Alzheimer's & Cognition

CHICAGO—Nonbenzodiazepine hypnotic “Z-drugs” (eg, zolpidem, zopiclone, and zaleplon) increase the risk of fractures in a dose-dependent manner in people with dementia, according to research presented at AAIC 2018. Patients with dementia who are receiving these drugs should be monitored, according to the researchers.

Approximately 60% of people with dementia have sleep disturbance. Z-drugs are often prescribed to help treat insomnia in older adults, but observers have raised concerns that these treatments may cause problems such as falls and fractures and increase confusion. Researchers have not fully investigated the safety and efficacy of Z-drugs in this patient population, however.

Chris Fox, MD, Professor of Psychiatry at Norwich Medical School at the University of East Anglia in the United Kingdom, and colleagues analyzed cohort studies using primary care data from the UK Clinical Practice Research Datalink that was linked to hospital admissions data. They also examined data from three clinical studies of people with dementia. To evaluate the benefits and harms of these medicines, the researchers compared data for 2,952 people with dementia who were newly prescribed Z-drugs with data for 1,651 people who were not prescribed sedatives or hypnotics.

Dr. Fox and colleagues defined the index date as the first date of a diagnosis of sleep disturbance or of a Z-drug prescription after dementia diagnosis. They excluded patients who had been prescribed a sedative during the previous year. Patients were followed for as long as two years or until 90 days after their last prescription. Dr. Fox’s group compared the two arms’ outcomes using Cox regression. They adjusted the data for sociodemographic variables, BMI, systolic blood pressure, diagnosed health conditions, and comedications.

The use of Z-drugs was associated with a 47% increased risk of any type of fracture. The risk increased among patients on higher doses. Z-drug use was also associated with greater risks of hip fracture and mortality. The study did not identify a higher risk of other events, such as falls, infections, stroke, or venous thromboembolism.

“Fractures in people with dementia can have a devastating impact, including loss of mobility, increased dependency, and worsening dementia,” said Dr. Fox. “We desperately need better alternatives to the drugs currently being prescribed for sleep problems and other noncognitive symptoms of dementia. Wherever possible, suitable nonpharmacologic alternatives should be considered, and where Z-drugs are prescribed, patients should receive care that reduces or prevents the occurrence of falls.”

CHICAGO—Nonbenzodiazepine hypnotic “Z-drugs” (eg, zolpidem, zopiclone, and zaleplon) increase the risk of fractures in a dose-dependent manner in people with dementia, according to research presented at AAIC 2018. Patients with dementia who are receiving these drugs should be monitored, according to the researchers.

Approximately 60% of people with dementia have sleep disturbance. Z-drugs are often prescribed to help treat insomnia in older adults, but observers have raised concerns that these treatments may cause problems such as falls and fractures and increase confusion. Researchers have not fully investigated the safety and efficacy of Z-drugs in this patient population, however.

Chris Fox, MD, Professor of Psychiatry at Norwich Medical School at the University of East Anglia in the United Kingdom, and colleagues analyzed cohort studies using primary care data from the UK Clinical Practice Research Datalink that was linked to hospital admissions data. They also examined data from three clinical studies of people with dementia. To evaluate the benefits and harms of these medicines, the researchers compared data for 2,952 people with dementia who were newly prescribed Z-drugs with data for 1,651 people who were not prescribed sedatives or hypnotics.

Dr. Fox and colleagues defined the index date as the first date of a diagnosis of sleep disturbance or of a Z-drug prescription after dementia diagnosis. They excluded patients who had been prescribed a sedative during the previous year. Patients were followed for as long as two years or until 90 days after their last prescription. Dr. Fox’s group compared the two arms’ outcomes using Cox regression. They adjusted the data for sociodemographic variables, BMI, systolic blood pressure, diagnosed health conditions, and comedications.

The use of Z-drugs was associated with a 47% increased risk of any type of fracture. The risk increased among patients on higher doses. Z-drug use was also associated with greater risks of hip fracture and mortality. The study did not identify a higher risk of other events, such as falls, infections, stroke, or venous thromboembolism.

“Fractures in people with dementia can have a devastating impact, including loss of mobility, increased dependency, and worsening dementia,” said Dr. Fox. “We desperately need better alternatives to the drugs currently being prescribed for sleep problems and other noncognitive symptoms of dementia. Wherever possible, suitable nonpharmacologic alternatives should be considered, and where Z-drugs are prescribed, patients should receive care that reduces or prevents the occurrence of falls.”

CHICAGO—Nonbenzodiazepine hypnotic “Z-drugs” (eg, zolpidem, zopiclone, and zaleplon) increase the risk of fractures in a dose-dependent manner in people with dementia, according to research presented at AAIC 2018. Patients with dementia who are receiving these drugs should be monitored, according to the researchers.

Approximately 60% of people with dementia have sleep disturbance. Z-drugs are often prescribed to help treat insomnia in older adults, but observers have raised concerns that these treatments may cause problems such as falls and fractures and increase confusion. Researchers have not fully investigated the safety and efficacy of Z-drugs in this patient population, however.

Chris Fox, MD, Professor of Psychiatry at Norwich Medical School at the University of East Anglia in the United Kingdom, and colleagues analyzed cohort studies using primary care data from the UK Clinical Practice Research Datalink that was linked to hospital admissions data. They also examined data from three clinical studies of people with dementia. To evaluate the benefits and harms of these medicines, the researchers compared data for 2,952 people with dementia who were newly prescribed Z-drugs with data for 1,651 people who were not prescribed sedatives or hypnotics.

Dr. Fox and colleagues defined the index date as the first date of a diagnosis of sleep disturbance or of a Z-drug prescription after dementia diagnosis. They excluded patients who had been prescribed a sedative during the previous year. Patients were followed for as long as two years or until 90 days after their last prescription. Dr. Fox’s group compared the two arms’ outcomes using Cox regression. They adjusted the data for sociodemographic variables, BMI, systolic blood pressure, diagnosed health conditions, and comedications.

The use of Z-drugs was associated with a 47% increased risk of any type of fracture. The risk increased among patients on higher doses. Z-drug use was also associated with greater risks of hip fracture and mortality. The study did not identify a higher risk of other events, such as falls, infections, stroke, or venous thromboembolism.

“Fractures in people with dementia can have a devastating impact, including loss of mobility, increased dependency, and worsening dementia,” said Dr. Fox. “We desperately need better alternatives to the drugs currently being prescribed for sleep problems and other noncognitive symptoms of dementia. Wherever possible, suitable nonpharmacologic alternatives should be considered, and where Z-drugs are prescribed, patients should receive care that reduces or prevents the occurrence of falls.”

BALTIMORE—Among patients with Alzheimer’s disease and related dementias, a lighting intervention may improve sleep, mood, and agitation, according to a study presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

The intervention “holds considerable promise as a novel, practically applied, nonpharmacologic intervention” for people with dementia who live in long-term care facilities, said Mariana G. Figueiro, PhD, Director of the Lighting Research Center and Professor of Architecture at Rensselaer Polytechnic Institute in Troy, New York.

People with dementia often have problems related to sleep and daytime irritability. A study in office workers found that exposure to light that stimulates the circadian system early in the day is associated with better sleep and improved behavior and mood. To assess whether a lighting intervention that delivers a circadian stimulus may improve sleep and behavior in patients with dementia in long-term care facilities, Dr. Figueiro and colleagues conducted a crossover, repeated-measures, within-subjects study. The study included 43 subjects (31 female) with Alzheimer’s disease or related dementias and Mini-Mental State Examination scores of less than 24.

The intervention consisted of an LED light table and individual room lights that were placed where patients spent most of their waking hours. The lights were turned on when participants woke up and remained on until 6 PM. Participants wore calibrated light meters that monitored their light exposure.

The trial included four weeks with an active circadian stimulus, four weeks with an inactive lighting intervention, and a four-week washout period in between.

