and patients with Parkinson’s disease without probable RBD.

Yang Hu, MD, a neurologist at Beijing Tiantan Hospital, and colleagues investigated clinical features and potential mechanisms involving α-synuclein oligomer and inflammation in patients with Parkinson’s disease and probable RBD. They recruited 225 patients with Parkinson’s disease from their specialized neurodegenerative outpatient clinic from April 2010 to July 2013. Patients with severe systemic diseases, such as anemia and heart failure, were excluded. Thirty-one controls also were selected.

Patients with Parkinson’s disease completed the RBD Screening Questionnaire (RBDSQ), a self-rating questionnaire comprising 13 items about clinical characteristics of RBD based on the International Classification of Sleep Disorders—Second Edition. Patients whose scores were 6 or greater were classified as having probable RBD. Patients whose scores were less than 6 were classified as not having probable RBD.

Approximately 31% of patients had probable RBD. The 69 patients in the probable RBD group had an average RBDSQ score of 8.01, while patients not classified as having probable RBD had an average score of 2.15. The probable RBD group had longer disease duration, more advanced disease stage, and more severe motor and nonmotor symptoms, including depression, anxiety, and fatigue. In 24 patients, probable RBD was identified before the onset of motor symptoms, indicating that RBD is a prodromal symptom of Parkinson’s disease, the authors said.

RBDSQ score increased with elevated α-synuclein oligomer levels in CSF, according to the authors. RBDSQ score also increased with higher interleukin 1β and nitric oxide levels in CSF, and with higher prostaglandin E₂ level in serum.

The only factor to influence RBDSQ score was α-synuclein oligomer level in CSF. “These results imply that elevation of α-synuclein oligomer in the brain may be the pathogenesis of probable RBD in patients with Parkinson’s disease,” said Dr. Hu.

Inhibition of α-synuclein oligomer-related inflammation could be a novel target for treatment of sleep disorders, such as RBD, in patients with Parkinson’s disease, the researchers concluded.

Among patients with Parkinson’s disease, probable REM sleep behavior disorder (RBD) is associated with longer disease duration and more severe symptoms, according to research published March 3 in Neurology. In addition, patients with Parkinson’s disease and probable RBD may have elevated levels of α-synuclein and inflammatory factors, including nitric oxide and interleukin 1β, in CSF, compared with controls and patients with Parkinson’s disease without probable RBD.

Yang Hu, MD, a neurologist at Beijing Tiantan Hospital, and colleagues investigated clinical features and potential mechanisms involving α-synuclein oligomer and inflammation in patients with Parkinson’s disease and probable RBD. They recruited 225 patients with Parkinson’s disease from their specialized neurodegenerative outpatient clinic from April 2010 to July 2013. Patients with severe systemic diseases, such as anemia and heart failure, were excluded. Thirty-one controls also were selected.

Patients with Parkinson’s disease completed the RBD Screening Questionnaire (RBDSQ), a self-rating questionnaire comprising 13 items about clinical characteristics of RBD based on the International Classification of Sleep Disorders—Second Edition. Patients whose scores were 6 or greater were classified as having probable RBD. Patients whose scores were less than 6 were classified as not having probable RBD.

Approximately 31% of patients had probable RBD. The 69 patients in the probable RBD group had an average RBDSQ score of 8.01, while patients not classified as having probable RBD had an average score of 2.15. The probable RBD group had longer disease duration, more advanced disease stage, and more severe motor and nonmotor symptoms, including depression, anxiety, and fatigue. In 24 patients, probable RBD was identified before the onset of motor symptoms, indicating that RBD is a prodromal symptom of Parkinson’s disease, the authors said.

RBDSQ score increased with elevated α-synuclein oligomer levels in CSF, according to the authors. RBDSQ score also increased with higher interleukin 1β and nitric oxide levels in CSF, and with higher prostaglandin E₂ level in serum.

The only factor to influence RBDSQ score was α-synuclein oligomer level in CSF. “These results imply that elevation of α-synuclein oligomer in the brain may be the pathogenesis of probable RBD in patients with Parkinson’s disease,” said Dr. Hu.

Inhibition of α-synuclein oligomer-related inflammation could be a novel target for treatment of sleep disorders, such as RBD, in patients with Parkinson’s disease, the researchers concluded.

