World Parkinson's Congress 2016

PORTLAND, ORE. – Implantation of dopamine-producing cells to replace those lost in the substantia nigra has been seen as the cure for Parkinson’s disease, with many attempts in patients over the years. Along the way, a few successes have occurred, but in general, cell-based therapies have produced mixed results.

“When it works well, it works very well with fetal dopamine cells, but it does not always work well,” said Roger Barker, MBBS, PhD, of the department of clinical neurosciences at the University of Cambridge (England). In his lecture to a large, capacity crowd at the World Parkinson Congress, he reviewed the field going back more than three decades and drew “lessons learned” from the results of animal experiments and human trials.

©Sohel Parvez Haque/Thinkstock

He said dopamine-producing cell therapy will never cure the disease, although it works well early in the disease “but creates problems later,” with off-target and nonphysiologic effects in other parts of the brain, such as overstimulation. One exception was the use of fetal dopamine cells in an animal model, showing that cells could survive long-term, connect and integrate into the brain, release dopamine, and restore behaviors to normal if cells from the same species were used at the right developmental stage of the animal and implanted where dopamine normally works, that is, in the striatum.

Other problems reported from human trials using embryonic dopamine neurons or fetal nigral transplants have been graft-induced dyskinesias, but without clinical benefit, as well as Lewy bodies in grafted neurons, suggesting host-to-graft disease propagation. However, in another report, a patient had a clinical benefit and showed extensive graft-derived dopaminergic innervation 24 years after transplantation, at which time the patient died.

Lessons learned over time

Dr. Barker explained that the variable results that have been achieved in various trials using different protocols and nonstandardized approaches over the years make it “extremely difficult to make any conclusions.” These variations included performing tests on different kinds of patients and using different doses of cells, delivery approaches, immunosuppression, primary endpoints of the trials, and levels of follow-up.

The age of the patient, disease stage, and graft technique emerged as key issues in data gathered from the trials, he said. The best chance of success occurred in younger patients with less advanced disease, when grafting occurred across the whole striatum evenly, and when contamination with 5-hydroxytryptamine (serotonin) neurons was avoided.

Going forward, trials in Parkinson’s disease are planned or underway using embryonic/fetal stem cells or adult stem cells. Such cells provide logistical advantages in that their differentiation can be controlled more easily and they are a defined product. Nigral dopaminergic cells can be produced from human embryonic stem cells that behave like human fetal ventral midbrain dopamine cells in vitro and in vivo in rats and show similar efficacy and potency.

The Center for iPS Cell Research and Application in Kyoto, Japan, will conduct a trial using induced pluripotent stem (iPS) cells beginning next year, the New York State Stem Cell Science Consortia (NYSTEM) will use human embryonic stem cells beginning in 2018, and around the same time the European Union’s NeuroStemCellRepair network will also use human embryonic stem cells. In addition, the European TRANSEURO trial, coordinated by Dr. Barker, is planning a single-arm, multicenter, dose-escalation trial for 2018/2019 using intracerebral neurotransplantation of dopaminergic neurons derived from human embryonic stem cells. Participating patients will be younger than 65 years with less than 10 years disease duration, no significant levodopa-induced dyskinesia, and no cognitive or psychiatric problems.

From these trials, scientists hope to eventually produce a human embryonic stem cell–derived dopaminergic cell product made under GMP (good manufacturing practice) conditions that can be tested for safety and efficacy and put into clinical trials, with an ultimate goal of production and commercialization.

Finally, Dr. Barker alerted physicians to published guidance from the International Society for Stem Cell Research that can help them critically evaluate any cell-based clinical trial that they may be asked to run. And for patients, large numbers of whom attended the conference, he advised avoiding any “trial” that would charge them to participate because legitimate research trials do not charge for experimental therapies.

Asked to comment on the field, Peter LeWitt, MD, director of the Parkinson’s Disease and Movement Disorders Program at Henry Ford Hospital, West Bloomfield, Mich., and professor of neurology at Wayne State University, Detroit, said, “The jury is out and is coming back on stem cells and its alternative, such as fetal tissue. It’s pointing to the bright future of restoring the brain and not just using drugs to mask symptoms.”

He said the critical review of evidence from past trials “sounds like it’s heading towards a more focused view of how to enhance the successes that have occurred already – the 24-year outcomes [of] the patients who have met all biological plausibility improvements at this point. ... The science has moved along to improve their techniques of judging success and failure and sorting out partial benefits.”

Dr. Barker reported that he sits on an advisory board of Teva-Lundbeck and has advised and received honoraria from Solvay, GSK, Eli Lilly, and Pfizer, receives royalties from Springer, Wiley, and Cambridge University Press, and receives grant support from various institutes and foundations, Dr. LeWitt reported no relevant conflicts of interest.

PORTLAND, ORE. – Implantation of dopamine-producing cells to replace those lost in the substantia nigra has been seen as the cure for Parkinson’s disease, with many attempts in patients over the years. Along the way, a few successes have occurred, but in general, cell-based therapies have produced mixed results.

“When it works well, it works very well with fetal dopamine cells, but it does not always work well,” said Roger Barker, MBBS, PhD, of the department of clinical neurosciences at the University of Cambridge (England). In his lecture to a large, capacity crowd at the World Parkinson Congress, he reviewed the field going back more than three decades and drew “lessons learned” from the results of animal experiments and human trials.