In addition, researchers collected subjective measures of sleep disturbances (Pittsburgh Sleep Quality Index [PSQI]), mood (Cornell Scale for Depression in Dementia [CSDD]), and agitation (Cohen-Mansfield Agitation Index [CMAI]) at baseline and during the last week of the active and placebo intervention periods.

The active lighting intervention significantly decreased scores for sleep disturbances, depression, and agitation, compared with placebo. During the active intervention, mean PSQI scores decreased from 10.3 to 6.7, CSDD scores decreased from 10.5 to 7.3, and CMAI scores decreased from 42.9 to 37.4.

A six-month study of the lighting intervention is underway. “A logical next step would be to test the short- and long-term effects of the tailored lighting intervention among those living at home,” Dr. Figueiro and colleagues said.

—Jake Remaly

Suggested Reading

Figueiro MG, Steverson B, Heerwagen J, et al. The impact of daytime light exposures on sleep and mood in office workers. Sleep Health. 2017;3(3):204-215.

BALTIMORE—Among patients with Alzheimer’s disease and related dementias, a lighting intervention may improve sleep, mood, and agitation, according to a study presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

The intervention “holds considerable promise as a novel, practically applied, nonpharmacologic intervention” for people with dementia who live in long-term care facilities, said Mariana G. Figueiro, PhD, Director of the Lighting Research Center and Professor of Architecture at Rensselaer Polytechnic Institute in Troy, New York.

People with dementia often have problems related to sleep and daytime irritability. A study in office workers found that exposure to light that stimulates the circadian system early in the day is associated with better sleep and improved behavior and mood. To assess whether a lighting intervention that delivers a circadian stimulus may improve sleep and behavior in patients with dementia in long-term care facilities, Dr. Figueiro and colleagues conducted a crossover, repeated-measures, within-subjects study. The study included 43 subjects (31 female) with Alzheimer’s disease or related dementias and Mini-Mental State Examination scores of less than 24.

The intervention consisted of an LED light table and individual room lights that were placed where patients spent most of their waking hours. The lights were turned on when participants woke up and remained on until 6 PM. Participants wore calibrated light meters that monitored their light exposure.

The trial included four weeks with an active circadian stimulus, four weeks with an inactive lighting intervention, and a four-week washout period in between.

In addition, researchers collected subjective measures of sleep disturbances (Pittsburgh Sleep Quality Index [PSQI]), mood (Cornell Scale for Depression in Dementia [CSDD]), and agitation (Cohen-Mansfield Agitation Index [CMAI]) at baseline and during the last week of the active and placebo intervention periods.

The active lighting intervention significantly decreased scores for sleep disturbances, depression, and agitation, compared with placebo. During the active intervention, mean PSQI scores decreased from 10.3 to 6.7, CSDD scores decreased from 10.5 to 7.3, and CMAI scores decreased from 42.9 to 37.4.

A six-month study of the lighting intervention is underway. “A logical next step would be to test the short- and long-term effects of the tailored lighting intervention among those living at home,” Dr. Figueiro and colleagues said.

—Jake Remaly

Suggested Reading

Figueiro MG, Steverson B, Heerwagen J, et al. The impact of daytime light exposures on sleep and mood in office workers. Sleep Health. 2017;3(3):204-215.

BALTIMORE—Among patients with Alzheimer’s disease and related dementias, a lighting intervention may improve sleep, mood, and agitation, according to a study presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

The intervention “holds considerable promise as a novel, practically applied, nonpharmacologic intervention” for people with dementia who live in long-term care facilities, said Mariana G. Figueiro, PhD, Director of the Lighting Research Center and Professor of Architecture at Rensselaer Polytechnic Institute in Troy, New York.

People with dementia often have problems related to sleep and daytime irritability. A study in office workers found that exposure to light that stimulates the circadian system early in the day is associated with better sleep and improved behavior and mood. To assess whether a lighting intervention that delivers a circadian stimulus may improve sleep and behavior in patients with dementia in long-term care facilities, Dr. Figueiro and colleagues conducted a crossover, repeated-measures, within-subjects study. The study included 43 subjects (31 female) with Alzheimer’s disease or related dementias and Mini-Mental State Examination scores of less than 24.

The intervention consisted of an LED light table and individual room lights that were placed where patients spent most of their waking hours. The lights were turned on when participants woke up and remained on until 6 PM. Participants wore calibrated light meters that monitored their light exposure.

The trial included four weeks with an active circadian stimulus, four weeks with an inactive lighting intervention, and a four-week washout period in between.

In addition, researchers collected subjective measures of sleep disturbances (Pittsburgh Sleep Quality Index [PSQI]), mood (Cornell Scale for Depression in Dementia [CSDD]), and agitation (Cohen-Mansfield Agitation Index [CMAI]) at baseline and during the last week of the active and placebo intervention periods.

The active lighting intervention significantly decreased scores for sleep disturbances, depression, and agitation, compared with placebo. During the active intervention, mean PSQI scores decreased from 10.3 to 6.7, CSDD scores decreased from 10.5 to 7.3, and CMAI scores decreased from 42.9 to 37.4.

A six-month study of the lighting intervention is underway. “A logical next step would be to test the short- and long-term effects of the tailored lighting intervention among those living at home,” Dr. Figueiro and colleagues said.

—Jake Remaly

Suggested Reading

Figueiro MG, Steverson B, Heerwagen J, et al. The impact of daytime light exposures on sleep and mood in office workers. Sleep Health. 2017;3(3):204-215.

CHICAGO—Transdermal buprenorphine is associated with a significant increase in harmful side effects in people with dementia, according to data described at AAIC 2018.

About half of people with dementia who are living in nursing homes have clinically significant pain. Previous research has suggested that pain often is underdiagnosed and poorly managed in people with dementia. These shortcomings affect patients’ quality of life.

Opioid-based painkillers often are second-line treatments for people with dementia, and clinicians prescribe them to approximately 40% of people with dementia who live in nursing homes. These drugs reduce pain effectively, yet current prescribing guidance does not account for the fact that people with dementia get effective pain relief from smaller doses than are commonly prescribed. In addition, people with dementia are particularly sensitive to adverse drug effects.

Clive Ballard, MD, Professor of Age-Related Diseases at the University of Exeter Medical School in the United Kingdom, and colleagues conducted a secondary analysis of a randomized, placebo-controlled trial to investigate the safety of the buprenorphine transdermal system in patients with dementia. They also analyzed the extent to which adverse events led patients to discontinue treatment with buprenorphine. The trial’s primary objective had been to examine the safety and efficacy of analgesic treatment for depression in this population.

The researchers examined 162 people with advanced dementia and significant depression from 47 Norwegian nursing homes. Participants were randomized to analgesic treatment with paracetamol, buprenorphine, or placebo for 13 weeks. The main outcomes of the investigators’ secondary analysis were time to and reasons for discontinuation of treatment due to adverse events. The secondary outcomes were change in daytime activity and intensity, as measured by actigraphy.

A total of 44 patients received 5 μg/h of active buprenorphine. Of this group, 23 (52.3%) discontinued treatment because of adverse events, compared with six (13.3%) in the placebo group. The most frequent adverse events were psychiatric and neurologic (69.6%) and included personality changes, confusion, and sedation. Concomitant use of antidepressants significantly increased the risk for discontinuation (hazard ratio, 23.2). After the researchers adjusted the data for age, sex, cognitive function, and pain at baseline, active buprenorphine was associated with a 20.9-times increased risk of discontinuation. Participants’ daytime activity decreased significantly (–21.4%) during the second day of active treatment and decreased by 12.9% during the first week.

“Pain is a symptom that can cause huge distress, and it is important that we can provide relief to people with dementia,” said Dr. Ballard. “Sadly, at the moment, we are harming people when we are trying to ease their pain. We urgently need more research in this area, and we must get this dosing right. We need to establish the best treatment pathway and examine appropriate dosing for people with dementia.”

Suggested Reading

Erdal A, Flo E, Aarsland D, et al. Efficacy and safety of analgesic treatment for depression in people with advanced dementia: randomised, multicentre, double-blind, placebo-controlled trial (DEP.PAIN.DEM). Drugs Aging. 2018;35(6):545-558.