Among patients with Parkinson’s disease, probable REM sleep behavior disorder (RBD) is associated with longer disease duration and more severe symptoms, according to research published March 3 in Neurology. In addition, patients with Parkinson’s disease and probable RBD may have elevated levels of α-synuclein and inflammatory factors, including nitric oxide and interleukin 1β, in CSF, compared with controls and patients with Parkinson’s disease without probable RBD.

Yang Hu, MD, a neurologist at Beijing Tiantan Hospital, and colleagues investigated clinical features and potential mechanisms involving α-synuclein oligomer and inflammation in patients with Parkinson’s disease and probable RBD. They recruited 225 patients with Parkinson’s disease from their specialized neurodegenerative outpatient clinic from April 2010 to July 2013. Patients with severe systemic diseases, such as anemia and heart failure, were excluded. Thirty-one controls also were selected.

Patients with Parkinson’s disease completed the RBD Screening Questionnaire (RBDSQ), a self-rating questionnaire comprising 13 items about clinical characteristics of RBD based on the International Classification of Sleep Disorders—Second Edition. Patients whose scores were 6 or greater were classified as having probable RBD. Patients whose scores were less than 6 were classified as not having probable RBD.

Approximately 31% of patients had probable RBD. The 69 patients in the probable RBD group had an average RBDSQ score of 8.01, while patients not classified as having probable RBD had an average score of 2.15. The probable RBD group had longer disease duration, more advanced disease stage, and more severe motor and nonmotor symptoms, including depression, anxiety, and fatigue. In 24 patients, probable RBD was identified before the onset of motor symptoms, indicating that RBD is a prodromal symptom of Parkinson’s disease, the authors said.

RBDSQ score increased with elevated α-synuclein oligomer levels in CSF, according to the authors. RBDSQ score also increased with higher interleukin 1β and nitric oxide levels in CSF, and with higher prostaglandin E₂ level in serum.

The only factor to influence RBDSQ score was α-synuclein oligomer level in CSF. “These results imply that elevation of α-synuclein oligomer in the brain may be the pathogenesis of probable RBD in patients with Parkinson’s disease,” said Dr. Hu.

Inhibition of α-synuclein oligomer-related inflammation could be a novel target for treatment of sleep disorders, such as RBD, in patients with Parkinson’s disease, the researchers concluded.

PET scans using radio-labeled flutemetamol are safe and confirm the presence or absence of neuritic β-amyloid levels “with high sensitivity and specificity,” according to research reported in the March issue of JAMA Neurology. “In vivo detection of brain β-amyloid may help increase diagnostic accuracy in cognitively impaired patients, compared with clinical diagnosis alone,” said Craig Curtis, MD, Chief Medical Officer at Compass Research in Orlando, and his associates.

The investigators conducted a phase III trial involving terminally ill older adults. The PET scanning agent used in the study, [18F]flutemetamol, binds with high affinity to β-amyloid but rapidly clears from normal brain tissue. The trial included 203 consecutive patients attending 19 dementia clinics, memory centers, and hospices in the United States and England who were age 55 or older and who had a life expectancy of one year or less. A total of 180 participants who underwent [18F]flutemetamol PET scanning made up the population for the safety analysis. A subset of 68 patients who died during the study underwent autopsy so that brain pathology could be compared with the PET images. These patients were the basis for the sensitivity and specificity analysis. Five specially trained readers who were blinded to patient information independently interpreted the PET scans as positive or negative for neuritic β-amyloid.

On postmortem examination, 25 of the 68 brains (37%) were β-amyloid negative, and 43 (63%) were β-amyloid positive. The sensitivity of [18F]flutemetamol PET scanning ranged from 81% to 93% (median, 88%) across the five scan readers, and the specificity ranged from 44% to 92% (median, 88%). One of the readers frequently overestimated the level of β-amyloid in the scans and was considered an outlier regarding specificity. Between-reader agreement was 90% or higher when that reader’s interpretations were excluded from the analysis.

Six (14%) of 43 brains found to be β-amyloid positive at autopsy were read as false negatives, and two (8%) of 25 brains found to be β-amyloid negative at autopsy were read as false positives.

The IV [18F]flutemetamol injections were well tolerated, and no adverse events were attributed to the agent or the PET procedure. However, four participants were withdrawn from the study because they could not remain motionless in the scanner.

