Parkinson's Disease

A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.

Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.

Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.

“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”

For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.

For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.

Dr. Cryan likened this process to an “artificial fecal transplant.”

“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”

While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.

“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.

He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.

“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”

In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.

“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”

According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.

Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.

“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”

In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.

In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.

“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”

To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.

“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.

Dr. Cryan concluded his presentation on an optimistic note.

“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”

Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.

A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.

Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.

Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.

“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”

For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.

For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.

Dr. Cryan likened this process to an “artificial fecal transplant.”

“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”

While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.

“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.

He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.

“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”

In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.

“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”

According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.

Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.

“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”

In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.

In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.

“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”

To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.

“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.

Dr. Cryan concluded his presentation on an optimistic note.

“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”

Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.

A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.

Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.

Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.

“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”

For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.

For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.

Dr. Cryan likened this process to an “artificial fecal transplant.”

“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”

While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.

“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.

He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.

“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”

In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.

“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”

According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.

Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.

“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”

In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.

In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.

“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”

To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.

“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.

Dr. Cryan concluded his presentation on an optimistic note.

“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”

Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.

Higher out-of-pocket costs for prescription drugs are associated with poorer adherence across common neurologic conditions, a new study has found, suggesting that physicians should take patient costs into consideration when choosing which drugs to prescribe.

For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.

The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.

Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.

Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.

Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.

“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.

Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.

The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.

SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.

Higher out-of-pocket costs for prescription drugs are associated with poorer adherence across common neurologic conditions, a new study has found, suggesting that physicians should take patient costs into consideration when choosing which drugs to prescribe.

For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.

The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.

Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.

Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.

Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.

“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.

Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.

The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.

SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.

Higher out-of-pocket costs for prescription drugs are associated with poorer adherence across common neurologic conditions, a new study has found, suggesting that physicians should take patient costs into consideration when choosing which drugs to prescribe.

For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.

The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.

Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.

Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.

Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.

“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.

Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.

The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.

SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.

After 12 months of receiving palliative care in an outpatient setting in addition to standard care, patients with Parkinson’s disease and related disorders (PDRD) had improved quality of life (QoL), compared with patients who received standard care alone, according to results from a randomized clinical trial in JAMA Neurology.

The benefits of palliative care even extended to patients’ caregivers, who also appeared to benefit from outpatient palliative care at the 12-month mark, according to lead author Benzi M. Kluger, MD, of the department of neurology, University of Colorado at Denver, Aurora, and colleagues.

Between November 2015 and September 2017, Dr. Kluger and colleagues included 210 patients into the trial from three participating academic tertiary care centers who had “moderate to high palliative care needs” as assessed by the Palliative Care Needs Assessment Tool, which the researchers said are “common reasons for referral” and “reflect a desire to meet patient-centered needs rather than disease-centered markers.” Patients were primarily non-Hispanic white men with a mean age of about 70 years. The researchers also included 175 caregivers in the trial, most of whom were women, spouses to the patients, and in their caregiver role for over 5.5 years.

Patients with PDRD were randomized to receive standard care – usual care through their primary care physician and a neurologist – or “integrated outpatient palliative care,” from a team consisting of a palliative neurologist, nurse, social worker, chaplain, and board-certified palliative medicine physician. The goal of palliative care was addressing “nonmotor symptoms, goals of care, anticipatory guidance, difficult emotions, and caregiver support,” which patients received every 3 months through an in-person outpatient visit or telemedicine.

Quality of life for patients was measured through the Quality of Life in Alzheimer’s Disease (QoL-AD) scale, and caregiver burden was assessed with the Zarit Burden Interview (ZBI-12). The researchers also measured symptom burden and other QoL measures using the Edmonton Symptom Assessment Scale–Revised for Parkinson’s Disease, Parkinson’s Disease Questionnaire, Hospital Anxiety and Depression Scale, Prolonged Grief Disorder questionnaire, and Functional Assessment of Chronic Illness Therapy–Spiritual Well-Being.

Overall, 87 of 105 (82.1%) of patients in the palliative care group went to all their outpatient palliative care visits, and 19 of 106 (17.9%) patients received palliative care through telemedicine. Patients in the palliative care group also attended more neurology visits (4.66 visits) than those in the standard care (3.16 visits) group.

Quality of life significantly improved for patients in the palliative care group, compared with patients receiving standard care only at 6 months (0.66 vs. –0.84; between-group difference, 1.87; 95% confidence interval, 0.47-3.27; P = .009) and at 12 months (0.68 vs. –0.42; between-group difference, 1.36; 95% CI, −0.01 to 2.73; P = .05). These results remained significant at 6 months and 12 months after researchers used multiple imputation to fill in missing data. While there was no significant difference in caregiver burden between groups at 6 months, there was a statistically significant difference at 12 months favoring the palliative care group (between-group difference, −2.60; 95% CI, −4.58 to −0.61; P = .01).

Patients receiving palliative care also had better nonmotor symptom burden, motor symptom severity, and were more likely to complete advance directives, compared with patients receiving standard care alone. “We hypothesize that motor improvements may have reflected an unanticipated benefit of our palliative care team’s general goal of encouraging activities that promoted joy, meaning, and connection,” Dr. Kluger and colleagues said. Researchers also noted that the intervention patients with greater need for palliative care tended to benefit more than patients with patients with lower palliative care needs.

“Because the palliative care intervention is time-intensive and resource-intensive, future studies should optimize triage tools and consider alternative models of care delivery, such as telemedicine or care navigators, to provide key aspects of the intervention at lower cost,” they said.

In a related editorial, Bastiaan R. Bloem, MD, PhD, from the Center of Expertise for Parkinson & Movement Disorders, at Radboud University Medical Center, in the Netherlands, and colleagues acknowledged that the study by Kluger et al. is “timely and practical” because it introduces a system for outpatient palliative care for patients with PDRD at a time when there is “growing awareness that palliative care may also benefit persons with neurodegenerative diseases like Parkinson’s disease.”

The study is also important because it highlights that patients at varying stages of disease, including mild disease, may benefit from an integrated outpatient palliative model, which is not usually considered when determining candidates for palliative care in other scenarios, such as in patients with cancer. Future studies are warranted to assess how palliative care models can be implemented in different disease states and health care settings, they said.

“These new studies should continue to highlight the fact that palliative care is not about terminal diseases and dying,” Dr. Bloem and colleagues concluded. “As Kluger and colleagues indicate in their important clinical trial, palliative care is about how to live well.”

Six authors reported receiving a grant from the Patient-Centered Outcomes Research Institute, which was the funding source for the study. Two authors reported receiving grants from the University Hospital Foundation during the study. One author reported receiving grants from Allergan and Merz Pharma and is a consultant for GE Pharmaceuticals and Sunovion Pharmaceuticals; another reported receiving grants from the Archstone Foundation, the California Health Care Foundation, the Cambia Health Foundation, the Gordon and Betty Moore Foundation, the National Institute of Nursing Research, the Stupski Foundation, and the UniHealth Foundation. Dr. Bloem and a colleague reported their institution received a center of excellence grant from the Parkinson’s Foundation.

SOURCE: Kluger B et al. JAMA Neurol. doi: 10.1001/jamaneurol.2019.4992.

After 12 months of receiving palliative care in an outpatient setting in addition to standard care, patients with Parkinson’s disease and related disorders (PDRD) had improved quality of life (QoL), compared with patients who received standard care alone, according to results from a randomized clinical trial in JAMA Neurology.

The benefits of palliative care even extended to patients’ caregivers, who also appeared to benefit from outpatient palliative care at the 12-month mark, according to lead author Benzi M. Kluger, MD, of the department of neurology, University of Colorado at Denver, Aurora, and colleagues.

Between November 2015 and September 2017, Dr. Kluger and colleagues included 210 patients into the trial from three participating academic tertiary care centers who had “moderate to high palliative care needs” as assessed by the Palliative Care Needs Assessment Tool, which the researchers said are “common reasons for referral” and “reflect a desire to meet patient-centered needs rather than disease-centered markers.” Patients were primarily non-Hispanic white men with a mean age of about 70 years. The researchers also included 175 caregivers in the trial, most of whom were women, spouses to the patients, and in their caregiver role for over 5.5 years.

Patients with PDRD were randomized to receive standard care – usual care through their primary care physician and a neurologist – or “integrated outpatient palliative care,” from a team consisting of a palliative neurologist, nurse, social worker, chaplain, and board-certified palliative medicine physician. The goal of palliative care was addressing “nonmotor symptoms, goals of care, anticipatory guidance, difficult emotions, and caregiver support,” which patients received every 3 months through an in-person outpatient visit or telemedicine.

Quality of life for patients was measured through the Quality of Life in Alzheimer’s Disease (QoL-AD) scale, and caregiver burden was assessed with the Zarit Burden Interview (ZBI-12). The researchers also measured symptom burden and other QoL measures using the Edmonton Symptom Assessment Scale–Revised for Parkinson’s Disease, Parkinson’s Disease Questionnaire, Hospital Anxiety and Depression Scale, Prolonged Grief Disorder questionnaire, and Functional Assessment of Chronic Illness Therapy–Spiritual Well-Being.

Overall, 87 of 105 (82.1%) of patients in the palliative care group went to all their outpatient palliative care visits, and 19 of 106 (17.9%) patients received palliative care through telemedicine. Patients in the palliative care group also attended more neurology visits (4.66 visits) than those in the standard care (3.16 visits) group.

Quality of life significantly improved for patients in the palliative care group, compared with patients receiving standard care only at 6 months (0.66 vs. –0.84; between-group difference, 1.87; 95% confidence interval, 0.47-3.27; P = .009) and at 12 months (0.68 vs. –0.42; between-group difference, 1.36; 95% CI, −0.01 to 2.73; P = .05). These results remained significant at 6 months and 12 months after researchers used multiple imputation to fill in missing data. While there was no significant difference in caregiver burden between groups at 6 months, there was a statistically significant difference at 12 months favoring the palliative care group (between-group difference, −2.60; 95% CI, −4.58 to −0.61; P = .01).

Patients receiving palliative care also had better nonmotor symptom burden, motor symptom severity, and were more likely to complete advance directives, compared with patients receiving standard care alone. “We hypothesize that motor improvements may have reflected an unanticipated benefit of our palliative care team’s general goal of encouraging activities that promoted joy, meaning, and connection,” Dr. Kluger and colleagues said. Researchers also noted that the intervention patients with greater need for palliative care tended to benefit more than patients with patients with lower palliative care needs.

“Because the palliative care intervention is time-intensive and resource-intensive, future studies should optimize triage tools and consider alternative models of care delivery, such as telemedicine or care navigators, to provide key aspects of the intervention at lower cost,” they said.

In a related editorial, Bastiaan R. Bloem, MD, PhD, from the Center of Expertise for Parkinson & Movement Disorders, at Radboud University Medical Center, in the Netherlands, and colleagues acknowledged that the study by Kluger et al. is “timely and practical” because it introduces a system for outpatient palliative care for patients with PDRD at a time when there is “growing awareness that palliative care may also benefit persons with neurodegenerative diseases like Parkinson’s disease.”

The study is also important because it highlights that patients at varying stages of disease, including mild disease, may benefit from an integrated outpatient palliative model, which is not usually considered when determining candidates for palliative care in other scenarios, such as in patients with cancer. Future studies are warranted to assess how palliative care models can be implemented in different disease states and health care settings, they said.

“These new studies should continue to highlight the fact that palliative care is not about terminal diseases and dying,” Dr. Bloem and colleagues concluded. “As Kluger and colleagues indicate in their important clinical trial, palliative care is about how to live well.”

Six authors reported receiving a grant from the Patient-Centered Outcomes Research Institute, which was the funding source for the study. Two authors reported receiving grants from the University Hospital Foundation during the study. One author reported receiving grants from Allergan and Merz Pharma and is a consultant for GE Pharmaceuticals and Sunovion Pharmaceuticals; another reported receiving grants from the Archstone Foundation, the California Health Care Foundation, the Cambia Health Foundation, the Gordon and Betty Moore Foundation, the National Institute of Nursing Research, the Stupski Foundation, and the UniHealth Foundation. Dr. Bloem and a colleague reported their institution received a center of excellence grant from the Parkinson’s Foundation.

SOURCE: Kluger B et al. JAMA Neurol. doi: 10.1001/jamaneurol.2019.4992.

After 12 months of receiving palliative care in an outpatient setting in addition to standard care, patients with Parkinson’s disease and related disorders (PDRD) had improved quality of life (QoL), compared with patients who received standard care alone, according to results from a randomized clinical trial in JAMA Neurology.

The benefits of palliative care even extended to patients’ caregivers, who also appeared to benefit from outpatient palliative care at the 12-month mark, according to lead author Benzi M. Kluger, MD, of the department of neurology, University of Colorado at Denver, Aurora, and colleagues.