CHICAGO—Transdermal buprenorphine is associated with a significant increase in harmful side effects in people with dementia, according to data described at AAIC 2018.

About half of people with dementia who are living in nursing homes have clinically significant pain. Previous research has suggested that pain often is underdiagnosed and poorly managed in people with dementia. These shortcomings affect patients’ quality of life.

Opioid-based painkillers often are second-line treatments for people with dementia, and clinicians prescribe them to approximately 40% of people with dementia who live in nursing homes. These drugs reduce pain effectively, yet current prescribing guidance does not account for the fact that people with dementia get effective pain relief from smaller doses than are commonly prescribed. In addition, people with dementia are particularly sensitive to adverse drug effects.

Clive Ballard, MD, Professor of Age-Related Diseases at the University of Exeter Medical School in the United Kingdom, and colleagues conducted a secondary analysis of a randomized, placebo-controlled trial to investigate the safety of the buprenorphine transdermal system in patients with dementia. They also analyzed the extent to which adverse events led patients to discontinue treatment with buprenorphine. The trial’s primary objective had been to examine the safety and efficacy of analgesic treatment for depression in this population.

The researchers examined 162 people with advanced dementia and significant depression from 47 Norwegian nursing homes. Participants were randomized to analgesic treatment with paracetamol, buprenorphine, or placebo for 13 weeks. The main outcomes of the investigators’ secondary analysis were time to and reasons for discontinuation of treatment due to adverse events. The secondary outcomes were change in daytime activity and intensity, as measured by actigraphy.

A total of 44 patients received 5 μg/h of active buprenorphine. Of this group, 23 (52.3%) discontinued treatment because of adverse events, compared with six (13.3%) in the placebo group. The most frequent adverse events were psychiatric and neurologic (69.6%) and included personality changes, confusion, and sedation. Concomitant use of antidepressants significantly increased the risk for discontinuation (hazard ratio, 23.2). After the researchers adjusted the data for age, sex, cognitive function, and pain at baseline, active buprenorphine was associated with a 20.9-times increased risk of discontinuation. Participants’ daytime activity decreased significantly (–21.4%) during the second day of active treatment and decreased by 12.9% during the first week.

“Pain is a symptom that can cause huge distress, and it is important that we can provide relief to people with dementia,” said Dr. Ballard. “Sadly, at the moment, we are harming people when we are trying to ease their pain. We urgently need more research in this area, and we must get this dosing right. We need to establish the best treatment pathway and examine appropriate dosing for people with dementia.”

Suggested Reading

Erdal A, Flo E, Aarsland D, et al. Efficacy and safety of analgesic treatment for depression in people with advanced dementia: randomised, multicentre, double-blind, placebo-controlled trial (DEP.PAIN.DEM). Drugs Aging. 2018;35(6):545-558.

CHICAGO—Transdermal buprenorphine is associated with a significant increase in harmful side effects in people with dementia, according to data described at AAIC 2018.

About half of people with dementia who are living in nursing homes have clinically significant pain. Previous research has suggested that pain often is underdiagnosed and poorly managed in people with dementia. These shortcomings affect patients’ quality of life.

Opioid-based painkillers often are second-line treatments for people with dementia, and clinicians prescribe them to approximately 40% of people with dementia who live in nursing homes. These drugs reduce pain effectively, yet current prescribing guidance does not account for the fact that people with dementia get effective pain relief from smaller doses than are commonly prescribed. In addition, people with dementia are particularly sensitive to adverse drug effects.

Clive Ballard, MD, Professor of Age-Related Diseases at the University of Exeter Medical School in the United Kingdom, and colleagues conducted a secondary analysis of a randomized, placebo-controlled trial to investigate the safety of the buprenorphine transdermal system in patients with dementia. They also analyzed the extent to which adverse events led patients to discontinue treatment with buprenorphine. The trial’s primary objective had been to examine the safety and efficacy of analgesic treatment for depression in this population.

The researchers examined 162 people with advanced dementia and significant depression from 47 Norwegian nursing homes. Participants were randomized to analgesic treatment with paracetamol, buprenorphine, or placebo for 13 weeks. The main outcomes of the investigators’ secondary analysis were time to and reasons for discontinuation of treatment due to adverse events. The secondary outcomes were change in daytime activity and intensity, as measured by actigraphy.

A total of 44 patients received 5 μg/h of active buprenorphine. Of this group, 23 (52.3%) discontinued treatment because of adverse events, compared with six (13.3%) in the placebo group. The most frequent adverse events were psychiatric and neurologic (69.6%) and included personality changes, confusion, and sedation. Concomitant use of antidepressants significantly increased the risk for discontinuation (hazard ratio, 23.2). After the researchers adjusted the data for age, sex, cognitive function, and pain at baseline, active buprenorphine was associated with a 20.9-times increased risk of discontinuation. Participants’ daytime activity decreased significantly (–21.4%) during the second day of active treatment and decreased by 12.9% during the first week.

“Pain is a symptom that can cause huge distress, and it is important that we can provide relief to people with dementia,” said Dr. Ballard. “Sadly, at the moment, we are harming people when we are trying to ease their pain. We urgently need more research in this area, and we must get this dosing right. We need to establish the best treatment pathway and examine appropriate dosing for people with dementia.”

Suggested Reading

Erdal A, Flo E, Aarsland D, et al. Efficacy and safety of analgesic treatment for depression in people with advanced dementia: randomised, multicentre, double-blind, placebo-controlled trial (DEP.PAIN.DEM). Drugs Aging. 2018;35(6):545-558.

HILTON HEAD, SC—Delusions of a common type, whether associated with neurologic or psychiatric disease, appear likely to involve common pathways in the brain, according to new studies using lesion network mapping. This type of mapping appears to reveal the pathways that explain why single focal neurologic lesions in different brain locations cause similar delusional symptoms.

Lesion network mapping “is an approach to look at neurologic and psychiatric symptoms at the level of networks to understand brain behavior relationships,” explained Ryan Darby, MD, Assistant Professor of Neurology and Director of the Frontotemporal Dementia Clinic at Vanderbilt University Medical Center in Nashville. From the neurologic perspective, this work may provide insight into brain function, but Dr. Darby, speaking at the 41st Annual Contemporary Clinical Neurology Symposium, sees broader implications.

“This [technique] might provide insight into psychiatric symptoms that we have had trouble truly understanding in relation to neuroanatomy,” Dr. Darby said. Some of the delusions associated with focal neurologic lesions have parallels with those associated with schizoaffective disorders, and this work may explain what areas of the brain are affected, even in the absence of visible lesions on imaging.

Lesion network mapping is a technique developed to identify functionally related regions of the brain. This goal is important because focal neurologic lesions associated with specific delusions are not necessarily located in the same brain region. The concept of networks connecting brain activity and network mapping recognizes that dysfunction in one brain area can lead to dysfunction in others. Lesion network mapping provides a strategy to identify these relationships.

Capgras Syndrome

Dr. Darby provided insight into lesion network mapping based on work he performed and published on Capgras syndrome, which describes an irrational belief that a familiar person or place is an impostor or a facsimile. As examples, he described a woman who thought her home, although familiar, was a replica. In another case, a man believed that his son-in-law, whom he recognized, was an impersonator. This type of delusion is complex, because it appears to involve a disruption of processes that mediate familiarity, as well as the cognitive processes employed to recognize and reject false beliefs.

One hypothesis about Capgras syndrome is that it involves “a two-hit phenomenon” in which dysfunction occurs simultaneously in distinct areas of the brain, according to Dr. Darby. His work with network lesion mapping in Capgras syndrome supports that hypothesis.

Lesion network mapping, a technique first described in a 2015 study, has established functional connectivity between regions of the brain in normal individuals in a resting state. A 2017 study tested the potential value of lesion network mapping in 17 cases of Capgras syndrome.

