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Out-of-pocket costs for neurologic medications rise sharply
The out-of-pocket cost of multiple sclerosis (MS) treatments increased the most, with a 20-fold increase during that time. The average out-of-pocket cost for MS therapy was $15/month in 2004, compared with $309/month in 2016. Patients also had to pay more for brand name medications for peripheral neuropathy, dementia, and Parkinson’s disease, researchers said.
“Out-of-pocket costs vary widely both across and within conditions,” said study author Brian C. Callaghan, MD, an assistant professor of neurology at the University of Michigan in Ann Arbor, and research colleagues. “To minimize patient financial burden, neurologists require access to precise cost information when making treatment decisions.”
Prior studies have found that high drug costs “can create burdens such as medical debt, skipping food or other essentials, or even not taking drugs as often as necessary,” Dr. Callaghan said in a news release.
To assess how out-of-pocket costs affect patients with neurologic conditions, the investigators analyzed data from a large, privately insured health care claims database. They determined medication costs for patients with MS, peripheral neuropathy, epilepsy, dementia, and Parkinson’s disease who were seen by outpatient neurologists. They also compared costs for high-deductible and traditional plans and explored cumulative out-of-pocket costs during the first 2 years after diagnosis.
The analysis examined the five most commonly prescribed drugs by neurologists for each condition based on Medicare data. In addition, the researchers included in their analysis all approved MS medications, lacosamide as a brand name epilepsy drug, and venlafaxine, a peripheral neuropathy medication that transitioned from brand to generic.
In all, the study population included 105,355 patients with MS, 314,530 with peripheral neuropathy, 281,073 with epilepsy, 120,720 with dementia, and 90,801 with Parkinson’s disease.
In 2016, patients in high-deductible health plans had an average monthly out-of-pocket expense that was approximately twice that of patients not in those plans – $661 versus $246 among patients with MS, and $40 versus $18 among patients with epilepsy.
In the 2 years after diagnosis in 2012 or 2013, cumulative out-of-pocket costs for patients with MS were a mean of $2,238, but costs varied widely. Cumulative costs were no more than $90 for patients in the bottom 5% of expenses, whereas they exceeded $9,800 for patients in the top 5% of expenses. Among patients with epilepsy, cumulative out-of-pocket costs were $230 in the 2 years after diagnosis.
“In 2004, out-of-pocket costs were of such low magnitude that physicians could typically ignore these costs for most patients and not adversely affect the financial status of patients or their adherence to medications. However, by 2016, out-of-pockets costs have risen to the point where neurologists should consider out-of-pocket costs for most medications and for most patients,” Dr. Callaghan and colleagues wrote.
Ralph L. Sacco, MD, president of the American Academy of Neurology (AAN), said in a news release that the AAN has created a Neurology Drug Pricing Task Force and is advocating for better drug-pricing policies. “This study provides important information to help us better understand how these problems can directly affect our patients,” Dr. Sacco said.
“Everyone deserves affordable access to the medications that will be most beneficial, but if the drugs are too expensive, people may simply not take them, possibly leading to medical complications and higher costs later,” Dr. Sacco said.
The study was supported by the AAN. Several authors are supported by National Institutes of Health grants. Dr. Callaghan receives research support from Impeto Medical and performs consulting work.
SOURCE: Callaghan BC et al. Neurology. 2019 May 1. doi: 10.1212/WNL.0000000000007564.
The out-of-pocket cost of multiple sclerosis (MS) treatments increased the most, with a 20-fold increase during that time. The average out-of-pocket cost for MS therapy was $15/month in 2004, compared with $309/month in 2016. Patients also had to pay more for brand name medications for peripheral neuropathy, dementia, and Parkinson’s disease, researchers said.
“Out-of-pocket costs vary widely both across and within conditions,” said study author Brian C. Callaghan, MD, an assistant professor of neurology at the University of Michigan in Ann Arbor, and research colleagues. “To minimize patient financial burden, neurologists require access to precise cost information when making treatment decisions.”
Prior studies have found that high drug costs “can create burdens such as medical debt, skipping food or other essentials, or even not taking drugs as often as necessary,” Dr. Callaghan said in a news release.
To assess how out-of-pocket costs affect patients with neurologic conditions, the investigators analyzed data from a large, privately insured health care claims database. They determined medication costs for patients with MS, peripheral neuropathy, epilepsy, dementia, and Parkinson’s disease who were seen by outpatient neurologists. They also compared costs for high-deductible and traditional plans and explored cumulative out-of-pocket costs during the first 2 years after diagnosis.
The analysis examined the five most commonly prescribed drugs by neurologists for each condition based on Medicare data. In addition, the researchers included in their analysis all approved MS medications, lacosamide as a brand name epilepsy drug, and venlafaxine, a peripheral neuropathy medication that transitioned from brand to generic.
In all, the study population included 105,355 patients with MS, 314,530 with peripheral neuropathy, 281,073 with epilepsy, 120,720 with dementia, and 90,801 with Parkinson’s disease.
In 2016, patients in high-deductible health plans had an average monthly out-of-pocket expense that was approximately twice that of patients not in those plans – $661 versus $246 among patients with MS, and $40 versus $18 among patients with epilepsy.
In the 2 years after diagnosis in 2012 or 2013, cumulative out-of-pocket costs for patients with MS were a mean of $2,238, but costs varied widely. Cumulative costs were no more than $90 for patients in the bottom 5% of expenses, whereas they exceeded $9,800 for patients in the top 5% of expenses. Among patients with epilepsy, cumulative out-of-pocket costs were $230 in the 2 years after diagnosis.
“In 2004, out-of-pocket costs were of such low magnitude that physicians could typically ignore these costs for most patients and not adversely affect the financial status of patients or their adherence to medications. However, by 2016, out-of-pockets costs have risen to the point where neurologists should consider out-of-pocket costs for most medications and for most patients,” Dr. Callaghan and colleagues wrote.
Ralph L. Sacco, MD, president of the American Academy of Neurology (AAN), said in a news release that the AAN has created a Neurology Drug Pricing Task Force and is advocating for better drug-pricing policies. “This study provides important information to help us better understand how these problems can directly affect our patients,” Dr. Sacco said.
“Everyone deserves affordable access to the medications that will be most beneficial, but if the drugs are too expensive, people may simply not take them, possibly leading to medical complications and higher costs later,” Dr. Sacco said.
The study was supported by the AAN. Several authors are supported by National Institutes of Health grants. Dr. Callaghan receives research support from Impeto Medical and performs consulting work.
SOURCE: Callaghan BC et al. Neurology. 2019 May 1. doi: 10.1212/WNL.0000000000007564.
The out-of-pocket cost of multiple sclerosis (MS) treatments increased the most, with a 20-fold increase during that time. The average out-of-pocket cost for MS therapy was $15/month in 2004, compared with $309/month in 2016. Patients also had to pay more for brand name medications for peripheral neuropathy, dementia, and Parkinson’s disease, researchers said.
“Out-of-pocket costs vary widely both across and within conditions,” said study author Brian C. Callaghan, MD, an assistant professor of neurology at the University of Michigan in Ann Arbor, and research colleagues. “To minimize patient financial burden, neurologists require access to precise cost information when making treatment decisions.”
Prior studies have found that high drug costs “can create burdens such as medical debt, skipping food or other essentials, or even not taking drugs as often as necessary,” Dr. Callaghan said in a news release.
To assess how out-of-pocket costs affect patients with neurologic conditions, the investigators analyzed data from a large, privately insured health care claims database. They determined medication costs for patients with MS, peripheral neuropathy, epilepsy, dementia, and Parkinson’s disease who were seen by outpatient neurologists. They also compared costs for high-deductible and traditional plans and explored cumulative out-of-pocket costs during the first 2 years after diagnosis.
The analysis examined the five most commonly prescribed drugs by neurologists for each condition based on Medicare data. In addition, the researchers included in their analysis all approved MS medications, lacosamide as a brand name epilepsy drug, and venlafaxine, a peripheral neuropathy medication that transitioned from brand to generic.
In all, the study population included 105,355 patients with MS, 314,530 with peripheral neuropathy, 281,073 with epilepsy, 120,720 with dementia, and 90,801 with Parkinson’s disease.
In 2016, patients in high-deductible health plans had an average monthly out-of-pocket expense that was approximately twice that of patients not in those plans – $661 versus $246 among patients with MS, and $40 versus $18 among patients with epilepsy.
In the 2 years after diagnosis in 2012 or 2013, cumulative out-of-pocket costs for patients with MS were a mean of $2,238, but costs varied widely. Cumulative costs were no more than $90 for patients in the bottom 5% of expenses, whereas they exceeded $9,800 for patients in the top 5% of expenses. Among patients with epilepsy, cumulative out-of-pocket costs were $230 in the 2 years after diagnosis.
“In 2004, out-of-pocket costs were of such low magnitude that physicians could typically ignore these costs for most patients and not adversely affect the financial status of patients or their adherence to medications. However, by 2016, out-of-pockets costs have risen to the point where neurologists should consider out-of-pocket costs for most medications and for most patients,” Dr. Callaghan and colleagues wrote.
Ralph L. Sacco, MD, president of the American Academy of Neurology (AAN), said in a news release that the AAN has created a Neurology Drug Pricing Task Force and is advocating for better drug-pricing policies. “This study provides important information to help us better understand how these problems can directly affect our patients,” Dr. Sacco said.
“Everyone deserves affordable access to the medications that will be most beneficial, but if the drugs are too expensive, people may simply not take them, possibly leading to medical complications and higher costs later,” Dr. Sacco said.
The study was supported by the AAN. Several authors are supported by National Institutes of Health grants. Dr. Callaghan receives research support from Impeto Medical and performs consulting work.
SOURCE: Callaghan BC et al. Neurology. 2019 May 1. doi: 10.1212/WNL.0000000000007564.
FROM NEUROLOGY
AD biomarker not tied to increased interest in physician-assisted death
Being diagnosed with an elevated amyloid-beta biomarker that indicates greater risk of Alzheimer’s disease did not lead to increased consideration of physician-assisted death (PAD), according to an analysis of patients interviewed during clinical trials on cognitive decline.
“Our findings suggest that learning one’s amyloid imaging result does not change baseline attitudes regarding the acceptability of PAD,” wrote Emily A. Largent, PhD, of the department of medical ethics and health policy at the University of Pennsylvania, Philadelphia, and coauthors. The study was published as a research letter in JAMA Neurology.
Participants were recruited from two ongoing clinical trials, one of which included patients with elevated amyloid-beta (n = 50), whereas the other did not (n = 30). All participants completed an interview 4-12 weeks after receiving their biomarker results; 47 and 30 participants, respectively, also completed a follow-up interview at 12 months.
When asked whether they had considered PAD, nearly two-thirds of interviewees with the Alzheimer’s disease biomarker stated that they neither had nor would. Roughly one in five from that group said they would pursue PAD if they began to suffer from cognitive impairment or became a burden on others. Interviewees who did not have elevated amyloid beta, when asked whether a reversed result would have led to PAD or suicide, showed interest in roughly similar proportion to their at-risk counterparts.
The coauthors acknowledged the limitations of their study, including not asking about other end-of-life preferences or perceived quality of life for people with dementia. They also noted that, although their sample mirrors the populations of the two studies they drew from, “its homogeneity limits generalizability.” As such, they stressed that
The study was supported by grants from the Alzheimer’s Association and the National Institute on Aging. One author reported receiving grants from those two organizations during the study; another reported receiving grants from Lilly and Novartis. No other conflicts of interest were reported.
SOURCE: Largent EA et al. JAMA Neurol. 2019 Apr 29. doi: 10.1001/jamaneurol.2019.0797.
The fascinating thing about this study is that the idea for it arose when some of the individuals spontaneously mentioned assisted suicide during their initial interview, Annette L. Hanson, MD, said in an interview.
“Would these subjects have thought of suicide in the absence of the Brittany Maynard publicity campaign? I doubt it.”
Dr. Hanson, a forensic psychiatrist, is assistant professor of psychiatry at the University of Maryland and at Johns Hopkins University, both in Baltimore.
The fascinating thing about this study is that the idea for it arose when some of the individuals spontaneously mentioned assisted suicide during their initial interview, Annette L. Hanson, MD, said in an interview.
“Would these subjects have thought of suicide in the absence of the Brittany Maynard publicity campaign? I doubt it.”
Dr. Hanson, a forensic psychiatrist, is assistant professor of psychiatry at the University of Maryland and at Johns Hopkins University, both in Baltimore.
The fascinating thing about this study is that the idea for it arose when some of the individuals spontaneously mentioned assisted suicide during their initial interview, Annette L. Hanson, MD, said in an interview.
“Would these subjects have thought of suicide in the absence of the Brittany Maynard publicity campaign? I doubt it.”
Dr. Hanson, a forensic psychiatrist, is assistant professor of psychiatry at the University of Maryland and at Johns Hopkins University, both in Baltimore.
Being diagnosed with an elevated amyloid-beta biomarker that indicates greater risk of Alzheimer’s disease did not lead to increased consideration of physician-assisted death (PAD), according to an analysis of patients interviewed during clinical trials on cognitive decline.
“Our findings suggest that learning one’s amyloid imaging result does not change baseline attitudes regarding the acceptability of PAD,” wrote Emily A. Largent, PhD, of the department of medical ethics and health policy at the University of Pennsylvania, Philadelphia, and coauthors. The study was published as a research letter in JAMA Neurology.
Participants were recruited from two ongoing clinical trials, one of which included patients with elevated amyloid-beta (n = 50), whereas the other did not (n = 30). All participants completed an interview 4-12 weeks after receiving their biomarker results; 47 and 30 participants, respectively, also completed a follow-up interview at 12 months.
When asked whether they had considered PAD, nearly two-thirds of interviewees with the Alzheimer’s disease biomarker stated that they neither had nor would. Roughly one in five from that group said they would pursue PAD if they began to suffer from cognitive impairment or became a burden on others. Interviewees who did not have elevated amyloid beta, when asked whether a reversed result would have led to PAD or suicide, showed interest in roughly similar proportion to their at-risk counterparts.
The coauthors acknowledged the limitations of their study, including not asking about other end-of-life preferences or perceived quality of life for people with dementia. They also noted that, although their sample mirrors the populations of the two studies they drew from, “its homogeneity limits generalizability.” As such, they stressed that
The study was supported by grants from the Alzheimer’s Association and the National Institute on Aging. One author reported receiving grants from those two organizations during the study; another reported receiving grants from Lilly and Novartis. No other conflicts of interest were reported.