Between November 2015 and September 2017, Dr. Kluger and colleagues included 210 patients into the trial from three participating academic tertiary care centers who had “moderate to high palliative care needs” as assessed by the Palliative Care Needs Assessment Tool, which the researchers said are “common reasons for referral” and “reflect a desire to meet patient-centered needs rather than disease-centered markers.” Patients were primarily non-Hispanic white men with a mean age of about 70 years. The researchers also included 175 caregivers in the trial, most of whom were women, spouses to the patients, and in their caregiver role for over 5.5 years.

Patients with PDRD were randomized to receive standard care – usual care through their primary care physician and a neurologist – or “integrated outpatient palliative care,” from a team consisting of a palliative neurologist, nurse, social worker, chaplain, and board-certified palliative medicine physician. The goal of palliative care was addressing “nonmotor symptoms, goals of care, anticipatory guidance, difficult emotions, and caregiver support,” which patients received every 3 months through an in-person outpatient visit or telemedicine.

Quality of life for patients was measured through the Quality of Life in Alzheimer’s Disease (QoL-AD) scale, and caregiver burden was assessed with the Zarit Burden Interview (ZBI-12). The researchers also measured symptom burden and other QoL measures using the Edmonton Symptom Assessment Scale–Revised for Parkinson’s Disease, Parkinson’s Disease Questionnaire, Hospital Anxiety and Depression Scale, Prolonged Grief Disorder questionnaire, and Functional Assessment of Chronic Illness Therapy–Spiritual Well-Being.

Overall, 87 of 105 (82.1%) of patients in the palliative care group went to all their outpatient palliative care visits, and 19 of 106 (17.9%) patients received palliative care through telemedicine. Patients in the palliative care group also attended more neurology visits (4.66 visits) than those in the standard care (3.16 visits) group.

Quality of life significantly improved for patients in the palliative care group, compared with patients receiving standard care only at 6 months (0.66 vs. –0.84; between-group difference, 1.87; 95% confidence interval, 0.47-3.27; P = .009) and at 12 months (0.68 vs. –0.42; between-group difference, 1.36; 95% CI, −0.01 to 2.73; P = .05). These results remained significant at 6 months and 12 months after researchers used multiple imputation to fill in missing data. While there was no significant difference in caregiver burden between groups at 6 months, there was a statistically significant difference at 12 months favoring the palliative care group (between-group difference, −2.60; 95% CI, −4.58 to −0.61; P = .01).

Patients receiving palliative care also had better nonmotor symptom burden, motor symptom severity, and were more likely to complete advance directives, compared with patients receiving standard care alone. “We hypothesize that motor improvements may have reflected an unanticipated benefit of our palliative care team’s general goal of encouraging activities that promoted joy, meaning, and connection,” Dr. Kluger and colleagues said. Researchers also noted that the intervention patients with greater need for palliative care tended to benefit more than patients with patients with lower palliative care needs.

“Because the palliative care intervention is time-intensive and resource-intensive, future studies should optimize triage tools and consider alternative models of care delivery, such as telemedicine or care navigators, to provide key aspects of the intervention at lower cost,” they said.

In a related editorial, Bastiaan R. Bloem, MD, PhD, from the Center of Expertise for Parkinson & Movement Disorders, at Radboud University Medical Center, in the Netherlands, and colleagues acknowledged that the study by Kluger et al. is “timely and practical” because it introduces a system for outpatient palliative care for patients with PDRD at a time when there is “growing awareness that palliative care may also benefit persons with neurodegenerative diseases like Parkinson’s disease.”

The study is also important because it highlights that patients at varying stages of disease, including mild disease, may benefit from an integrated outpatient palliative model, which is not usually considered when determining candidates for palliative care in other scenarios, such as in patients with cancer. Future studies are warranted to assess how palliative care models can be implemented in different disease states and health care settings, they said.

“These new studies should continue to highlight the fact that palliative care is not about terminal diseases and dying,” Dr. Bloem and colleagues concluded. “As Kluger and colleagues indicate in their important clinical trial, palliative care is about how to live well.”

Six authors reported receiving a grant from the Patient-Centered Outcomes Research Institute, which was the funding source for the study. Two authors reported receiving grants from the University Hospital Foundation during the study. One author reported receiving grants from Allergan and Merz Pharma and is a consultant for GE Pharmaceuticals and Sunovion Pharmaceuticals; another reported receiving grants from the Archstone Foundation, the California Health Care Foundation, the Cambia Health Foundation, the Gordon and Betty Moore Foundation, the National Institute of Nursing Research, the Stupski Foundation, and the UniHealth Foundation. Dr. Bloem and a colleague reported their institution received a center of excellence grant from the Parkinson’s Foundation.

SOURCE: Kluger B et al. JAMA Neurol. doi: 10.1001/jamaneurol.2019.4992.

Apolipoprotein E epsilon 4 (APOE4) directly and independently exacerbates accumulation of alpha-synuclein in patients with Lewy body dementia, whereas APOE2 may have a protective effect, based on two recent studies involving mouse models and human patients.

These insights confirm the importance of APOE in synucleinopathies, and may lead to new treatments, according to Eliezer Masliah, MD, director of the division of neuroscience at the National Institute on Aging.

“These [studies] definitely implicate a role of APOE4,” Dr. Masliah said in an interview.

According to Dr. Masliah, previous studies linked the APOE4 genotype with cognitive decline in synucleinopathies, but underlying molecular mechanisms remained unknown.

“We [now] have more direct confirmation [based on] different experimental animal models,” Dr. Masliah said. “It also means that APOE4 could be a therapeutic target for dementia with Lewy bodies.”

The two studies were published simultaneously in Science Translational Medicine. The first study was conducted by Albert A. Davis, MD, PhD, of Washington University, St. Louis, and colleagues; the second was led by Na Zhao, MD, PhD, of the Mayo Clinic in Jacksonville, Fla.

“The studies are very synergistic, but used different techniques,” said Dr. Masliah, who was not involved in the studies.

Both studies involved mice that expressed a human variant of APOE: APOE2, APOE3, or APOE4. Three independent techniques were used to concurrently overexpress alpha-synuclein; Dr. Davis and colleagues used a transgenic approach, as well as striatal injection of alpha-synuclein preformed fibrils, whereas Dr. Zhao and colleagues turned to a viral vector. Regardless of technique, each APOE variant had a distinct impact on the level of alpha-synuclein accumulation.

“In a nutshell, [Dr. Davis and colleagues] found that those mice that have synuclein and APOE4 have a much more rapid progression of the disease,” Dr. Masliah said. “They become Parkinsonian much faster, but also, they become cognitively impaired much faster, and they have more synuclein in the brain. Remarkably, on the opposite side, those that were expressing APOE2, which we know is a protective allele, actually were far less impaired. So that’s really a remarkable finding.”

The study at the Mayo Clinic echoed these findings.

“Essentially, [Dr. Zhao and colleagues] had very similar results,” Dr. Masliah said. “[In mice expressing] APOE4, synuclein accumulation was worse and pathology was worse, and with APOE2, there was relative protection.”

Both studies found that the exacerbating effect of APOE4 translated to human patients.

Dr. Davis and colleagues evaluated data from 251 patients in the Parkinson’s Progression Markers Initiative. A multivariate model showed that patients with the APOE4 genotype had faster cognitive decline, an impact that was independent of other variables, including cerebrospinal fluid concentrations of amyloid beta and tau protein (P = .0119). This finding was further supported by additional analyses involving 177 patients with Parkinson’s disease from the Washington University Movement Disorders Center, and another 1,030 patients enrolled in the NeuroGenetics Research Consortium study.

Dr. Zhao and colleagues evaluated postmortem samples from patients with Lewy body dementia who had minimal amyloid pathology. Comparing 22 APOE4 carriers versus 22 age- and sex-matched noncarriers, they found that carriers had significantly greater accumulations of alpha-synuclein (P less than .05).

According to the investigators, these findings could have both prognostic and therapeutic implications.

“[I]t is intriguing to speculate whether APOE and other potential genetic risk or resilience genes could be useful as screening tools to stratify risk for individual patients,” Dr. Davis and colleagues wrote in their paper. They went on to suggest that APOE genotyping may one day be used to personalize treatments for patients with neurodegenerative disease.

According to Dr. Masliah, several treatment strategies are under investigation.

“There are some pharmaceutical companies and also some academic groups that have been developing antibodies against APOE4 for Alzheimer’s disease, but certainly that could also be used for dementia with Lewy bodies,” he said. “There are other ways. One could [be] to suppress the expression of APOE4 with antisense or other technologies.

“There is also a very innovative technology that has been developed by the group at the Gladstone Institutes in San Francisco, which is to switch APOE4 to APOE3.” This technique, Dr. Masliah explained, is accomplished by breaking a disulfide bond in APOE4, which opens the structure into an isoform that mimics APOE3. “They have developed small molecules that actually can break that bond and essentially chemically switch APOE4 to APOE3,” he said.

Although multiple techniques are feasible, Dr. Masliah stressed that these therapeutic efforts are still in their infancy.

“We need to better understand the mechanisms as to how APOE4 and alpha-synuclein interact,” he said. “I think we need a lot more work in this area.”

The Davis study was funded by the American Academy of Neurology/American Brain Foundation, the BrightFocus Foundation, the Mary E. Groff Charitable Trust, and others; the investigators reported additional relationships with Biogen, Alector, Parabon, and others. The Zhao study was funded by the National Institutes of Health and the Lewy Body Dementia Center Without Walls; the investigators reported no competing interests. Dr. Masliah reported no conflicts of interest.

SOURCES: Davis AA et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay3069; Zhao N et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay1809.

Apolipoprotein E epsilon 4 (APOE4) directly and independently exacerbates accumulation of alpha-synuclein in patients with Lewy body dementia, whereas APOE2 may have a protective effect, based on two recent studies involving mouse models and human patients.

These insights confirm the importance of APOE in synucleinopathies, and may lead to new treatments, according to Eliezer Masliah, MD, director of the division of neuroscience at the National Institute on Aging.

“These [studies] definitely implicate a role of APOE4,” Dr. Masliah said in an interview.

According to Dr. Masliah, previous studies linked the APOE4 genotype with cognitive decline in synucleinopathies, but underlying molecular mechanisms remained unknown.

“We [now] have more direct confirmation [based on] different experimental animal models,” Dr. Masliah said. “It also means that APOE4 could be a therapeutic target for dementia with Lewy bodies.”

The two studies were published simultaneously in Science Translational Medicine. The first study was conducted by Albert A. Davis, MD, PhD, of Washington University, St. Louis, and colleagues; the second was led by Na Zhao, MD, PhD, of the Mayo Clinic in Jacksonville, Fla.

“The studies are very synergistic, but used different techniques,” said Dr. Masliah, who was not involved in the studies.

Both studies involved mice that expressed a human variant of APOE: APOE2, APOE3, or APOE4. Three independent techniques were used to concurrently overexpress alpha-synuclein; Dr. Davis and colleagues used a transgenic approach, as well as striatal injection of alpha-synuclein preformed fibrils, whereas Dr. Zhao and colleagues turned to a viral vector. Regardless of technique, each APOE variant had a distinct impact on the level of alpha-synuclein accumulation.

“In a nutshell, [Dr. Davis and colleagues] found that those mice that have synuclein and APOE4 have a much more rapid progression of the disease,” Dr. Masliah said. “They become Parkinsonian much faster, but also, they become cognitively impaired much faster, and they have more synuclein in the brain. Remarkably, on the opposite side, those that were expressing APOE2, which we know is a protective allele, actually were far less impaired. So that’s really a remarkable finding.”

The study at the Mayo Clinic echoed these findings.

“Essentially, [Dr. Zhao and colleagues] had very similar results,” Dr. Masliah said. “[In mice expressing] APOE4, synuclein accumulation was worse and pathology was worse, and with APOE2, there was relative protection.”

Both studies found that the exacerbating effect of APOE4 translated to human patients.

Dr. Davis and colleagues evaluated data from 251 patients in the Parkinson’s Progression Markers Initiative. A multivariate model showed that patients with the APOE4 genotype had faster cognitive decline, an impact that was independent of other variables, including cerebrospinal fluid concentrations of amyloid beta and tau protein (P = .0119). This finding was further supported by additional analyses involving 177 patients with Parkinson’s disease from the Washington University Movement Disorders Center, and another 1,030 patients enrolled in the NeuroGenetics Research Consortium study.

Dr. Zhao and colleagues evaluated postmortem samples from patients with Lewy body dementia who had minimal amyloid pathology. Comparing 22 APOE4 carriers versus 22 age- and sex-matched noncarriers, they found that carriers had significantly greater accumulations of alpha-synuclein (P less than .05).