Most of the cases, including the imaging data, were retrieved from previously published studies, although several contemporary cases were included. In the investigation, Dr. Darby and his coinvestigators first demonstrated the heterogeneity in lesion location. Captured on MRI scans and traced onto a brain atlas, all but one of the lesions in patients with Capgras syndrome were found in the right hemisphere, but many of the lesions had nonoverlapping areas of involvement.

Despite the heterogeneity in lesion location, lesion network mapping demonstrated that all 17 lesions were functionally connected to the retrosplenial cortex. In addition, 16 of the 17 lesions were functionally connected to the right frontal cortex.

According to Dr. Darby, both associations are potentially important. On the basis of previously published studies with functional MRI (fMRI), the left retrosplenial cortex has been implicated in mediating familiarity. The right frontal cortex has been associated with belief evaluation. Moreover, in a control evaluation of published cases in which delusions did not involve misidentification, no functional connections to either the left retrosplenial cortex or the right frontal cortex were observed, according to Dr. Darby. In contrast, patients with disorders consistent with an impaired belief evaluation, such as paranoia or pathologic jealousy, did have lesions in the right frontal cortex as predicted.

 

Insights Into Other Neuropsychiatric Disorders

Lesion network mapping is now being applied to other types of delusions. Dr. Darby described work with neurologic and psychiatric disorders associated with a perception that free will has been lost. These include neuropsychiatric conditions such as akinetic mutism, alien limb syndrome, catatonia, and psychogenic nonepileptic seizures. According to Dr. Darby, there are two potential components involved in a delusion involving an impaired sense of free will. There is a change in the volitional component that captures the motivation and desire to move, as well as an impaired sense of agency, which refers to the feeling of responsibility for movement.

Describing ongoing work with these types of delusions, Dr. Darby reported that neurologic lesion locations, like those in Capgras syndrome, were heterogeneous. Again, most of these lesions could be connected to a network functional map that was not shared by those without these symptoms.

“For many of these complex disorders, what we are seeing is that pathology in different areas causes the same behavior syndrome by affecting different parts of the same network,” Dr. Darby said. He believes neurologic and psychiatric diseases producing the same delusions are likely to be mediated by dysfunction in the same areas of the brain.

In patients with psychiatric diseases who have delusions associated with loss of a sense of free will, lesions are not readily observed, but Dr. Darby reported that there is evidence of modest changes, such as atrophy or diminished metabolism, that can be “linked up to those areas of the brain involved in agency and volition, and not to areas that are associated with other comorbid symptoms.”

Broader Implications

The fact that the same or similar delusions are shared by neurologic and psychiatric disorders provides the basis for speculating that this work may lead to a more detailed understanding of brain function. According to Dr. Darby, the work with lesion network mapping in neurologic disorders “may tell us where to look for the pathology in psychiatric diseases.”

The lesion network testing may be an important tool for understanding the relationship of brain pathology to behavior, according to Dr. Darby. Prior to lesion network mapping, the heterogeneity of lesion location for patients with shared types of delusion has been difficult to understand, but Dr. Darby indicated that lesion network mapping shows potential for placing specific symptom expression into a context of neuroanatomy.

—Theodore Bosworth

Suggested Reading

Boes AD, Prasad S, Liu Q, et al. Network localization of neurological symptoms from focal brain lesions. Brain. 2015;138(Pt 10):3061-3075.

Darby RR, Laganiere S, Pascual-Leone A, et al. Finding the imposter: brain connectivity of lesions causing delusional misidentifications. Brain. 2017;140(2):497-507.

HILTON HEAD, SC—Delusions of a common type, whether associated with neurologic or psychiatric disease, appear likely to involve common pathways in the brain, according to new studies using lesion network mapping. This type of mapping appears to reveal the pathways that explain why single focal neurologic lesions in different brain locations cause similar delusional symptoms.

Lesion network mapping “is an approach to look at neurologic and psychiatric symptoms at the level of networks to understand brain behavior relationships,” explained Ryan Darby, MD, Assistant Professor of Neurology and Director of the Frontotemporal Dementia Clinic at Vanderbilt University Medical Center in Nashville. From the neurologic perspective, this work may provide insight into brain function, but Dr. Darby, speaking at the 41st Annual Contemporary Clinical Neurology Symposium, sees broader implications.

“This [technique] might provide insight into psychiatric symptoms that we have had trouble truly understanding in relation to neuroanatomy,” Dr. Darby said. Some of the delusions associated with focal neurologic lesions have parallels with those associated with schizoaffective disorders, and this work may explain what areas of the brain are affected, even in the absence of visible lesions on imaging.

Lesion network mapping is a technique developed to identify functionally related regions of the brain. This goal is important because focal neurologic lesions associated with specific delusions are not necessarily located in the same brain region. The concept of networks connecting brain activity and network mapping recognizes that dysfunction in one brain area can lead to dysfunction in others. Lesion network mapping provides a strategy to identify these relationships.

Capgras Syndrome

Dr. Darby provided insight into lesion network mapping based on work he performed and published on Capgras syndrome, which describes an irrational belief that a familiar person or place is an impostor or a facsimile. As examples, he described a woman who thought her home, although familiar, was a replica. In another case, a man believed that his son-in-law, whom he recognized, was an impersonator. This type of delusion is complex, because it appears to involve a disruption of processes that mediate familiarity, as well as the cognitive processes employed to recognize and reject false beliefs.

One hypothesis about Capgras syndrome is that it involves “a two-hit phenomenon” in which dysfunction occurs simultaneously in distinct areas of the brain, according to Dr. Darby. His work with network lesion mapping in Capgras syndrome supports that hypothesis.

Lesion network mapping, a technique first described in a 2015 study, has established functional connectivity between regions of the brain in normal individuals in a resting state. A 2017 study tested the potential value of lesion network mapping in 17 cases of Capgras syndrome.

Most of the cases, including the imaging data, were retrieved from previously published studies, although several contemporary cases were included. In the investigation, Dr. Darby and his coinvestigators first demonstrated the heterogeneity in lesion location. Captured on MRI scans and traced onto a brain atlas, all but one of the lesions in patients with Capgras syndrome were found in the right hemisphere, but many of the lesions had nonoverlapping areas of involvement.

Despite the heterogeneity in lesion location, lesion network mapping demonstrated that all 17 lesions were functionally connected to the retrosplenial cortex. In addition, 16 of the 17 lesions were functionally connected to the right frontal cortex.

According to Dr. Darby, both associations are potentially important. On the basis of previously published studies with functional MRI (fMRI), the left retrosplenial cortex has been implicated in mediating familiarity. The right frontal cortex has been associated with belief evaluation. Moreover, in a control evaluation of published cases in which delusions did not involve misidentification, no functional connections to either the left retrosplenial cortex or the right frontal cortex were observed, according to Dr. Darby. In contrast, patients with disorders consistent with an impaired belief evaluation, such as paranoia or pathologic jealousy, did have lesions in the right frontal cortex as predicted.

 

Insights Into Other Neuropsychiatric Disorders

Lesion network mapping is now being applied to other types of delusions. Dr. Darby described work with neurologic and psychiatric disorders associated with a perception that free will has been lost. These include neuropsychiatric conditions such as akinetic mutism, alien limb syndrome, catatonia, and psychogenic nonepileptic seizures. According to Dr. Darby, there are two potential components involved in a delusion involving an impaired sense of free will. There is a change in the volitional component that captures the motivation and desire to move, as well as an impaired sense of agency, which refers to the feeling of responsibility for movement.

Describing ongoing work with these types of delusions, Dr. Darby reported that neurologic lesion locations, like those in Capgras syndrome, were heterogeneous. Again, most of these lesions could be connected to a network functional map that was not shared by those without these symptoms.

“For many of these complex disorders, what we are seeing is that pathology in different areas causes the same behavior syndrome by affecting different parts of the same network,” Dr. Darby said. He believes neurologic and psychiatric diseases producing the same delusions are likely to be mediated by dysfunction in the same areas of the brain.