SOURCE: Largent EA et al. JAMA Neurol. 2019 Apr 29. doi: 10.1001/jamaneurol.2019.0797.
Being diagnosed with an elevated amyloid-beta biomarker that indicates greater risk of Alzheimer’s disease did not lead to increased consideration of physician-assisted death (PAD), according to an analysis of patients interviewed during clinical trials on cognitive decline.
“Our findings suggest that learning one’s amyloid imaging result does not change baseline attitudes regarding the acceptability of PAD,” wrote Emily A. Largent, PhD, of the department of medical ethics and health policy at the University of Pennsylvania, Philadelphia, and coauthors. The study was published as a research letter in JAMA Neurology.
Participants were recruited from two ongoing clinical trials, one of which included patients with elevated amyloid-beta (n = 50), whereas the other did not (n = 30). All participants completed an interview 4-12 weeks after receiving their biomarker results; 47 and 30 participants, respectively, also completed a follow-up interview at 12 months.
When asked whether they had considered PAD, nearly two-thirds of interviewees with the Alzheimer’s disease biomarker stated that they neither had nor would. Roughly one in five from that group said they would pursue PAD if they began to suffer from cognitive impairment or became a burden on others. Interviewees who did not have elevated amyloid beta, when asked whether a reversed result would have led to PAD or suicide, showed interest in roughly similar proportion to their at-risk counterparts.
The coauthors acknowledged the limitations of their study, including not asking about other end-of-life preferences or perceived quality of life for people with dementia. They also noted that, although their sample mirrors the populations of the two studies they drew from, “its homogeneity limits generalizability.” As such, they stressed that
The study was supported by grants from the Alzheimer’s Association and the National Institute on Aging. One author reported receiving grants from those two organizations during the study; another reported receiving grants from Lilly and Novartis. No other conflicts of interest were reported.
SOURCE: Largent EA et al. JAMA Neurol. 2019 Apr 29. doi: 10.1001/jamaneurol.2019.0797.
FROM JAMA NEUROLOGY
TMS is associated with improved recollection in older adults
according to a small pilot study published online ahead of print April 17 in Neurology. Stimulation also increased functional MRI signals associated with recollection throughout the hippocampal-cortical network.
“Disruption and abnormal functioning of the hippocampal-cortical network, the region of the brain involved in memory formation, has been linked to age-related memory decline, so it’s exciting to see that, by targeting this region, magnetic stimulation may help improve memory in older adults,” said Joel L. Voss, PhD, of Northwestern University in Chicago. “These results may help us better understand how this network supports memory.”
Recollection is the type of memory most impaired during normal aging. Other types of memory, such as recognition, are relatively spared. Research indicates that multiple sessions of TMS improve recollection and hippocampal-cortical network function in young adults.
Dr. Voss and colleagues performed a pilot study to evaluate whether TMS could improve recollection in older adults. They enrolled 15 cognitively normal older adults (mean age, 72.46 years) into a sham-controlled, single-blind, counterbalanced experiment. Eleven subjects were women. Participants underwent fMRI while learning objects paired with scenes and locations. Investigators administered TMS to lateral parietal locations that were based on each participant’s fMRI connectivity with the hippocampus. Using a within-subjects crossover design, Dr. Voss’s group assessed participants’ recollection and recognition memory at baseline and 24 hours and also 1 week after five consecutive daily sessions of full-intensity stimulation, compared with low-intensity sham stimulation.
At baseline, participants had impaired recollection, but not impaired recognition, compared with a historical sample of younger adults. At 24 hours, TMS provided robust recollection improvement and weak recognition improvement, compared with sham. TMS improved recollection by 31.1% from baseline, and sham yielded a nonsignificant change of −3.1%. Recollection improvements after TMS were consistent across participants. Recognition changed by a nonsignificant 2.8% following TMS and by a nonsignificant −2.9% following sham.
The investigators also found a significant and consistent increase in fMRI recollection activity for the targeted hippocampal-cortical network, but not for the control frontal-parietal network. They observed no increased fMRI activity for recognition.
“These findings demonstrate a causal link between recollection and the hippocampal-cortical network in older adults,” said Dr. Voss. “While our small study examined age-related memory loss, it did not examine this stimulation in people with memory loss from more serious conditions such as mild cognitive impairment or Alzheimer’s disease.” Furthermore, the study was designed to test for neural and behavioral target engagement, but not clinical efficacy, he added.
The study’s limitations included its small sample size, its single-site design, and its lack of active control stimulation. Nevertheless, it identified specific and consistent effects of stimulation across participants that were consistent with previous findings in younger adults. “These findings motivate future studies to optimize the effectiveness of noninvasive stimulation for treatment of age-related memory impairment and to improve mechanistic understanding of the hippocampal-cortical networks that support episodic memory across the lifespan,” said Dr. Voss.
The National Institute on Aging, as well as the Northwestern University Cognitive Neurology and Alzheimer’s Disease Center, supported the study.
SOURCE: Nilakantan AS et al. Neurology. 2019 Apr 17 doi: 10.1212/WNL.0000000000007502.
according to a small pilot study published online ahead of print April 17 in Neurology. Stimulation also increased functional MRI signals associated with recollection throughout the hippocampal-cortical network.
“Disruption and abnormal functioning of the hippocampal-cortical network, the region of the brain involved in memory formation, has been linked to age-related memory decline, so it’s exciting to see that, by targeting this region, magnetic stimulation may help improve memory in older adults,” said Joel L. Voss, PhD, of Northwestern University in Chicago. “These results may help us better understand how this network supports memory.”
Recollection is the type of memory most impaired during normal aging. Other types of memory, such as recognition, are relatively spared. Research indicates that multiple sessions of TMS improve recollection and hippocampal-cortical network function in young adults.
Dr. Voss and colleagues performed a pilot study to evaluate whether TMS could improve recollection in older adults. They enrolled 15 cognitively normal older adults (mean age, 72.46 years) into a sham-controlled, single-blind, counterbalanced experiment. Eleven subjects were women. Participants underwent fMRI while learning objects paired with scenes and locations. Investigators administered TMS to lateral parietal locations that were based on each participant’s fMRI connectivity with the hippocampus. Using a within-subjects crossover design, Dr. Voss’s group assessed participants’ recollection and recognition memory at baseline and 24 hours and also 1 week after five consecutive daily sessions of full-intensity stimulation, compared with low-intensity sham stimulation.
At baseline, participants had impaired recollection, but not impaired recognition, compared with a historical sample of younger adults. At 24 hours, TMS provided robust recollection improvement and weak recognition improvement, compared with sham. TMS improved recollection by 31.1% from baseline, and sham yielded a nonsignificant change of −3.1%. Recollection improvements after TMS were consistent across participants. Recognition changed by a nonsignificant 2.8% following TMS and by a nonsignificant −2.9% following sham.
The investigators also found a significant and consistent increase in fMRI recollection activity for the targeted hippocampal-cortical network, but not for the control frontal-parietal network. They observed no increased fMRI activity for recognition.
“These findings demonstrate a causal link between recollection and the hippocampal-cortical network in older adults,” said Dr. Voss. “While our small study examined age-related memory loss, it did not examine this stimulation in people with memory loss from more serious conditions such as mild cognitive impairment or Alzheimer’s disease.” Furthermore, the study was designed to test for neural and behavioral target engagement, but not clinical efficacy, he added.
The study’s limitations included its small sample size, its single-site design, and its lack of active control stimulation. Nevertheless, it identified specific and consistent effects of stimulation across participants that were consistent with previous findings in younger adults. “These findings motivate future studies to optimize the effectiveness of noninvasive stimulation for treatment of age-related memory impairment and to improve mechanistic understanding of the hippocampal-cortical networks that support episodic memory across the lifespan,” said Dr. Voss.
The National Institute on Aging, as well as the Northwestern University Cognitive Neurology and Alzheimer’s Disease Center, supported the study.
SOURCE: Nilakantan AS et al. Neurology. 2019 Apr 17 doi: 10.1212/WNL.0000000000007502.
according to a small pilot study published online ahead of print April 17 in Neurology. Stimulation also increased functional MRI signals associated with recollection throughout the hippocampal-cortical network.
“Disruption and abnormal functioning of the hippocampal-cortical network, the region of the brain involved in memory formation, has been linked to age-related memory decline, so it’s exciting to see that, by targeting this region, magnetic stimulation may help improve memory in older adults,” said Joel L. Voss, PhD, of Northwestern University in Chicago. “These results may help us better understand how this network supports memory.”
Recollection is the type of memory most impaired during normal aging. Other types of memory, such as recognition, are relatively spared. Research indicates that multiple sessions of TMS improve recollection and hippocampal-cortical network function in young adults.
Dr. Voss and colleagues performed a pilot study to evaluate whether TMS could improve recollection in older adults. They enrolled 15 cognitively normal older adults (mean age, 72.46 years) into a sham-controlled, single-blind, counterbalanced experiment. Eleven subjects were women. Participants underwent fMRI while learning objects paired with scenes and locations. Investigators administered TMS to lateral parietal locations that were based on each participant’s fMRI connectivity with the hippocampus. Using a within-subjects crossover design, Dr. Voss’s group assessed participants’ recollection and recognition memory at baseline and 24 hours and also 1 week after five consecutive daily sessions of full-intensity stimulation, compared with low-intensity sham stimulation.
At baseline, participants had impaired recollection, but not impaired recognition, compared with a historical sample of younger adults. At 24 hours, TMS provided robust recollection improvement and weak recognition improvement, compared with sham. TMS improved recollection by 31.1% from baseline, and sham yielded a nonsignificant change of −3.1%. Recollection improvements after TMS were consistent across participants. Recognition changed by a nonsignificant 2.8% following TMS and by a nonsignificant −2.9% following sham.
The investigators also found a significant and consistent increase in fMRI recollection activity for the targeted hippocampal-cortical network, but not for the control frontal-parietal network. They observed no increased fMRI activity for recognition.
“These findings demonstrate a causal link between recollection and the hippocampal-cortical network in older adults,” said Dr. Voss. “While our small study examined age-related memory loss, it did not examine this stimulation in people with memory loss from more serious conditions such as mild cognitive impairment or Alzheimer’s disease.” Furthermore, the study was designed to test for neural and behavioral target engagement, but not clinical efficacy, he added.
The study’s limitations included its small sample size, its single-site design, and its lack of active control stimulation. Nevertheless, it identified specific and consistent effects of stimulation across participants that were consistent with previous findings in younger adults. “These findings motivate future studies to optimize the effectiveness of noninvasive stimulation for treatment of age-related memory impairment and to improve mechanistic understanding of the hippocampal-cortical networks that support episodic memory across the lifespan,” said Dr. Voss.
The National Institute on Aging, as well as the Northwestern University Cognitive Neurology and Alzheimer’s Disease Center, supported the study.
SOURCE: Nilakantan AS et al. Neurology. 2019 Apr 17 doi: 10.1212/WNL.0000000000007502.
FROM NEUROLOGY
Plasma levels of neurofilament light track neurodegeneration in MCI and Alzheimer’s disease
Plasma levels of the axonal protein also correlated with its presence in cerebrospinal fluid, and mirrored the changes in amyloid beta (Abeta) 42, Niklas Mattsson, MD, and colleagues wrote in JAMA Neurology.
“Taken together, these findings suggest that the neurofilament light level is a dynamic biomarker that changes throughout the course of Alzheimer’s disease and is sensitive to progressive neurodegeneration,” wrote Dr. Mattsson of Lund (Sweden) University and his coauthors. “This has important implications, given the unmet need for noninvasive blood-based methods to objectively track longitudinal neurodegeneration in Alzheimer’s disease.”
A blood-based biomarker of Alzheimer’s disease progression could open a new door for drug trials, the authors noted. Previously, NfL levels have only been available by lumbar puncture – a invasive and expensive test that many patients resist. If NfL plasma levels do reliably track dementia progression, the test could become a standard part of clinical trials, providing regular drug response data as the study progresses.
Neurofilaments are polypeptides that give structure to the neuronal cytoskeleton and regulate microtubule function. Injured cells release the protein very quickly. Neurofilaments are elevated in traumatic brain injury, multiple sclerosis, and some psychiatric illnesses. Neurofilament levels have even been used to predict neurologic recovery after cardiac arrest.
Dr. Mattsson and his team used data obtained over 11 years from 1,583 subjects enrolled in the Alzheimer’s Disease Neuroimaging Initiative study. The sample comprised three groups: cognitively unimpaired controls (401), patients with MCI (855), and patients with Alzheimer’s dementia (327). The investigators analyzed 4,326 samples.
In addition to the NfL measurements, they tracked Abeta and tau in cerebrospinal fluid (CSF), structural brain changes by 18fluorodeoxyglucose (FDG)–PET and MRI, and cognitive and functional performance. The primary outcome was NfL’s association with these changes. The team set the lower limit of NfL as 6.7 ng/L and the upper, 1,620 ng/L.
At baseline, only advancing age correlated with NfL levels. But it was significantly higher in patients with MCI (37.9 ng/L) and Alzheimer’s dementia (45.9 ng/L) than it was in the control subjects (32.1 ng/L). Over the years of follow-up, levels increased in all groups, but NfL increased more rapidly among patients with MCI and Alzheimer’s dementia than controls (2.7 vs. 2.4 ng/L per year). The difference was most pronounced when comparing levels in patients with Alzheimer’s dementia and MCI with controls. However, control subjects who were Abeta positive by CSF had greater NfL changes than Abeta-negative controls.
Baseline measures of CSF Abeta and tau, as well as hippocampal and ventricular volume and cortical thickness, also correlated with NfL levels, as did cognition and functional scores.
During follow-up, the diagnostic groups showed different NfL trajectories, which correlated strongly with the other measures.
In the control group, NfL increases correlated with lower FDG-PET measures, lower CSF Abeta, reduced hippocampal volume, and higher ventricular volume. Among patients with MCI, NfL increases correlated most strongly with hippocampal volume, temporal region, and cognition. Among patients with Alzheimer’s dementia, the NfL increase most strongly tracked cognitive decline,
When the investigators applied these findings to the A/T/N (amyloid, tau, neurodegeneration) classification system, NfL most often correlated with neurodegeneration, but not always. This might suggest that the neuronal damage occurred separately from Abeta changes. In all three groups, rapid NfL increases mirrored the rate of change in most other measures.