“A scan that accurately detects β-amyloid is not the same thing as a test for Alzheimer’s disease,” said Gil D. Rabinovici, MD, Associate Professor of Neurology at the University of California, San Francisco’s Memory and Aging Center, in an accompanying editorial. “Approximately 25% of cognitively normal older adults and nearly 50% of people older than 80 years also show β-amyloid on PET scans, as do patients with conditions such as dementia with Lewy bodies and cerebral amyloid angiopathy.

“It is concerning that one of the five rigorously trained PET scan readers frequently overestimated the amount of β-amyloid and showed worryingly low specificity (44%) in interpreting these scans,” he continued. “PET amyloid imaging should be considered only for patients in whom there is considerable diagnostic uncertainty after a comprehensive clinical evaluation and in whom knowledge of β-amyloid status is likely to change diagnosis and management. This would include patients with unexplained mild cognitive impairment, with atypical or mixed presentations, and those who present with dementia at an unusually early age.”

—Mary Ann Moon

PET scans using radio-labeled flutemetamol are safe and confirm the presence or absence of neuritic β-amyloid levels “with high sensitivity and specificity,” according to research reported in the March issue of JAMA Neurology. “In vivo detection of brain β-amyloid may help increase diagnostic accuracy in cognitively impaired patients, compared with clinical diagnosis alone,” said Craig Curtis, MD, Chief Medical Officer at Compass Research in Orlando, and his associates.

The investigators conducted a phase III trial involving terminally ill older adults. The PET scanning agent used in the study, [18F]flutemetamol, binds with high affinity to β-amyloid but rapidly clears from normal brain tissue. The trial included 203 consecutive patients attending 19 dementia clinics, memory centers, and hospices in the United States and England who were age 55 or older and who had a life expectancy of one year or less. A total of 180 participants who underwent [18F]flutemetamol PET scanning made up the population for the safety analysis. A subset of 68 patients who died during the study underwent autopsy so that brain pathology could be compared with the PET images. These patients were the basis for the sensitivity and specificity analysis. Five specially trained readers who were blinded to patient information independently interpreted the PET scans as positive or negative for neuritic β-amyloid.

On postmortem examination, 25 of the 68 brains (37%) were β-amyloid negative, and 43 (63%) were β-amyloid positive. The sensitivity of [18F]flutemetamol PET scanning ranged from 81% to 93% (median, 88%) across the five scan readers, and the specificity ranged from 44% to 92% (median, 88%). One of the readers frequently overestimated the level of β-amyloid in the scans and was considered an outlier regarding specificity. Between-reader agreement was 90% or higher when that reader’s interpretations were excluded from the analysis.

Six (14%) of 43 brains found to be β-amyloid positive at autopsy were read as false negatives, and two (8%) of 25 brains found to be β-amyloid negative at autopsy were read as false positives.

The IV [18F]flutemetamol injections were well tolerated, and no adverse events were attributed to the agent or the PET procedure. However, four participants were withdrawn from the study because they could not remain motionless in the scanner.

“A scan that accurately detects β-amyloid is not the same thing as a test for Alzheimer’s disease,” said Gil D. Rabinovici, MD, Associate Professor of Neurology at the University of California, San Francisco’s Memory and Aging Center, in an accompanying editorial. “Approximately 25% of cognitively normal older adults and nearly 50% of people older than 80 years also show β-amyloid on PET scans, as do patients with conditions such as dementia with Lewy bodies and cerebral amyloid angiopathy.

“It is concerning that one of the five rigorously trained PET scan readers frequently overestimated the amount of β-amyloid and showed worryingly low specificity (44%) in interpreting these scans,” he continued. “PET amyloid imaging should be considered only for patients in whom there is considerable diagnostic uncertainty after a comprehensive clinical evaluation and in whom knowledge of β-amyloid status is likely to change diagnosis and management. This would include patients with unexplained mild cognitive impairment, with atypical or mixed presentations, and those who present with dementia at an unusually early age.”

—Mary Ann Moon

PET scans using radio-labeled flutemetamol are safe and confirm the presence or absence of neuritic β-amyloid levels “with high sensitivity and specificity,” according to research reported in the March issue of JAMA Neurology. “In vivo detection of brain β-amyloid may help increase diagnostic accuracy in cognitively impaired patients, compared with clinical diagnosis alone,” said Craig Curtis, MD, Chief Medical Officer at Compass Research in Orlando, and his associates.