In patients with psychiatric diseases who have delusions associated with loss of a sense of free will, lesions are not readily observed, but Dr. Darby reported that there is evidence of modest changes, such as atrophy or diminished metabolism, that can be “linked up to those areas of the brain involved in agency and volition, and not to areas that are associated with other comorbid symptoms.”

Broader Implications

The fact that the same or similar delusions are shared by neurologic and psychiatric disorders provides the basis for speculating that this work may lead to a more detailed understanding of brain function. According to Dr. Darby, the work with lesion network mapping in neurologic disorders “may tell us where to look for the pathology in psychiatric diseases.”

The lesion network testing may be an important tool for understanding the relationship of brain pathology to behavior, according to Dr. Darby. Prior to lesion network mapping, the heterogeneity of lesion location for patients with shared types of delusion has been difficult to understand, but Dr. Darby indicated that lesion network mapping shows potential for placing specific symptom expression into a context of neuroanatomy.

—Theodore Bosworth

Suggested Reading

Boes AD, Prasad S, Liu Q, et al. Network localization of neurological symptoms from focal brain lesions. Brain. 2015;138(Pt 10):3061-3075.

Darby RR, Laganiere S, Pascual-Leone A, et al. Finding the imposter: brain connectivity of lesions causing delusional misidentifications. Brain. 2017;140(2):497-507.

HILTON HEAD, SC—Delusions of a common type, whether associated with neurologic or psychiatric disease, appear likely to involve common pathways in the brain, according to new studies using lesion network mapping. This type of mapping appears to reveal the pathways that explain why single focal neurologic lesions in different brain locations cause similar delusional symptoms.

Lesion network mapping “is an approach to look at neurologic and psychiatric symptoms at the level of networks to understand brain behavior relationships,” explained Ryan Darby, MD, Assistant Professor of Neurology and Director of the Frontotemporal Dementia Clinic at Vanderbilt University Medical Center in Nashville. From the neurologic perspective, this work may provide insight into brain function, but Dr. Darby, speaking at the 41st Annual Contemporary Clinical Neurology Symposium, sees broader implications.

“This [technique] might provide insight into psychiatric symptoms that we have had trouble truly understanding in relation to neuroanatomy,” Dr. Darby said. Some of the delusions associated with focal neurologic lesions have parallels with those associated with schizoaffective disorders, and this work may explain what areas of the brain are affected, even in the absence of visible lesions on imaging.

Lesion network mapping is a technique developed to identify functionally related regions of the brain. This goal is important because focal neurologic lesions associated with specific delusions are not necessarily located in the same brain region. The concept of networks connecting brain activity and network mapping recognizes that dysfunction in one brain area can lead to dysfunction in others. Lesion network mapping provides a strategy to identify these relationships.

Capgras Syndrome

Dr. Darby provided insight into lesion network mapping based on work he performed and published on Capgras syndrome, which describes an irrational belief that a familiar person or place is an impostor or a facsimile. As examples, he described a woman who thought her home, although familiar, was a replica. In another case, a man believed that his son-in-law, whom he recognized, was an impersonator. This type of delusion is complex, because it appears to involve a disruption of processes that mediate familiarity, as well as the cognitive processes employed to recognize and reject false beliefs.

One hypothesis about Capgras syndrome is that it involves “a two-hit phenomenon” in which dysfunction occurs simultaneously in distinct areas of the brain, according to Dr. Darby. His work with network lesion mapping in Capgras syndrome supports that hypothesis.

Lesion network mapping, a technique first described in a 2015 study, has established functional connectivity between regions of the brain in normal individuals in a resting state. A 2017 study tested the potential value of lesion network mapping in 17 cases of Capgras syndrome.

Most of the cases, including the imaging data, were retrieved from previously published studies, although several contemporary cases were included. In the investigation, Dr. Darby and his coinvestigators first demonstrated the heterogeneity in lesion location. Captured on MRI scans and traced onto a brain atlas, all but one of the lesions in patients with Capgras syndrome were found in the right hemisphere, but many of the lesions had nonoverlapping areas of involvement.

Despite the heterogeneity in lesion location, lesion network mapping demonstrated that all 17 lesions were functionally connected to the retrosplenial cortex. In addition, 16 of the 17 lesions were functionally connected to the right frontal cortex.

According to Dr. Darby, both associations are potentially important. On the basis of previously published studies with functional MRI (fMRI), the left retrosplenial cortex has been implicated in mediating familiarity. The right frontal cortex has been associated with belief evaluation. Moreover, in a control evaluation of published cases in which delusions did not involve misidentification, no functional connections to either the left retrosplenial cortex or the right frontal cortex were observed, according to Dr. Darby. In contrast, patients with disorders consistent with an impaired belief evaluation, such as paranoia or pathologic jealousy, did have lesions in the right frontal cortex as predicted.

 

Insights Into Other Neuropsychiatric Disorders

Lesion network mapping is now being applied to other types of delusions. Dr. Darby described work with neurologic and psychiatric disorders associated with a perception that free will has been lost. These include neuropsychiatric conditions such as akinetic mutism, alien limb syndrome, catatonia, and psychogenic nonepileptic seizures. According to Dr. Darby, there are two potential components involved in a delusion involving an impaired sense of free will. There is a change in the volitional component that captures the motivation and desire to move, as well as an impaired sense of agency, which refers to the feeling of responsibility for movement.

Describing ongoing work with these types of delusions, Dr. Darby reported that neurologic lesion locations, like those in Capgras syndrome, were heterogeneous. Again, most of these lesions could be connected to a network functional map that was not shared by those without these symptoms.

“For many of these complex disorders, what we are seeing is that pathology in different areas causes the same behavior syndrome by affecting different parts of the same network,” Dr. Darby said. He believes neurologic and psychiatric diseases producing the same delusions are likely to be mediated by dysfunction in the same areas of the brain.

In patients with psychiatric diseases who have delusions associated with loss of a sense of free will, lesions are not readily observed, but Dr. Darby reported that there is evidence of modest changes, such as atrophy or diminished metabolism, that can be “linked up to those areas of the brain involved in agency and volition, and not to areas that are associated with other comorbid symptoms.”

Broader Implications

The fact that the same or similar delusions are shared by neurologic and psychiatric disorders provides the basis for speculating that this work may lead to a more detailed understanding of brain function. According to Dr. Darby, the work with lesion network mapping in neurologic disorders “may tell us where to look for the pathology in psychiatric diseases.”

The lesion network testing may be an important tool for understanding the relationship of brain pathology to behavior, according to Dr. Darby. Prior to lesion network mapping, the heterogeneity of lesion location for patients with shared types of delusion has been difficult to understand, but Dr. Darby indicated that lesion network mapping shows potential for placing specific symptom expression into a context of neuroanatomy.

—Theodore Bosworth

Suggested Reading

Boes AD, Prasad S, Liu Q, et al. Network localization of neurological symptoms from focal brain lesions. Brain. 2015;138(Pt 10):3061-3075.

Darby RR, Laganiere S, Pascual-Leone A, et al. Finding the imposter: brain connectivity of lesions causing delusional misidentifications. Brain. 2017;140(2):497-507.

BALTIMORE—Levels of peripheral microRNAs (miRNAs) change in response to total sleep deprivation (TSD) and psychologic stress, according to a study described at the 32nd Annual Meeting of the Associated Professional Sleep Societies. The molecules also predict individual differences in cognitive performance following these conditions. The results suggest that miRNAs can “identify individuals ahead of time who are in need of countermeasures or interventions such as caffeine or naps to mitigate or prevent impairments associated with insufficient sleep,” said Namni Goel, PhD, Research Associate Professor of Psychology in Psychiatry at the University of Pennsylvania in Philadelphia.

Sleep loss is associated with Alz­heimer’s disease and psychiatric dis­orders and impairs cognitive performance. Deficits in cognitive performance following sleep loss vary between individuals, however. Predicting and detecting individual deficits arising from sleep loss has been difficult.

One set of molecules that regulate gene expression is miRNAs, which are small, noncoding RNAs that typically repress the expression of their target messenger RNAs. Dr. Goel and colleagues investigated whether sleep deprivation or the combination of sleep deprivation and psychologic stress affects miRNA responses in humans. They also examined whether these miRNA responses predict cognitive performance during sleep deprivation.