According to the investigators, these findings could have both prognostic and therapeutic implications.

“[I]t is intriguing to speculate whether APOE and other potential genetic risk or resilience genes could be useful as screening tools to stratify risk for individual patients,” Dr. Davis and colleagues wrote in their paper. They went on to suggest that APOE genotyping may one day be used to personalize treatments for patients with neurodegenerative disease.

According to Dr. Masliah, several treatment strategies are under investigation.

“There are some pharmaceutical companies and also some academic groups that have been developing antibodies against APOE4 for Alzheimer’s disease, but certainly that could also be used for dementia with Lewy bodies,” he said. “There are other ways. One could [be] to suppress the expression of APOE4 with antisense or other technologies.

“There is also a very innovative technology that has been developed by the group at the Gladstone Institutes in San Francisco, which is to switch APOE4 to APOE3.” This technique, Dr. Masliah explained, is accomplished by breaking a disulfide bond in APOE4, which opens the structure into an isoform that mimics APOE3. “They have developed small molecules that actually can break that bond and essentially chemically switch APOE4 to APOE3,” he said.

Although multiple techniques are feasible, Dr. Masliah stressed that these therapeutic efforts are still in their infancy.

“We need to better understand the mechanisms as to how APOE4 and alpha-synuclein interact,” he said. “I think we need a lot more work in this area.”

The Davis study was funded by the American Academy of Neurology/American Brain Foundation, the BrightFocus Foundation, the Mary E. Groff Charitable Trust, and others; the investigators reported additional relationships with Biogen, Alector, Parabon, and others. The Zhao study was funded by the National Institutes of Health and the Lewy Body Dementia Center Without Walls; the investigators reported no competing interests. Dr. Masliah reported no conflicts of interest.

SOURCES: Davis AA et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay3069; Zhao N et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay1809.

Apolipoprotein E epsilon 4 (APOE4) directly and independently exacerbates accumulation of alpha-synuclein in patients with Lewy body dementia, whereas APOE2 may have a protective effect, based on two recent studies involving mouse models and human patients.

These insights confirm the importance of APOE in synucleinopathies, and may lead to new treatments, according to Eliezer Masliah, MD, director of the division of neuroscience at the National Institute on Aging.

“These [studies] definitely implicate a role of APOE4,” Dr. Masliah said in an interview.

According to Dr. Masliah, previous studies linked the APOE4 genotype with cognitive decline in synucleinopathies, but underlying molecular mechanisms remained unknown.

“We [now] have more direct confirmation [based on] different experimental animal models,” Dr. Masliah said. “It also means that APOE4 could be a therapeutic target for dementia with Lewy bodies.”

The two studies were published simultaneously in Science Translational Medicine. The first study was conducted by Albert A. Davis, MD, PhD, of Washington University, St. Louis, and colleagues; the second was led by Na Zhao, MD, PhD, of the Mayo Clinic in Jacksonville, Fla.

“The studies are very synergistic, but used different techniques,” said Dr. Masliah, who was not involved in the studies.

Both studies involved mice that expressed a human variant of APOE: APOE2, APOE3, or APOE4. Three independent techniques were used to concurrently overexpress alpha-synuclein; Dr. Davis and colleagues used a transgenic approach, as well as striatal injection of alpha-synuclein preformed fibrils, whereas Dr. Zhao and colleagues turned to a viral vector. Regardless of technique, each APOE variant had a distinct impact on the level of alpha-synuclein accumulation.

“In a nutshell, [Dr. Davis and colleagues] found that those mice that have synuclein and APOE4 have a much more rapid progression of the disease,” Dr. Masliah said. “They become Parkinsonian much faster, but also, they become cognitively impaired much faster, and they have more synuclein in the brain. Remarkably, on the opposite side, those that were expressing APOE2, which we know is a protective allele, actually were far less impaired. So that’s really a remarkable finding.”

The study at the Mayo Clinic echoed these findings.

“Essentially, [Dr. Zhao and colleagues] had very similar results,” Dr. Masliah said. “[In mice expressing] APOE4, synuclein accumulation was worse and pathology was worse, and with APOE2, there was relative protection.”

Both studies found that the exacerbating effect of APOE4 translated to human patients.

Dr. Davis and colleagues evaluated data from 251 patients in the Parkinson’s Progression Markers Initiative. A multivariate model showed that patients with the APOE4 genotype had faster cognitive decline, an impact that was independent of other variables, including cerebrospinal fluid concentrations of amyloid beta and tau protein (P = .0119). This finding was further supported by additional analyses involving 177 patients with Parkinson’s disease from the Washington University Movement Disorders Center, and another 1,030 patients enrolled in the NeuroGenetics Research Consortium study.

Dr. Zhao and colleagues evaluated postmortem samples from patients with Lewy body dementia who had minimal amyloid pathology. Comparing 22 APOE4 carriers versus 22 age- and sex-matched noncarriers, they found that carriers had significantly greater accumulations of alpha-synuclein (P less than .05).

According to the investigators, these findings could have both prognostic and therapeutic implications.

“[I]t is intriguing to speculate whether APOE and other potential genetic risk or resilience genes could be useful as screening tools to stratify risk for individual patients,” Dr. Davis and colleagues wrote in their paper. They went on to suggest that APOE genotyping may one day be used to personalize treatments for patients with neurodegenerative disease.

According to Dr. Masliah, several treatment strategies are under investigation.

“There are some pharmaceutical companies and also some academic groups that have been developing antibodies against APOE4 for Alzheimer’s disease, but certainly that could also be used for dementia with Lewy bodies,” he said. “There are other ways. One could [be] to suppress the expression of APOE4 with antisense or other technologies.

“There is also a very innovative technology that has been developed by the group at the Gladstone Institutes in San Francisco, which is to switch APOE4 to APOE3.” This technique, Dr. Masliah explained, is accomplished by breaking a disulfide bond in APOE4, which opens the structure into an isoform that mimics APOE3. “They have developed small molecules that actually can break that bond and essentially chemically switch APOE4 to APOE3,” he said.

Although multiple techniques are feasible, Dr. Masliah stressed that these therapeutic efforts are still in their infancy.

“We need to better understand the mechanisms as to how APOE4 and alpha-synuclein interact,” he said. “I think we need a lot more work in this area.”

The Davis study was funded by the American Academy of Neurology/American Brain Foundation, the BrightFocus Foundation, the Mary E. Groff Charitable Trust, and others; the investigators reported additional relationships with Biogen, Alector, Parabon, and others. The Zhao study was funded by the National Institutes of Health and the Lewy Body Dementia Center Without Walls; the investigators reported no competing interests. Dr. Masliah reported no conflicts of interest.

SOURCES: Davis AA et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay3069; Zhao N et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay1809.

SAN DIEGO – Pimavanserin, a second-generation antipsychotic approved for hallucinations and delusions in patients with Parkinson’s disease, may also be helpful for psychotic symptoms in other dementia patients, Erin P. Foff, MD, said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

In fact, the phase 3 HARMONY trial was stopped early, after an interim efficacy analysis determined that treatment with pimavanserin (Nuplazid) had achieved its primary endpoint – a statistically significant threefold reduction in the risk of relapse (P less than .0033).

Importantly, pimavanserin didn’t significantly affect cognition nor, at least in this controlled setting, did it appear to increase falls or other adverse events often seen with antipsychotic use in elderly patients, said Dr. Foff, clinical lead for the dementia-related psychosis program at Acadia Pharmaceuticals, which makes the drug and sponsored the study.

Based on the positive results, Acadia intends to submit a supplemental new drug application for this indication, according to an investor presentation posted on the company website.

“There is a critical need for an intervention [for psychosis symptoms] in this population,” Dr. Foff said. “We saw a robust response that was well tolerated and well maintained with no negative impact on cognitive scores.”

The second-generation antipsychotic was approved in 2016 for treating hallucinations and delusions in patients with Parkinson’s disease.

The drug is a selective antagonist of 5-HT₂ receptors, with low affinity for dopamine receptors. This slightly differentiates it from other second-generation antipsychotics that affect dopamine receptors as well as 5-HT₂ receptors.

HARMONY was not a typical placebo-controlled, randomized efficacy trial. Rather, it employed a two-phase design: an open-label treatment response period followed by a placebo-controlled randomization limited to open-label responders. Overall, HARMONY involved 392 patients with mild to severe dementia of numerous etiologies, including Alzheimer’s disease (66.8%), Parkinson’s disease dementia (14.3%), frontotemporal dementia (1.8%), vascular dementia (9.7%), and dementia with Lewy bodies (7.4%). All patients entered a 12-week, open-label period during which they received pimavanserin 34 mg daily. The primary endpoint was a combination of least a 30% reduction on the total Scale for the Assessment of Positive Symptom–Hallucinations and Delusions (SAPS-HD) scale plus a score of 1-2 on the Clinical Global Impressions–Improvement (CGI-I) scale, meaning better or very much better.

At 12 weeks, all responders were then randomized to placebo or continued therapy for 26 weeks. The primary endpoint was relapse, defined as at least a 30% worsening of the SAPS-HD relative to open-label baseline, plus a CGI-I score of 6-7 (worse or very much worse).

Patients were aged a mean of 74 years. Most (about 90%) were living at home. Visual hallucinations occurred in 80% and delusions in 83%. At baseline, the mean SAPS-HD score was 24.4, and the mean CGI-Severity score was 4.7. The mean Mini-Mental State Exam (MMSE) score was 16.7.

In the open-label period, pimavanserin reduced the SAPS-HD score at 12 weeks by a mean of 75%. Symptoms began to decline in the first week of treatment, with continuing improvement throughout the treatment period. By week 4, 30% had hit the response target. This number increased steadily, with 51% responding by week 4, 75% by week 8, and 88% by week 12.

By probable diagnosis, response rates were 59.8% in Alzheimer’s patients, 45.5% for those with Lewy body dementia, 71.2% among patients with Parkinson’s disease, 71% in patients with vascular dementia, and 50% in patients with frontotemporal dementia. In the final analysis, 80% of patients overall were considered responders.

The randomized potion began immediately thereafter with no washout period. About 62% (194) of the entire cohort – all responders – entered into the placebo-controlled phase. The remaining patients were either not responders (20%), dropped out because of an adverse event (7.7%), or left the study for unspecified reasons (10%). There was one death, which was not related to the study medication. A total of 41 patients were still being treated when the study was discontinued, and they were excluded from the final analysis.

When the randomized study ended, relapses had occurred in 28.3% of those taking placebo and in 12.6% of those taking pimavanserin – a statistically significant difference (hazard ratio, 0.353). This translated to a 180% reduction in relapse.

The rate of adverse events was similar in both active and placebo groups (41% vs. 36.6%). Serious adverse events occurred in 4.8% and 3.6%, respectively. The most commonly reported adverse events were headache (9.5% vs. 4.5%) and urinary tract infection (6.7% vs. 3.6%). Asthenia occurred in 2.9% of treated patients and 0.9% of placebo patients, but no falls were reported. Anxiety and dizziness were also reported in three patients taking the study medication.

Three patients (2.9%) experienced a prolonged QT phase on ECG, with a mean delay of 5.4 milliseconds from baseline. “Pimavanserin is known to have this effect of QT prolongation,” Dr. Foff said. “This 5.4-ms change is exactly in line with what we already know about pimavanserin and is not clinically significant. We saw no effect on motor function, consistent with the mechanism of action, and very low levels of agitation or aggression.”

Pimavanserin didn’t significantly change cognition from baseline in the open-label period, and in the randomized period, MMSE never differed significantly between groups.

The company also conducted an exploratory subgroup analysis that looked at placebo versus pimavanserin relapse by probable clinical diagnosis. Among the types of dementia, relapse rates for placebo versus pimavanserin were 23% versus 13% among Alzheimer’s patients, 67% versus 0% in Lewy body dementia patients, 50% versus 7% in patients with Parkinson’s, and 17% each among vascular dementia patients. Only one patient in the randomized period had frontotemporal dementia, and that patient relapsed on treatment.

Whether pimavanserin is effective specifically for psychosis in Alzheimer’s disease patients, however, remains in question. In 2018, Acadia published a negative phase 2 trial in a targeted group of 181 Alzheimer’s patients. The primary outcome in each study was mean change on the Neuropsychiatric Inventory–Nursing Home Version psychosis score (NPI-NH-PS). Clive Ballard, MD, of the University of Exeter (England), was the primary investigator.

After 6 weeks, those taking pimavanserin had a 3.76-point change in the NPI-NH-PS, compared with a 1.93-point change in the placebo group. The mean 1.84-point difference was not statistically significant.