The investigators conducted a phase III trial involving terminally ill older adults. The PET scanning agent used in the study, [18F]flutemetamol, binds with high affinity to β-amyloid but rapidly clears from normal brain tissue. The trial included 203 consecutive patients attending 19 dementia clinics, memory centers, and hospices in the United States and England who were age 55 or older and who had a life expectancy of one year or less. A total of 180 participants who underwent [18F]flutemetamol PET scanning made up the population for the safety analysis. A subset of 68 patients who died during the study underwent autopsy so that brain pathology could be compared with the PET images. These patients were the basis for the sensitivity and specificity analysis. Five specially trained readers who were blinded to patient information independently interpreted the PET scans as positive or negative for neuritic β-amyloid.

On postmortem examination, 25 of the 68 brains (37%) were β-amyloid negative, and 43 (63%) were β-amyloid positive. The sensitivity of [18F]flutemetamol PET scanning ranged from 81% to 93% (median, 88%) across the five scan readers, and the specificity ranged from 44% to 92% (median, 88%). One of the readers frequently overestimated the level of β-amyloid in the scans and was considered an outlier regarding specificity. Between-reader agreement was 90% or higher when that reader’s interpretations were excluded from the analysis.

Six (14%) of 43 brains found to be β-amyloid positive at autopsy were read as false negatives, and two (8%) of 25 brains found to be β-amyloid negative at autopsy were read as false positives.

The IV [18F]flutemetamol injections were well tolerated, and no adverse events were attributed to the agent or the PET procedure. However, four participants were withdrawn from the study because they could not remain motionless in the scanner.

“A scan that accurately detects β-amyloid is not the same thing as a test for Alzheimer’s disease,” said Gil D. Rabinovici, MD, Associate Professor of Neurology at the University of California, San Francisco’s Memory and Aging Center, in an accompanying editorial. “Approximately 25% of cognitively normal older adults and nearly 50% of people older than 80 years also show β-amyloid on PET scans, as do patients with conditions such as dementia with Lewy bodies and cerebral amyloid angiopathy.

“It is concerning that one of the five rigorously trained PET scan readers frequently overestimated the amount of β-amyloid and showed worryingly low specificity (44%) in interpreting these scans,” he continued. “PET amyloid imaging should be considered only for patients in whom there is considerable diagnostic uncertainty after a comprehensive clinical evaluation and in whom knowledge of β-amyloid status is likely to change diagnosis and management. This would include patients with unexplained mild cognitive impairment, with atypical or mixed presentations, and those who present with dementia at an unusually early age.”

—Mary Ann Moon

Behaviors that enhance cognitive reserve or improve certain other psychosocial and health factors may offer a degree of protection from the cognitive decline associated with the APOE ε4 allele, according to research published in the March issue of JAMA Neurology.

Allison R. Kaup, PhD, of the Sierra Pacific Mental Illness Research, Education, and Clinical Center at the San Francisco Veterans Affairs Medical Center, and her associates analyzed data collected in the prospective Health, Aging, and Body Composition study to identify factors that may promote cognitive resilience in carriers of the APOE ε4 allele. The study examined aging-related health in 3,075 older adults residing in Pittsburgh or Memphis between 1997 and 1998. These study participants, who were between ages 69 and 80 at baseline, had repeated cognitive testing during 11 years of follow-up. A subset of 670 individuals were APOE ε4 carriers.

As expected, APOE ε4 carriers had greater cognitive decline over time than noncarriers did. A subset of APOE ε4 carriers, however, showed high retention of cognitive status in comparison with demographically similar noncarriers. Among Caucasian carriers, the factors that strongly predicted cognitive resilience were, in order of importance, an absence of recent negative life events, higher literacy level, older age, higher education level, and more time spent reading. Among African American carriers, the factors that most strongly predicted cognitive resilience were higher literacy level, higher education level, female sex, and absence of diabetes mellitus.

The reasons why some predictors differed by race aren’t yet understood. The investigators analyzed the two races separately because the prevalence of APOE ε4 differs by race, as does the gene’s impact. APOE ε4 occurs more frequently among African Americans than among Caucasians, and the gene’s deleterious effects on cognition are weaker in African Americans than in Caucasians.

The current findings “raise the possibility that interventions targeting the modifiable factors among these predictors could help promote cognitive resilience in APOE ε4 carriers,” said Dr. Kaup. For example, promoting cognitive reserve would likely be protective for both races. In addition, Caucasians would likely benefit most from stress reduction or stress management, while African Americans would likely benefit most from prevention or close management of diabetes.