The investigators enrolled 32 healthy adults (mean age, 35.1; 14 women) in a five-day experiment. Participants underwent two baseline nights with eight hours in bed, followed by 39 hours of TSD and two recovery nights with eight to 10 hours in bed. On the day after TSD, participants underwent a modified Trier Social Stress Test intended to induce psychologic stress. The researchers administered the Psychomotor Vigilance Test (PVT), Digit Symbol Substitution Task (DSST), and Digit Span Task (DS) throughout the experiment. They took blood samples at six time points and analyzed miRNAs in plasma using microarrays.

At the end of the study, levels of 10 miRNAs changed after TSD alone, and levels of 18 miRNAs changed after TSD and psychologic stress, compared with baseline. The former miRNAs target 2,309 genes, and the latter target 2,823 genes. The two groups of miRNAs have 700 targets in common. The researchers also observed that at baseline, 14 miRNAs predicted lapses and errors on PVT during TSD, seven miRNAs predicted DSST performance, and 10 miRNAs predicted DS performance.

“These findings show for the first time that miRNAs can track responses to TSD and its detrimental combination with psychologic stress and predict robust individual differences in various types of cognitive performance,” said Dr. Goel.

—Erik Greb

BALTIMORE—Levels of peripheral microRNAs (miRNAs) change in response to total sleep deprivation (TSD) and psychologic stress, according to a study described at the 32nd Annual Meeting of the Associated Professional Sleep Societies. The molecules also predict individual differences in cognitive performance following these conditions. The results suggest that miRNAs can “identify individuals ahead of time who are in need of countermeasures or interventions such as caffeine or naps to mitigate or prevent impairments associated with insufficient sleep,” said Namni Goel, PhD, Research Associate Professor of Psychology in Psychiatry at the University of Pennsylvania in Philadelphia.

Sleep loss is associated with Alz­heimer’s disease and psychiatric dis­orders and impairs cognitive performance. Deficits in cognitive performance following sleep loss vary between individuals, however. Predicting and detecting individual deficits arising from sleep loss has been difficult.

One set of molecules that regulate gene expression is miRNAs, which are small, noncoding RNAs that typically repress the expression of their target messenger RNAs. Dr. Goel and colleagues investigated whether sleep deprivation or the combination of sleep deprivation and psychologic stress affects miRNA responses in humans. They also examined whether these miRNA responses predict cognitive performance during sleep deprivation.

The investigators enrolled 32 healthy adults (mean age, 35.1; 14 women) in a five-day experiment. Participants underwent two baseline nights with eight hours in bed, followed by 39 hours of TSD and two recovery nights with eight to 10 hours in bed. On the day after TSD, participants underwent a modified Trier Social Stress Test intended to induce psychologic stress. The researchers administered the Psychomotor Vigilance Test (PVT), Digit Symbol Substitution Task (DSST), and Digit Span Task (DS) throughout the experiment. They took blood samples at six time points and analyzed miRNAs in plasma using microarrays.

At the end of the study, levels of 10 miRNAs changed after TSD alone, and levels of 18 miRNAs changed after TSD and psychologic stress, compared with baseline. The former miRNAs target 2,309 genes, and the latter target 2,823 genes. The two groups of miRNAs have 700 targets in common. The researchers also observed that at baseline, 14 miRNAs predicted lapses and errors on PVT during TSD, seven miRNAs predicted DSST performance, and 10 miRNAs predicted DS performance.

“These findings show for the first time that miRNAs can track responses to TSD and its detrimental combination with psychologic stress and predict robust individual differences in various types of cognitive performance,” said Dr. Goel.

—Erik Greb

BALTIMORE—Levels of peripheral microRNAs (miRNAs) change in response to total sleep deprivation (TSD) and psychologic stress, according to a study described at the 32nd Annual Meeting of the Associated Professional Sleep Societies. The molecules also predict individual differences in cognitive performance following these conditions. The results suggest that miRNAs can “identify individuals ahead of time who are in need of countermeasures or interventions such as caffeine or naps to mitigate or prevent impairments associated with insufficient sleep,” said Namni Goel, PhD, Research Associate Professor of Psychology in Psychiatry at the University of Pennsylvania in Philadelphia.

Sleep loss is associated with Alz­heimer’s disease and psychiatric dis­orders and impairs cognitive performance. Deficits in cognitive performance following sleep loss vary between individuals, however. Predicting and detecting individual deficits arising from sleep loss has been difficult.

One set of molecules that regulate gene expression is miRNAs, which are small, noncoding RNAs that typically repress the expression of their target messenger RNAs. Dr. Goel and colleagues investigated whether sleep deprivation or the combination of sleep deprivation and psychologic stress affects miRNA responses in humans. They also examined whether these miRNA responses predict cognitive performance during sleep deprivation.

The investigators enrolled 32 healthy adults (mean age, 35.1; 14 women) in a five-day experiment. Participants underwent two baseline nights with eight hours in bed, followed by 39 hours of TSD and two recovery nights with eight to 10 hours in bed. On the day after TSD, participants underwent a modified Trier Social Stress Test intended to induce psychologic stress. The researchers administered the Psychomotor Vigilance Test (PVT), Digit Symbol Substitution Task (DSST), and Digit Span Task (DS) throughout the experiment. They took blood samples at six time points and analyzed miRNAs in plasma using microarrays.

At the end of the study, levels of 10 miRNAs changed after TSD alone, and levels of 18 miRNAs changed after TSD and psychologic stress, compared with baseline. The former miRNAs target 2,309 genes, and the latter target 2,823 genes. The two groups of miRNAs have 700 targets in common. The researchers also observed that at baseline, 14 miRNAs predicted lapses and errors on PVT during TSD, seven miRNAs predicted DSST performance, and 10 miRNAs predicted DS performance.

“These findings show for the first time that miRNAs can track responses to TSD and its detrimental combination with psychologic stress and predict robust individual differences in various types of cognitive performance,” said Dr. Goel.

—Erik Greb

 

In a segment aired on a recent episode of “60 Minutes,” Mike and Carol Daly continued to share details of their life in the decade since Carol was diagnosed with Alzheimer’s disease. Since that diagnosis, the couple has been interviewed every year or so over the last 10 years. Chronicling the couple’s journey was a way of showing the devastating impact of the disease.

©roberthyrons/thinkstockphotos.com

In 2008, Carol was still active, aware, and determined to make the best of her life. (Early on, CBS told the couple about the Music & Memory program, which works with people with dementia to create personalized music playlists.) In the intervening years, however, the progressive loss of mental acuity forced Carol to stop reading and watching movies. Within 3 years, she had lost the ability to gauge the passage of time. When CBS News chief medical correspondent Jon LaPook, MD, asked Carol her age, she pegged it at 80 years. Her actual age was 67.

By then, Mike, a former New York City police officer, had become her go-to for dressing and makeup. “She had a job. She cleaned house. She did the wash. She made the beds and she put up with me. Now I do the wash. I make the beds. I help Carol,” Mike said at the time.

Is this what he had signed up for in his life? “Yes,” Mike emphatically said. “When we took our [vows], it was for better or for worse. So I did sign up for it in the beginning.”

After 2 more years, Carol had forgotten that she was married and the identity of the husband sitting next to her, and was losing functional control of her body. An additional 2 years and Mike had hired a home care aide to the tune of nearly $40,000 annually. The mental and physical burden had become a financial burden.

Now, Carol spends her days in silence. She is unable to understand the world around her. “We can’t communicate; it’s lonely,” Mike said. Yet, until very recently, she remained home under the watchful care of her husband. Still, at that point, she still reacted to music that she once enjoyed.

Mike’s resolve to be Carol’s guide through life has been severely tested by the ongoing ordeal. In fact, Mike, who has put on weight and started taking medicine for anxiety, confided that he had considered suicide.