©Sohel Parvez Haque/Thinkstock

He said dopamine-producing cell therapy will never cure the disease, although it works well early in the disease “but creates problems later,” with off-target and nonphysiologic effects in other parts of the brain, such as overstimulation. One exception was the use of fetal dopamine cells in an animal model, showing that cells could survive long-term, connect and integrate into the brain, release dopamine, and restore behaviors to normal if cells from the same species were used at the right developmental stage of the animal and implanted where dopamine normally works, that is, in the striatum.

Other problems reported from human trials using embryonic dopamine neurons or fetal nigral transplants have been graft-induced dyskinesias, but without clinical benefit, as well as Lewy bodies in grafted neurons, suggesting host-to-graft disease propagation. However, in another report, a patient had a clinical benefit and showed extensive graft-derived dopaminergic innervation 24 years after transplantation, at which time the patient died.

Lessons learned over time

Dr. Barker explained that the variable results that have been achieved in various trials using different protocols and nonstandardized approaches over the years make it “extremely difficult to make any conclusions.” These variations included performing tests on different kinds of patients and using different doses of cells, delivery approaches, immunosuppression, primary endpoints of the trials, and levels of follow-up.

The age of the patient, disease stage, and graft technique emerged as key issues in data gathered from the trials, he said. The best chance of success occurred in younger patients with less advanced disease, when grafting occurred across the whole striatum evenly, and when contamination with 5-hydroxytryptamine (serotonin) neurons was avoided.

Going forward, trials in Parkinson’s disease are planned or underway using embryonic/fetal stem cells or adult stem cells. Such cells provide logistical advantages in that their differentiation can be controlled more easily and they are a defined product. Nigral dopaminergic cells can be produced from human embryonic stem cells that behave like human fetal ventral midbrain dopamine cells in vitro and in vivo in rats and show similar efficacy and potency.

The Center for iPS Cell Research and Application in Kyoto, Japan, will conduct a trial using induced pluripotent stem (iPS) cells beginning next year, the New York State Stem Cell Science Consortia (NYSTEM) will use human embryonic stem cells beginning in 2018, and around the same time the European Union’s NeuroStemCellRepair network will also use human embryonic stem cells. In addition, the European TRANSEURO trial, coordinated by Dr. Barker, is planning a single-arm, multicenter, dose-escalation trial for 2018/2019 using intracerebral neurotransplantation of dopaminergic neurons derived from human embryonic stem cells. Participating patients will be younger than 65 years with less than 10 years disease duration, no significant levodopa-induced dyskinesia, and no cognitive or psychiatric problems.

From these trials, scientists hope to eventually produce a human embryonic stem cell–derived dopaminergic cell product made under GMP (good manufacturing practice) conditions that can be tested for safety and efficacy and put into clinical trials, with an ultimate goal of production and commercialization.

Finally, Dr. Barker alerted physicians to published guidance from the International Society for Stem Cell Research that can help them critically evaluate any cell-based clinical trial that they may be asked to run. And for patients, large numbers of whom attended the conference, he advised avoiding any “trial” that would charge them to participate because legitimate research trials do not charge for experimental therapies.

Asked to comment on the field, Peter LeWitt, MD, director of the Parkinson’s Disease and Movement Disorders Program at Henry Ford Hospital, West Bloomfield, Mich., and professor of neurology at Wayne State University, Detroit, said, “The jury is out and is coming back on stem cells and its alternative, such as fetal tissue. It’s pointing to the bright future of restoring the brain and not just using drugs to mask symptoms.”

He said the critical review of evidence from past trials “sounds like it’s heading towards a more focused view of how to enhance the successes that have occurred already – the 24-year outcomes [of] the patients who have met all biological plausibility improvements at this point. ... The science has moved along to improve their techniques of judging success and failure and sorting out partial benefits.”

Dr. Barker reported that he sits on an advisory board of Teva-Lundbeck and has advised and received honoraria from Solvay, GSK, Eli Lilly, and Pfizer, receives royalties from Springer, Wiley, and Cambridge University Press, and receives grant support from various institutes and foundations, Dr. LeWitt reported no relevant conflicts of interest.

PORTLAND, ORE. – Implantation of dopamine-producing cells to replace those lost in the substantia nigra has been seen as the cure for Parkinson’s disease, with many attempts in patients over the years. Along the way, a few successes have occurred, but in general, cell-based therapies have produced mixed results.

“When it works well, it works very well with fetal dopamine cells, but it does not always work well,” said Roger Barker, MBBS, PhD, of the department of clinical neurosciences at the University of Cambridge (England). In his lecture to a large, capacity crowd at the World Parkinson Congress, he reviewed the field going back more than three decades and drew “lessons learned” from the results of animal experiments and human trials.

©Sohel Parvez Haque/Thinkstock

He said dopamine-producing cell therapy will never cure the disease, although it works well early in the disease “but creates problems later,” with off-target and nonphysiologic effects in other parts of the brain, such as overstimulation. One exception was the use of fetal dopamine cells in an animal model, showing that cells could survive long-term, connect and integrate into the brain, release dopamine, and restore behaviors to normal if cells from the same species were used at the right developmental stage of the animal and implanted where dopamine normally works, that is, in the striatum.