—Mary Ann Moon

Behaviors that enhance cognitive reserve or improve certain other psychosocial and health factors may offer a degree of protection from the cognitive decline associated with the APOE ε4 allele, according to research published in the March issue of JAMA Neurology.

Allison R. Kaup, PhD, of the Sierra Pacific Mental Illness Research, Education, and Clinical Center at the San Francisco Veterans Affairs Medical Center, and her associates analyzed data collected in the prospective Health, Aging, and Body Composition study to identify factors that may promote cognitive resilience in carriers of the APOE ε4 allele. The study examined aging-related health in 3,075 older adults residing in Pittsburgh or Memphis between 1997 and 1998. These study participants, who were between ages 69 and 80 at baseline, had repeated cognitive testing during 11 years of follow-up. A subset of 670 individuals were APOE ε4 carriers.

As expected, APOE ε4 carriers had greater cognitive decline over time than noncarriers did. A subset of APOE ε4 carriers, however, showed high retention of cognitive status in comparison with demographically similar noncarriers. Among Caucasian carriers, the factors that strongly predicted cognitive resilience were, in order of importance, an absence of recent negative life events, higher literacy level, older age, higher education level, and more time spent reading. Among African American carriers, the factors that most strongly predicted cognitive resilience were higher literacy level, higher education level, female sex, and absence of diabetes mellitus.

The reasons why some predictors differed by race aren’t yet understood. The investigators analyzed the two races separately because the prevalence of APOE ε4 differs by race, as does the gene’s impact. APOE ε4 occurs more frequently among African Americans than among Caucasians, and the gene’s deleterious effects on cognition are weaker in African Americans than in Caucasians.

The current findings “raise the possibility that interventions targeting the modifiable factors among these predictors could help promote cognitive resilience in APOE ε4 carriers,” said Dr. Kaup. For example, promoting cognitive reserve would likely be protective for both races. In addition, Caucasians would likely benefit most from stress reduction or stress management, while African Americans would likely benefit most from prevention or close management of diabetes.

—Mary Ann Moon

Behaviors that enhance cognitive reserve or improve certain other psychosocial and health factors may offer a degree of protection from the cognitive decline associated with the APOE ε4 allele, according to research published in the March issue of JAMA Neurology.

Allison R. Kaup, PhD, of the Sierra Pacific Mental Illness Research, Education, and Clinical Center at the San Francisco Veterans Affairs Medical Center, and her associates analyzed data collected in the prospective Health, Aging, and Body Composition study to identify factors that may promote cognitive resilience in carriers of the APOE ε4 allele. The study examined aging-related health in 3,075 older adults residing in Pittsburgh or Memphis between 1997 and 1998. These study participants, who were between ages 69 and 80 at baseline, had repeated cognitive testing during 11 years of follow-up. A subset of 670 individuals were APOE ε4 carriers.

As expected, APOE ε4 carriers had greater cognitive decline over time than noncarriers did. A subset of APOE ε4 carriers, however, showed high retention of cognitive status in comparison with demographically similar noncarriers. Among Caucasian carriers, the factors that strongly predicted cognitive resilience were, in order of importance, an absence of recent negative life events, higher literacy level, older age, higher education level, and more time spent reading. Among African American carriers, the factors that most strongly predicted cognitive resilience were higher literacy level, higher education level, female sex, and absence of diabetes mellitus.

The reasons why some predictors differed by race aren’t yet understood. The investigators analyzed the two races separately because the prevalence of APOE ε4 differs by race, as does the gene’s impact. APOE ε4 occurs more frequently among African Americans than among Caucasians, and the gene’s deleterious effects on cognition are weaker in African Americans than in Caucasians.

The current findings “raise the possibility that interventions targeting the modifiable factors among these predictors could help promote cognitive resilience in APOE ε4 carriers,” said Dr. Kaup. For example, promoting cognitive reserve would likely be protective for both races. In addition, Caucasians would likely benefit most from stress reduction or stress management, while African Americans would likely benefit most from prevention or close management of diabetes.

—Mary Ann Moon

Patients with cluster headache show worse working memory, disturbance of mood, and poorer quality of life, compared with healthy controls, according to a report in the February issue of Headache. Furthermore, there are discernable differences between patients with episodic and chronic cluster headache with regard to mood and cognitive function.