Carol declined to a point that she now lives in a nursing home. “I love Carol who was Carol,” Mike said. “But now Carol’s not Carol anymore.”

Click here to watch the “60 Minutes” segment.

 

In a segment aired on a recent episode of “60 Minutes,” Mike and Carol Daly continued to share details of their life in the decade since Carol was diagnosed with Alzheimer’s disease. Since that diagnosis, the couple has been interviewed every year or so over the last 10 years. Chronicling the couple’s journey was a way of showing the devastating impact of the disease.

©roberthyrons/thinkstockphotos.com

In 2008, Carol was still active, aware, and determined to make the best of her life. (Early on, CBS told the couple about the Music & Memory program, which works with people with dementia to create personalized music playlists.) In the intervening years, however, the progressive loss of mental acuity forced Carol to stop reading and watching movies. Within 3 years, she had lost the ability to gauge the passage of time. When CBS News chief medical correspondent Jon LaPook, MD, asked Carol her age, she pegged it at 80 years. Her actual age was 67.

By then, Mike, a former New York City police officer, had become her go-to for dressing and makeup. “She had a job. She cleaned house. She did the wash. She made the beds and she put up with me. Now I do the wash. I make the beds. I help Carol,” Mike said at the time.

Is this what he had signed up for in his life? “Yes,” Mike emphatically said. “When we took our [vows], it was for better or for worse. So I did sign up for it in the beginning.”

After 2 more years, Carol had forgotten that she was married and the identity of the husband sitting next to her, and was losing functional control of her body. An additional 2 years and Mike had hired a home care aide to the tune of nearly $40,000 annually. The mental and physical burden had become a financial burden.

Now, Carol spends her days in silence. She is unable to understand the world around her. “We can’t communicate; it’s lonely,” Mike said. Yet, until very recently, she remained home under the watchful care of her husband. Still, at that point, she still reacted to music that she once enjoyed.

Mike’s resolve to be Carol’s guide through life has been severely tested by the ongoing ordeal. In fact, Mike, who has put on weight and started taking medicine for anxiety, confided that he had considered suicide.

Carol declined to a point that she now lives in a nursing home. “I love Carol who was Carol,” Mike said. “But now Carol’s not Carol anymore.”

Click here to watch the “60 Minutes” segment.

 

In a segment aired on a recent episode of “60 Minutes,” Mike and Carol Daly continued to share details of their life in the decade since Carol was diagnosed with Alzheimer’s disease. Since that diagnosis, the couple has been interviewed every year or so over the last 10 years. Chronicling the couple’s journey was a way of showing the devastating impact of the disease.

©roberthyrons/thinkstockphotos.com

In 2008, Carol was still active, aware, and determined to make the best of her life. (Early on, CBS told the couple about the Music & Memory program, which works with people with dementia to create personalized music playlists.) In the intervening years, however, the progressive loss of mental acuity forced Carol to stop reading and watching movies. Within 3 years, she had lost the ability to gauge the passage of time. When CBS News chief medical correspondent Jon LaPook, MD, asked Carol her age, she pegged it at 80 years. Her actual age was 67.

By then, Mike, a former New York City police officer, had become her go-to for dressing and makeup. “She had a job. She cleaned house. She did the wash. She made the beds and she put up with me. Now I do the wash. I make the beds. I help Carol,” Mike said at the time.

Is this what he had signed up for in his life? “Yes,” Mike emphatically said. “When we took our [vows], it was for better or for worse. So I did sign up for it in the beginning.”

After 2 more years, Carol had forgotten that she was married and the identity of the husband sitting next to her, and was losing functional control of her body. An additional 2 years and Mike had hired a home care aide to the tune of nearly $40,000 annually. The mental and physical burden had become a financial burden.

Now, Carol spends her days in silence. She is unable to understand the world around her. “We can’t communicate; it’s lonely,” Mike said. Yet, until very recently, she remained home under the watchful care of her husband. Still, at that point, she still reacted to music that she once enjoyed.

Mike’s resolve to be Carol’s guide through life has been severely tested by the ongoing ordeal. In fact, Mike, who has put on weight and started taking medicine for anxiety, confided that he had considered suicide.

Carol declined to a point that she now lives in a nursing home. “I love Carol who was Carol,” Mike said. “But now Carol’s not Carol anymore.”

Click here to watch the “60 Minutes” segment.

 

CHICAGO – BAN2401, a monoclonal antibody that targets soluble amyloid-beta oligomers, slowed cognitive decline by up to 47% while clearing brain amyloid in 81% of patients with mild cognitive impairment and very mild Alzheimer’s disease, a phase 2 study has shown.

At the Alzheimer’s Association International Conference, Eisai, which is developing the antibody along with Biogen, touted it the study results as an important step forward in a field desperate for success. But questions remain, especially about the unequal distribution of apolipoprotein E4 (APOE4)-positive patients across the six treatment groups: BAN2401 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly, or placebo. This troubled some researchers, who said the mix could have biased cognitive results in the antibody’s favor. APOE4 carriers comprised about 70%-80% of every unsuccessful treatment arm in the trial, and 29% of the arm that conferred significant cognitive benefits.

“This is a big confound,” Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer’s Association, said when he saw the numbers. “An important point is that, according to the trial sponsors, for a period of time a regulatory body requested that people with the APOE4 Alzheimer’s risk gene not be included in the highest dose group, for safety reasons. Because of this, the people in the highest-dose group are different from people in the other groups on an important dimension; they were much less likely to have the APOE4 gene, which is known to be a major risk factor for cognitive decline. So it is plausible that the people on the highest dose declined differently due to genetic differences rather than due to being on the highest dose. A planned subgroup analysis will shed more light on this, and whether it reduces confidence in the overall findings. We eagerly await the results of this analysis.”

The decision to restructure the randomization was not Eisai’s, according to David Knopman, MD, chair of the Alzheimer’s Association Medical and Scientific Advisory Council.

“European regulators did not allow randomization of [some] APOE4 carriers to the highest dose,” he said in an interview. “I ultimately don’t know what it would do to the results, except make them even more difficult to justify as sufficient for registration. In general, in symptomatic Alzheimer’s dementia patients, APOE4 carriage has no substantial impact on rate of decline, but whether [APOE4] status interacted with the treatment is of course completely unknown. Bottom line: Just another feature that makes this a phase 2 study that needs to be followed by a phase 3 study with a simple design using the high dose.”

Alzheimer’s researcher Michael S. Wolfe, PhD, was more candid.

“Regardless of who made the decision and why, the data is what it is, and the question remains,” said Dr. Wolfe, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence. “Given the numbers of E4-positive vs. E4-negative for each treatment group, the interpretation of the results is now seriously thrown into question. The one group that showed a clear slowing of cognitive decline versus placebo (10 mg/kg biweekly) also has far fewer E4-positive vs. E4-negative. This difference in proportion of E4-positive could be a major factor in the apparent reduced rate of cognitive decline and confounds the ability to tell if the 10-mg/kg biweekly dose is effective. In contrast, the 10-mg/kg monthly dose group has an E4-positive/-negative ratio more comparable to that of placebo, and the effect of the drug on cognitive decline under this dosing regimen is not clearly distinguishable from that seen with placebo.”

Additionally, BAN2401 failed to meet its 12-month prespecified primary cognitive endpoints, a conclusion determined by a complex Bayesian analysis that strove to predict an 80% probability of reaching at least a 25% cognitive benefit. In December, the company announced that the study hit just a 64% probability. But because Eisai felt the numbers were moving in the right direction, it continued with the additional 6 months of treatment, as allowed for in the study design, and then reanalyzed results with a simpler and more straightforward method. This analysis concluded that 10 mg/kg infused biweekly conferred a 30% slowing of decline on the Alzheimer’s Disease Composite Score (ADCOMS), a new tool developed and promoted by Eisai, and a 47% slowing of decline on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog). It also cleared brain amyloid in 81% of subjects and sent cerebrospinal fluid (CSF) biomarkers in the right direction. CSF amyloid levels went up – to be expected if the antibody was clearing it from the brain – and CSF total tau went down, an indication of decreased neuronal injury.