This Alzheimer’s-only cohort group also experienced more adverse events than the HARMONY mixed-diagnosis cohort did, although the differences between pimavanserin and placebo groups were not significant. Adverse events included falls (23% of each group) and agitation (21% with pimavanserin vs. 14% with placebo). Cognition was unaffected.

Later that year, Acadia published a subgroup analysis of the same cohort parsing response by symptom severity, again with Dr. Ballard as the lead investigator.

The analysis focused on 57 patients with a baseline NPI-NH-PS of at least 12, indicating severe symptoms of psychosis.

Treatment effects were more pronounced in this group, significantly favoring pimavanserin. On the NPI-NH-PS, 88.9% of the pimavanserin group and 43.3% of the placebo group had at least a 30% improvement; 77.8% and 43.3% experienced at least a 50% improvement. The rate of serious adverse events was similar (18% with pimavanserin and 17% with placebo) and cognition was unaffected. Falls occurred in 14% of the treated group and 20% of the placebo group.

“These findings coupled with the results from other studies of pimavanserin suggest a potential role for pimavanserin in treating psychosis in patients across a range of neuropsychiatric conditions,” Dr. Ballard wrote.

[email protected]

SOURCE: Foff EP et al. CTAD 2019, Late-breaker 1

SAN DIEGO – Pimavanserin, a second-generation antipsychotic approved for hallucinations and delusions in patients with Parkinson’s disease, may also be helpful for psychotic symptoms in other dementia patients, Erin P. Foff, MD, said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

In fact, the phase 3 HARMONY trial was stopped early, after an interim efficacy analysis determined that treatment with pimavanserin (Nuplazid) had achieved its primary endpoint – a statistically significant threefold reduction in the risk of relapse (P less than .0033).

Importantly, pimavanserin didn’t significantly affect cognition nor, at least in this controlled setting, did it appear to increase falls or other adverse events often seen with antipsychotic use in elderly patients, said Dr. Foff, clinical lead for the dementia-related psychosis program at Acadia Pharmaceuticals, which makes the drug and sponsored the study.

Based on the positive results, Acadia intends to submit a supplemental new drug application for this indication, according to an investor presentation posted on the company website.

“There is a critical need for an intervention [for psychosis symptoms] in this population,” Dr. Foff said. “We saw a robust response that was well tolerated and well maintained with no negative impact on cognitive scores.”

The second-generation antipsychotic was approved in 2016 for treating hallucinations and delusions in patients with Parkinson’s disease.

The drug is a selective antagonist of 5-HT₂ receptors, with low affinity for dopamine receptors. This slightly differentiates it from other second-generation antipsychotics that affect dopamine receptors as well as 5-HT₂ receptors.

HARMONY was not a typical placebo-controlled, randomized efficacy trial. Rather, it employed a two-phase design: an open-label treatment response period followed by a placebo-controlled randomization limited to open-label responders. Overall, HARMONY involved 392 patients with mild to severe dementia of numerous etiologies, including Alzheimer’s disease (66.8%), Parkinson’s disease dementia (14.3%), frontotemporal dementia (1.8%), vascular dementia (9.7%), and dementia with Lewy bodies (7.4%). All patients entered a 12-week, open-label period during which they received pimavanserin 34 mg daily. The primary endpoint was a combination of least a 30% reduction on the total Scale for the Assessment of Positive Symptom–Hallucinations and Delusions (SAPS-HD) scale plus a score of 1-2 on the Clinical Global Impressions–Improvement (CGI-I) scale, meaning better or very much better.

At 12 weeks, all responders were then randomized to placebo or continued therapy for 26 weeks. The primary endpoint was relapse, defined as at least a 30% worsening of the SAPS-HD relative to open-label baseline, plus a CGI-I score of 6-7 (worse or very much worse).

Patients were aged a mean of 74 years. Most (about 90%) were living at home. Visual hallucinations occurred in 80% and delusions in 83%. At baseline, the mean SAPS-HD score was 24.4, and the mean CGI-Severity score was 4.7. The mean Mini-Mental State Exam (MMSE) score was 16.7.

In the open-label period, pimavanserin reduced the SAPS-HD score at 12 weeks by a mean of 75%. Symptoms began to decline in the first week of treatment, with continuing improvement throughout the treatment period. By week 4, 30% had hit the response target. This number increased steadily, with 51% responding by week 4, 75% by week 8, and 88% by week 12.

By probable diagnosis, response rates were 59.8% in Alzheimer’s patients, 45.5% for those with Lewy body dementia, 71.2% among patients with Parkinson’s disease, 71% in patients with vascular dementia, and 50% in patients with frontotemporal dementia. In the final analysis, 80% of patients overall were considered responders.

The randomized potion began immediately thereafter with no washout period. About 62% (194) of the entire cohort – all responders – entered into the placebo-controlled phase. The remaining patients were either not responders (20%), dropped out because of an adverse event (7.7%), or left the study for unspecified reasons (10%). There was one death, which was not related to the study medication. A total of 41 patients were still being treated when the study was discontinued, and they were excluded from the final analysis.

When the randomized study ended, relapses had occurred in 28.3% of those taking placebo and in 12.6% of those taking pimavanserin – a statistically significant difference (hazard ratio, 0.353). This translated to a 180% reduction in relapse.

The rate of adverse events was similar in both active and placebo groups (41% vs. 36.6%). Serious adverse events occurred in 4.8% and 3.6%, respectively. The most commonly reported adverse events were headache (9.5% vs. 4.5%) and urinary tract infection (6.7% vs. 3.6%). Asthenia occurred in 2.9% of treated patients and 0.9% of placebo patients, but no falls were reported. Anxiety and dizziness were also reported in three patients taking the study medication.

Three patients (2.9%) experienced a prolonged QT phase on ECG, with a mean delay of 5.4 milliseconds from baseline. “Pimavanserin is known to have this effect of QT prolongation,” Dr. Foff said. “This 5.4-ms change is exactly in line with what we already know about pimavanserin and is not clinically significant. We saw no effect on motor function, consistent with the mechanism of action, and very low levels of agitation or aggression.”

Pimavanserin didn’t significantly change cognition from baseline in the open-label period, and in the randomized period, MMSE never differed significantly between groups.

The company also conducted an exploratory subgroup analysis that looked at placebo versus pimavanserin relapse by probable clinical diagnosis. Among the types of dementia, relapse rates for placebo versus pimavanserin were 23% versus 13% among Alzheimer’s patients, 67% versus 0% in Lewy body dementia patients, 50% versus 7% in patients with Parkinson’s, and 17% each among vascular dementia patients. Only one patient in the randomized period had frontotemporal dementia, and that patient relapsed on treatment.

Whether pimavanserin is effective specifically for psychosis in Alzheimer’s disease patients, however, remains in question. In 2018, Acadia published a negative phase 2 trial in a targeted group of 181 Alzheimer’s patients. The primary outcome in each study was mean change on the Neuropsychiatric Inventory–Nursing Home Version psychosis score (NPI-NH-PS). Clive Ballard, MD, of the University of Exeter (England), was the primary investigator.

After 6 weeks, those taking pimavanserin had a 3.76-point change in the NPI-NH-PS, compared with a 1.93-point change in the placebo group. The mean 1.84-point difference was not statistically significant.

This Alzheimer’s-only cohort group also experienced more adverse events than the HARMONY mixed-diagnosis cohort did, although the differences between pimavanserin and placebo groups were not significant. Adverse events included falls (23% of each group) and agitation (21% with pimavanserin vs. 14% with placebo). Cognition was unaffected.

Later that year, Acadia published a subgroup analysis of the same cohort parsing response by symptom severity, again with Dr. Ballard as the lead investigator.

The analysis focused on 57 patients with a baseline NPI-NH-PS of at least 12, indicating severe symptoms of psychosis.

Treatment effects were more pronounced in this group, significantly favoring pimavanserin. On the NPI-NH-PS, 88.9% of the pimavanserin group and 43.3% of the placebo group had at least a 30% improvement; 77.8% and 43.3% experienced at least a 50% improvement. The rate of serious adverse events was similar (18% with pimavanserin and 17% with placebo) and cognition was unaffected. Falls occurred in 14% of the treated group and 20% of the placebo group.

“These findings coupled with the results from other studies of pimavanserin suggest a potential role for pimavanserin in treating psychosis in patients across a range of neuropsychiatric conditions,” Dr. Ballard wrote.

[email protected]

SOURCE: Foff EP et al. CTAD 2019, Late-breaker 1

SAN DIEGO – Pimavanserin, a second-generation antipsychotic approved for hallucinations and delusions in patients with Parkinson’s disease, may also be helpful for psychotic symptoms in other dementia patients, Erin P. Foff, MD, said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

In fact, the phase 3 HARMONY trial was stopped early, after an interim efficacy analysis determined that treatment with pimavanserin (Nuplazid) had achieved its primary endpoint – a statistically significant threefold reduction in the risk of relapse (P less than .0033).

Importantly, pimavanserin didn’t significantly affect cognition nor, at least in this controlled setting, did it appear to increase falls or other adverse events often seen with antipsychotic use in elderly patients, said Dr. Foff, clinical lead for the dementia-related psychosis program at Acadia Pharmaceuticals, which makes the drug and sponsored the study.

Based on the positive results, Acadia intends to submit a supplemental new drug application for this indication, according to an investor presentation posted on the company website.

“There is a critical need for an intervention [for psychosis symptoms] in this population,” Dr. Foff said. “We saw a robust response that was well tolerated and well maintained with no negative impact on cognitive scores.”

The second-generation antipsychotic was approved in 2016 for treating hallucinations and delusions in patients with Parkinson’s disease.

The drug is a selective antagonist of 5-HT₂ receptors, with low affinity for dopamine receptors. This slightly differentiates it from other second-generation antipsychotics that affect dopamine receptors as well as 5-HT₂ receptors.

HARMONY was not a typical placebo-controlled, randomized efficacy trial. Rather, it employed a two-phase design: an open-label treatment response period followed by a placebo-controlled randomization limited to open-label responders. Overall, HARMONY involved 392 patients with mild to severe dementia of numerous etiologies, including Alzheimer’s disease (66.8%), Parkinson’s disease dementia (14.3%), frontotemporal dementia (1.8%), vascular dementia (9.7%), and dementia with Lewy bodies (7.4%). All patients entered a 12-week, open-label period during which they received pimavanserin 34 mg daily. The primary endpoint was a combination of least a 30% reduction on the total Scale for the Assessment of Positive Symptom–Hallucinations and Delusions (SAPS-HD) scale plus a score of 1-2 on the Clinical Global Impressions–Improvement (CGI-I) scale, meaning better or very much better.

At 12 weeks, all responders were then randomized to placebo or continued therapy for 26 weeks. The primary endpoint was relapse, defined as at least a 30% worsening of the SAPS-HD relative to open-label baseline, plus a CGI-I score of 6-7 (worse or very much worse).

Patients were aged a mean of 74 years. Most (about 90%) were living at home. Visual hallucinations occurred in 80% and delusions in 83%. At baseline, the mean SAPS-HD score was 24.4, and the mean CGI-Severity score was 4.7. The mean Mini-Mental State Exam (MMSE) score was 16.7.

In the open-label period, pimavanserin reduced the SAPS-HD score at 12 weeks by a mean of 75%. Symptoms began to decline in the first week of treatment, with continuing improvement throughout the treatment period. By week 4, 30% had hit the response target. This number increased steadily, with 51% responding by week 4, 75% by week 8, and 88% by week 12.

By probable diagnosis, response rates were 59.8% in Alzheimer’s patients, 45.5% for those with Lewy body dementia, 71.2% among patients with Parkinson’s disease, 71% in patients with vascular dementia, and 50% in patients with frontotemporal dementia. In the final analysis, 80% of patients overall were considered responders.

The randomized potion began immediately thereafter with no washout period. About 62% (194) of the entire cohort – all responders – entered into the placebo-controlled phase. The remaining patients were either not responders (20%), dropped out because of an adverse event (7.7%), or left the study for unspecified reasons (10%). There was one death, which was not related to the study medication. A total of 41 patients were still being treated when the study was discontinued, and they were excluded from the final analysis.

When the randomized study ended, relapses had occurred in 28.3% of those taking placebo and in 12.6% of those taking pimavanserin – a statistically significant difference (hazard ratio, 0.353). This translated to a 180% reduction in relapse.

The rate of adverse events was similar in both active and placebo groups (41% vs. 36.6%). Serious adverse events occurred in 4.8% and 3.6%, respectively. The most commonly reported adverse events were headache (9.5% vs. 4.5%) and urinary tract infection (6.7% vs. 3.6%). Asthenia occurred in 2.9% of treated patients and 0.9% of placebo patients, but no falls were reported. Anxiety and dizziness were also reported in three patients taking the study medication.