“In controls and patients with MCI and Alzheimer’s dementia, greater rates of NfL were associated with accelerated reduction in FDG-PET measures … expansion of ventricular volume,” and a reduction in cognitive and functional performance, Dr. Mattsson and his colleagues wrote.“ In addition, greater increases in NfL levels were associated with accelerated loss of hippocampal volume and entorhinal cortical thickness in controls and patients with MCI and with accelerated increases in total tau level, phosphorylated tau level, and white matter lesions in patients with MCI. In general, the concentrations of blood-based NfL appears to reflect the intensity of the neuronal injury.”
Dr Mattsson reported being a consultant for the Alzheimer’s Disease Neuroimaging Initiative.
SOURCE: Mattsson N et al. JAMA Neurol. 2019 Apr 22. doi: 10.1001/jamaneurol.2019.0765.
This is an impressive study that convincingly demonstrates the sensitivity of plasma neurofilament light (NfL) to disease progression in patients with mild cognitive impairment and dementia in the Alzheimer’s Disease Neuroimaging Initiative cohort.
It is known that NfL is sensitive to neuronal damage that can result from a variety of pathologies, not limited to Alzheimer’s disease, so it is not diagnostically specific. In the present study there was even overlap of values between the cognitively unimpaired and mild cognitive impairment groups at baseline as well, although the levels separated over time.
In the right setting, NfL might still be a clinically useful diagnostic marker, especially for mild-stage disease when other clinical measures such as mental status scores and structural brain scans are inconclusive, and further study seems warranted for such a possibility.
Its greatest utility, however, will likely be in clinical trials. It would have been of the greatest interest to know how NfL levels changed in the setting of demonstrated cerebral amyloid clearance by agents such as aducanumab that failed to halt dementia progression, or in the setting of BACE1 inhibitor-related worsening of cognition. Did NfL levels remain static in the former and rise in the latter? Looking ahead, it seems likely that this easily accessed biomarker will become an integral part of clinical trial design. Assuming cost is not overly burdensome, it may even find its way eventually into clinical practice.
Dr. Caselli is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
This is an impressive study that convincingly demonstrates the sensitivity of plasma neurofilament light (NfL) to disease progression in patients with mild cognitive impairment and dementia in the Alzheimer’s Disease Neuroimaging Initiative cohort.
It is known that NfL is sensitive to neuronal damage that can result from a variety of pathologies, not limited to Alzheimer’s disease, so it is not diagnostically specific. In the present study there was even overlap of values between the cognitively unimpaired and mild cognitive impairment groups at baseline as well, although the levels separated over time.
In the right setting, NfL might still be a clinically useful diagnostic marker, especially for mild-stage disease when other clinical measures such as mental status scores and structural brain scans are inconclusive, and further study seems warranted for such a possibility.
Its greatest utility, however, will likely be in clinical trials. It would have been of the greatest interest to know how NfL levels changed in the setting of demonstrated cerebral amyloid clearance by agents such as aducanumab that failed to halt dementia progression, or in the setting of BACE1 inhibitor-related worsening of cognition. Did NfL levels remain static in the former and rise in the latter? Looking ahead, it seems likely that this easily accessed biomarker will become an integral part of clinical trial design. Assuming cost is not overly burdensome, it may even find its way eventually into clinical practice.
Dr. Caselli is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
This is an impressive study that convincingly demonstrates the sensitivity of plasma neurofilament light (NfL) to disease progression in patients with mild cognitive impairment and dementia in the Alzheimer’s Disease Neuroimaging Initiative cohort.
It is known that NfL is sensitive to neuronal damage that can result from a variety of pathologies, not limited to Alzheimer’s disease, so it is not diagnostically specific. In the present study there was even overlap of values between the cognitively unimpaired and mild cognitive impairment groups at baseline as well, although the levels separated over time.
In the right setting, NfL might still be a clinically useful diagnostic marker, especially for mild-stage disease when other clinical measures such as mental status scores and structural brain scans are inconclusive, and further study seems warranted for such a possibility.
Its greatest utility, however, will likely be in clinical trials. It would have been of the greatest interest to know how NfL levels changed in the setting of demonstrated cerebral amyloid clearance by agents such as aducanumab that failed to halt dementia progression, or in the setting of BACE1 inhibitor-related worsening of cognition. Did NfL levels remain static in the former and rise in the latter? Looking ahead, it seems likely that this easily accessed biomarker will become an integral part of clinical trial design. Assuming cost is not overly burdensome, it may even find its way eventually into clinical practice.
Dr. Caselli is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
Plasma levels of the axonal protein also correlated with its presence in cerebrospinal fluid, and mirrored the changes in amyloid beta (Abeta) 42, Niklas Mattsson, MD, and colleagues wrote in JAMA Neurology.
“Taken together, these findings suggest that the neurofilament light level is a dynamic biomarker that changes throughout the course of Alzheimer’s disease and is sensitive to progressive neurodegeneration,” wrote Dr. Mattsson of Lund (Sweden) University and his coauthors. “This has important implications, given the unmet need for noninvasive blood-based methods to objectively track longitudinal neurodegeneration in Alzheimer’s disease.”
A blood-based biomarker of Alzheimer’s disease progression could open a new door for drug trials, the authors noted. Previously, NfL levels have only been available by lumbar puncture – a invasive and expensive test that many patients resist. If NfL plasma levels do reliably track dementia progression, the test could become a standard part of clinical trials, providing regular drug response data as the study progresses.
Neurofilaments are polypeptides that give structure to the neuronal cytoskeleton and regulate microtubule function. Injured cells release the protein very quickly. Neurofilaments are elevated in traumatic brain injury, multiple sclerosis, and some psychiatric illnesses. Neurofilament levels have even been used to predict neurologic recovery after cardiac arrest.
Dr. Mattsson and his team used data obtained over 11 years from 1,583 subjects enrolled in the Alzheimer’s Disease Neuroimaging Initiative study. The sample comprised three groups: cognitively unimpaired controls (401), patients with MCI (855), and patients with Alzheimer’s dementia (327). The investigators analyzed 4,326 samples.
In addition to the NfL measurements, they tracked Abeta and tau in cerebrospinal fluid (CSF), structural brain changes by 18fluorodeoxyglucose (FDG)–PET and MRI, and cognitive and functional performance. The primary outcome was NfL’s association with these changes. The team set the lower limit of NfL as 6.7 ng/L and the upper, 1,620 ng/L.
At baseline, only advancing age correlated with NfL levels. But it was significantly higher in patients with MCI (37.9 ng/L) and Alzheimer’s dementia (45.9 ng/L) than it was in the control subjects (32.1 ng/L). Over the years of follow-up, levels increased in all groups, but NfL increased more rapidly among patients with MCI and Alzheimer’s dementia than controls (2.7 vs. 2.4 ng/L per year). The difference was most pronounced when comparing levels in patients with Alzheimer’s dementia and MCI with controls. However, control subjects who were Abeta positive by CSF had greater NfL changes than Abeta-negative controls.
Baseline measures of CSF Abeta and tau, as well as hippocampal and ventricular volume and cortical thickness, also correlated with NfL levels, as did cognition and functional scores.
During follow-up, the diagnostic groups showed different NfL trajectories, which correlated strongly with the other measures.
In the control group, NfL increases correlated with lower FDG-PET measures, lower CSF Abeta, reduced hippocampal volume, and higher ventricular volume. Among patients with MCI, NfL increases correlated most strongly with hippocampal volume, temporal region, and cognition. Among patients with Alzheimer’s dementia, the NfL increase most strongly tracked cognitive decline,
When the investigators applied these findings to the A/T/N (amyloid, tau, neurodegeneration) classification system, NfL most often correlated with neurodegeneration, but not always. This might suggest that the neuronal damage occurred separately from Abeta changes. In all three groups, rapid NfL increases mirrored the rate of change in most other measures.
“In controls and patients with MCI and Alzheimer’s dementia, greater rates of NfL were associated with accelerated reduction in FDG-PET measures … expansion of ventricular volume,” and a reduction in cognitive and functional performance, Dr. Mattsson and his colleagues wrote.“ In addition, greater increases in NfL levels were associated with accelerated loss of hippocampal volume and entorhinal cortical thickness in controls and patients with MCI and with accelerated increases in total tau level, phosphorylated tau level, and white matter lesions in patients with MCI. In general, the concentrations of blood-based NfL appears to reflect the intensity of the neuronal injury.”
Dr Mattsson reported being a consultant for the Alzheimer’s Disease Neuroimaging Initiative.
SOURCE: Mattsson N et al. JAMA Neurol. 2019 Apr 22. doi: 10.1001/jamaneurol.2019.0765.
Plasma levels of the axonal protein also correlated with its presence in cerebrospinal fluid, and mirrored the changes in amyloid beta (Abeta) 42, Niklas Mattsson, MD, and colleagues wrote in JAMA Neurology.
“Taken together, these findings suggest that the neurofilament light level is a dynamic biomarker that changes throughout the course of Alzheimer’s disease and is sensitive to progressive neurodegeneration,” wrote Dr. Mattsson of Lund (Sweden) University and his coauthors. “This has important implications, given the unmet need for noninvasive blood-based methods to objectively track longitudinal neurodegeneration in Alzheimer’s disease.”
A blood-based biomarker of Alzheimer’s disease progression could open a new door for drug trials, the authors noted. Previously, NfL levels have only been available by lumbar puncture – a invasive and expensive test that many patients resist. If NfL plasma levels do reliably track dementia progression, the test could become a standard part of clinical trials, providing regular drug response data as the study progresses.
Neurofilaments are polypeptides that give structure to the neuronal cytoskeleton and regulate microtubule function. Injured cells release the protein very quickly. Neurofilaments are elevated in traumatic brain injury, multiple sclerosis, and some psychiatric illnesses. Neurofilament levels have even been used to predict neurologic recovery after cardiac arrest.
Dr. Mattsson and his team used data obtained over 11 years from 1,583 subjects enrolled in the Alzheimer’s Disease Neuroimaging Initiative study. The sample comprised three groups: cognitively unimpaired controls (401), patients with MCI (855), and patients with Alzheimer’s dementia (327). The investigators analyzed 4,326 samples.
In addition to the NfL measurements, they tracked Abeta and tau in cerebrospinal fluid (CSF), structural brain changes by 18fluorodeoxyglucose (FDG)–PET and MRI, and cognitive and functional performance. The primary outcome was NfL’s association with these changes. The team set the lower limit of NfL as 6.7 ng/L and the upper, 1,620 ng/L.
At baseline, only advancing age correlated with NfL levels. But it was significantly higher in patients with MCI (37.9 ng/L) and Alzheimer’s dementia (45.9 ng/L) than it was in the control subjects (32.1 ng/L). Over the years of follow-up, levels increased in all groups, but NfL increased more rapidly among patients with MCI and Alzheimer’s dementia than controls (2.7 vs. 2.4 ng/L per year). The difference was most pronounced when comparing levels in patients with Alzheimer’s dementia and MCI with controls. However, control subjects who were Abeta positive by CSF had greater NfL changes than Abeta-negative controls.
Baseline measures of CSF Abeta and tau, as well as hippocampal and ventricular volume and cortical thickness, also correlated with NfL levels, as did cognition and functional scores.
During follow-up, the diagnostic groups showed different NfL trajectories, which correlated strongly with the other measures.
In the control group, NfL increases correlated with lower FDG-PET measures, lower CSF Abeta, reduced hippocampal volume, and higher ventricular volume. Among patients with MCI, NfL increases correlated most strongly with hippocampal volume, temporal region, and cognition. Among patients with Alzheimer’s dementia, the NfL increase most strongly tracked cognitive decline,
When the investigators applied these findings to the A/T/N (amyloid, tau, neurodegeneration) classification system, NfL most often correlated with neurodegeneration, but not always. This might suggest that the neuronal damage occurred separately from Abeta changes. In all three groups, rapid NfL increases mirrored the rate of change in most other measures.
“In controls and patients with MCI and Alzheimer’s dementia, greater rates of NfL were associated with accelerated reduction in FDG-PET measures … expansion of ventricular volume,” and a reduction in cognitive and functional performance, Dr. Mattsson and his colleagues wrote.“ In addition, greater increases in NfL levels were associated with accelerated loss of hippocampal volume and entorhinal cortical thickness in controls and patients with MCI and with accelerated increases in total tau level, phosphorylated tau level, and white matter lesions in patients with MCI. In general, the concentrations of blood-based NfL appears to reflect the intensity of the neuronal injury.”
Dr Mattsson reported being a consultant for the Alzheimer’s Disease Neuroimaging Initiative.
SOURCE: Mattsson N et al. JAMA Neurol. 2019 Apr 22. doi: 10.1001/jamaneurol.2019.0765.
FROM JAMA NEUROLOGY
ACE inhibitors may improve neuropsychiatric lupus
SAN FRANCISCO – The announcement of a first-ever multicenter randomized trial of ACE inhibitors for the treatment of cognitive impairment in systemic lupus erythematosus patients generated some of the biggest buzz at LUPUS 2019.
“The time has come to implement clinical trials in lupus to see if we can address what is one of the most distressing aspects of the disease to patients,” Betty Diamond, MD, said in announcing the planned trial at an international congress on systemic lupus erythematosus (SLE).
Neuropsychiatric lupus, characterized most often by cognitive impairment, affects 40%-90% of SLE patients, according to various epidemiologic studies. This confusion and memory loss has been shown to be independent of systemic disease activity.
“Cognitive impairment is a very common problem and a very insidious problem in lupus patients,” emphasized Dr. Diamond, professor and head of the Center for Autoimmune Musculoskeletal and Hematopoietic Diseases at the Feinstein Institute for Medical Research in Manhasset, New York.
Dr. Diamond was the recipient of the 2018 Lupus Insight Prize awarded by the Lupus Research Alliance, which is funding the multicenter randomized trial. For the study, roughly 70 SLE patients with cognitive impairment not associated with a focal brain lesion will be randomized to receive a centrally acting ACE inhibitor – captopril was the one she and her coinvestigators have used in their mouse model and preliminary clinical studies – or to a non–centrally acting ACE inhibitor, such as enalapril.
“The clinical trial compares an ACE inhibitor that crosses the blood-brain barrier with one that doesn’t. They both have the same renal protection and systemic anti-inflammatory effects,” explained Dr. Diamond, who is also professor of molecular medicine and of medicine at the Zucker School of Medicine at Hofstra/Northwell, East Garden City, N.Y.