Cluster headache is commonly regarded as one of the most disabling headache conditions. In a recent report, lead author Mariam Torkamani, BSc, and colleagues sought to expand what limited research is available on the severe impact of cluster headache by further characterizing its impact on quality of life and other neuropsychiatric dimensions. Ms. Torkamani is an Honorary Research Assistant in the Cognitive Motor Neuroscience Group at the University College of London.

The investigators conducted a cross-sectional study to investigate various aspects of cognitive function, including intelligence, executive function, memory, mood, disability, and quality of life in 22 patients with episodic or chronic cluster headache, compared with age-matched healthy controls.

Their results showed that intelligence and executive function are intact in patients with cluster headache, but that patients with cluster headache perform significantly worse than healthy controls on tests of working memory and report greater cognitive failures. Approximately one-third of the episodic and chronic cluster headache groups achieved “caseness” for depression. Self-reported anxiety was greater in people with chronic cluster headache than in people with episodic cluster headache. Approximately 75% of the former participants, compared with 38% of the latter group, achieved “caseness” on the measure of anxiety. Patients with cluster headache reported high levels of disability that were not significantly different between the two groups. On the whole, patients with cluster headache reported poor quality of life, compared with healthy controls, but this difference was not statistically significant.

According to the authors, the results highlight the severe impact of cluster headache on the mental health of patients with episodic cluster headache and those with chronic cluster headache, compared with healthy controls. The findings particularly highlight “the high incidence of anxiety disorders in this painful and unpredictable condition. The results also indicate poor quality of life and the severely disabling nature of cluster headache. Despite the impairment in quality of life and high levels of health-related disability and psychiatric comorbidity found in cluster headache, cognitive function remained largely intact in both episodic cluster headache and chronic cluster headache patients.”

The authors further reported that “the high levels of disability and mood disturbance in cluster headache warrant direct management of these problems in clinical practice. Antidepressant medication and/or psychotherapy to help patients come to terms with the disabling nature of their cluster headache may both prove of value.”

Patients with cluster headache show worse working memory, disturbance of mood, and poorer quality of life, compared with healthy controls, according to a report in the February issue of Headache. Furthermore, there are discernable differences between patients with episodic and chronic cluster headache with regard to mood and cognitive function.

Cluster headache is commonly regarded as one of the most disabling headache conditions. In a recent report, lead author Mariam Torkamani, BSc, and colleagues sought to expand what limited research is available on the severe impact of cluster headache by further characterizing its impact on quality of life and other neuropsychiatric dimensions. Ms. Torkamani is an Honorary Research Assistant in the Cognitive Motor Neuroscience Group at the University College of London.

The investigators conducted a cross-sectional study to investigate various aspects of cognitive function, including intelligence, executive function, memory, mood, disability, and quality of life in 22 patients with episodic or chronic cluster headache, compared with age-matched healthy controls.

Their results showed that intelligence and executive function are intact in patients with cluster headache, but that patients with cluster headache perform significantly worse than healthy controls on tests of working memory and report greater cognitive failures. Approximately one-third of the episodic and chronic cluster headache groups achieved “caseness” for depression. Self-reported anxiety was greater in people with chronic cluster headache than in people with episodic cluster headache. Approximately 75% of the former participants, compared with 38% of the latter group, achieved “caseness” on the measure of anxiety. Patients with cluster headache reported high levels of disability that were not significantly different between the two groups. On the whole, patients with cluster headache reported poor quality of life, compared with healthy controls, but this difference was not statistically significant.

According to the authors, the results highlight the severe impact of cluster headache on the mental health of patients with episodic cluster headache and those with chronic cluster headache, compared with healthy controls. The findings particularly highlight “the high incidence of anxiety disorders in this painful and unpredictable condition. The results also indicate poor quality of life and the severely disabling nature of cluster headache. Despite the impairment in quality of life and high levels of health-related disability and psychiatric comorbidity found in cluster headache, cognitive function remained largely intact in both episodic cluster headache and chronic cluster headache patients.”

The authors further reported that “the high levels of disability and mood disturbance in cluster headache warrant direct management of these problems in clinical practice. Antidepressant medication and/or psychotherapy to help patients come to terms with the disabling nature of their cluster headache may both prove of value.”