Three patients (2.9%) experienced a prolonged QT phase on ECG, with a mean delay of 5.4 milliseconds from baseline. “Pimavanserin is known to have this effect of QT prolongation,” Dr. Foff said. “This 5.4-ms change is exactly in line with what we already know about pimavanserin and is not clinically significant. We saw no effect on motor function, consistent with the mechanism of action, and very low levels of agitation or aggression.”

Pimavanserin didn’t significantly change cognition from baseline in the open-label period, and in the randomized period, MMSE never differed significantly between groups.

The company also conducted an exploratory subgroup analysis that looked at placebo versus pimavanserin relapse by probable clinical diagnosis. Among the types of dementia, relapse rates for placebo versus pimavanserin were 23% versus 13% among Alzheimer’s patients, 67% versus 0% in Lewy body dementia patients, 50% versus 7% in patients with Parkinson’s, and 17% each among vascular dementia patients. Only one patient in the randomized period had frontotemporal dementia, and that patient relapsed on treatment.

Whether pimavanserin is effective specifically for psychosis in Alzheimer’s disease patients, however, remains in question. In 2018, Acadia published a negative phase 2 trial in a targeted group of 181 Alzheimer’s patients. The primary outcome in each study was mean change on the Neuropsychiatric Inventory–Nursing Home Version psychosis score (NPI-NH-PS). Clive Ballard, MD, of the University of Exeter (England), was the primary investigator.

After 6 weeks, those taking pimavanserin had a 3.76-point change in the NPI-NH-PS, compared with a 1.93-point change in the placebo group. The mean 1.84-point difference was not statistically significant.

This Alzheimer’s-only cohort group also experienced more adverse events than the HARMONY mixed-diagnosis cohort did, although the differences between pimavanserin and placebo groups were not significant. Adverse events included falls (23% of each group) and agitation (21% with pimavanserin vs. 14% with placebo). Cognition was unaffected.

Later that year, Acadia published a subgroup analysis of the same cohort parsing response by symptom severity, again with Dr. Ballard as the lead investigator.

The analysis focused on 57 patients with a baseline NPI-NH-PS of at least 12, indicating severe symptoms of psychosis.

Treatment effects were more pronounced in this group, significantly favoring pimavanserin. On the NPI-NH-PS, 88.9% of the pimavanserin group and 43.3% of the placebo group had at least a 30% improvement; 77.8% and 43.3% experienced at least a 50% improvement. The rate of serious adverse events was similar (18% with pimavanserin and 17% with placebo) and cognition was unaffected. Falls occurred in 14% of the treated group and 20% of the placebo group.

“These findings coupled with the results from other studies of pimavanserin suggest a potential role for pimavanserin in treating psychosis in patients across a range of neuropsychiatric conditions,” Dr. Ballard wrote.

[email protected]

SOURCE: Foff EP et al. CTAD 2019, Late-breaker 1

Successful deep brain stimulation of the subthalamic nucleus may have unforeseen effects on the ability to swim in some patients with Parkinson’s disease, according to findings from a case series of nine patients published in Neurology.

All nine patients in the report were experienced swimmers, including two who competed in several competition-level races. They reported losing their ability to swim after successful deep brain stimulation of the subthalamic nucleus (STN-DBS) procedures. The Neurology paper focuses on three of the patients.

All of the patients achieved good to excellent motor control and cut their L-dopa dosage by impressive amounts. But they also lost the ability to coordinate limb movement when in the water, reported Daniel Waldvogel, MD, of the University of Zurich, and associates.

“All found their ability to swim came back immediately, with improved coordination of the limbs,” when stimulation was discontinued, the team noted. But soon after the stimulation ceased, their motor symptoms also rapidly returned, leading all to resume continuous stimulation.

One possible explanation is that STN-DBS does not strongly improve dopamine levels in the supplementary motor area, which controls independent limb movements.

It “may be that DBS affects the supplementary motor area (SMA) differently than levodopa. The SMA is a main output area of the basal ganglia, with connections to the primary motor cortex and the spinal cord,” wrote Dr. Waldvogel and associates. “Functionally, the SMA is thought to be crucial for facilitating independent movements of the limbs, which is a key requirement for swimming.”

Although the SMA also partly manages gait, walking was unaffected in all nine of the patients.

The authors described three patients in more detail:

• Case 1 was a 69-year-old man who was a proficient swimmer before DBS. His Unified Parkinson’s Disease Rating Scale (UPDRS) motor score on medication fell from 28 with dyskinesia before DBS to 17 after DBS, and his levodopa-equivalent dosage declined from 1,570 mg to 920 mg. The man almost drowned after he jumped into a lake and had to be rescued by another swimmer.
• Case 4 was a 59-year-old woman who was an accomplished and competitive swimmer and had been swimming up until the DBS procedure. After DBS, her UPDRS motor score on medication fell from 9 with dyskinesia to 6, and her levodopa-equivalent dosage dropped from 825 mg to 150 mg. She had good motor outcome after DBS but lost the ability to swim. “She regularly practiced swimming with her physiotherapist, but never came close to her previous level,” the authors said.
• Case 5 was a 61-year-old woman who was a competitive swimmer, including swimming across Lake Zurich, and held a lifesaving certification. Her UPDRS motor score on medication fell from 11 with dyskinesia to 9, and her levodopa-equivalent dosage decreased from 800 mg to 180 mg. After DBS, she could swim only a quarter of a kilometer and complained of “awkward posture” during her efforts.

The phenomenon has been reported just one other time by a group from the University of Western Australia. This reported patient was a 68-year-old man with a 5-year history of medication-refractory, tremor-predominant Parkinson’s. He received DBS of the posterior subthalamic area (PSA-DBS).

The patient was a dedicated lap swimmer at his local pool. When he returned to his hobby, “he quickly realized he could not propel himself adequately and that he required assistance to get to safety. In a supervised swimming situation, he was unable to float or perform freestyle, breaststroke, or back stroke. With the stimulator turned off for 30 minutes, he regained swimming ability and lost it when the stimulator was turned on.

The Australian team noted that three similar cases presented to them, but they did not discuss those cases in the paper.

Dr. Waldvogel and coauthors wrote that they might also have unreported cases in their cohort of patients with STN-DBS.

“Our cohort of patients with PD who underwent STN-DBS at the time of this retrospective study consisted of 217 patients, but we did not assess patients systematically for their swimming skills or loss thereof,” the authors said. “Until the mechanism of the reported deterioration of the ability to swim after STN-DBS is elucidated, it is crucial that we advise patients of the potential risk of drowning and the need for a carefully supervised assessment of their swimming skills before going into deep water.”

The report received no funding, and one author disclosed financial relationships with industry.

[email protected]

SOURCE: Waldvogel D et al Neurology. 2019 Nov 27. doi: 10.1212/WNL.0000000000008664.

Successful deep brain stimulation of the subthalamic nucleus may have unforeseen effects on the ability to swim in some patients with Parkinson’s disease, according to findings from a case series of nine patients published in Neurology.

All nine patients in the report were experienced swimmers, including two who competed in several competition-level races. They reported losing their ability to swim after successful deep brain stimulation of the subthalamic nucleus (STN-DBS) procedures. The Neurology paper focuses on three of the patients.

All of the patients achieved good to excellent motor control and cut their L-dopa dosage by impressive amounts. But they also lost the ability to coordinate limb movement when in the water, reported Daniel Waldvogel, MD, of the University of Zurich, and associates.

“All found their ability to swim came back immediately, with improved coordination of the limbs,” when stimulation was discontinued, the team noted. But soon after the stimulation ceased, their motor symptoms also rapidly returned, leading all to resume continuous stimulation.

One possible explanation is that STN-DBS does not strongly improve dopamine levels in the supplementary motor area, which controls independent limb movements.

It “may be that DBS affects the supplementary motor area (SMA) differently than levodopa. The SMA is a main output area of the basal ganglia, with connections to the primary motor cortex and the spinal cord,” wrote Dr. Waldvogel and associates. “Functionally, the SMA is thought to be crucial for facilitating independent movements of the limbs, which is a key requirement for swimming.”

Although the SMA also partly manages gait, walking was unaffected in all nine of the patients.

The authors described three patients in more detail:

• Case 1 was a 69-year-old man who was a proficient swimmer before DBS. His Unified Parkinson’s Disease Rating Scale (UPDRS) motor score on medication fell from 28 with dyskinesia before DBS to 17 after DBS, and his levodopa-equivalent dosage declined from 1,570 mg to 920 mg. The man almost drowned after he jumped into a lake and had to be rescued by another swimmer.
• Case 4 was a 59-year-old woman who was an accomplished and competitive swimmer and had been swimming up until the DBS procedure. After DBS, her UPDRS motor score on medication fell from 9 with dyskinesia to 6, and her levodopa-equivalent dosage dropped from 825 mg to 150 mg. She had good motor outcome after DBS but lost the ability to swim. “She regularly practiced swimming with her physiotherapist, but never came close to her previous level,” the authors said.
• Case 5 was a 61-year-old woman who was a competitive swimmer, including swimming across Lake Zurich, and held a lifesaving certification. Her UPDRS motor score on medication fell from 11 with dyskinesia to 9, and her levodopa-equivalent dosage decreased from 800 mg to 180 mg. After DBS, she could swim only a quarter of a kilometer and complained of “awkward posture” during her efforts.

The phenomenon has been reported just one other time by a group from the University of Western Australia. This reported patient was a 68-year-old man with a 5-year history of medication-refractory, tremor-predominant Parkinson’s. He received DBS of the posterior subthalamic area (PSA-DBS).

The patient was a dedicated lap swimmer at his local pool. When he returned to his hobby, “he quickly realized he could not propel himself adequately and that he required assistance to get to safety. In a supervised swimming situation, he was unable to float or perform freestyle, breaststroke, or back stroke. With the stimulator turned off for 30 minutes, he regained swimming ability and lost it when the stimulator was turned on.

The Australian team noted that three similar cases presented to them, but they did not discuss those cases in the paper.

Dr. Waldvogel and coauthors wrote that they might also have unreported cases in their cohort of patients with STN-DBS.

“Our cohort of patients with PD who underwent STN-DBS at the time of this retrospective study consisted of 217 patients, but we did not assess patients systematically for their swimming skills or loss thereof,” the authors said. “Until the mechanism of the reported deterioration of the ability to swim after STN-DBS is elucidated, it is crucial that we advise patients of the potential risk of drowning and the need for a carefully supervised assessment of their swimming skills before going into deep water.”

The report received no funding, and one author disclosed financial relationships with industry.

[email protected]

SOURCE: Waldvogel D et al Neurology. 2019 Nov 27. doi: 10.1212/WNL.0000000000008664.

Successful deep brain stimulation of the subthalamic nucleus may have unforeseen effects on the ability to swim in some patients with Parkinson’s disease, according to findings from a case series of nine patients published in Neurology.

All nine patients in the report were experienced swimmers, including two who competed in several competition-level races. They reported losing their ability to swim after successful deep brain stimulation of the subthalamic nucleus (STN-DBS) procedures. The Neurology paper focuses on three of the patients.

All of the patients achieved good to excellent motor control and cut their L-dopa dosage by impressive amounts. But they also lost the ability to coordinate limb movement when in the water, reported Daniel Waldvogel, MD, of the University of Zurich, and associates.

“All found their ability to swim came back immediately, with improved coordination of the limbs,” when stimulation was discontinued, the team noted. But soon after the stimulation ceased, their motor symptoms also rapidly returned, leading all to resume continuous stimulation.

One possible explanation is that STN-DBS does not strongly improve dopamine levels in the supplementary motor area, which controls independent limb movements.

It “may be that DBS affects the supplementary motor area (SMA) differently than levodopa. The SMA is a main output area of the basal ganglia, with connections to the primary motor cortex and the spinal cord,” wrote Dr. Waldvogel and associates. “Functionally, the SMA is thought to be crucial for facilitating independent movements of the limbs, which is a key requirement for swimming.”

Although the SMA also partly manages gait, walking was unaffected in all nine of the patients.

The authors described three patients in more detail:

• Case 1 was a 69-year-old man who was a proficient swimmer before DBS. His Unified Parkinson’s Disease Rating Scale (UPDRS) motor score on medication fell from 28 with dyskinesia before DBS to 17 after DBS, and his levodopa-equivalent dosage declined from 1,570 mg to 920 mg. The man almost drowned after he jumped into a lake and had to be rescued by another swimmer.
• Case 4 was a 59-year-old woman who was an accomplished and competitive swimmer and had been swimming up until the DBS procedure. After DBS, her UPDRS motor score on medication fell from 9 with dyskinesia to 6, and her levodopa-equivalent dosage dropped from 825 mg to 150 mg. She had good motor outcome after DBS but lost the ability to swim. “She regularly practiced swimming with her physiotherapist, but never came close to her previous level,” the authors said.
• Case 5 was a 61-year-old woman who was a competitive swimmer, including swimming across Lake Zurich, and held a lifesaving certification. Her UPDRS motor score on medication fell from 11 with dyskinesia to 9, and her levodopa-equivalent dosage decreased from 800 mg to 180 mg. After DBS, she could swim only a quarter of a kilometer and complained of “awkward posture” during her efforts.