In a recent publication (J Exp Med. 2018 Oct 1;215[10]:2554-66), Dr. Diamond and her coinvestigators presented much of the background work that underpins the upcoming randomized trial. Sixteen years ago, they discovered two anti-DNA antibodies that cross-react with the N-methyl-D-aspartate receptor (NMDAR) and enhance NMDAR signaling. They showed that while the NMDARs are critical in learning and memory, their prolonged stimulation results in a high degree of calcium influx, causing neuronal death. These anti-DNA/anti-NMDAR antibodies, known as DNRAbs, are present at elevated titers in 30%-40% of SLE patients, and in a higher proportion of those with neuropsychiatric lupus.
“Most importantly, DNRAbs are present in the cerebrospinal fluid of patients who have nonfocal CNS manifestations of lupus,” Dr. Diamond said.
She and her coworkers developed a mouse model of cognitive impairment in lupus and utilized it to identify a two-stage model of the pathogenesis of DNRAb-mediated neuropsychiatric lupus. First, a traumatic event such as an infection causes a temporary opening in the blood-brain barrier, allowing the DNRAbs to reach the brain. This results in acute excitotoxic neuronal death. This is followed by a second stage, which entails activation of microglia – known as the macrophages of the CNS – with resultant loss of neuronal dendritic arborization and complexity. In the mouse model, this causes a selective impairment in spatial memory that corresponds well to the spatial memory deficit the investigators documented in DNRAb-positive SLE patients, compared with healthy controls and DNRAb-negative lupus patients.
A key finding in this project, Dr. Diamond continued, was that activated microglia turn out to be critical for dendritic loss. If the microglia are deactivated, regrowth of the dendritic processes occurs. This raises a possibility that attendees at LUPUS 2019 found thrilling: Perhaps the cognitive impairment of neuropsychiatric SLE can be prevented and even reversed by suppressing microglial activation.
Promising work in the field of Alzheimer’s disease suggests that centrally acting ACE inhibitors can indeed suppress microglial activation and actually improve cognition. Dr. Diamond and her colleagues showed this also was the case in their mouse model. Moreover, in a small clinical study they used PET brain imaging to show that captopril reduced the increased glucose uptake and hippocampal hypermetabolism associated with DNRAb-positive neuropsychiatric lupus, an effect maintained through 18 months of follow-up.
“We think DNRAbs contribute to cognitive impairment in SLE patients, but we certainly wouldn’t say that antibodies are the only mechanism. Other investigators have shown that interferon can also do this, and that, like the antibodies, interferon acts through microglial activation. We think that this microglial activation is going to be a general paradigm in cognitive impairment in lupus and in other diseases, so microglia are a very good therapeutic target,” Dr. Diamond said.
The primary outcomes in the forthcoming randomized trial involve PET neuronal imaging. They investigators are hoping to see reduced hippocampal hypermetabolism and suppression of activated microglial cells.
“We’ll see if we’re actually hitting our target. We’re doing neuropsychologic testing, too, but we’re really concentrating on imaging outcomes, because those are objective and have many fewer variables to confound them,” according to Dr. Diamond.
Microglial activation is a current topic of intense research interest within the pharmaceutical industry, she added. If the imaging study is positive, she anticipates drug companies will quickly ramp up and conduct large clinical trials powered to show significant results in terms of neuropsychologic test scores and clinical outcomes.
Dr. Diamond reported having no financial conflicts regarding her work, which has been supported largely by the National Institutes of Health.
SAN FRANCISCO – The announcement of a first-ever multicenter randomized trial of ACE inhibitors for the treatment of cognitive impairment in systemic lupus erythematosus patients generated some of the biggest buzz at LUPUS 2019.
“The time has come to implement clinical trials in lupus to see if we can address what is one of the most distressing aspects of the disease to patients,” Betty Diamond, MD, said in announcing the planned trial at an international congress on systemic lupus erythematosus (SLE).
Neuropsychiatric lupus, characterized most often by cognitive impairment, affects 40%-90% of SLE patients, according to various epidemiologic studies. This confusion and memory loss has been shown to be independent of systemic disease activity.
“Cognitive impairment is a very common problem and a very insidious problem in lupus patients,” emphasized Dr. Diamond, professor and head of the Center for Autoimmune Musculoskeletal and Hematopoietic Diseases at the Feinstein Institute for Medical Research in Manhasset, New York.
Dr. Diamond was the recipient of the 2018 Lupus Insight Prize awarded by the Lupus Research Alliance, which is funding the multicenter randomized trial. For the study, roughly 70 SLE patients with cognitive impairment not associated with a focal brain lesion will be randomized to receive a centrally acting ACE inhibitor – captopril was the one she and her coinvestigators have used in their mouse model and preliminary clinical studies – or to a non–centrally acting ACE inhibitor, such as enalapril.
“The clinical trial compares an ACE inhibitor that crosses the blood-brain barrier with one that doesn’t. They both have the same renal protection and systemic anti-inflammatory effects,” explained Dr. Diamond, who is also professor of molecular medicine and of medicine at the Zucker School of Medicine at Hofstra/Northwell, East Garden City, N.Y.
In a recent publication (J Exp Med. 2018 Oct 1;215[10]:2554-66), Dr. Diamond and her coinvestigators presented much of the background work that underpins the upcoming randomized trial. Sixteen years ago, they discovered two anti-DNA antibodies that cross-react with the N-methyl-D-aspartate receptor (NMDAR) and enhance NMDAR signaling. They showed that while the NMDARs are critical in learning and memory, their prolonged stimulation results in a high degree of calcium influx, causing neuronal death. These anti-DNA/anti-NMDAR antibodies, known as DNRAbs, are present at elevated titers in 30%-40% of SLE patients, and in a higher proportion of those with neuropsychiatric lupus.
“Most importantly, DNRAbs are present in the cerebrospinal fluid of patients who have nonfocal CNS manifestations of lupus,” Dr. Diamond said.
She and her coworkers developed a mouse model of cognitive impairment in lupus and utilized it to identify a two-stage model of the pathogenesis of DNRAb-mediated neuropsychiatric lupus. First, a traumatic event such as an infection causes a temporary opening in the blood-brain barrier, allowing the DNRAbs to reach the brain. This results in acute excitotoxic neuronal death. This is followed by a second stage, which entails activation of microglia – known as the macrophages of the CNS – with resultant loss of neuronal dendritic arborization and complexity. In the mouse model, this causes a selective impairment in spatial memory that corresponds well to the spatial memory deficit the investigators documented in DNRAb-positive SLE patients, compared with healthy controls and DNRAb-negative lupus patients.
A key finding in this project, Dr. Diamond continued, was that activated microglia turn out to be critical for dendritic loss. If the microglia are deactivated, regrowth of the dendritic processes occurs. This raises a possibility that attendees at LUPUS 2019 found thrilling: Perhaps the cognitive impairment of neuropsychiatric SLE can be prevented and even reversed by suppressing microglial activation.
Promising work in the field of Alzheimer’s disease suggests that centrally acting ACE inhibitors can indeed suppress microglial activation and actually improve cognition. Dr. Diamond and her colleagues showed this also was the case in their mouse model. Moreover, in a small clinical study they used PET brain imaging to show that captopril reduced the increased glucose uptake and hippocampal hypermetabolism associated with DNRAb-positive neuropsychiatric lupus, an effect maintained through 18 months of follow-up.
“We think DNRAbs contribute to cognitive impairment in SLE patients, but we certainly wouldn’t say that antibodies are the only mechanism. Other investigators have shown that interferon can also do this, and that, like the antibodies, interferon acts through microglial activation. We think that this microglial activation is going to be a general paradigm in cognitive impairment in lupus and in other diseases, so microglia are a very good therapeutic target,” Dr. Diamond said.
The primary outcomes in the forthcoming randomized trial involve PET neuronal imaging. They investigators are hoping to see reduced hippocampal hypermetabolism and suppression of activated microglial cells.
“We’ll see if we’re actually hitting our target. We’re doing neuropsychologic testing, too, but we’re really concentrating on imaging outcomes, because those are objective and have many fewer variables to confound them,” according to Dr. Diamond.
Microglial activation is a current topic of intense research interest within the pharmaceutical industry, she added. If the imaging study is positive, she anticipates drug companies will quickly ramp up and conduct large clinical trials powered to show significant results in terms of neuropsychologic test scores and clinical outcomes.
Dr. Diamond reported having no financial conflicts regarding her work, which has been supported largely by the National Institutes of Health.
SAN FRANCISCO – The announcement of a first-ever multicenter randomized trial of ACE inhibitors for the treatment of cognitive impairment in systemic lupus erythematosus patients generated some of the biggest buzz at LUPUS 2019.
“The time has come to implement clinical trials in lupus to see if we can address what is one of the most distressing aspects of the disease to patients,” Betty Diamond, MD, said in announcing the planned trial at an international congress on systemic lupus erythematosus (SLE).
Neuropsychiatric lupus, characterized most often by cognitive impairment, affects 40%-90% of SLE patients, according to various epidemiologic studies. This confusion and memory loss has been shown to be independent of systemic disease activity.
“Cognitive impairment is a very common problem and a very insidious problem in lupus patients,” emphasized Dr. Diamond, professor and head of the Center for Autoimmune Musculoskeletal and Hematopoietic Diseases at the Feinstein Institute for Medical Research in Manhasset, New York.
Dr. Diamond was the recipient of the 2018 Lupus Insight Prize awarded by the Lupus Research Alliance, which is funding the multicenter randomized trial. For the study, roughly 70 SLE patients with cognitive impairment not associated with a focal brain lesion will be randomized to receive a centrally acting ACE inhibitor – captopril was the one she and her coinvestigators have used in their mouse model and preliminary clinical studies – or to a non–centrally acting ACE inhibitor, such as enalapril.
“The clinical trial compares an ACE inhibitor that crosses the blood-brain barrier with one that doesn’t. They both have the same renal protection and systemic anti-inflammatory effects,” explained Dr. Diamond, who is also professor of molecular medicine and of medicine at the Zucker School of Medicine at Hofstra/Northwell, East Garden City, N.Y.
In a recent publication (J Exp Med. 2018 Oct 1;215[10]:2554-66), Dr. Diamond and her coinvestigators presented much of the background work that underpins the upcoming randomized trial. Sixteen years ago, they discovered two anti-DNA antibodies that cross-react with the N-methyl-D-aspartate receptor (NMDAR) and enhance NMDAR signaling. They showed that while the NMDARs are critical in learning and memory, their prolonged stimulation results in a high degree of calcium influx, causing neuronal death. These anti-DNA/anti-NMDAR antibodies, known as DNRAbs, are present at elevated titers in 30%-40% of SLE patients, and in a higher proportion of those with neuropsychiatric lupus.
“Most importantly, DNRAbs are present in the cerebrospinal fluid of patients who have nonfocal CNS manifestations of lupus,” Dr. Diamond said.
She and her coworkers developed a mouse model of cognitive impairment in lupus and utilized it to identify a two-stage model of the pathogenesis of DNRAb-mediated neuropsychiatric lupus. First, a traumatic event such as an infection causes a temporary opening in the blood-brain barrier, allowing the DNRAbs to reach the brain. This results in acute excitotoxic neuronal death. This is followed by a second stage, which entails activation of microglia – known as the macrophages of the CNS – with resultant loss of neuronal dendritic arborization and complexity. In the mouse model, this causes a selective impairment in spatial memory that corresponds well to the spatial memory deficit the investigators documented in DNRAb-positive SLE patients, compared with healthy controls and DNRAb-negative lupus patients.
A key finding in this project, Dr. Diamond continued, was that activated microglia turn out to be critical for dendritic loss. If the microglia are deactivated, regrowth of the dendritic processes occurs. This raises a possibility that attendees at LUPUS 2019 found thrilling: Perhaps the cognitive impairment of neuropsychiatric SLE can be prevented and even reversed by suppressing microglial activation.
Promising work in the field of Alzheimer’s disease suggests that centrally acting ACE inhibitors can indeed suppress microglial activation and actually improve cognition. Dr. Diamond and her colleagues showed this also was the case in their mouse model. Moreover, in a small clinical study they used PET brain imaging to show that captopril reduced the increased glucose uptake and hippocampal hypermetabolism associated with DNRAb-positive neuropsychiatric lupus, an effect maintained through 18 months of follow-up.
“We think DNRAbs contribute to cognitive impairment in SLE patients, but we certainly wouldn’t say that antibodies are the only mechanism. Other investigators have shown that interferon can also do this, and that, like the antibodies, interferon acts through microglial activation. We think that this microglial activation is going to be a general paradigm in cognitive impairment in lupus and in other diseases, so microglia are a very good therapeutic target,” Dr. Diamond said.
The primary outcomes in the forthcoming randomized trial involve PET neuronal imaging. They investigators are hoping to see reduced hippocampal hypermetabolism and suppression of activated microglial cells.
“We’ll see if we’re actually hitting our target. We’re doing neuropsychologic testing, too, but we’re really concentrating on imaging outcomes, because those are objective and have many fewer variables to confound them,” according to Dr. Diamond.
Microglial activation is a current topic of intense research interest within the pharmaceutical industry, she added. If the imaging study is positive, she anticipates drug companies will quickly ramp up and conduct large clinical trials powered to show significant results in terms of neuropsychologic test scores and clinical outcomes.
Dr. Diamond reported having no financial conflicts regarding her work, which has been supported largely by the National Institutes of Health.
REPORTING FROM LUPUS 2019
Key clinical point: ACE inhibitor therapy may prevent and/or improve neuropsychiatric lupus.
Major finding: The first-ever multicenter randomized trial of ACE inhibitor therapy for neuropsychiatric SLE will soon get underway.
Study details: The planned – and funded – trial will include roughly 70 patients with neuropsychiatric lupus.
Disclosures: The presenter reported having no financial conflicts regarding her work, which has been supported largely by the National Institutes of Health.
BACE-1 inhibition worsens cognition in patients with prodromal Alzheimer’s disease
More bad news for Alzheimer’s research. Two more BACE inhibitors fall far short of the finish line.
Declining cognitive scores, falls, suicidal ideation, and liver enzyme abnormalities were all seen in clinical trials.
The news doesn’t bode well for the therapeutic target of BACE (beta-site APP cleaving enzyme) inhibition. BACE is one of the enzymes that trims the amyloid precursor protein (APP). Inhibiting it does reduce the amount of toxic amyloid-beta in cerebrospinal fluid, and amyloid plaque in the brain. But none of these molecules has shown clinical benefit in dementia patients, whether their disease is mild, or moderate or – now – prodromal. And it is now apparent that inhibiting BACE also produces serious off-target problems.