Other problems reported from human trials using embryonic dopamine neurons or fetal nigral transplants have been graft-induced dyskinesias, but without clinical benefit, as well as Lewy bodies in grafted neurons, suggesting host-to-graft disease propagation. However, in another report, a patient had a clinical benefit and showed extensive graft-derived dopaminergic innervation 24 years after transplantation, at which time the patient died.

Lessons learned over time

Dr. Barker explained that the variable results that have been achieved in various trials using different protocols and nonstandardized approaches over the years make it “extremely difficult to make any conclusions.” These variations included performing tests on different kinds of patients and using different doses of cells, delivery approaches, immunosuppression, primary endpoints of the trials, and levels of follow-up.

The age of the patient, disease stage, and graft technique emerged as key issues in data gathered from the trials, he said. The best chance of success occurred in younger patients with less advanced disease, when grafting occurred across the whole striatum evenly, and when contamination with 5-hydroxytryptamine (serotonin) neurons was avoided.

Going forward, trials in Parkinson’s disease are planned or underway using embryonic/fetal stem cells or adult stem cells. Such cells provide logistical advantages in that their differentiation can be controlled more easily and they are a defined product. Nigral dopaminergic cells can be produced from human embryonic stem cells that behave like human fetal ventral midbrain dopamine cells in vitro and in vivo in rats and show similar efficacy and potency.

The Center for iPS Cell Research and Application in Kyoto, Japan, will conduct a trial using induced pluripotent stem (iPS) cells beginning next year, the New York State Stem Cell Science Consortia (NYSTEM) will use human embryonic stem cells beginning in 2018, and around the same time the European Union’s NeuroStemCellRepair network will also use human embryonic stem cells. In addition, the European TRANSEURO trial, coordinated by Dr. Barker, is planning a single-arm, multicenter, dose-escalation trial for 2018/2019 using intracerebral neurotransplantation of dopaminergic neurons derived from human embryonic stem cells. Participating patients will be younger than 65 years with less than 10 years disease duration, no significant levodopa-induced dyskinesia, and no cognitive or psychiatric problems.

From these trials, scientists hope to eventually produce a human embryonic stem cell–derived dopaminergic cell product made under GMP (good manufacturing practice) conditions that can be tested for safety and efficacy and put into clinical trials, with an ultimate goal of production and commercialization.

Finally, Dr. Barker alerted physicians to published guidance from the International Society for Stem Cell Research that can help them critically evaluate any cell-based clinical trial that they may be asked to run. And for patients, large numbers of whom attended the conference, he advised avoiding any “trial” that would charge them to participate because legitimate research trials do not charge for experimental therapies.

Asked to comment on the field, Peter LeWitt, MD, director of the Parkinson’s Disease and Movement Disorders Program at Henry Ford Hospital, West Bloomfield, Mich., and professor of neurology at Wayne State University, Detroit, said, “The jury is out and is coming back on stem cells and its alternative, such as fetal tissue. It’s pointing to the bright future of restoring the brain and not just using drugs to mask symptoms.”

He said the critical review of evidence from past trials “sounds like it’s heading towards a more focused view of how to enhance the successes that have occurred already – the 24-year outcomes [of] the patients who have met all biological plausibility improvements at this point. ... The science has moved along to improve their techniques of judging success and failure and sorting out partial benefits.”

Dr. Barker reported that he sits on an advisory board of Teva-Lundbeck and has advised and received honoraria from Solvay, GSK, Eli Lilly, and Pfizer, receives royalties from Springer, Wiley, and Cambridge University Press, and receives grant support from various institutes and foundations, Dr. LeWitt reported no relevant conflicts of interest.

PORTLAND, OR—Most patients with advanced Parkinson’s disease who received levodopa–carbidopa intestinal gel in an open-label, continued-access-to-treatment study had, at five years, transitioned to using the therapy outside of the study when it became commercially available or continued to participate in the extension study, according to data presented at the Fourth World Parkinson Congress.

Forty-two percent of the patients in the phase III extension study transitioned to commercially available drug (designated as carbidopa–levodopa enteral suspension in the United States), and 24% of patients remained in the multinational study, said Hubert H. Fernandez, MD, Head of Movement Disorders at the Center for Neurological Restoration at the Cleveland Clinic in Ohio, and colleagues. Patients may remain in the extension study until a commercially available product is available in the country where they live.

Levodopa–carbidopa intestinal gel is infused continuously directly to the jejunum using a portable pump during approximately 16 hours of wakefulness. The therapy is designed to overcome some of the limitations of oral levodopa, which may lose effectiveness as Parkinson’s disease progresses.

Although investigators observed a high incidence of adverse events, long-term use of levodopa–carbidopa intestinal gel was well tolerated, the researchers said. The average discontinuation rate of 9.6% per year, including all causes of death, was relatively low, Dr. Fernandez and colleagues said.

The most frequently reported adverse events were associated with complications related to percutaneous gastrojejunostomy, such as stoma site maintenance. Other adverse events were associated with advanced Parkinson’s disease, aging, or levodopa. Most patients experienced device malfunctions and required pump replacement during the study.