Patients with cluster headache show worse working memory, disturbance of mood, and poorer quality of life, compared with healthy controls, according to a report in the February issue of Headache. Furthermore, there are discernable differences between patients with episodic and chronic cluster headache with regard to mood and cognitive function.

Cluster headache is commonly regarded as one of the most disabling headache conditions. In a recent report, lead author Mariam Torkamani, BSc, and colleagues sought to expand what limited research is available on the severe impact of cluster headache by further characterizing its impact on quality of life and other neuropsychiatric dimensions. Ms. Torkamani is an Honorary Research Assistant in the Cognitive Motor Neuroscience Group at the University College of London.

The investigators conducted a cross-sectional study to investigate various aspects of cognitive function, including intelligence, executive function, memory, mood, disability, and quality of life in 22 patients with episodic or chronic cluster headache, compared with age-matched healthy controls.

Their results showed that intelligence and executive function are intact in patients with cluster headache, but that patients with cluster headache perform significantly worse than healthy controls on tests of working memory and report greater cognitive failures. Approximately one-third of the episodic and chronic cluster headache groups achieved “caseness” for depression. Self-reported anxiety was greater in people with chronic cluster headache than in people with episodic cluster headache. Approximately 75% of the former participants, compared with 38% of the latter group, achieved “caseness” on the measure of anxiety. Patients with cluster headache reported high levels of disability that were not significantly different between the two groups. On the whole, patients with cluster headache reported poor quality of life, compared with healthy controls, but this difference was not statistically significant.

According to the authors, the results highlight the severe impact of cluster headache on the mental health of patients with episodic cluster headache and those with chronic cluster headache, compared with healthy controls. The findings particularly highlight “the high incidence of anxiety disorders in this painful and unpredictable condition. The results also indicate poor quality of life and the severely disabling nature of cluster headache. Despite the impairment in quality of life and high levels of health-related disability and psychiatric comorbidity found in cluster headache, cognitive function remained largely intact in both episodic cluster headache and chronic cluster headache patients.”

The authors further reported that “the high levels of disability and mood disturbance in cluster headache warrant direct management of these problems in clinical practice. Antidepressant medication and/or psychotherapy to help patients come to terms with the disabling nature of their cluster headache may both prove of value.”

People at risk for dementia who were assigned to an intervention program that included healthy eating guidance, personalized exercise plans, and computer-based brain training scored better on cognitive tests after two years than a control group that only received general medical advice, according to research published online ahead of print March 11 in Lancet. Results from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) show that multidomain interventions may help people at risk for dementia improve or maintain cognitive function, researchers said.

Miia Kivipelto, MD, PhD, Professor of Clinical Geriatric Epidemiology at the Karolinska Institutet Center for Alzheimer’s Research in Stockholm and Professor at the National Institute for Health and Welfare in Helsinki, and colleagues identified 1,260 participants, ages 60 to 77, who had a dementia risk score on the Cardiovascular Risk Factors, Aging, and Dementia tool of at least 6 points and cognition at mean level or slightly lower than expected. Participants randomly were assigned to the intervention or control groups. The intervention program included sessions with nutritionists who tailored the participants’ diets, physiotherapists who created individualized strength training and aerobic exercise programs, and psychologists who led group sessions that reviewed memory and reasoning strategies. Intervention group participants also were assigned computer-based brain training exercises. Physicians and nurses measured metabolic and vascular risk factors and made lifestyle management recommendations.

After two years, participants’ cognitive performance was scored using an extended version of the neuropsychologic test battery (NTB). Estimated mean change in NTB Z score at two years was 0.20 in the intervention group and 0.16 in the control group. Improvement in NTB total score after two years was 25% higher in the intervention group than in the control group. Improvement in executive functioning was 83% higher in the intervention group than in the control group, and improvement in processing speed was 150% higher in the intervention group. The intervention was not associated with significant change in memory. NTB total score fell in 28% of participants, and the risk of cognitive decline increased in the control group.

“Much previous research has shown that there are links between cognitive decline in older people and factors such as diet, heart health, and fitness. However, our study is the first large randomized controlled trial to show that an intensive program aimed at addressing these risk factors might be able to prevent cognitive decline in elderly people who are at risk of dementia,” Dr. Kivipelto said.

Researchers plan to follow study participants for at least seven years to determine whether the diminished cognitive decline seen in the trial is followed by reduced levels of dementia and diagnoses of Alzheimer’s disease.