“BACE-1 inhibition certainly seemed to have a sound rationale assuming the basis for amyloid’s role in Alzheimer’s disease pathogenesis is a gain of toxicity,” Richard J. Caselli, MD, of the Mayo Clinic, Rochester, Minn., said in an interview. “That APP is important for Alzheimer’s pathogenesis still seems clear but whether amyloid-beta toxicity is the driving force is no longer clear. Further, interruption of the APP system disrupts more than amyloid-beta peptide, possibly explaining the adverse cognitive effects of BACE-1 inhibition shown exhibited now by three different BACE-1 inhibitors.”
Verubecestat
Researchers got their first dose of bad news regarding verubecestat at the 2017 Clinical Trials in Alzheimer’s Disease meeting. There, Michael F. Egan, MD, Merck’s associate vice president of clinical neuroscience, discussed the molecule’s failure to slow cognitive decline in patients with mild to moderate Alzheimer’s disease. There was plenty of biomarker evidence that the drug did block amyloid-beta production, but there also was a plethora of concerning adverse events, Dr. Egan said in an interview.
However, verubecestat still was being pursued in patients with prodromal Alzheimer’s disease. In February, Merck stopped the trial after a futility analysis and announced that the company was terminating studies of verubecestat in that population as well. In the April 11 issue of the New England Journal of Medicine, Dr. Egan and his colleagues report the full extent of verubecestat’s failure in prodromal patients, and the accompanying adverse events.
At the time of termination, 1,454 patients had been enrolled. Of these, 485 received 12 mg/day, 484 received 40 mg/day, and 485 received placebo. About half of each group completed 104 weeks of treatment in the study, which was designed to extend up to 5 years.
The primary outcome was change in the Clinical Dementia Rating Scale–Sum of Boxes score (CDR-SB). Seven secondary outcomes examined other cognitive and functional end points, along with changes in hippocampal volume on MRI and amyloid burden as determined in PET imaging.
Not only did verubecestat fail to slow cognitive decline, it appeared to exacerbate it. The mean change on the CDR-SB was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group, favoring placebo.
“In an exploratory analysis according to time point, scores on the CDR-SB were also higher [signifying more impairment of cognition and daily functioning] in the 40-mg group than in the placebo group at 13, 26, and 52 weeks ... suggesting but not confirming the possibility of worse performance at these earlier time points in the high-dose verubecestat group,” the investigators said.
Verubecestat also was associated with more conversions to Alzheimer’s disease. Per 100 patient-years, the Alzheimer’s disease event rates were 24.5 in the 12-mg group, 25.5 in the 40-mg group, and 19.3 in the placebo group. Compared with placebo, those taking 12-mg doses were 30% more likely to develop Alzheimer’s disease and those taking 40-mg doses were 38% more likely. The findings suggest that “verubecestat may have accelerated the progression to diagnosis of dementia due to Alzheimer’s disease,” the investigators said.
The negative impact of verubecestat was apparent quite early in the study. “In exploratory analyses, both dose levels of verubecestat were associated with poorer outcomes on the [Composite Cognition Score-3 Domain] and the ADAS-Cog [Alzheimer’s Disease Assessment Scale–Cognitive Subscale] measures of cognition that, relative to placebo, appeared worse at week 13 and did not appear to progress thereafter.”
Results of the secondary end points, including the ADAS-Cog and the Mini-Mental State Exam, also indicated that verubecestat may have worsened cognitive performance.
Imaging outcomes were positive, however. Hippocampal volume was 6,448 mL in the 12-mg group, 6,469 mL in the 40-mg group, and 6,435 mL in the placebo group. Brain amyloid increased in the placebo group, as expected, and decreased in the active groups. The small group of patients who underwent cerebrospinal fluid sampling showed reductions of more than 60% in amyloid-beta and soluble APP-beta associated with verubecestat. These results show that the molecule was indeed hitting its intended target, but that doing so was not clinically beneficial.
Adverse events were more common in the verubecestat groups. These included rash, dermatitis, urticaria, sleep disturbance, weight loss, and cough. Hair coloring changed in 2.5% of patients in the 12-mg group and 5% of the 40-mg group, but in none of the subjects taking placebo.
Patients taking verubecestat were more likely to sustain falls and injuries and to express suicidal ideation.
The results of this trial differ from the study of verubecestat in mild to moderate Alzheimer’s disease, the investigators noted. Those patients did not decline cognitively as did those with prodromal disease.
“Patients at an earlier stage of the disease may be more sensitive to the effects of substantial BACE-1 inhibition, perhaps because of a role of BACE-1 in normal synaptic function. It is also possible that the effects of verubecestat are due to inhibition of BACE-2,” they said.
Atabecestat
In a research letter in the same issue of the New England Journal of Medicine (2019 Apr 11;380:1483-5), David Henley, MD, senior director of Janssen’s Alzheimer’s clinical development core, released similarly negative results from an interim analysis of EARLY (Efficacy and Safety Study of Atabecestat in Participants Who Are Asymptomatic at Risk for Developing Alzheimer’s Dementia) trial, a randomized study of the BACE-1 inhibitor candidate, atabecestat.
The phase 2 trial enrolled 557 patients with prodromal Alzheimer’s disease. The primary cognitive end point was change from baseline in the Preclinical Alzheimer’s Cognitive Composite (PACC) score.
This trial was discontinued in May 2018 because of liver-related adverse events, although safety follow-up continues. The research letter did not disclose details of the hepatic events, but a company press release from May 2018 referred to them in a general sense.
“Elevations of liver enzymes, which were serious in nature, have been observed in some study participants who received the Janssen BACE inhibitor, atabecestat. After a thorough evaluation of all available liver safety data from our studies, Janssen has concluded that the benefit-risk ratio is no longer favorable to continue development of atabecestat for people who have late-onset preclinical stage Alzheimer’s disease.”
Patients in EARLY were randomized to 5 mg, 25 mg, or placebo. As in the verubecestat trial, those randomized to placebo did better. The mean changes from baseline in the PACC score were −1.44 in the 25-mg group, −0.58 in the 5-mg group, and −0.32 in the placebo group.
“At month 6, the difference between the 25-mg group and the placebo group was −1.12 and the difference between the 5-mg group and the placebo group was −0.26, favoring placebo over the higher dose,” the authors said.
This theme reemerged in a secondary end point, the Repeatable Battery for the Assessment of Neuropsychological Status. The 25-mg group declined 3.58 points more than placebo, and the 5-mg group, 1.43 points more.
Adverse events were more common in the active groups and included depression, effects on sleep and dreams, and anxiety.
“The differences in cognitive performance between the groups are of uncertain clinical significance; however, given similar findings favoring placebo over BACE-1 inhibitors in other trial, we are communicating this potential signal of worsening cognitive function in the treated groups,” Dr. Henley said.
SOURCE: Egan MF et al. N Engl J Med. 2019 Apr 11;380:1408-20.
“Some trials fail because the experimental treatment proves to be no different than a control or standard intervention,” David Knopman, MD, wrote in an accompanying editorial (N Engl J Med. 2019 Apr 11;380:1476-8). “Others fail because of unacceptable side effects. In this issue of the Journal, an article by Egan et al. and a letter to the editor by Henley et al. (N Engl J Med. 2019 Apr 11;380:1483-5) describe a third reason for failure – a treatment worsens the target symptoms.
Certainly, beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibition makes sense when viewed in the light of the current understanding of Alzheimer’s disease neuropathology. The amyloid cascade hypothesis holds that toxic amyloid-beta fragments accumulate in the brain, form dense neuritic plaques, and lead to neuronal death and cognitive decline.
“The model is rooted in the inseparability of Alzheimer’s disease from abundant amyloid-beta pathologic features,” Dr. Knopman wrote. But, “Over the past 2 decades, the amyloid-beta–lowering strategy has been put to the test in trials of antiamyloid antibodies, none of which have been successful.”
Therefore, hitting amyloid at the source – the transmembrane cleavage domain – seemed important and, potentially, effective. But three BACE inhibitors (verubecestat, atabecestat, and lanabecestat) have shown similarly negative cognitive effects. “Together, these results suggest that preserved BACE-1 activity may be critical to normal synaptic functions. These observations place a limitation on how amyloid-beta lowering can be accomplished.”
It is possible that decreasing the level of BACE inhibition might ameliorate off-target effects and neuronal compromise but still be enough to reduce the generation of toxic amyloid-beta fragments, Dr. Knopman said. But, “Adjustments in the dose to a narrow window of BACE-1 inhibition would be difficult to accomplish in a clinical trial until there are peripheral biomarkers that reflect the activity of the agent in the brain.”
Thus far, most of the studied antiamyloid drugs have indeed reduced amyloid-beta levels, but none of those reductions affected cognition. A rethinking of amyloid-beta’s place in dementia progression may be in order.
“The dissociation between amyloid-beta lowering and cognitive benefits with both BACE-1 inhibition and antiamyloid antibody therapy is troubling. To be blunt, amyloid-beta lowering seems to be an ineffective approach, and it is time to focus on other targets to move therapeutics for Alzheimer’s disease forward.”
Dr. Knopman is a clinical neurologist and Alzheimer’s researcher at the Mayo Clinic, Rochester, Minn.
“Some trials fail because the experimental treatment proves to be no different than a control or standard intervention,” David Knopman, MD, wrote in an accompanying editorial (N Engl J Med. 2019 Apr 11;380:1476-8). “Others fail because of unacceptable side effects. In this issue of the Journal, an article by Egan et al. and a letter to the editor by Henley et al. (N Engl J Med. 2019 Apr 11;380:1483-5) describe a third reason for failure – a treatment worsens the target symptoms.
Certainly, beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibition makes sense when viewed in the light of the current understanding of Alzheimer’s disease neuropathology. The amyloid cascade hypothesis holds that toxic amyloid-beta fragments accumulate in the brain, form dense neuritic plaques, and lead to neuronal death and cognitive decline.
“The model is rooted in the inseparability of Alzheimer’s disease from abundant amyloid-beta pathologic features,” Dr. Knopman wrote. But, “Over the past 2 decades, the amyloid-beta–lowering strategy has been put to the test in trials of antiamyloid antibodies, none of which have been successful.”
Therefore, hitting amyloid at the source – the transmembrane cleavage domain – seemed important and, potentially, effective. But three BACE inhibitors (verubecestat, atabecestat, and lanabecestat) have shown similarly negative cognitive effects. “Together, these results suggest that preserved BACE-1 activity may be critical to normal synaptic functions. These observations place a limitation on how amyloid-beta lowering can be accomplished.”
It is possible that decreasing the level of BACE inhibition might ameliorate off-target effects and neuronal compromise but still be enough to reduce the generation of toxic amyloid-beta fragments, Dr. Knopman said. But, “Adjustments in the dose to a narrow window of BACE-1 inhibition would be difficult to accomplish in a clinical trial until there are peripheral biomarkers that reflect the activity of the agent in the brain.”
Thus far, most of the studied antiamyloid drugs have indeed reduced amyloid-beta levels, but none of those reductions affected cognition. A rethinking of amyloid-beta’s place in dementia progression may be in order.
“The dissociation between amyloid-beta lowering and cognitive benefits with both BACE-1 inhibition and antiamyloid antibody therapy is troubling. To be blunt, amyloid-beta lowering seems to be an ineffective approach, and it is time to focus on other targets to move therapeutics for Alzheimer’s disease forward.”
Dr. Knopman is a clinical neurologist and Alzheimer’s researcher at the Mayo Clinic, Rochester, Minn.
“Some trials fail because the experimental treatment proves to be no different than a control or standard intervention,” David Knopman, MD, wrote in an accompanying editorial (N Engl J Med. 2019 Apr 11;380:1476-8). “Others fail because of unacceptable side effects. In this issue of the Journal, an article by Egan et al. and a letter to the editor by Henley et al. (N Engl J Med. 2019 Apr 11;380:1483-5) describe a third reason for failure – a treatment worsens the target symptoms.
Certainly, beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibition makes sense when viewed in the light of the current understanding of Alzheimer’s disease neuropathology. The amyloid cascade hypothesis holds that toxic amyloid-beta fragments accumulate in the brain, form dense neuritic plaques, and lead to neuronal death and cognitive decline.
“The model is rooted in the inseparability of Alzheimer’s disease from abundant amyloid-beta pathologic features,” Dr. Knopman wrote. But, “Over the past 2 decades, the amyloid-beta–lowering strategy has been put to the test in trials of antiamyloid antibodies, none of which have been successful.”
Therefore, hitting amyloid at the source – the transmembrane cleavage domain – seemed important and, potentially, effective. But three BACE inhibitors (verubecestat, atabecestat, and lanabecestat) have shown similarly negative cognitive effects. “Together, these results suggest that preserved BACE-1 activity may be critical to normal synaptic functions. These observations place a limitation on how amyloid-beta lowering can be accomplished.”
It is possible that decreasing the level of BACE inhibition might ameliorate off-target effects and neuronal compromise but still be enough to reduce the generation of toxic amyloid-beta fragments, Dr. Knopman said. But, “Adjustments in the dose to a narrow window of BACE-1 inhibition would be difficult to accomplish in a clinical trial until there are peripheral biomarkers that reflect the activity of the agent in the brain.”
Thus far, most of the studied antiamyloid drugs have indeed reduced amyloid-beta levels, but none of those reductions affected cognition. A rethinking of amyloid-beta’s place in dementia progression may be in order.
“The dissociation between amyloid-beta lowering and cognitive benefits with both BACE-1 inhibition and antiamyloid antibody therapy is troubling. To be blunt, amyloid-beta lowering seems to be an ineffective approach, and it is time to focus on other targets to move therapeutics for Alzheimer’s disease forward.”
Dr. Knopman is a clinical neurologist and Alzheimer’s researcher at the Mayo Clinic, Rochester, Minn.
More bad news for Alzheimer’s research. Two more BACE inhibitors fall far short of the finish line.
Declining cognitive scores, falls, suicidal ideation, and liver enzyme abnormalities were all seen in clinical trials.
The news doesn’t bode well for the therapeutic target of BACE (beta-site APP cleaving enzyme) inhibition. BACE is one of the enzymes that trims the amyloid precursor protein (APP). Inhibiting it does reduce the amount of toxic amyloid-beta in cerebrospinal fluid, and amyloid plaque in the brain. But none of these molecules has shown clinical benefit in dementia patients, whether their disease is mild, or moderate or – now – prodromal. And it is now apparent that inhibiting BACE also produces serious off-target problems.