The extension study began in November 2009. Data through September 30, 2015, were used in the present study. The study enrolled 262 patients with advanced Parkinson’s disease from 11 countries who had completed a 12-week double-blind study and its 52-week open-label extension or who had completed a separate 54-week open-label study. Participants attended scheduled study visits every six months.

Patients had a mean age of 64, 62% were male, and mean disease duration was 11.4 years. Mean exposure to levodopa–carbidopa intestinal gel was 3.1 years in the present study. Patients’ mean total exposure to the treatment was 4.1 years. Fifty-six percent of patients were exposed to the treatment for at least five years.

Adverse events led to discontinuation in 62 patients (24%). Device complaints occurred in 244 patients (93%). The most common device complaints included device malfunction (85%), device occlusion (57%), and device dislocation (56%). Thirty-eight patients died during the study. Two patients died as a result of intestinal dilatation and cardiac arrest, which an investigator considered possibly related to the treatment.

As part of an amended study protocol, patients in the United States began completing efficacy assessments in December 2013 (ie, Parkinson’s disease diary, Unified Parkinson’s Disease Rating Scale, and the Parkinson’s Disease Questionnaire). Patients in the United States showed sustained and clinically meaningful benefits of treatment that were demonstrated by decreased off time and increased on time without troublesome dyskinesia, the researchers concluded.

—Jake Remaly

PORTLAND, OR—Most patients with advanced Parkinson’s disease who received levodopa–carbidopa intestinal gel in an open-label, continued-access-to-treatment study had, at five years, transitioned to using the therapy outside of the study when it became commercially available or continued to participate in the extension study, according to data presented at the Fourth World Parkinson Congress.

Forty-two percent of the patients in the phase III extension study transitioned to commercially available drug (designated as carbidopa–levodopa enteral suspension in the United States), and 24% of patients remained in the multinational study, said Hubert H. Fernandez, MD, Head of Movement Disorders at the Center for Neurological Restoration at the Cleveland Clinic in Ohio, and colleagues. Patients may remain in the extension study until a commercially available product is available in the country where they live.

Levodopa–carbidopa intestinal gel is infused continuously directly to the jejunum using a portable pump during approximately 16 hours of wakefulness. The therapy is designed to overcome some of the limitations of oral levodopa, which may lose effectiveness as Parkinson’s disease progresses.

Although investigators observed a high incidence of adverse events, long-term use of levodopa–carbidopa intestinal gel was well tolerated, the researchers said. The average discontinuation rate of 9.6% per year, including all causes of death, was relatively low, Dr. Fernandez and colleagues said.

The most frequently reported adverse events were associated with complications related to percutaneous gastrojejunostomy, such as stoma site maintenance. Other adverse events were associated with advanced Parkinson’s disease, aging, or levodopa. Most patients experienced device malfunctions and required pump replacement during the study.

The extension study began in November 2009. Data through September 30, 2015, were used in the present study. The study enrolled 262 patients with advanced Parkinson’s disease from 11 countries who had completed a 12-week double-blind study and its 52-week open-label extension or who had completed a separate 54-week open-label study. Participants attended scheduled study visits every six months.

Patients had a mean age of 64, 62% were male, and mean disease duration was 11.4 years. Mean exposure to levodopa–carbidopa intestinal gel was 3.1 years in the present study. Patients’ mean total exposure to the treatment was 4.1 years. Fifty-six percent of patients were exposed to the treatment for at least five years.

Adverse events led to discontinuation in 62 patients (24%). Device complaints occurred in 244 patients (93%). The most common device complaints included device malfunction (85%), device occlusion (57%), and device dislocation (56%). Thirty-eight patients died during the study. Two patients died as a result of intestinal dilatation and cardiac arrest, which an investigator considered possibly related to the treatment.

As part of an amended study protocol, patients in the United States began completing efficacy assessments in December 2013 (ie, Parkinson’s disease diary, Unified Parkinson’s Disease Rating Scale, and the Parkinson’s Disease Questionnaire). Patients in the United States showed sustained and clinically meaningful benefits of treatment that were demonstrated by decreased off time and increased on time without troublesome dyskinesia, the researchers concluded.

—Jake Remaly

PORTLAND, OR—Most patients with advanced Parkinson’s disease who received levodopa–carbidopa intestinal gel in an open-label, continued-access-to-treatment study had, at five years, transitioned to using the therapy outside of the study when it became commercially available or continued to participate in the extension study, according to data presented at the Fourth World Parkinson Congress.

Forty-two percent of the patients in the phase III extension study transitioned to commercially available drug (designated as carbidopa–levodopa enteral suspension in the United States), and 24% of patients remained in the multinational study, said Hubert H. Fernandez, MD, Head of Movement Disorders at the Center for Neurological Restoration at the Cleveland Clinic in Ohio, and colleagues. Patients may remain in the extension study until a commercially available product is available in the country where they live.

Levodopa–carbidopa intestinal gel is infused continuously directly to the jejunum using a portable pump during approximately 16 hours of wakefulness. The therapy is designed to overcome some of the limitations of oral levodopa, which may lose effectiveness as Parkinson’s disease progresses.

Although investigators observed a high incidence of adverse events, long-term use of levodopa–carbidopa intestinal gel was well tolerated, the researchers said. The average discontinuation rate of 9.6% per year, including all causes of death, was relatively low, Dr. Fernandez and colleagues said.