The phenomenon has been reported just one other time by a group from the University of Western Australia. This reported patient was a 68-year-old man with a 5-year history of medication-refractory, tremor-predominant Parkinson’s. He received DBS of the posterior subthalamic area (PSA-DBS).

The patient was a dedicated lap swimmer at his local pool. When he returned to his hobby, “he quickly realized he could not propel himself adequately and that he required assistance to get to safety. In a supervised swimming situation, he was unable to float or perform freestyle, breaststroke, or back stroke. With the stimulator turned off for 30 minutes, he regained swimming ability and lost it when the stimulator was turned on.

The Australian team noted that three similar cases presented to them, but they did not discuss those cases in the paper.

Dr. Waldvogel and coauthors wrote that they might also have unreported cases in their cohort of patients with STN-DBS.

“Our cohort of patients with PD who underwent STN-DBS at the time of this retrospective study consisted of 217 patients, but we did not assess patients systematically for their swimming skills or loss thereof,” the authors said. “Until the mechanism of the reported deterioration of the ability to swim after STN-DBS is elucidated, it is crucial that we advise patients of the potential risk of drowning and the need for a carefully supervised assessment of their swimming skills before going into deep water.”

The report received no funding, and one author disclosed financial relationships with industry.

[email protected]

SOURCE: Waldvogel D et al Neurology. 2019 Nov 27. doi: 10.1212/WNL.0000000000008664.

Certain types of oral antibiotics seem to be associated with an elevated risk of Parkinson’s disease with a delay that is consistent with the proposed duration of a prodromal period, according to a report published in Movement Disorders. Associations were found for broad-spectrum antibiotics and those that act against anaerobic bacteria and fungi. The timing of antibiotic exposure also seemed to matter.

In a nationwide case-control study, Finnish researchers compared data on antibiotic use in 13,976 individuals diagnosed with Parkinson’s disease between 1998 and 2014 with antibiotic-use data from 40,697 controls. The strongest connection with Parkinson’s disease risk was found for oral exposure to macrolides and lincosamides (adjusted odds ratio up to 1.416). After correction for multiple comparisons, exposure to antianaerobics and tetracyclines 10-15 years before the index date, and antifungal medications 1-5 years before the index date were positively associated with Parkinson’s disease risk. In post hoc analyses, further positive associations were found for broad-spectrum antibiotics.

Tuomas H. Mertsalmi, MD, from the Helsinki University Hospital and coauthors reported that this was the first study to explore a possible connection between antimicrobial use and Parkinson’s disease.

“In Parkinson’s disease, several studies have described alterations of gut microbiota composition, and changes in fecal microbiota abundance have been found to be associated with gastrointestinal and motor symptoms,” they wrote.

Commenting on the delay between the exposure and diagnosis for the most strongly associated antimicrobials, the authors noted that this 10-15 year lag was comparable with what has been found between the peripheral initiation of Parkinson’s disease and its motor manifestation.

“This would also explain the lack of association between antibiotic exposure 1-5 years before index date – if antibiotic exposure could induce or contribute to the pathogenesis of Parkinson’s disease in the gastrointestinal tract, it would probably take several years before the clinical manifestation of Parkinson’s disease,” they wrote.

With regards to the association seen for sulfonamides and trimethoprim – which was 1-5 years before the index date – they speculated this could reflect treatment for urinary tract infections, which individuals with Parkinson’s disease might be more susceptible to in the prodromal phase of the disease.

The authors noted that infectious disease has also been associated with Parkinson’s disease, and that their analysis did not include information about why the antimicrobial agents were prescribed. However, they pointed out that the associations were only for certain antibiotic classes, which makes it unlikely that the association was related to greater burden of infectious disease among individuals with Parkinson’s disease.

The pattern of associations supports the hypothesis that effects on gut microbiota could link antibiotics to Parkinson’s disease. “The link between antibiotic exposure and Parkinson’s disease fits the current view that in a significant proportion of patients the pathology of Parkinson’s disease may originate in the gut, possibly related to microbial changes, years before the onset of typical Parkinson’s disease motor symptoms such as slowness, muscle stiffness, and shaking of the extremities. It was known that bacterial composition of the intestine in patients with Parkinson’s disease is abnormal, but the cause is unclear. Our results suggest that some commonly used antibiotics, which are known to strongly influence the gut microbiota, could be a predisposing factor,” said lead investigator Filip Scheperjans, MD, PhD, from the department of neurology at Helsinki University Hospital.

The findings may have implications for antibiotic prescribing practices in the future, said Dr. Scheperjans. “In addition to the problem of antibiotic resistance, antimicrobial prescribing should also take into account their potentially long-lasting effects on the gut microbiome and the development of certain diseases.”

The study was funded by the Finnish Parkinson Foundation, the Finnish Medical Foundation, the Maire Taponen Foundation, and the Academy of Finland. One author declared relevant patents and his position as founder and chief executive of a private company. No other conflicts of interest were declared.

SOURCE: Mertsalmi TH et al. Mov Disord. 2019 Nov 18. doi: 10.1002/mds.27924.

Certain types of oral antibiotics seem to be associated with an elevated risk of Parkinson’s disease with a delay that is consistent with the proposed duration of a prodromal period, according to a report published in Movement Disorders. Associations were found for broad-spectrum antibiotics and those that act against anaerobic bacteria and fungi. The timing of antibiotic exposure also seemed to matter.

In a nationwide case-control study, Finnish researchers compared data on antibiotic use in 13,976 individuals diagnosed with Parkinson’s disease between 1998 and 2014 with antibiotic-use data from 40,697 controls. The strongest connection with Parkinson’s disease risk was found for oral exposure to macrolides and lincosamides (adjusted odds ratio up to 1.416). After correction for multiple comparisons, exposure to antianaerobics and tetracyclines 10-15 years before the index date, and antifungal medications 1-5 years before the index date were positively associated with Parkinson’s disease risk. In post hoc analyses, further positive associations were found for broad-spectrum antibiotics.

Tuomas H. Mertsalmi, MD, from the Helsinki University Hospital and coauthors reported that this was the first study to explore a possible connection between antimicrobial use and Parkinson’s disease.

“In Parkinson’s disease, several studies have described alterations of gut microbiota composition, and changes in fecal microbiota abundance have been found to be associated with gastrointestinal and motor symptoms,” they wrote.

Commenting on the delay between the exposure and diagnosis for the most strongly associated antimicrobials, the authors noted that this 10-15 year lag was comparable with what has been found between the peripheral initiation of Parkinson’s disease and its motor manifestation.

“This would also explain the lack of association between antibiotic exposure 1-5 years before index date – if antibiotic exposure could induce or contribute to the pathogenesis of Parkinson’s disease in the gastrointestinal tract, it would probably take several years before the clinical manifestation of Parkinson’s disease,” they wrote.

With regards to the association seen for sulfonamides and trimethoprim – which was 1-5 years before the index date – they speculated this could reflect treatment for urinary tract infections, which individuals with Parkinson’s disease might be more susceptible to in the prodromal phase of the disease.

The authors noted that infectious disease has also been associated with Parkinson’s disease, and that their analysis did not include information about why the antimicrobial agents were prescribed. However, they pointed out that the associations were only for certain antibiotic classes, which makes it unlikely that the association was related to greater burden of infectious disease among individuals with Parkinson’s disease.

The pattern of associations supports the hypothesis that effects on gut microbiota could link antibiotics to Parkinson’s disease. “The link between antibiotic exposure and Parkinson’s disease fits the current view that in a significant proportion of patients the pathology of Parkinson’s disease may originate in the gut, possibly related to microbial changes, years before the onset of typical Parkinson’s disease motor symptoms such as slowness, muscle stiffness, and shaking of the extremities. It was known that bacterial composition of the intestine in patients with Parkinson’s disease is abnormal, but the cause is unclear. Our results suggest that some commonly used antibiotics, which are known to strongly influence the gut microbiota, could be a predisposing factor,” said lead investigator Filip Scheperjans, MD, PhD, from the department of neurology at Helsinki University Hospital.

The findings may have implications for antibiotic prescribing practices in the future, said Dr. Scheperjans. “In addition to the problem of antibiotic resistance, antimicrobial prescribing should also take into account their potentially long-lasting effects on the gut microbiome and the development of certain diseases.”

The study was funded by the Finnish Parkinson Foundation, the Finnish Medical Foundation, the Maire Taponen Foundation, and the Academy of Finland. One author declared relevant patents and his position as founder and chief executive of a private company. No other conflicts of interest were declared.

SOURCE: Mertsalmi TH et al. Mov Disord. 2019 Nov 18. doi: 10.1002/mds.27924.

Certain types of oral antibiotics seem to be associated with an elevated risk of Parkinson’s disease with a delay that is consistent with the proposed duration of a prodromal period, according to a report published in Movement Disorders. Associations were found for broad-spectrum antibiotics and those that act against anaerobic bacteria and fungi. The timing of antibiotic exposure also seemed to matter.

In a nationwide case-control study, Finnish researchers compared data on antibiotic use in 13,976 individuals diagnosed with Parkinson’s disease between 1998 and 2014 with antibiotic-use data from 40,697 controls. The strongest connection with Parkinson’s disease risk was found for oral exposure to macrolides and lincosamides (adjusted odds ratio up to 1.416). After correction for multiple comparisons, exposure to antianaerobics and tetracyclines 10-15 years before the index date, and antifungal medications 1-5 years before the index date were positively associated with Parkinson’s disease risk. In post hoc analyses, further positive associations were found for broad-spectrum antibiotics.

Tuomas H. Mertsalmi, MD, from the Helsinki University Hospital and coauthors reported that this was the first study to explore a possible connection between antimicrobial use and Parkinson’s disease.

“In Parkinson’s disease, several studies have described alterations of gut microbiota composition, and changes in fecal microbiota abundance have been found to be associated with gastrointestinal and motor symptoms,” they wrote.

Commenting on the delay between the exposure and diagnosis for the most strongly associated antimicrobials, the authors noted that this 10-15 year lag was comparable with what has been found between the peripheral initiation of Parkinson’s disease and its motor manifestation.

“This would also explain the lack of association between antibiotic exposure 1-5 years before index date – if antibiotic exposure could induce or contribute to the pathogenesis of Parkinson’s disease in the gastrointestinal tract, it would probably take several years before the clinical manifestation of Parkinson’s disease,” they wrote.

With regards to the association seen for sulfonamides and trimethoprim – which was 1-5 years before the index date – they speculated this could reflect treatment for urinary tract infections, which individuals with Parkinson’s disease might be more susceptible to in the prodromal phase of the disease.

The authors noted that infectious disease has also been associated with Parkinson’s disease, and that their analysis did not include information about why the antimicrobial agents were prescribed. However, they pointed out that the associations were only for certain antibiotic classes, which makes it unlikely that the association was related to greater burden of infectious disease among individuals with Parkinson’s disease.

The pattern of associations supports the hypothesis that effects on gut microbiota could link antibiotics to Parkinson’s disease. “The link between antibiotic exposure and Parkinson’s disease fits the current view that in a significant proportion of patients the pathology of Parkinson’s disease may originate in the gut, possibly related to microbial changes, years before the onset of typical Parkinson’s disease motor symptoms such as slowness, muscle stiffness, and shaking of the extremities. It was known that bacterial composition of the intestine in patients with Parkinson’s disease is abnormal, but the cause is unclear. Our results suggest that some commonly used antibiotics, which are known to strongly influence the gut microbiota, could be a predisposing factor,” said lead investigator Filip Scheperjans, MD, PhD, from the department of neurology at Helsinki University Hospital.

The findings may have implications for antibiotic prescribing practices in the future, said Dr. Scheperjans. “In addition to the problem of antibiotic resistance, antimicrobial prescribing should also take into account their potentially long-lasting effects on the gut microbiome and the development of certain diseases.”

The study was funded by the Finnish Parkinson Foundation, the Finnish Medical Foundation, the Maire Taponen Foundation, and the Academy of Finland. One author declared relevant patents and his position as founder and chief executive of a private company. No other conflicts of interest were declared.

SOURCE: Mertsalmi TH et al. Mov Disord. 2019 Nov 18. doi: 10.1002/mds.27924.