People at risk for dementia who were assigned to an intervention program that included healthy eating guidance, personalized exercise plans, and computer-based brain training scored better on cognitive tests after two years than a control group that only received general medical advice, according to research published online ahead of print March 11 in Lancet. Results from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) show that multidomain interventions may help people at risk for dementia improve or maintain cognitive function, researchers said.

Miia Kivipelto, MD, PhD, Professor of Clinical Geriatric Epidemiology at the Karolinska Institutet Center for Alzheimer’s Research in Stockholm and Professor at the National Institute for Health and Welfare in Helsinki, and colleagues identified 1,260 participants, ages 60 to 77, who had a dementia risk score on the Cardiovascular Risk Factors, Aging, and Dementia tool of at least 6 points and cognition at mean level or slightly lower than expected. Participants randomly were assigned to the intervention or control groups. The intervention program included sessions with nutritionists who tailored the participants’ diets, physiotherapists who created individualized strength training and aerobic exercise programs, and psychologists who led group sessions that reviewed memory and reasoning strategies. Intervention group participants also were assigned computer-based brain training exercises. Physicians and nurses measured metabolic and vascular risk factors and made lifestyle management recommendations.

After two years, participants’ cognitive performance was scored using an extended version of the neuropsychologic test battery (NTB). Estimated mean change in NTB Z score at two years was 0.20 in the intervention group and 0.16 in the control group. Improvement in NTB total score after two years was 25% higher in the intervention group than in the control group. Improvement in executive functioning was 83% higher in the intervention group than in the control group, and improvement in processing speed was 150% higher in the intervention group. The intervention was not associated with significant change in memory. NTB total score fell in 28% of participants, and the risk of cognitive decline increased in the control group.

“Much previous research has shown that there are links between cognitive decline in older people and factors such as diet, heart health, and fitness. However, our study is the first large randomized controlled trial to show that an intensive program aimed at addressing these risk factors might be able to prevent cognitive decline in elderly people who are at risk of dementia,” Dr. Kivipelto said.

Researchers plan to follow study participants for at least seven years to determine whether the diminished cognitive decline seen in the trial is followed by reduced levels of dementia and diagnoses of Alzheimer’s disease.

People at risk for dementia who were assigned to an intervention program that included healthy eating guidance, personalized exercise plans, and computer-based brain training scored better on cognitive tests after two years than a control group that only received general medical advice, according to research published online ahead of print March 11 in Lancet. Results from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) show that multidomain interventions may help people at risk for dementia improve or maintain cognitive function, researchers said.

Miia Kivipelto, MD, PhD, Professor of Clinical Geriatric Epidemiology at the Karolinska Institutet Center for Alzheimer’s Research in Stockholm and Professor at the National Institute for Health and Welfare in Helsinki, and colleagues identified 1,260 participants, ages 60 to 77, who had a dementia risk score on the Cardiovascular Risk Factors, Aging, and Dementia tool of at least 6 points and cognition at mean level or slightly lower than expected. Participants randomly were assigned to the intervention or control groups. The intervention program included sessions with nutritionists who tailored the participants’ diets, physiotherapists who created individualized strength training and aerobic exercise programs, and psychologists who led group sessions that reviewed memory and reasoning strategies. Intervention group participants also were assigned computer-based brain training exercises. Physicians and nurses measured metabolic and vascular risk factors and made lifestyle management recommendations.

After two years, participants’ cognitive performance was scored using an extended version of the neuropsychologic test battery (NTB). Estimated mean change in NTB Z score at two years was 0.20 in the intervention group and 0.16 in the control group. Improvement in NTB total score after two years was 25% higher in the intervention group than in the control group. Improvement in executive functioning was 83% higher in the intervention group than in the control group, and improvement in processing speed was 150% higher in the intervention group. The intervention was not associated with significant change in memory. NTB total score fell in 28% of participants, and the risk of cognitive decline increased in the control group.

“Much previous research has shown that there are links between cognitive decline in older people and factors such as diet, heart health, and fitness. However, our study is the first large randomized controlled trial to show that an intensive program aimed at addressing these risk factors might be able to prevent cognitive decline in elderly people who are at risk of dementia,” Dr. Kivipelto said.

Researchers plan to follow study participants for at least seven years to determine whether the diminished cognitive decline seen in the trial is followed by reduced levels of dementia and diagnoses of Alzheimer’s disease.