The most frequently reported adverse events were associated with complications related to percutaneous gastrojejunostomy, such as stoma site maintenance. Other adverse events were associated with advanced Parkinson’s disease, aging, or levodopa. Most patients experienced device malfunctions and required pump replacement during the study.

The extension study began in November 2009. Data through September 30, 2015, were used in the present study. The study enrolled 262 patients with advanced Parkinson’s disease from 11 countries who had completed a 12-week double-blind study and its 52-week open-label extension or who had completed a separate 54-week open-label study. Participants attended scheduled study visits every six months.

Patients had a mean age of 64, 62% were male, and mean disease duration was 11.4 years. Mean exposure to levodopa–carbidopa intestinal gel was 3.1 years in the present study. Patients’ mean total exposure to the treatment was 4.1 years. Fifty-six percent of patients were exposed to the treatment for at least five years.

Adverse events led to discontinuation in 62 patients (24%). Device complaints occurred in 244 patients (93%). The most common device complaints included device malfunction (85%), device occlusion (57%), and device dislocation (56%). Thirty-eight patients died during the study. Two patients died as a result of intestinal dilatation and cardiac arrest, which an investigator considered possibly related to the treatment.

As part of an amended study protocol, patients in the United States began completing efficacy assessments in December 2013 (ie, Parkinson’s disease diary, Unified Parkinson’s Disease Rating Scale, and the Parkinson’s Disease Questionnaire). Patients in the United States showed sustained and clinically meaningful benefits of treatment that were demonstrated by decreased off time and increased on time without troublesome dyskinesia, the researchers concluded.

—Jake Remaly

PORTLAND, OR—Higher serum levels of polychlorinated biphenyls (PCBs) are associated with increased risk of Parkinson’s disease in two independent study populations, according to research presented at the Fourth World Parkinson Congress.

PCBs are persistent environmental pollutants that are detectable in most people despite a worldwide ban on their production that has been in place for more than 20 years. PCBs cause selective dopaminergic toxicity in animal models, but have been minimally studied in Parkinson’s disease, the researchers said.

The investigators recently reported a significantly increased risk of Parkinson’s disease associated with higher levels of serum PCBs in a case–control study of Alaska Native people. In the present study, they investigated this association in a demographically dissimilar study population.

They identified people with Parkinson’s disease within the Agricultural Health Study, a cohort of pesticide applicators and their spouses in Iowa and North Carolina. They also randomly selected controls matched for age, sex, and state. They confirmed Parkinson’s disease diagnoses by in-person neurologist evaluation and consensus review. PCB congeners 118, 138, 153, and 180 were measured as ng/g lipid in serum using gas chromatography-mass spectroscopy. To assess dose-response, the researchers constructed quartiles for each congener and for the sum of congeners. The used logistic regression, adjusting for age, gender, and state, to calculate odds ratios.

Ninety-seven people with Parkinson’s disease and 113 controls were included in the study. About 25% of the participants were women. Mean age was 69. Parkinson’s disease was associated with higher levels of PCBs. A significant dose-response was seen across quartiles. Participants in the second, third, and fourth quartiles of total PCB levels had a 1.7-, 2.4-, and 2.7-fold greater risk of Parkinson’s disease, respectively, compared with participants in the lowest quartile of total PCB levels. Odds ratios were similar in the Agricultural Heath Study and the Alaska study. In both studies, PCB levels correlated positively with age but not with disease duration, which argues against reverse causation, the researchers said.

—Jake Remaly

PORTLAND, OR—Higher serum levels of polychlorinated biphenyls (PCBs) are associated with increased risk of Parkinson’s disease in two independent study populations, according to research presented at the Fourth World Parkinson Congress.

PCBs are persistent environmental pollutants that are detectable in most people despite a worldwide ban on their production that has been in place for more than 20 years. PCBs cause selective dopaminergic toxicity in animal models, but have been minimally studied in Parkinson’s disease, the researchers said.

The investigators recently reported a significantly increased risk of Parkinson’s disease associated with higher levels of serum PCBs in a case–control study of Alaska Native people. In the present study, they investigated this association in a demographically dissimilar study population.

They identified people with Parkinson’s disease within the Agricultural Health Study, a cohort of pesticide applicators and their spouses in Iowa and North Carolina. They also randomly selected controls matched for age, sex, and state. They confirmed Parkinson’s disease diagnoses by in-person neurologist evaluation and consensus review. PCB congeners 118, 138, 153, and 180 were measured as ng/g lipid in serum using gas chromatography-mass spectroscopy. To assess dose-response, the researchers constructed quartiles for each congener and for the sum of congeners. The used logistic regression, adjusting for age, gender, and state, to calculate odds ratios.

Ninety-seven people with Parkinson’s disease and 113 controls were included in the study. About 25% of the participants were women. Mean age was 69. Parkinson’s disease was associated with higher levels of PCBs. A significant dose-response was seen across quartiles. Participants in the second, third, and fourth quartiles of total PCB levels had a 1.7-, 2.4-, and 2.7-fold greater risk of Parkinson’s disease, respectively, compared with participants in the lowest quartile of total PCB levels. Odds ratios were similar in the Agricultural Heath Study and the Alaska study. In both studies, PCB levels correlated positively with age but not with disease duration, which argues against reverse causation, the researchers said.