ST. LOUIS – Dementia and death were about four times more likely after 11 years in patients with Parkinson’s disease and cognitive or psychiatric symptoms at baseline, versus those with motor symptoms alone, according to the results of a longitudinal study of 162 patients at Washington University, St. Louis.

Parkinson’s disease is often only staged as mild, moderate, or severe, and sometimes cognitive and psychiatric symptoms are not assessed. The St. Louis team wanted to see if there are actual subtypes, and if they have clinical relevance, said lead investigator Peter Myers, PhD, a postdoctoral research associate at Washington University.

The magnitude of the findings was “surprising. ... We don’t think we are seeing stages” because the different symptom patterns were apparent at baseline. Instead, “we are seeing really distinct clinical subtypes that could inform patient prognosis and help prepare families and caregivers. It is important that you assess more than just motor symptoms,” he said at the annual meeting of the American Neurological Association.

Some of the subjects were newly diagnosed and others diagnosed years earlier. At baseline, they had symptoms for an average of 6 years, and none had dementia.

After a battery of cognitive, psychiatric, and movement tests, Dr. Myers and his colleagues found that their subjects fell into three patterns: motor symptoms only, with normal cognitive and psychiatric performance (63 subjects); motor symptoms plus prominent anxiety or depression (17); and motor symptoms plus cognitive deficits (82).

A total of 42 patients developed dementia – a score of at least 1 on the Clinical Dementia Rating evaluation – including three in the motor-only group (5%), two in the psychiatric/motor group (12%), and 37 in the cognitive/motor group (45%).

After controlling for age, sex, and symptom duration, the risk of dementia conversion was far higher in the cognitive/motor group (relative risk, 4.16, 95% confidence interval, 1.18-14.65) and psychiatric/motor group (RR, 3.08; 95% CI, 0.72-13.28), compared with motor-only subjects.

Thirty-eight patients died, the majority because of Parkinson’s disease-related causes, including five in the motor-only group (8%), two in the psychiatric/motor group (12%), and 31 in the cognitive/motor group (38%).

The risk of death, relative to motor-only patients, was higher with both the cognitive/motor (RR, 4.06; 95% CI, 1.37-12.03) and psychiatric/motor subtypes (RR, 4.17; 95% CI, 0.70-24.91).

It is unclear what leads to the progression differences, but the researchers’ hypothesis is that the broader scope of symptoms indicates a greater extent of brain pathology. The St. Louis team is looking at brain-imaging data to see if that is true, and if the subtypes can be distinguished on imaging. They are also interested in seeing if genetics plays a role in susceptibility to the different subtypes, and if the baseline subtypes are stable over time or if patients convert between them.

Subjects were, on average, 66 years old, and 62% were men. The mean levodopa-equivalent daily dose was 613 mg in the motor-only group, 1,004 mg in the psychiatric/motor group, and 783 mg in the cognitive/motor group (P = .03). Mean symptom duration was shorter in motor-only patients (5.1 years) versus the psychiatric/motor group (7.2 years) and cognitive/motor group (6.9 years, P less than .01).

Although relative risks crossed 1 in the psychiatric/motor group, it was probably because there were only 17 patients. “We do think there is a very strong likelihood that” the psychiatric/motor findings, like the cognitive/motor findings, “are valid,” Dr. Myer said.

“I think [the findings] could be real,” said Clair Henchcliffe, MD, DPhil, vice chair for clinical research in the department of neurology at Weill Cornell Medical College in New York.

“Other publications have shown that people who have cognitive symptoms at onset are more likely to go on to develop dementia down the line. This is much in line with that,” she said when asked for comment.

The field has “always been interested in finding data that help us personalize treatment, and a lot of people are looking to subtype Parkinson’s disease to help us plan with our patients.” It could also help with frequency of follow-up, trial participation, and maybe someday treatment selection. “We are always thinking a few years ahead” with Parkinson’s disease, she said.

There was no industry funding, and the investigators did not have any relevant disclosures.

[email protected]

ST. LOUIS – Dementia and death were about four times more likely after 11 years in patients with Parkinson’s disease and cognitive or psychiatric symptoms at baseline, versus those with motor symptoms alone, according to the results of a longitudinal study of 162 patients at Washington University, St. Louis.

Parkinson’s disease is often only staged as mild, moderate, or severe, and sometimes cognitive and psychiatric symptoms are not assessed. The St. Louis team wanted to see if there are actual subtypes, and if they have clinical relevance, said lead investigator Peter Myers, PhD, a postdoctoral research associate at Washington University.

The magnitude of the findings was “surprising. ... We don’t think we are seeing stages” because the different symptom patterns were apparent at baseline. Instead, “we are seeing really distinct clinical subtypes that could inform patient prognosis and help prepare families and caregivers. It is important that you assess more than just motor symptoms,” he said at the annual meeting of the American Neurological Association.

Some of the subjects were newly diagnosed and others diagnosed years earlier. At baseline, they had symptoms for an average of 6 years, and none had dementia.

After a battery of cognitive, psychiatric, and movement tests, Dr. Myers and his colleagues found that their subjects fell into three patterns: motor symptoms only, with normal cognitive and psychiatric performance (63 subjects); motor symptoms plus prominent anxiety or depression (17); and motor symptoms plus cognitive deficits (82).

A total of 42 patients developed dementia – a score of at least 1 on the Clinical Dementia Rating evaluation – including three in the motor-only group (5%), two in the psychiatric/motor group (12%), and 37 in the cognitive/motor group (45%).

After controlling for age, sex, and symptom duration, the risk of dementia conversion was far higher in the cognitive/motor group (relative risk, 4.16, 95% confidence interval, 1.18-14.65) and psychiatric/motor group (RR, 3.08; 95% CI, 0.72-13.28), compared with motor-only subjects.

Thirty-eight patients died, the majority because of Parkinson’s disease-related causes, including five in the motor-only group (8%), two in the psychiatric/motor group (12%), and 31 in the cognitive/motor group (38%).

The risk of death, relative to motor-only patients, was higher with both the cognitive/motor (RR, 4.06; 95% CI, 1.37-12.03) and psychiatric/motor subtypes (RR, 4.17; 95% CI, 0.70-24.91).

It is unclear what leads to the progression differences, but the researchers’ hypothesis is that the broader scope of symptoms indicates a greater extent of brain pathology. The St. Louis team is looking at brain-imaging data to see if that is true, and if the subtypes can be distinguished on imaging. They are also interested in seeing if genetics plays a role in susceptibility to the different subtypes, and if the baseline subtypes are stable over time or if patients convert between them.

Subjects were, on average, 66 years old, and 62% were men. The mean levodopa-equivalent daily dose was 613 mg in the motor-only group, 1,004 mg in the psychiatric/motor group, and 783 mg in the cognitive/motor group (P = .03). Mean symptom duration was shorter in motor-only patients (5.1 years) versus the psychiatric/motor group (7.2 years) and cognitive/motor group (6.9 years, P less than .01).

Although relative risks crossed 1 in the psychiatric/motor group, it was probably because there were only 17 patients. “We do think there is a very strong likelihood that” the psychiatric/motor findings, like the cognitive/motor findings, “are valid,” Dr. Myer said.

“I think [the findings] could be real,” said Clair Henchcliffe, MD, DPhil, vice chair for clinical research in the department of neurology at Weill Cornell Medical College in New York.

“Other publications have shown that people who have cognitive symptoms at onset are more likely to go on to develop dementia down the line. This is much in line with that,” she said when asked for comment.

The field has “always been interested in finding data that help us personalize treatment, and a lot of people are looking to subtype Parkinson’s disease to help us plan with our patients.” It could also help with frequency of follow-up, trial participation, and maybe someday treatment selection. “We are always thinking a few years ahead” with Parkinson’s disease, she said.

There was no industry funding, and the investigators did not have any relevant disclosures.

[email protected]

ST. LOUIS – Dementia and death were about four times more likely after 11 years in patients with Parkinson’s disease and cognitive or psychiatric symptoms at baseline, versus those with motor symptoms alone, according to the results of a longitudinal study of 162 patients at Washington University, St. Louis.

Parkinson’s disease is often only staged as mild, moderate, or severe, and sometimes cognitive and psychiatric symptoms are not assessed. The St. Louis team wanted to see if there are actual subtypes, and if they have clinical relevance, said lead investigator Peter Myers, PhD, a postdoctoral research associate at Washington University.

The magnitude of the findings was “surprising. ... We don’t think we are seeing stages” because the different symptom patterns were apparent at baseline. Instead, “we are seeing really distinct clinical subtypes that could inform patient prognosis and help prepare families and caregivers. It is important that you assess more than just motor symptoms,” he said at the annual meeting of the American Neurological Association.

Some of the subjects were newly diagnosed and others diagnosed years earlier. At baseline, they had symptoms for an average of 6 years, and none had dementia.

After a battery of cognitive, psychiatric, and movement tests, Dr. Myers and his colleagues found that their subjects fell into three patterns: motor symptoms only, with normal cognitive and psychiatric performance (63 subjects); motor symptoms plus prominent anxiety or depression (17); and motor symptoms plus cognitive deficits (82).

A total of 42 patients developed dementia – a score of at least 1 on the Clinical Dementia Rating evaluation – including three in the motor-only group (5%), two in the psychiatric/motor group (12%), and 37 in the cognitive/motor group (45%).

After controlling for age, sex, and symptom duration, the risk of dementia conversion was far higher in the cognitive/motor group (relative risk, 4.16, 95% confidence interval, 1.18-14.65) and psychiatric/motor group (RR, 3.08; 95% CI, 0.72-13.28), compared with motor-only subjects.

Thirty-eight patients died, the majority because of Parkinson’s disease-related causes, including five in the motor-only group (8%), two in the psychiatric/motor group (12%), and 31 in the cognitive/motor group (38%).

The risk of death, relative to motor-only patients, was higher with both the cognitive/motor (RR, 4.06; 95% CI, 1.37-12.03) and psychiatric/motor subtypes (RR, 4.17; 95% CI, 0.70-24.91).

It is unclear what leads to the progression differences, but the researchers’ hypothesis is that the broader scope of symptoms indicates a greater extent of brain pathology. The St. Louis team is looking at brain-imaging data to see if that is true, and if the subtypes can be distinguished on imaging. They are also interested in seeing if genetics plays a role in susceptibility to the different subtypes, and if the baseline subtypes are stable over time or if patients convert between them.

Subjects were, on average, 66 years old, and 62% were men. The mean levodopa-equivalent daily dose was 613 mg in the motor-only group, 1,004 mg in the psychiatric/motor group, and 783 mg in the cognitive/motor group (P = .03). Mean symptom duration was shorter in motor-only patients (5.1 years) versus the psychiatric/motor group (7.2 years) and cognitive/motor group (6.9 years, P less than .01).

Although relative risks crossed 1 in the psychiatric/motor group, it was probably because there were only 17 patients. “We do think there is a very strong likelihood that” the psychiatric/motor findings, like the cognitive/motor findings, “are valid,” Dr. Myer said.

“I think [the findings] could be real,” said Clair Henchcliffe, MD, DPhil, vice chair for clinical research in the department of neurology at Weill Cornell Medical College in New York.

“Other publications have shown that people who have cognitive symptoms at onset are more likely to go on to develop dementia down the line. This is much in line with that,” she said when asked for comment.

The field has “always been interested in finding data that help us personalize treatment, and a lot of people are looking to subtype Parkinson’s disease to help us plan with our patients.” It could also help with frequency of follow-up, trial participation, and maybe someday treatment selection. “We are always thinking a few years ahead” with Parkinson’s disease, she said.

There was no industry funding, and the investigators did not have any relevant disclosures.

[email protected]

Patients with bipolar disorder may be at increased risk of Parkinson’s disease in later life, according to a systematic review and meta-analysis published in JAMA Neurology.

Patrícia R. Faustino, MD, from the faculty of medicine at the University of Lisboa (Portgual), and coauthors reviewed and analyzed seven articles – four cohort studies and three cross-sectional studies – that reported data on idiopathic Parkinson’s disease in patients with bipolar disorder, compared with those without. The meta-analysis found that individuals with a previous diagnosis of bipolar disorder had a 235% higher risk of being later diagnosed with Parkinson’s disease. Even after removing studies with a high risk of bias, the risk was still 3.21 times higher in those with bipolar disorder, compared with those without.

“The pathophysiological rationale between bipolar disorder and Parkinson’s disease might be explained by the dopamine dysregulation hypothesis, which states that the cyclical process of bipolar disorder in manic states leads to a down-regulation of dopamine receptor sensitivity (depression phase), which is later compensated by up-regulation (manic state),” the authors wrote. “Over time, this phenomenon may lead to an overall reduction of dopaminergic activity, the prototypical Parkinson’s disease state.”