“BACE-1 inhibition certainly seemed to have a sound rationale assuming the basis for amyloid’s role in Alzheimer’s disease pathogenesis is a gain of toxicity,” Richard J. Caselli, MD, of the Mayo Clinic, Rochester, Minn., said in an interview. “That APP is important for Alzheimer’s pathogenesis still seems clear but whether amyloid-beta toxicity is the driving force is no longer clear. Further, interruption of the APP system disrupts more than amyloid-beta peptide, possibly explaining the adverse cognitive effects of BACE-1 inhibition shown exhibited now by three different BACE-1 inhibitors.”
Verubecestat
Researchers got their first dose of bad news regarding verubecestat at the 2017 Clinical Trials in Alzheimer’s Disease meeting. There, Michael F. Egan, MD, Merck’s associate vice president of clinical neuroscience, discussed the molecule’s failure to slow cognitive decline in patients with mild to moderate Alzheimer’s disease. There was plenty of biomarker evidence that the drug did block amyloid-beta production, but there also was a plethora of concerning adverse events, Dr. Egan said in an interview.
However, verubecestat still was being pursued in patients with prodromal Alzheimer’s disease. In February, Merck stopped the trial after a futility analysis and announced that the company was terminating studies of verubecestat in that population as well. In the April 11 issue of the New England Journal of Medicine, Dr. Egan and his colleagues report the full extent of verubecestat’s failure in prodromal patients, and the accompanying adverse events.
At the time of termination, 1,454 patients had been enrolled. Of these, 485 received 12 mg/day, 484 received 40 mg/day, and 485 received placebo. About half of each group completed 104 weeks of treatment in the study, which was designed to extend up to 5 years.
The primary outcome was change in the Clinical Dementia Rating Scale–Sum of Boxes score (CDR-SB). Seven secondary outcomes examined other cognitive and functional end points, along with changes in hippocampal volume on MRI and amyloid burden as determined in PET imaging.
Not only did verubecestat fail to slow cognitive decline, it appeared to exacerbate it. The mean change on the CDR-SB was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group, favoring placebo.
“In an exploratory analysis according to time point, scores on the CDR-SB were also higher [signifying more impairment of cognition and daily functioning] in the 40-mg group than in the placebo group at 13, 26, and 52 weeks ... suggesting but not confirming the possibility of worse performance at these earlier time points in the high-dose verubecestat group,” the investigators said.
Verubecestat also was associated with more conversions to Alzheimer’s disease. Per 100 patient-years, the Alzheimer’s disease event rates were 24.5 in the 12-mg group, 25.5 in the 40-mg group, and 19.3 in the placebo group. Compared with placebo, those taking 12-mg doses were 30% more likely to develop Alzheimer’s disease and those taking 40-mg doses were 38% more likely. The findings suggest that “verubecestat may have accelerated the progression to diagnosis of dementia due to Alzheimer’s disease,” the investigators said.
The negative impact of verubecestat was apparent quite early in the study. “In exploratory analyses, both dose levels of verubecestat were associated with poorer outcomes on the [Composite Cognition Score-3 Domain] and the ADAS-Cog [Alzheimer’s Disease Assessment Scale–Cognitive Subscale] measures of cognition that, relative to placebo, appeared worse at week 13 and did not appear to progress thereafter.”
Results of the secondary end points, including the ADAS-Cog and the Mini-Mental State Exam, also indicated that verubecestat may have worsened cognitive performance.
Imaging outcomes were positive, however. Hippocampal volume was 6,448 mL in the 12-mg group, 6,469 mL in the 40-mg group, and 6,435 mL in the placebo group. Brain amyloid increased in the placebo group, as expected, and decreased in the active groups. The small group of patients who underwent cerebrospinal fluid sampling showed reductions of more than 60% in amyloid-beta and soluble APP-beta associated with verubecestat. These results show that the molecule was indeed hitting its intended target, but that doing so was not clinically beneficial.
Adverse events were more common in the verubecestat groups. These included rash, dermatitis, urticaria, sleep disturbance, weight loss, and cough. Hair coloring changed in 2.5% of patients in the 12-mg group and 5% of the 40-mg group, but in none of the subjects taking placebo.
Patients taking verubecestat were more likely to sustain falls and injuries and to express suicidal ideation.
The results of this trial differ from the study of verubecestat in mild to moderate Alzheimer’s disease, the investigators noted. Those patients did not decline cognitively as did those with prodromal disease.
“Patients at an earlier stage of the disease may be more sensitive to the effects of substantial BACE-1 inhibition, perhaps because of a role of BACE-1 in normal synaptic function. It is also possible that the effects of verubecestat are due to inhibition of BACE-2,” they said.
Atabecestat
In a research letter in the same issue of the New England Journal of Medicine (2019 Apr 11;380:1483-5), David Henley, MD, senior director of Janssen’s Alzheimer’s clinical development core, released similarly negative results from an interim analysis of EARLY (Efficacy and Safety Study of Atabecestat in Participants Who Are Asymptomatic at Risk for Developing Alzheimer’s Dementia) trial, a randomized study of the BACE-1 inhibitor candidate, atabecestat.
The phase 2 trial enrolled 557 patients with prodromal Alzheimer’s disease. The primary cognitive end point was change from baseline in the Preclinical Alzheimer’s Cognitive Composite (PACC) score.
This trial was discontinued in May 2018 because of liver-related adverse events, although safety follow-up continues. The research letter did not disclose details of the hepatic events, but a company press release from May 2018 referred to them in a general sense.
“Elevations of liver enzymes, which were serious in nature, have been observed in some study participants who received the Janssen BACE inhibitor, atabecestat. After a thorough evaluation of all available liver safety data from our studies, Janssen has concluded that the benefit-risk ratio is no longer favorable to continue development of atabecestat for people who have late-onset preclinical stage Alzheimer’s disease.”
Patients in EARLY were randomized to 5 mg, 25 mg, or placebo. As in the verubecestat trial, those randomized to placebo did better. The mean changes from baseline in the PACC score were −1.44 in the 25-mg group, −0.58 in the 5-mg group, and −0.32 in the placebo group.
“At month 6, the difference between the 25-mg group and the placebo group was −1.12 and the difference between the 5-mg group and the placebo group was −0.26, favoring placebo over the higher dose,” the authors said.
This theme reemerged in a secondary end point, the Repeatable Battery for the Assessment of Neuropsychological Status. The 25-mg group declined 3.58 points more than placebo, and the 5-mg group, 1.43 points more.
Adverse events were more common in the active groups and included depression, effects on sleep and dreams, and anxiety.
“The differences in cognitive performance between the groups are of uncertain clinical significance; however, given similar findings favoring placebo over BACE-1 inhibitors in other trial, we are communicating this potential signal of worsening cognitive function in the treated groups,” Dr. Henley said.
SOURCE: Egan MF et al. N Engl J Med. 2019 Apr 11;380:1408-20.
More bad news for Alzheimer’s research. Two more BACE inhibitors fall far short of the finish line.
Declining cognitive scores, falls, suicidal ideation, and liver enzyme abnormalities were all seen in clinical trials.
The news doesn’t bode well for the therapeutic target of BACE (beta-site APP cleaving enzyme) inhibition. BACE is one of the enzymes that trims the amyloid precursor protein (APP). Inhibiting it does reduce the amount of toxic amyloid-beta in cerebrospinal fluid, and amyloid plaque in the brain. But none of these molecules has shown clinical benefit in dementia patients, whether their disease is mild, or moderate or – now – prodromal. And it is now apparent that inhibiting BACE also produces serious off-target problems.
“BACE-1 inhibition certainly seemed to have a sound rationale assuming the basis for amyloid’s role in Alzheimer’s disease pathogenesis is a gain of toxicity,” Richard J. Caselli, MD, of the Mayo Clinic, Rochester, Minn., said in an interview. “That APP is important for Alzheimer’s pathogenesis still seems clear but whether amyloid-beta toxicity is the driving force is no longer clear. Further, interruption of the APP system disrupts more than amyloid-beta peptide, possibly explaining the adverse cognitive effects of BACE-1 inhibition shown exhibited now by three different BACE-1 inhibitors.”
Verubecestat
Researchers got their first dose of bad news regarding verubecestat at the 2017 Clinical Trials in Alzheimer’s Disease meeting. There, Michael F. Egan, MD, Merck’s associate vice president of clinical neuroscience, discussed the molecule’s failure to slow cognitive decline in patients with mild to moderate Alzheimer’s disease. There was plenty of biomarker evidence that the drug did block amyloid-beta production, but there also was a plethora of concerning adverse events, Dr. Egan said in an interview.
However, verubecestat still was being pursued in patients with prodromal Alzheimer’s disease. In February, Merck stopped the trial after a futility analysis and announced that the company was terminating studies of verubecestat in that population as well. In the April 11 issue of the New England Journal of Medicine, Dr. Egan and his colleagues report the full extent of verubecestat’s failure in prodromal patients, and the accompanying adverse events.
At the time of termination, 1,454 patients had been enrolled. Of these, 485 received 12 mg/day, 484 received 40 mg/day, and 485 received placebo. About half of each group completed 104 weeks of treatment in the study, which was designed to extend up to 5 years.
The primary outcome was change in the Clinical Dementia Rating Scale–Sum of Boxes score (CDR-SB). Seven secondary outcomes examined other cognitive and functional end points, along with changes in hippocampal volume on MRI and amyloid burden as determined in PET imaging.
Not only did verubecestat fail to slow cognitive decline, it appeared to exacerbate it. The mean change on the CDR-SB was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group, favoring placebo.
“In an exploratory analysis according to time point, scores on the CDR-SB were also higher [signifying more impairment of cognition and daily functioning] in the 40-mg group than in the placebo group at 13, 26, and 52 weeks ... suggesting but not confirming the possibility of worse performance at these earlier time points in the high-dose verubecestat group,” the investigators said.
Verubecestat also was associated with more conversions to Alzheimer’s disease. Per 100 patient-years, the Alzheimer’s disease event rates were 24.5 in the 12-mg group, 25.5 in the 40-mg group, and 19.3 in the placebo group. Compared with placebo, those taking 12-mg doses were 30% more likely to develop Alzheimer’s disease and those taking 40-mg doses were 38% more likely. The findings suggest that “verubecestat may have accelerated the progression to diagnosis of dementia due to Alzheimer’s disease,” the investigators said.
The negative impact of verubecestat was apparent quite early in the study. “In exploratory analyses, both dose levels of verubecestat were associated with poorer outcomes on the [Composite Cognition Score-3 Domain] and the ADAS-Cog [Alzheimer’s Disease Assessment Scale–Cognitive Subscale] measures of cognition that, relative to placebo, appeared worse at week 13 and did not appear to progress thereafter.”
Results of the secondary end points, including the ADAS-Cog and the Mini-Mental State Exam, also indicated that verubecestat may have worsened cognitive performance.
Imaging outcomes were positive, however. Hippocampal volume was 6,448 mL in the 12-mg group, 6,469 mL in the 40-mg group, and 6,435 mL in the placebo group. Brain amyloid increased in the placebo group, as expected, and decreased in the active groups. The small group of patients who underwent cerebrospinal fluid sampling showed reductions of more than 60% in amyloid-beta and soluble APP-beta associated with verubecestat. These results show that the molecule was indeed hitting its intended target, but that doing so was not clinically beneficial.
Adverse events were more common in the verubecestat groups. These included rash, dermatitis, urticaria, sleep disturbance, weight loss, and cough. Hair coloring changed in 2.5% of patients in the 12-mg group and 5% of the 40-mg group, but in none of the subjects taking placebo.
Patients taking verubecestat were more likely to sustain falls and injuries and to express suicidal ideation.
The results of this trial differ from the study of verubecestat in mild to moderate Alzheimer’s disease, the investigators noted. Those patients did not decline cognitively as did those with prodromal disease.
“Patients at an earlier stage of the disease may be more sensitive to the effects of substantial BACE-1 inhibition, perhaps because of a role of BACE-1 in normal synaptic function. It is also possible that the effects of verubecestat are due to inhibition of BACE-2,” they said.
Atabecestat
In a research letter in the same issue of the New England Journal of Medicine (2019 Apr 11;380:1483-5), David Henley, MD, senior director of Janssen’s Alzheimer’s clinical development core, released similarly negative results from an interim analysis of EARLY (Efficacy and Safety Study of Atabecestat in Participants Who Are Asymptomatic at Risk for Developing Alzheimer’s Dementia) trial, a randomized study of the BACE-1 inhibitor candidate, atabecestat.
The phase 2 trial enrolled 557 patients with prodromal Alzheimer’s disease. The primary cognitive end point was change from baseline in the Preclinical Alzheimer’s Cognitive Composite (PACC) score.
This trial was discontinued in May 2018 because of liver-related adverse events, although safety follow-up continues. The research letter did not disclose details of the hepatic events, but a company press release from May 2018 referred to them in a general sense.
“Elevations of liver enzymes, which were serious in nature, have been observed in some study participants who received the Janssen BACE inhibitor, atabecestat. After a thorough evaluation of all available liver safety data from our studies, Janssen has concluded that the benefit-risk ratio is no longer favorable to continue development of atabecestat for people who have late-onset preclinical stage Alzheimer’s disease.”
Patients in EARLY were randomized to 5 mg, 25 mg, or placebo. As in the verubecestat trial, those randomized to placebo did better. The mean changes from baseline in the PACC score were −1.44 in the 25-mg group, −0.58 in the 5-mg group, and −0.32 in the placebo group.
“At month 6, the difference between the 25-mg group and the placebo group was −1.12 and the difference between the 5-mg group and the placebo group was −0.26, favoring placebo over the higher dose,” the authors said.
This theme reemerged in a secondary end point, the Repeatable Battery for the Assessment of Neuropsychological Status. The 25-mg group declined 3.58 points more than placebo, and the 5-mg group, 1.43 points more.
Adverse events were more common in the active groups and included depression, effects on sleep and dreams, and anxiety.
“The differences in cognitive performance between the groups are of uncertain clinical significance; however, given similar findings favoring placebo over BACE-1 inhibitors in other trial, we are communicating this potential signal of worsening cognitive function in the treated groups,” Dr. Henley said.
SOURCE: Egan MF et al. N Engl J Med. 2019 Apr 11;380:1408-20.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Amyloid brain imaging changed clinical management in 60% of MCI and dementia patients
.
Diagnoses changed from Alzheimer’s disease to non–Alzheimer’s disease in 25% of 11,409 patients and from non–Alzheimer’s disease to Alzheimer’s disease in 10.5%, reported Gil Rabinovici, MD, and his colleagues. The use of Alzheimer’s disease drugs doubled in amyloid-positive MCI patients, and increased by a third in amyloid-positive dementia patients. Physicians involved in the study said the scans provided key clinical information in 82% of cases with post-scan management changes.