—Jake Remaly

PORTLAND, OR—Higher serum levels of polychlorinated biphenyls (PCBs) are associated with increased risk of Parkinson’s disease in two independent study populations, according to research presented at the Fourth World Parkinson Congress.

PCBs are persistent environmental pollutants that are detectable in most people despite a worldwide ban on their production that has been in place for more than 20 years. PCBs cause selective dopaminergic toxicity in animal models, but have been minimally studied in Parkinson’s disease, the researchers said.

The investigators recently reported a significantly increased risk of Parkinson’s disease associated with higher levels of serum PCBs in a case–control study of Alaska Native people. In the present study, they investigated this association in a demographically dissimilar study population.

They identified people with Parkinson’s disease within the Agricultural Health Study, a cohort of pesticide applicators and their spouses in Iowa and North Carolina. They also randomly selected controls matched for age, sex, and state. They confirmed Parkinson’s disease diagnoses by in-person neurologist evaluation and consensus review. PCB congeners 118, 138, 153, and 180 were measured as ng/g lipid in serum using gas chromatography-mass spectroscopy. To assess dose-response, the researchers constructed quartiles for each congener and for the sum of congeners. The used logistic regression, adjusting for age, gender, and state, to calculate odds ratios.

Ninety-seven people with Parkinson’s disease and 113 controls were included in the study. About 25% of the participants were women. Mean age was 69. Parkinson’s disease was associated with higher levels of PCBs. A significant dose-response was seen across quartiles. Participants in the second, third, and fourth quartiles of total PCB levels had a 1.7-, 2.4-, and 2.7-fold greater risk of Parkinson’s disease, respectively, compared with participants in the lowest quartile of total PCB levels. Odds ratios were similar in the Agricultural Heath Study and the Alaska study. In both studies, PCB levels correlated positively with age but not with disease duration, which argues against reverse causation, the researchers said.

—Jake Remaly

PORTLAND, OR—High doses of transdermal nicotine failed to improve off motor symptoms in patients with Parkinson’s disease, according to trial results presented at the Fourth World Parkinson Congress. Nicotine may have provided benefit on secondary outcome measures, researchers said.

Gabriel Villafane, MD, a neurologist at Henri Mondor University Hospital in Créteil, France, and colleagues conducted the Nicopark2 Study, a single-blind, controlled, randomized trial to evaluate the effect of high doses of transdermal nicotine (approximately 90 mg per day) on motor symptoms in Parkinson’s disease.

Cigarette smoking is associated with a dose-dependent reduction in risk of Parkinson’s disease. Nicotine’s effect on motor symptoms in Parkinson’s disease is controversial. Seven of eight open-label studies suggested that nicotine improves motor symptoms, but four placebo-controlled studies were negative.

The investigators enrolled 40 patients with Parkinson’s disease in the study. Eligible patients were nonsmokers age 35 to 70 with a Hoehn and Yahr off stage of four or less and a Hoehn and Yahr on stage of three or less. Patients had received levodopa treatment for at least three years. Exclusion criteria included neurosurgery, psychiatric disease, and symptomatic orthostatic hypotension.

The primary outcome was mean difference between groups in change of Unified Parkinson’s Disease Rating Scale off motor score from baseline to week 39 on blinded video rating.

Twenty patients were randomized to receive transdermal nicotine, and 20 patients were randomized to a control group. The change in motor score between groups was not statistically significant. Change in quality of life assessed by the Parkinson’s Disease Questionnaire was not statistically significant. At 39 weeks, a reduction in levodopa doses, a reduction in dyskinesias, and an improvement in activities of daily living were observed in the nicotine group, the researchers said.

Adverse events occurred in more patients the nicotine group than in the control group. They included worsening of parkinsonism (30% vs 5%), cutaneous reactions (35% vs 5%), gastrointestinal complaints (65% vs 15%), hypotension (25% vs 5%), insomnia (25% vs 5%), and nervousness and anxiety (20% vs 0%). Ten patients in the nicotine group had a serious adverse event, compared with three patients in the control group.

—Jake Remaly

PORTLAND, OR—High doses of transdermal nicotine failed to improve off motor symptoms in patients with Parkinson’s disease, according to trial results presented at the Fourth World Parkinson Congress. Nicotine may have provided benefit on secondary outcome measures, researchers said.

Gabriel Villafane, MD, a neurologist at Henri Mondor University Hospital in Créteil, France, and colleagues conducted the Nicopark2 Study, a single-blind, controlled, randomized trial to evaluate the effect of high doses of transdermal nicotine (approximately 90 mg per day) on motor symptoms in Parkinson’s disease.

Cigarette smoking is associated with a dose-dependent reduction in risk of Parkinson’s disease. Nicotine’s effect on motor symptoms in Parkinson’s disease is controversial. Seven of eight open-label studies suggested that nicotine improves motor symptoms, but four placebo-controlled studies were negative.

The investigators enrolled 40 patients with Parkinson’s disease in the study. Eligible patients were nonsmokers age 35 to 70 with a Hoehn and Yahr off stage of four or less and a Hoehn and Yahr on stage of three or less. Patients had received levodopa treatment for at least three years. Exclusion criteria included neurosurgery, psychiatric disease, and symptomatic orthostatic hypotension.