Inquiries to Eisai to clarify these issues had not been returned at press time.

This is a developing story.

[email protected]

 

CHICAGO – BAN2401, a monoclonal antibody that targets soluble amyloid-beta oligomers, slowed cognitive decline by up to 47% while clearing brain amyloid in 81% of patients with mild cognitive impairment and very mild Alzheimer’s disease, a phase 2 study has shown.

At the Alzheimer’s Association International Conference, Eisai, which is developing the antibody along with Biogen, touted it the study results as an important step forward in a field desperate for success. But questions remain, especially about the unequal distribution of apolipoprotein E4 (APOE4)-positive patients across the six treatment groups: BAN2401 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly, or placebo. This troubled some researchers, who said the mix could have biased cognitive results in the antibody’s favor. APOE4 carriers comprised about 70%-80% of every unsuccessful treatment arm in the trial, and 29% of the arm that conferred significant cognitive benefits.

“This is a big confound,” Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer’s Association, said when he saw the numbers. “An important point is that, according to the trial sponsors, for a period of time a regulatory body requested that people with the APOE4 Alzheimer’s risk gene not be included in the highest dose group, for safety reasons. Because of this, the people in the highest-dose group are different from people in the other groups on an important dimension; they were much less likely to have the APOE4 gene, which is known to be a major risk factor for cognitive decline. So it is plausible that the people on the highest dose declined differently due to genetic differences rather than due to being on the highest dose. A planned subgroup analysis will shed more light on this, and whether it reduces confidence in the overall findings. We eagerly await the results of this analysis.”

The decision to restructure the randomization was not Eisai’s, according to David Knopman, MD, chair of the Alzheimer’s Association Medical and Scientific Advisory Council.

“European regulators did not allow randomization of [some] APOE4 carriers to the highest dose,” he said in an interview. “I ultimately don’t know what it would do to the results, except make them even more difficult to justify as sufficient for registration. In general, in symptomatic Alzheimer’s dementia patients, APOE4 carriage has no substantial impact on rate of decline, but whether [APOE4] status interacted with the treatment is of course completely unknown. Bottom line: Just another feature that makes this a phase 2 study that needs to be followed by a phase 3 study with a simple design using the high dose.”

Alzheimer’s researcher Michael S. Wolfe, PhD, was more candid.

“Regardless of who made the decision and why, the data is what it is, and the question remains,” said Dr. Wolfe, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence. “Given the numbers of E4-positive vs. E4-negative for each treatment group, the interpretation of the results is now seriously thrown into question. The one group that showed a clear slowing of cognitive decline versus placebo (10 mg/kg biweekly) also has far fewer E4-positive vs. E4-negative. This difference in proportion of E4-positive could be a major factor in the apparent reduced rate of cognitive decline and confounds the ability to tell if the 10-mg/kg biweekly dose is effective. In contrast, the 10-mg/kg monthly dose group has an E4-positive/-negative ratio more comparable to that of placebo, and the effect of the drug on cognitive decline under this dosing regimen is not clearly distinguishable from that seen with placebo.”

Additionally, BAN2401 failed to meet its 12-month prespecified primary cognitive endpoints, a conclusion determined by a complex Bayesian analysis that strove to predict an 80% probability of reaching at least a 25% cognitive benefit. In December, the company announced that the study hit just a 64% probability. But because Eisai felt the numbers were moving in the right direction, it continued with the additional 6 months of treatment, as allowed for in the study design, and then reanalyzed results with a simpler and more straightforward method. This analysis concluded that 10 mg/kg infused biweekly conferred a 30% slowing of decline on the Alzheimer’s Disease Composite Score (ADCOMS), a new tool developed and promoted by Eisai, and a 47% slowing of decline on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog). It also cleared brain amyloid in 81% of subjects and sent cerebrospinal fluid (CSF) biomarkers in the right direction. CSF amyloid levels went up – to be expected if the antibody was clearing it from the brain – and CSF total tau went down, an indication of decreased neuronal injury.

Inquiries to Eisai to clarify these issues had not been returned at press time.

This is a developing story.

[email protected]

 

CHICAGO – BAN2401, a monoclonal antibody that targets soluble amyloid-beta oligomers, slowed cognitive decline by up to 47% while clearing brain amyloid in 81% of patients with mild cognitive impairment and very mild Alzheimer’s disease, a phase 2 study has shown.

At the Alzheimer’s Association International Conference, Eisai, which is developing the antibody along with Biogen, touted it the study results as an important step forward in a field desperate for success. But questions remain, especially about the unequal distribution of apolipoprotein E4 (APOE4)-positive patients across the six treatment groups: BAN2401 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly, or placebo. This troubled some researchers, who said the mix could have biased cognitive results in the antibody’s favor. APOE4 carriers comprised about 70%-80% of every unsuccessful treatment arm in the trial, and 29% of the arm that conferred significant cognitive benefits.

“This is a big confound,” Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer’s Association, said when he saw the numbers. “An important point is that, according to the trial sponsors, for a period of time a regulatory body requested that people with the APOE4 Alzheimer’s risk gene not be included in the highest dose group, for safety reasons. Because of this, the people in the highest-dose group are different from people in the other groups on an important dimension; they were much less likely to have the APOE4 gene, which is known to be a major risk factor for cognitive decline. So it is plausible that the people on the highest dose declined differently due to genetic differences rather than due to being on the highest dose. A planned subgroup analysis will shed more light on this, and whether it reduces confidence in the overall findings. We eagerly await the results of this analysis.”

The decision to restructure the randomization was not Eisai’s, according to David Knopman, MD, chair of the Alzheimer’s Association Medical and Scientific Advisory Council.

“European regulators did not allow randomization of [some] APOE4 carriers to the highest dose,” he said in an interview. “I ultimately don’t know what it would do to the results, except make them even more difficult to justify as sufficient for registration. In general, in symptomatic Alzheimer’s dementia patients, APOE4 carriage has no substantial impact on rate of decline, but whether [APOE4] status interacted with the treatment is of course completely unknown. Bottom line: Just another feature that makes this a phase 2 study that needs to be followed by a phase 3 study with a simple design using the high dose.”

Alzheimer’s researcher Michael S. Wolfe, PhD, was more candid.

“Regardless of who made the decision and why, the data is what it is, and the question remains,” said Dr. Wolfe, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence. “Given the numbers of E4-positive vs. E4-negative for each treatment group, the interpretation of the results is now seriously thrown into question. The one group that showed a clear slowing of cognitive decline versus placebo (10 mg/kg biweekly) also has far fewer E4-positive vs. E4-negative. This difference in proportion of E4-positive could be a major factor in the apparent reduced rate of cognitive decline and confounds the ability to tell if the 10-mg/kg biweekly dose is effective. In contrast, the 10-mg/kg monthly dose group has an E4-positive/-negative ratio more comparable to that of placebo, and the effect of the drug on cognitive decline under this dosing regimen is not clearly distinguishable from that seen with placebo.”

Additionally, BAN2401 failed to meet its 12-month prespecified primary cognitive endpoints, a conclusion determined by a complex Bayesian analysis that strove to predict an 80% probability of reaching at least a 25% cognitive benefit. In December, the company announced that the study hit just a 64% probability. But because Eisai felt the numbers were moving in the right direction, it continued with the additional 6 months of treatment, as allowed for in the study design, and then reanalyzed results with a simpler and more straightforward method. This analysis concluded that 10 mg/kg infused biweekly conferred a 30% slowing of decline on the Alzheimer’s Disease Composite Score (ADCOMS), a new tool developed and promoted by Eisai, and a 47% slowing of decline on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog). It also cleared brain amyloid in 81% of subjects and sent cerebrospinal fluid (CSF) biomarkers in the right direction. CSF amyloid levels went up – to be expected if the antibody was clearing it from the brain – and CSF total tau went down, an indication of decreased neuronal injury.

Inquiries to Eisai to clarify these issues had not been returned at press time.

This is a developing story.

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