Scans also benefited amyloid-negative patients. Before the scan, 71% of these carried an Alzheimer’s disease diagnosis; afterward, just 10% did, opening the way for an accurate diagnosis and more effective treatment.
The study was powered to detect a 30% or greater change in the MCI and dementia groups. The 60% change emphasize how useful amyloid PET scans could be in clinical practice, Dr. Rabinovici, the study’s lead author and principal investigator, said in a press statement.
“We are impressed by the magnitude of these results, which make it clear that amyloid PET imaging can have a major impact on how we diagnose and care for patients with Alzheimer’s disease and other forms of cognitive decline,” said Dr. Rabinovici of the University of California, San Francisco.
Alzheimer’s Association leaders were similarly pleased.
“These results present highly credible, large-scale evidence that amyloid PET imaging can be a powerful tool to improve the accuracy of Alzheimer’s diagnosis and lead to better medical management, especially in difficult-to-diagnose cases,” said Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association and a coauthor of the study. “It is important that amyloid PET imaging be more broadly accessible to those who need it.”
Next steps
Ultimately, investigators hope the nationwide-wide, open-label study will prove the clinical value of amyloid PET scanning and convince the Centers for Medicare & Medicaid Services to make the test a fully covered service for those who meet the appropriate use criteria set forth by the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging.
IDEAS’ second goal – showing that the scans improve health outcomes – is scheduled for 2020. These data are a key component of the CMS decision, but they might be a tough sell, Clifford R. Jack Jr., MD, and Ronald C. Petersen, MD, PhD, wrote in an accompanying editorial. Dr. Jack and Dr. Petersen are affiliated with the Mayo Clinic in Rochester, Minn.
“For CMS to cover the cost of amyloid PET, it must be demonstrated that the result of a scan has an effect on patient outcomes, not just patient care processes – and, without a disease-modifying therapy available, that might be a challenge,” they wrote.
IDEAS is a funding collaboration of the CMS, the Alzheimer’s Association, Avid Radiopharmaceuticals/Eli Lilly, General Electric Healthcare, Piramal Imaging, and the American College of Radiology. Dr. Rabinovici had no financial disclosures.
SOURCE: Rabinovici GD et al. JAMA. 2019 Apr 2. doi: 10.1001/jama.2019.2000.
Current clinical practice does not routinely include biomarkers, and if given a choice, most patients would prefer brain imaging to spinal fluid-based testing, so IDEAS may be making imaging-based biomarker characterization a real possibility in the future. 
Richard J. Caselli, MD, is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center. He made these comments in an interview.
Current clinical practice does not routinely include biomarkers, and if given a choice, most patients would prefer brain imaging to spinal fluid-based testing, so IDEAS may be making imaging-based biomarker characterization a real possibility in the future.
Richard J. Caselli, MD, is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center. He made these comments in an interview.
Current clinical practice does not routinely include biomarkers, and if given a choice, most patients would prefer brain imaging to spinal fluid-based testing, so IDEAS may be making imaging-based biomarker characterization a real possibility in the future.
Richard J. Caselli, MD, is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center. He made these comments in an interview.
.
Diagnoses changed from Alzheimer’s disease to non–Alzheimer’s disease in 25% of 11,409 patients and from non–Alzheimer’s disease to Alzheimer’s disease in 10.5%, reported Gil Rabinovici, MD, and his colleagues. The use of Alzheimer’s disease drugs doubled in amyloid-positive MCI patients, and increased by a third in amyloid-positive dementia patients. Physicians involved in the study said the scans provided key clinical information in 82% of cases with post-scan management changes.
Scans also benefited amyloid-negative patients. Before the scan, 71% of these carried an Alzheimer’s disease diagnosis; afterward, just 10% did, opening the way for an accurate diagnosis and more effective treatment.
The study was powered to detect a 30% or greater change in the MCI and dementia groups. The 60% change emphasize how useful amyloid PET scans could be in clinical practice, Dr. Rabinovici, the study’s lead author and principal investigator, said in a press statement.
“We are impressed by the magnitude of these results, which make it clear that amyloid PET imaging can have a major impact on how we diagnose and care for patients with Alzheimer’s disease and other forms of cognitive decline,” said Dr. Rabinovici of the University of California, San Francisco.
Alzheimer’s Association leaders were similarly pleased.
“These results present highly credible, large-scale evidence that amyloid PET imaging can be a powerful tool to improve the accuracy of Alzheimer’s diagnosis and lead to better medical management, especially in difficult-to-diagnose cases,” said Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association and a coauthor of the study. “It is important that amyloid PET imaging be more broadly accessible to those who need it.”
Next steps
Ultimately, investigators hope the nationwide-wide, open-label study will prove the clinical value of amyloid PET scanning and convince the Centers for Medicare & Medicaid Services to make the test a fully covered service for those who meet the appropriate use criteria set forth by the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging.
IDEAS’ second goal – showing that the scans improve health outcomes – is scheduled for 2020. These data are a key component of the CMS decision, but they might be a tough sell, Clifford R. Jack Jr., MD, and Ronald C. Petersen, MD, PhD, wrote in an accompanying editorial. Dr. Jack and Dr. Petersen are affiliated with the Mayo Clinic in Rochester, Minn.
“For CMS to cover the cost of amyloid PET, it must be demonstrated that the result of a scan has an effect on patient outcomes, not just patient care processes – and, without a disease-modifying therapy available, that might be a challenge,” they wrote.
IDEAS is a funding collaboration of the CMS, the Alzheimer’s Association, Avid Radiopharmaceuticals/Eli Lilly, General Electric Healthcare, Piramal Imaging, and the American College of Radiology. Dr. Rabinovici had no financial disclosures.
SOURCE: Rabinovici GD et al. JAMA. 2019 Apr 2. doi: 10.1001/jama.2019.2000.
.
Diagnoses changed from Alzheimer’s disease to non–Alzheimer’s disease in 25% of 11,409 patients and from non–Alzheimer’s disease to Alzheimer’s disease in 10.5%, reported Gil Rabinovici, MD, and his colleagues. The use of Alzheimer’s disease drugs doubled in amyloid-positive MCI patients, and increased by a third in amyloid-positive dementia patients. Physicians involved in the study said the scans provided key clinical information in 82% of cases with post-scan management changes.
Scans also benefited amyloid-negative patients. Before the scan, 71% of these carried an Alzheimer’s disease diagnosis; afterward, just 10% did, opening the way for an accurate diagnosis and more effective treatment.
The study was powered to detect a 30% or greater change in the MCI and dementia groups. The 60% change emphasize how useful amyloid PET scans could be in clinical practice, Dr. Rabinovici, the study’s lead author and principal investigator, said in a press statement.
“We are impressed by the magnitude of these results, which make it clear that amyloid PET imaging can have a major impact on how we diagnose and care for patients with Alzheimer’s disease and other forms of cognitive decline,” said Dr. Rabinovici of the University of California, San Francisco.
Alzheimer’s Association leaders were similarly pleased.
“These results present highly credible, large-scale evidence that amyloid PET imaging can be a powerful tool to improve the accuracy of Alzheimer’s diagnosis and lead to better medical management, especially in difficult-to-diagnose cases,” said Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association and a coauthor of the study. “It is important that amyloid PET imaging be more broadly accessible to those who need it.”
Next steps
Ultimately, investigators hope the nationwide-wide, open-label study will prove the clinical value of amyloid PET scanning and convince the Centers for Medicare & Medicaid Services to make the test a fully covered service for those who meet the appropriate use criteria set forth by the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging.
IDEAS’ second goal – showing that the scans improve health outcomes – is scheduled for 2020. These data are a key component of the CMS decision, but they might be a tough sell, Clifford R. Jack Jr., MD, and Ronald C. Petersen, MD, PhD, wrote in an accompanying editorial. Dr. Jack and Dr. Petersen are affiliated with the Mayo Clinic in Rochester, Minn.
“For CMS to cover the cost of amyloid PET, it must be demonstrated that the result of a scan has an effect on patient outcomes, not just patient care processes – and, without a disease-modifying therapy available, that might be a challenge,” they wrote.
IDEAS is a funding collaboration of the CMS, the Alzheimer’s Association, Avid Radiopharmaceuticals/Eli Lilly, General Electric Healthcare, Piramal Imaging, and the American College of Radiology. Dr. Rabinovici had no financial disclosures.
SOURCE: Rabinovici GD et al. JAMA. 2019 Apr 2. doi: 10.1001/jama.2019.2000.
FROM THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
BP control slowed brain damage in elderly hypertensives
NEW ORLEANS – Hypertensive elderly patients treated to maintain an ambulatory systolic blood pressure of 130 mm Hg had significantly slower progression of white matter lesions in their brains than did control hypertensive patients maintained at an ambulatory systolic pressure of about 145 mm Hg during 3 years of follow-up in a randomized, single-center study with 199 patients.
The results also showed similar rates of death, syncope episodes, and falls in the intensively and less rigorously treated subgroups, and the patients treated to a systolic of 130 mm Hg also had significantly fewer nonfatal cardiovascular disease events, further documenting the safety and efficacy in elderly patients of a more aggressive blood pressure goal like the one promoted in current guidelines from the American College of Cardiology and American Heart Association, William B. White, MD, said at the annual meeting of the American College of Cardiology.
The study’s findings also showed that in one measure of cognitive function, the serial reaction time task, the patients treated to a systolic pressure of 130 mm Hg had an average 23 millisecond improvement in their reaction time from baseline to their 3-year follow-up, while patients in the control group treated to a systolic pressure of 145 mm Hg had a 33 millisecond increase in their average reaction time during follow-up. This 56 millisecond between-group difference from baseline in average change in reaction time over 3 years was both statistically significant and represents a clinically meaningful difference for a measure of both processing speed and executive function, said Dr. White, professor of medicine at the University of Connecticut in Farmington. However, the participants also underwent assessment by five other clinical measures of cognitive function and in none of the other five tests did more intensive blood pressure control link with an improvement, compared with the results in control patients.
The study had two primary endpoints. One was progression of white matter hyperintensity on brain MR images, which is a measure of neuron necrosis in the brain, and this analysis showed that the growth of white matter occurred at a 40% reduced rate among 99 patients treated to an average ambulatory systolic blood pressure of 130 mm Hg, compared with the average progression among 100 controls treated to an average ambulatory systolic of 145 mm Hg. The second measure was improvement during 3 years, compared with controls, in any of six different measures of mobility, including gait speed. The results showed no significant differences between the treatment arms in any of these measures. The average progression of white matter disease among control patients after 3 years was of a magnitude that would trigger concern in a neurologist who saw these scans, said Dr. White. The researchers could already begin to see a between-group difference in the accumulation of white matter hyperintensity on the MR scans of patients at 18 months in the study, he added.
During his presentation, Dr. White suggested that the absence of discerned improvements in mobility from more aggressive blood pressure control despite the observed slowed progression of white matter disease may have resulted from the study’s relatively brief follow-up.
The INFINITY (Intensive versus Standard Ambulatory Blood Pressure Lowering to Prevent Functional Decline in the Elderly) study enrolled hypertensive patients at least 75 years old who already showed visible evidence of white matter hypertrophy on their brain MR scan at baseline but also had normal mobility and mental function (their baseline score on the mini mental state examination had to be within the normal range, with an average score of 28 among enrolled patients), and they had no history of any chronic neurological condition (Am Heart J. 2013 Mar;165[3]:258-65). The median age of enrolled patients was 80 years. They had an average of 15 years of education, indicating a study cohort with a high level of education and function, Dr. White noted. The inclusion and exclusion criteria led to a study population that was substantially older but without as much comorbidity as patients enrolled in the SPRINT MIND study (JAMA. 2019 Jan 28;321[6]:553-61), he said. The study exclusively used 24-hour ambulatory monitoring for baseline and follow-up blood pressure measurements.
The participating clinicians successfully maintained patients in each of the treatment groups at close to their goal systolic blood pressures. At 18 months, the actual average systolic pressures among patients in the two study groups were 132 mm Hg and 146 mm Hg, and at 36 months their pressures averaged 131 mm Hg and 146 mm Hg for 163 patients who remained in the study out to 36-months. Maintenance of the lower pressure generally required treatment with one additional antihypertensive medication, compared with the control patients’ treatment, Dr. White said.
The rates of total falls and falls causing injury were virtually identical in the two treatment groups. The incidence of nonfatal cardiovascular disease events over 3 years, including MI, strokes, and cardiovascular disease hospitalizations, was 4 cases in the intensively-treated patients and 17 among those treated to a higher systolic pressure, a statistically significant and unexpected difference, Dr. White reported.
This is another dataset showing that blood pressure reduction in elderly people with hypertension is safe and extremely important. Clinicians today often exclude elderly patients from aggressive blood pressure control because of an unrealized fear of causing hypotension and falls. These new data add to what’s already been reported in support of the American College of Cardiology and American Heart Association blood pressure treatment target of less than 130/80 mm Hg for noninstitutionalized, ambulatory, community-dwelling adults who are aged at least 65 years (Hypertension. 2018 June;71[6]:e13-e115). Many clinicians continue to have concerns about what this guideline says about treating older patients. These new findings support the idea that blood pressure can safely be treated to the level the guideline recommends while producing signals of beneficial changes in brain health and in cognitive function.
Providers worry a lot about the potential for harm from treatment. These findings add to the data that say clinicians can safely follow the blood pressure management guideline to benefit even very old patients.
Eileen Handberg, PhD , is a research professor of medicine and director of the Cardiovascular Clinical Trials Program at the University of Florida in Gainesville. She had no relevant disclosures. She made these comments in an interview.
This is another dataset showing that blood pressure reduction in elderly people with hypertension is safe and extremely important. Clinicians today often exclude elderly patients from aggressive blood pressure control because of an unrealized fear of causing hypotension and falls. These new data add to what’s already been reported in support of the American College of Cardiology and American Heart Association blood pressure treatment target of less than 130/80 mm Hg for noninstitutionalized, ambulatory, community-dwelling adults who are aged at least 65 years (Hypertension. 2018 June;71[6]:e13-e115). Many clinicians continue to have concerns about what this guideline says about treating older patients. These new findings support the idea that blood pressure can safely be treated to the level the guideline recommends while producing signals of beneficial changes in brain health and in cognitive function.