The primary outcome was mean difference between groups in change of Unified Parkinson’s Disease Rating Scale off motor score from baseline to week 39 on blinded video rating.

Twenty patients were randomized to receive transdermal nicotine, and 20 patients were randomized to a control group. The change in motor score between groups was not statistically significant. Change in quality of life assessed by the Parkinson’s Disease Questionnaire was not statistically significant. At 39 weeks, a reduction in levodopa doses, a reduction in dyskinesias, and an improvement in activities of daily living were observed in the nicotine group, the researchers said.

Adverse events occurred in more patients the nicotine group than in the control group. They included worsening of parkinsonism (30% vs 5%), cutaneous reactions (35% vs 5%), gastrointestinal complaints (65% vs 15%), hypotension (25% vs 5%), insomnia (25% vs 5%), and nervousness and anxiety (20% vs 0%). Ten patients in the nicotine group had a serious adverse event, compared with three patients in the control group.

—Jake Remaly

PORTLAND, OR—High doses of transdermal nicotine failed to improve off motor symptoms in patients with Parkinson’s disease, according to trial results presented at the Fourth World Parkinson Congress. Nicotine may have provided benefit on secondary outcome measures, researchers said.

Gabriel Villafane, MD, a neurologist at Henri Mondor University Hospital in Créteil, France, and colleagues conducted the Nicopark2 Study, a single-blind, controlled, randomized trial to evaluate the effect of high doses of transdermal nicotine (approximately 90 mg per day) on motor symptoms in Parkinson’s disease.

Cigarette smoking is associated with a dose-dependent reduction in risk of Parkinson’s disease. Nicotine’s effect on motor symptoms in Parkinson’s disease is controversial. Seven of eight open-label studies suggested that nicotine improves motor symptoms, but four placebo-controlled studies were negative.

The investigators enrolled 40 patients with Parkinson’s disease in the study. Eligible patients were nonsmokers age 35 to 70 with a Hoehn and Yahr off stage of four or less and a Hoehn and Yahr on stage of three or less. Patients had received levodopa treatment for at least three years. Exclusion criteria included neurosurgery, psychiatric disease, and symptomatic orthostatic hypotension.

The primary outcome was mean difference between groups in change of Unified Parkinson’s Disease Rating Scale off motor score from baseline to week 39 on blinded video rating.

Twenty patients were randomized to receive transdermal nicotine, and 20 patients were randomized to a control group. The change in motor score between groups was not statistically significant. Change in quality of life assessed by the Parkinson’s Disease Questionnaire was not statistically significant. At 39 weeks, a reduction in levodopa doses, a reduction in dyskinesias, and an improvement in activities of daily living were observed in the nicotine group, the researchers said.

Adverse events occurred in more patients the nicotine group than in the control group. They included worsening of parkinsonism (30% vs 5%), cutaneous reactions (35% vs 5%), gastrointestinal complaints (65% vs 15%), hypotension (25% vs 5%), insomnia (25% vs 5%), and nervousness and anxiety (20% vs 0%). Ten patients in the nicotine group had a serious adverse event, compared with three patients in the control group.

—Jake Remaly

Prior studies have found that people who consume green tea, coffee, and blueberries and avoid dairy may have a lower risk of Parkinson’s disease. Whether nutrition is associated with rate of disease progression in patients with Parkinson’s disease, however, is not known.

To evaluate whether diet, exercise, and supplements are associated with rate of Parkinson’s disease progression, Laurie Mischley, ND, PhD, MPH, Assistant Research Scientist at Bastyr University Research Institute in Kenmore, Washington, and Richard Lau, MPH, a PhD student in the College of Public Health and Human Sciences at Oregon State University in Corvalis conducted an Internet-based natural history study. A total of 1,024 patients participated in the study. Participants had a mean age of 60.7 and had been diagnosed with Parkinson’s disease for an average of 6.7 years.

The researchers used the Patient-Reported Outcomes in Parkinson’s Disease (PRO-PD) scale to assess Parkinson’s disease severity. Disease progression was defined as PRO-PD score adjusted for age and years since diagnosis. They used baseline food frequency questionnaires to quantify dietary intake in the cross-sectional analysis.

Fresh fruit, fresh vegetables, nuts and seeds, olive oil, fish (non-fried), wine, eggs, and fresh herbs were associated with a statistically significant improvement in PRO-PD score, the researchers said. Fried foods, beef, diet soda, canned fruits, and canned vegetables were associated with more severe disease. Dairy consumption was not associated with disease severity.

Of the supplements and pharmaceuticals studied, oral glutathione, rasagiline, and coenzyme Q10 were associated with improved PRO-PD scores, whereas iron was associated with more severe disease. The effect of melatonin was not significant, however, when the researchers considered poor sleep.The researchers observed a dose response curve with exercise. Exercising at least 30 minutes daily was associated with the greatest reduction in disease severity.

“Whether iron, fried foods, diet soda, or canned goods provide environmental insults that accelerate disease progression warrants immediate attention,” the researchers concluded. “This pragmatic natural history study offers the first evidence base for prescribing lifestyle modification (beyond exercise) to patients with Parkinson’s disease. Patients should be empowered to know that they can make choices that affect outcomes."