Subgroup analysis revealed that subgroups with shorter follow-up periods – less than 9 years – had a greater increase in the risk of a later Parkinson’s disease diagnosis. The authors noted that this could represent misdiagnosis of parkinsonism – possibly drug induced – as Parkinson’s disease. The researchers also raised the possibility that the increased risk of Parkinson’s disease in patients with bipolar disorder could relate to long-term lithium use, rather than being a causal relationship. “However, treatment with lithium is foundational in bipolar disorder, and so to separate the causal effect from a potential confounder would be particularly difficult,” they wrote.

One of the studies included did explore the use of lithium, and found that lithium monotherapy was associated with a significant increase in the risk of being diagnosed with Parkinson’s disease or taking antiparkinsonism medication, compared with antidepressant therapy. However the authors commented that the diagnostic code may not differentiate Parkinson’s disease from other causes of parkinsonism.

Given their findings, the authors suggested that, if patients with bipolar disorder present with parkinsonism features, it may not necessarily be drug induced. In these patients, they recommended an investigation for Parkinson’s disease, perhaps using functional neuroimaging “as Parkinson’s disease classically presents with nigrostriatal degeneration while drug-induced parkinsonism does not.”

Two authors declared grants and personal fees from the pharmaceutical sector. No other conflicts of interest were reported.

SOURCE: Faustino PR et al. JAMA Neurol. 2019 Oct 14. doi: 10.1001/jamaneurol.2019.3446.

Patients with bipolar disorder may be at increased risk of Parkinson’s disease in later life, according to a systematic review and meta-analysis published in JAMA Neurology.

Patrícia R. Faustino, MD, from the faculty of medicine at the University of Lisboa (Portgual), and coauthors reviewed and analyzed seven articles – four cohort studies and three cross-sectional studies – that reported data on idiopathic Parkinson’s disease in patients with bipolar disorder, compared with those without. The meta-analysis found that individuals with a previous diagnosis of bipolar disorder had a 235% higher risk of being later diagnosed with Parkinson’s disease. Even after removing studies with a high risk of bias, the risk was still 3.21 times higher in those with bipolar disorder, compared with those without.

“The pathophysiological rationale between bipolar disorder and Parkinson’s disease might be explained by the dopamine dysregulation hypothesis, which states that the cyclical process of bipolar disorder in manic states leads to a down-regulation of dopamine receptor sensitivity (depression phase), which is later compensated by up-regulation (manic state),” the authors wrote. “Over time, this phenomenon may lead to an overall reduction of dopaminergic activity, the prototypical Parkinson’s disease state.”

Subgroup analysis revealed that subgroups with shorter follow-up periods – less than 9 years – had a greater increase in the risk of a later Parkinson’s disease diagnosis. The authors noted that this could represent misdiagnosis of parkinsonism – possibly drug induced – as Parkinson’s disease. The researchers also raised the possibility that the increased risk of Parkinson’s disease in patients with bipolar disorder could relate to long-term lithium use, rather than being a causal relationship. “However, treatment with lithium is foundational in bipolar disorder, and so to separate the causal effect from a potential confounder would be particularly difficult,” they wrote.

One of the studies included did explore the use of lithium, and found that lithium monotherapy was associated with a significant increase in the risk of being diagnosed with Parkinson’s disease or taking antiparkinsonism medication, compared with antidepressant therapy. However the authors commented that the diagnostic code may not differentiate Parkinson’s disease from other causes of parkinsonism.

Given their findings, the authors suggested that, if patients with bipolar disorder present with parkinsonism features, it may not necessarily be drug induced. In these patients, they recommended an investigation for Parkinson’s disease, perhaps using functional neuroimaging “as Parkinson’s disease classically presents with nigrostriatal degeneration while drug-induced parkinsonism does not.”

Two authors declared grants and personal fees from the pharmaceutical sector. No other conflicts of interest were reported.

SOURCE: Faustino PR et al. JAMA Neurol. 2019 Oct 14. doi: 10.1001/jamaneurol.2019.3446.

Patients with bipolar disorder may be at increased risk of Parkinson’s disease in later life, according to a systematic review and meta-analysis published in JAMA Neurology.

Patrícia R. Faustino, MD, from the faculty of medicine at the University of Lisboa (Portgual), and coauthors reviewed and analyzed seven articles – four cohort studies and three cross-sectional studies – that reported data on idiopathic Parkinson’s disease in patients with bipolar disorder, compared with those without. The meta-analysis found that individuals with a previous diagnosis of bipolar disorder had a 235% higher risk of being later diagnosed with Parkinson’s disease. Even after removing studies with a high risk of bias, the risk was still 3.21 times higher in those with bipolar disorder, compared with those without.

“The pathophysiological rationale between bipolar disorder and Parkinson’s disease might be explained by the dopamine dysregulation hypothesis, which states that the cyclical process of bipolar disorder in manic states leads to a down-regulation of dopamine receptor sensitivity (depression phase), which is later compensated by up-regulation (manic state),” the authors wrote. “Over time, this phenomenon may lead to an overall reduction of dopaminergic activity, the prototypical Parkinson’s disease state.”

Subgroup analysis revealed that subgroups with shorter follow-up periods – less than 9 years – had a greater increase in the risk of a later Parkinson’s disease diagnosis. The authors noted that this could represent misdiagnosis of parkinsonism – possibly drug induced – as Parkinson’s disease. The researchers also raised the possibility that the increased risk of Parkinson’s disease in patients with bipolar disorder could relate to long-term lithium use, rather than being a causal relationship. “However, treatment with lithium is foundational in bipolar disorder, and so to separate the causal effect from a potential confounder would be particularly difficult,” they wrote.

One of the studies included did explore the use of lithium, and found that lithium monotherapy was associated with a significant increase in the risk of being diagnosed with Parkinson’s disease or taking antiparkinsonism medication, compared with antidepressant therapy. However the authors commented that the diagnostic code may not differentiate Parkinson’s disease from other causes of parkinsonism.

Given their findings, the authors suggested that, if patients with bipolar disorder present with parkinsonism features, it may not necessarily be drug induced. In these patients, they recommended an investigation for Parkinson’s disease, perhaps using functional neuroimaging “as Parkinson’s disease classically presents with nigrostriatal degeneration while drug-induced parkinsonism does not.”

Two authors declared grants and personal fees from the pharmaceutical sector. No other conflicts of interest were reported.

SOURCE: Faustino PR et al. JAMA Neurol. 2019 Oct 14. doi: 10.1001/jamaneurol.2019.3446.

The Food and Drug Administration on Aug. 27 approved Nourianz (istradefylline) tablets as an add-on treatment to levodopa/carbidopa in adult patients with Parkinson’s disease experiencing off episodes. During off episodes, patients’ medications do not work well, and symptoms such as tremor and difficulty walking increase.

bankrx/Getty Images

The effectiveness of Nourianz for this indication was shown in four 12-week placebo-controlled clinical studies that included 1,143 participants. In all four studies, patients treated with Nourianz experienced a statistically significant decrease from baseline in daily off time, compared with patients who received placebo.

The most common adverse reactions to istradefylline with an incidence of 5% or greater and occurring more frequently than with placebo were dyskinesia (15%, 17%, and 8%, for Nourianz 20 mg, 40 mg, and placebo, respectively), dizziness (3%, 6%, and 4%), constipation (5%, 6%, and 3%), nausea (4%, 6%, and 5%), hallucination (2%, 6%, and 3%), and insomnia (1%, 6%, and 4%). In clinical trials, 1% of patients treated with Nourianz 20 mg or 40 mg discontinued treatment because of dyskinesia, compared with no patients who received placebo.

In addition,one patient treated with Nourianz 40 mg experienced impulse control disorder, compared with no patients who received Nourianz 20 mg or placebo.

If hallucinations, psychotic behavior, or impulsive or compulsive behavior occurs, a dosage reduction or stoppage should be considered, according to the FDA. Use of Nourianz during pregnancy is not recommended, and women of childbearing potential should be advised to use contraception during treatment.

The maximum recommended dosage in patients taking strong CYP3A4 inhibitors is 20 mg once daily, and clinicians should avoid use of Nourianz with strong CYP3A4 inducers.

Istradefylline is the first adenosine A_2A receptor antagonist for use in Parkinson’s disease in the United States, and the drug provides patients with a novel nondopaminergic daily oral treatment option, according to a news release from Kyowa Kirin, the company that markets the drug.

Since 2013, istradefylline has been marketed at Nouriast in Japan, where it is indicated for the wearing-off phenomenon in patients with Parkinson’s disease who take preparations containing levodopa.

[email protected]

The Food and Drug Administration on Aug. 27 approved Nourianz (istradefylline) tablets as an add-on treatment to levodopa/carbidopa in adult patients with Parkinson’s disease experiencing off episodes. During off episodes, patients’ medications do not work well, and symptoms such as tremor and difficulty walking increase.

bankrx/Getty Images

The effectiveness of Nourianz for this indication was shown in four 12-week placebo-controlled clinical studies that included 1,143 participants. In all four studies, patients treated with Nourianz experienced a statistically significant decrease from baseline in daily off time, compared with patients who received placebo.

The most common adverse reactions to istradefylline with an incidence of 5% or greater and occurring more frequently than with placebo were dyskinesia (15%, 17%, and 8%, for Nourianz 20 mg, 40 mg, and placebo, respectively), dizziness (3%, 6%, and 4%), constipation (5%, 6%, and 3%), nausea (4%, 6%, and 5%), hallucination (2%, 6%, and 3%), and insomnia (1%, 6%, and 4%). In clinical trials, 1% of patients treated with Nourianz 20 mg or 40 mg discontinued treatment because of dyskinesia, compared with no patients who received placebo.

In addition,one patient treated with Nourianz 40 mg experienced impulse control disorder, compared with no patients who received Nourianz 20 mg or placebo.

If hallucinations, psychotic behavior, or impulsive or compulsive behavior occurs, a dosage reduction or stoppage should be considered, according to the FDA. Use of Nourianz during pregnancy is not recommended, and women of childbearing potential should be advised to use contraception during treatment.

The maximum recommended dosage in patients taking strong CYP3A4 inhibitors is 20 mg once daily, and clinicians should avoid use of Nourianz with strong CYP3A4 inducers.

Istradefylline is the first adenosine A_2A receptor antagonist for use in Parkinson’s disease in the United States, and the drug provides patients with a novel nondopaminergic daily oral treatment option, according to a news release from Kyowa Kirin, the company that markets the drug.

Since 2013, istradefylline has been marketed at Nouriast in Japan, where it is indicated for the wearing-off phenomenon in patients with Parkinson’s disease who take preparations containing levodopa.

[email protected]

The Food and Drug Administration on Aug. 27 approved Nourianz (istradefylline) tablets as an add-on treatment to levodopa/carbidopa in adult patients with Parkinson’s disease experiencing off episodes. During off episodes, patients’ medications do not work well, and symptoms such as tremor and difficulty walking increase.

bankrx/Getty Images

The effectiveness of Nourianz for this indication was shown in four 12-week placebo-controlled clinical studies that included 1,143 participants. In all four studies, patients treated with Nourianz experienced a statistically significant decrease from baseline in daily off time, compared with patients who received placebo.

The most common adverse reactions to istradefylline with an incidence of 5% or greater and occurring more frequently than with placebo were dyskinesia (15%, 17%, and 8%, for Nourianz 20 mg, 40 mg, and placebo, respectively), dizziness (3%, 6%, and 4%), constipation (5%, 6%, and 3%), nausea (4%, 6%, and 5%), hallucination (2%, 6%, and 3%), and insomnia (1%, 6%, and 4%). In clinical trials, 1% of patients treated with Nourianz 20 mg or 40 mg discontinued treatment because of dyskinesia, compared with no patients who received placebo.

In addition,one patient treated with Nourianz 40 mg experienced impulse control disorder, compared with no patients who received Nourianz 20 mg or placebo.

If hallucinations, psychotic behavior, or impulsive or compulsive behavior occurs, a dosage reduction or stoppage should be considered, according to the FDA. Use of Nourianz during pregnancy is not recommended, and women of childbearing potential should be advised to use contraception during treatment.

The maximum recommended dosage in patients taking strong CYP3A4 inhibitors is 20 mg once daily, and clinicians should avoid use of Nourianz with strong CYP3A4 inducers.

Istradefylline is the first adenosine A_2A receptor antagonist for use in Parkinson’s disease in the United States, and the drug provides patients with a novel nondopaminergic daily oral treatment option, according to a news release from Kyowa Kirin, the company that markets the drug.

Since 2013, istradefylline has been marketed at Nouriast in Japan, where it is indicated for the wearing-off phenomenon in patients with Parkinson’s disease who take preparations containing levodopa.

[email protected]