Providers worry a lot about the potential for harm from treatment. These findings add to the data that say clinicians can safely follow the blood pressure management guideline to benefit even very old patients.
Eileen Handberg, PhD , is a research professor of medicine and director of the Cardiovascular Clinical Trials Program at the University of Florida in Gainesville. She had no relevant disclosures. She made these comments in an interview.
This is another dataset showing that blood pressure reduction in elderly people with hypertension is safe and extremely important. Clinicians today often exclude elderly patients from aggressive blood pressure control because of an unrealized fear of causing hypotension and falls. These new data add to what’s already been reported in support of the American College of Cardiology and American Heart Association blood pressure treatment target of less than 130/80 mm Hg for noninstitutionalized, ambulatory, community-dwelling adults who are aged at least 65 years (Hypertension. 2018 June;71[6]:e13-e115). Many clinicians continue to have concerns about what this guideline says about treating older patients. These new findings support the idea that blood pressure can safely be treated to the level the guideline recommends while producing signals of beneficial changes in brain health and in cognitive function.
Providers worry a lot about the potential for harm from treatment. These findings add to the data that say clinicians can safely follow the blood pressure management guideline to benefit even very old patients.
Eileen Handberg, PhD , is a research professor of medicine and director of the Cardiovascular Clinical Trials Program at the University of Florida in Gainesville. She had no relevant disclosures. She made these comments in an interview.
NEW ORLEANS – Hypertensive elderly patients treated to maintain an ambulatory systolic blood pressure of 130 mm Hg had significantly slower progression of white matter lesions in their brains than did control hypertensive patients maintained at an ambulatory systolic pressure of about 145 mm Hg during 3 years of follow-up in a randomized, single-center study with 199 patients.
The results also showed similar rates of death, syncope episodes, and falls in the intensively and less rigorously treated subgroups, and the patients treated to a systolic of 130 mm Hg also had significantly fewer nonfatal cardiovascular disease events, further documenting the safety and efficacy in elderly patients of a more aggressive blood pressure goal like the one promoted in current guidelines from the American College of Cardiology and American Heart Association, William B. White, MD, said at the annual meeting of the American College of Cardiology.
The study’s findings also showed that in one measure of cognitive function, the serial reaction time task, the patients treated to a systolic pressure of 130 mm Hg had an average 23 millisecond improvement in their reaction time from baseline to their 3-year follow-up, while patients in the control group treated to a systolic pressure of 145 mm Hg had a 33 millisecond increase in their average reaction time during follow-up. This 56 millisecond between-group difference from baseline in average change in reaction time over 3 years was both statistically significant and represents a clinically meaningful difference for a measure of both processing speed and executive function, said Dr. White, professor of medicine at the University of Connecticut in Farmington. However, the participants also underwent assessment by five other clinical measures of cognitive function and in none of the other five tests did more intensive blood pressure control link with an improvement, compared with the results in control patients.
The study had two primary endpoints. One was progression of white matter hyperintensity on brain MR images, which is a measure of neuron necrosis in the brain, and this analysis showed that the growth of white matter occurred at a 40% reduced rate among 99 patients treated to an average ambulatory systolic blood pressure of 130 mm Hg, compared with the average progression among 100 controls treated to an average ambulatory systolic of 145 mm Hg. The second measure was improvement during 3 years, compared with controls, in any of six different measures of mobility, including gait speed. The results showed no significant differences between the treatment arms in any of these measures. The average progression of white matter disease among control patients after 3 years was of a magnitude that would trigger concern in a neurologist who saw these scans, said Dr. White. The researchers could already begin to see a between-group difference in the accumulation of white matter hyperintensity on the MR scans of patients at 18 months in the study, he added.
During his presentation, Dr. White suggested that the absence of discerned improvements in mobility from more aggressive blood pressure control despite the observed slowed progression of white matter disease may have resulted from the study’s relatively brief follow-up.
The INFINITY (Intensive versus Standard Ambulatory Blood Pressure Lowering to Prevent Functional Decline in the Elderly) study enrolled hypertensive patients at least 75 years old who already showed visible evidence of white matter hypertrophy on their brain MR scan at baseline but also had normal mobility and mental function (their baseline score on the mini mental state examination had to be within the normal range, with an average score of 28 among enrolled patients), and they had no history of any chronic neurological condition (Am Heart J. 2013 Mar;165[3]:258-65). The median age of enrolled patients was 80 years. They had an average of 15 years of education, indicating a study cohort with a high level of education and function, Dr. White noted. The inclusion and exclusion criteria led to a study population that was substantially older but without as much comorbidity as patients enrolled in the SPRINT MIND study (JAMA. 2019 Jan 28;321[6]:553-61), he said. The study exclusively used 24-hour ambulatory monitoring for baseline and follow-up blood pressure measurements.
The participating clinicians successfully maintained patients in each of the treatment groups at close to their goal systolic blood pressures. At 18 months, the actual average systolic pressures among patients in the two study groups were 132 mm Hg and 146 mm Hg, and at 36 months their pressures averaged 131 mm Hg and 146 mm Hg for 163 patients who remained in the study out to 36-months. Maintenance of the lower pressure generally required treatment with one additional antihypertensive medication, compared with the control patients’ treatment, Dr. White said.
The rates of total falls and falls causing injury were virtually identical in the two treatment groups. The incidence of nonfatal cardiovascular disease events over 3 years, including MI, strokes, and cardiovascular disease hospitalizations, was 4 cases in the intensively-treated patients and 17 among those treated to a higher systolic pressure, a statistically significant and unexpected difference, Dr. White reported.
NEW ORLEANS – Hypertensive elderly patients treated to maintain an ambulatory systolic blood pressure of 130 mm Hg had significantly slower progression of white matter lesions in their brains than did control hypertensive patients maintained at an ambulatory systolic pressure of about 145 mm Hg during 3 years of follow-up in a randomized, single-center study with 199 patients.
The results also showed similar rates of death, syncope episodes, and falls in the intensively and less rigorously treated subgroups, and the patients treated to a systolic of 130 mm Hg also had significantly fewer nonfatal cardiovascular disease events, further documenting the safety and efficacy in elderly patients of a more aggressive blood pressure goal like the one promoted in current guidelines from the American College of Cardiology and American Heart Association, William B. White, MD, said at the annual meeting of the American College of Cardiology.
The study’s findings also showed that in one measure of cognitive function, the serial reaction time task, the patients treated to a systolic pressure of 130 mm Hg had an average 23 millisecond improvement in their reaction time from baseline to their 3-year follow-up, while patients in the control group treated to a systolic pressure of 145 mm Hg had a 33 millisecond increase in their average reaction time during follow-up. This 56 millisecond between-group difference from baseline in average change in reaction time over 3 years was both statistically significant and represents a clinically meaningful difference for a measure of both processing speed and executive function, said Dr. White, professor of medicine at the University of Connecticut in Farmington. However, the participants also underwent assessment by five other clinical measures of cognitive function and in none of the other five tests did more intensive blood pressure control link with an improvement, compared with the results in control patients.
The study had two primary endpoints. One was progression of white matter hyperintensity on brain MR images, which is a measure of neuron necrosis in the brain, and this analysis showed that the growth of white matter occurred at a 40% reduced rate among 99 patients treated to an average ambulatory systolic blood pressure of 130 mm Hg, compared with the average progression among 100 controls treated to an average ambulatory systolic of 145 mm Hg. The second measure was improvement during 3 years, compared with controls, in any of six different measures of mobility, including gait speed. The results showed no significant differences between the treatment arms in any of these measures. The average progression of white matter disease among control patients after 3 years was of a magnitude that would trigger concern in a neurologist who saw these scans, said Dr. White. The researchers could already begin to see a between-group difference in the accumulation of white matter hyperintensity on the MR scans of patients at 18 months in the study, he added.
During his presentation, Dr. White suggested that the absence of discerned improvements in mobility from more aggressive blood pressure control despite the observed slowed progression of white matter disease may have resulted from the study’s relatively brief follow-up.
The INFINITY (Intensive versus Standard Ambulatory Blood Pressure Lowering to Prevent Functional Decline in the Elderly) study enrolled hypertensive patients at least 75 years old who already showed visible evidence of white matter hypertrophy on their brain MR scan at baseline but also had normal mobility and mental function (their baseline score on the mini mental state examination had to be within the normal range, with an average score of 28 among enrolled patients), and they had no history of any chronic neurological condition (Am Heart J. 2013 Mar;165[3]:258-65). The median age of enrolled patients was 80 years. They had an average of 15 years of education, indicating a study cohort with a high level of education and function, Dr. White noted. The inclusion and exclusion criteria led to a study population that was substantially older but without as much comorbidity as patients enrolled in the SPRINT MIND study (JAMA. 2019 Jan 28;321[6]:553-61), he said. The study exclusively used 24-hour ambulatory monitoring for baseline and follow-up blood pressure measurements.
The participating clinicians successfully maintained patients in each of the treatment groups at close to their goal systolic blood pressures. At 18 months, the actual average systolic pressures among patients in the two study groups were 132 mm Hg and 146 mm Hg, and at 36 months their pressures averaged 131 mm Hg and 146 mm Hg for 163 patients who remained in the study out to 36-months. Maintenance of the lower pressure generally required treatment with one additional antihypertensive medication, compared with the control patients’ treatment, Dr. White said.
The rates of total falls and falls causing injury were virtually identical in the two treatment groups. The incidence of nonfatal cardiovascular disease events over 3 years, including MI, strokes, and cardiovascular disease hospitalizations, was 4 cases in the intensively-treated patients and 17 among those treated to a higher systolic pressure, a statistically significant and unexpected difference, Dr. White reported.
REPORTING FROM ACC 19
Biogen, Eisai discontinue aducanumab Alzheimer’s trials
Biogen and Eisai have announced that they are discontinuing the ENGAGE and EMERGE trials, which were designed to test the efficacy and safety of aducanumab in patients with mild cognitive impairment caused by Alzheimer’s disease and mild Alzheimer’s disease dementia.
The phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials were canceled not because of safety concerns but because of a futility analysis conducted by an independent data monitoring committee that indicated the drug would not meet the trials’ primary endpoint, which was the slowing of cognitive and functional impairment as measured by changes in Clinical Dementia Rating–Sum of Boxes score, compared with placebo.
In addition to ENGAGE and EMERGE, the phase 2 EVOLVE safety study and the long-term extension of the phase 1b PRIME study have also been canceled. Data from the ENGAGE and EMERGE trials will be presented at future medical meetings.
Aducanumab is a human monoclonal antibody derived from B cells collected from healthy elderly subjects with no cognitive decline or those with unusually slow cognitive decline through Neurimmune’s technology platform called Reverse Translational Medicine. It was granted Fast Track designation by the Food and Drug Administration.
“This disappointing news confirms the complexity of treating Alzheimer’s disease and the need to further advance knowledge in neuroscience. We are incredibly grateful to all the Alzheimer’s disease patients, their families, and the investigators who participated in the trials and contributed greatly to this research,” Michel Vounatsos, CEO at Biogen, said in a press release.
Biogen and Eisai have announced that they are discontinuing the ENGAGE and EMERGE trials, which were designed to test the efficacy and safety of aducanumab in patients with mild cognitive impairment caused by Alzheimer’s disease and mild Alzheimer’s disease dementia.
The phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials were canceled not because of safety concerns but because of a futility analysis conducted by an independent data monitoring committee that indicated the drug would not meet the trials’ primary endpoint, which was the slowing of cognitive and functional impairment as measured by changes in Clinical Dementia Rating–Sum of Boxes score, compared with placebo.
In addition to ENGAGE and EMERGE, the phase 2 EVOLVE safety study and the long-term extension of the phase 1b PRIME study have also been canceled. Data from the ENGAGE and EMERGE trials will be presented at future medical meetings.
Aducanumab is a human monoclonal antibody derived from B cells collected from healthy elderly subjects with no cognitive decline or those with unusually slow cognitive decline through Neurimmune’s technology platform called Reverse Translational Medicine. It was granted Fast Track designation by the Food and Drug Administration.
“This disappointing news confirms the complexity of treating Alzheimer’s disease and the need to further advance knowledge in neuroscience. We are incredibly grateful to all the Alzheimer’s disease patients, their families, and the investigators who participated in the trials and contributed greatly to this research,” Michel Vounatsos, CEO at Biogen, said in a press release.
Biogen and Eisai have announced that they are discontinuing the ENGAGE and EMERGE trials, which were designed to test the efficacy and safety of aducanumab in patients with mild cognitive impairment caused by Alzheimer’s disease and mild Alzheimer’s disease dementia.
The phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials were canceled not because of safety concerns but because of a futility analysis conducted by an independent data monitoring committee that indicated the drug would not meet the trials’ primary endpoint, which was the slowing of cognitive and functional impairment as measured by changes in Clinical Dementia Rating–Sum of Boxes score, compared with placebo.
In addition to ENGAGE and EMERGE, the phase 2 EVOLVE safety study and the long-term extension of the phase 1b PRIME study have also been canceled. Data from the ENGAGE and EMERGE trials will be presented at future medical meetings.
Aducanumab is a human monoclonal antibody derived from B cells collected from healthy elderly subjects with no cognitive decline or those with unusually slow cognitive decline through Neurimmune’s technology platform called Reverse Translational Medicine. It was granted Fast Track designation by the Food and Drug Administration.
“This disappointing news confirms the complexity of treating Alzheimer’s disease and the need to further advance knowledge in neuroscience. We are incredibly grateful to all the Alzheimer’s disease patients, their families, and the investigators who participated in the trials and contributed greatly to this research,” Michel Vounatsos, CEO at Biogen, said in a press release.
Alzheimer’s update: George Grossberg
Dr. Grossberg is the Samuel W. Fordyce professor and director of geriatric psychiatry at Saint Louis University.
And later, Dr. RK talks MDQ.
You can find more from Dr. Grossberg, including videos and articles, by clicking here.
Amazon
Apple Podcasts
Google Podcasts
Spotify
Dr. Grossberg is the Samuel W. Fordyce professor and director of geriatric psychiatry at Saint Louis University.
And later, Dr. RK talks MDQ.
You can find more from Dr. Grossberg, including videos and articles, by clicking here.
Amazon
Apple Podcasts
Google Podcasts
Spotify
Dr. Grossberg is the Samuel W. Fordyce professor and director of geriatric psychiatry at Saint Louis University.
And later, Dr. RK talks MDQ.
You can find more from Dr. Grossberg, including videos and articles, by clicking here.
Amazon
Apple Podcasts
Google Podcasts
Spotify