—Jake Remaly

Prior studies have found that people who consume green tea, coffee, and blueberries and avoid dairy may have a lower risk of Parkinson’s disease. Whether nutrition is associated with rate of disease progression in patients with Parkinson’s disease, however, is not known.

To evaluate whether diet, exercise, and supplements are associated with rate of Parkinson’s disease progression, Laurie Mischley, ND, PhD, MPH, Assistant Research Scientist at Bastyr University Research Institute in Kenmore, Washington, and Richard Lau, MPH, a PhD student in the College of Public Health and Human Sciences at Oregon State University in Corvalis conducted an Internet-based natural history study. A total of 1,024 patients participated in the study. Participants had a mean age of 60.7 and had been diagnosed with Parkinson’s disease for an average of 6.7 years.

The researchers used the Patient-Reported Outcomes in Parkinson’s Disease (PRO-PD) scale to assess Parkinson’s disease severity. Disease progression was defined as PRO-PD score adjusted for age and years since diagnosis. They used baseline food frequency questionnaires to quantify dietary intake in the cross-sectional analysis.

Fresh fruit, fresh vegetables, nuts and seeds, olive oil, fish (non-fried), wine, eggs, and fresh herbs were associated with a statistically significant improvement in PRO-PD score, the researchers said. Fried foods, beef, diet soda, canned fruits, and canned vegetables were associated with more severe disease. Dairy consumption was not associated with disease severity.

Of the supplements and pharmaceuticals studied, oral glutathione, rasagiline, and coenzyme Q10 were associated with improved PRO-PD scores, whereas iron was associated with more severe disease. The effect of melatonin was not significant, however, when the researchers considered poor sleep.The researchers observed a dose response curve with exercise. Exercising at least 30 minutes daily was associated with the greatest reduction in disease severity.

“Whether iron, fried foods, diet soda, or canned goods provide environmental insults that accelerate disease progression warrants immediate attention,” the researchers concluded. “This pragmatic natural history study offers the first evidence base for prescribing lifestyle modification (beyond exercise) to patients with Parkinson’s disease. Patients should be empowered to know that they can make choices that affect outcomes."

—Jake Remaly

Prior studies have found that people who consume green tea, coffee, and blueberries and avoid dairy may have a lower risk of Parkinson’s disease. Whether nutrition is associated with rate of disease progression in patients with Parkinson’s disease, however, is not known.

To evaluate whether diet, exercise, and supplements are associated with rate of Parkinson’s disease progression, Laurie Mischley, ND, PhD, MPH, Assistant Research Scientist at Bastyr University Research Institute in Kenmore, Washington, and Richard Lau, MPH, a PhD student in the College of Public Health and Human Sciences at Oregon State University in Corvalis conducted an Internet-based natural history study. A total of 1,024 patients participated in the study. Participants had a mean age of 60.7 and had been diagnosed with Parkinson’s disease for an average of 6.7 years.

The researchers used the Patient-Reported Outcomes in Parkinson’s Disease (PRO-PD) scale to assess Parkinson’s disease severity. Disease progression was defined as PRO-PD score adjusted for age and years since diagnosis. They used baseline food frequency questionnaires to quantify dietary intake in the cross-sectional analysis.

Fresh fruit, fresh vegetables, nuts and seeds, olive oil, fish (non-fried), wine, eggs, and fresh herbs were associated with a statistically significant improvement in PRO-PD score, the researchers said. Fried foods, beef, diet soda, canned fruits, and canned vegetables were associated with more severe disease. Dairy consumption was not associated with disease severity.

Of the supplements and pharmaceuticals studied, oral glutathione, rasagiline, and coenzyme Q10 were associated with improved PRO-PD scores, whereas iron was associated with more severe disease. The effect of melatonin was not significant, however, when the researchers considered poor sleep.The researchers observed a dose response curve with exercise. Exercising at least 30 minutes daily was associated with the greatest reduction in disease severity.

“Whether iron, fried foods, diet soda, or canned goods provide environmental insults that accelerate disease progression warrants immediate attention,” the researchers concluded. “This pragmatic natural history study offers the first evidence base for prescribing lifestyle modification (beyond exercise) to patients with Parkinson’s disease. Patients should be empowered to know that they can make choices that affect outcomes."

—Jake Remaly

PORTLAND, OR—In patients with idiopathic REM sleep behavior disorder, microglial activation is increased in the substantia nigra, compared with controls, and microglial activation correlates with putamenal dopaminergic dysfunction, according to research presented at the Fourth World Parkinson Congress. These findings suggest that “anti-inflammatory agents could possibly delay progression to a manifest synucleinopathy in subjects with idiopathic REM sleep behavior disorder,” researchers said.

Longitudinal studies have found that patients with idiopathic REM sleep behavior disorder have an increased risk of Parkinson’s disease and related Lewy body disorders. “This implies that, in idiopathic REM sleep behavior disorder, the underlying pathology of developing neurodegenerative disorders can be investigated years prior to the development of manifest symptoms,” said Morten Gersel Stokholm, MD, a researcher in the Department of Clinical Medicine at Aarhus University and the Department of Nuclear Medicine & PET-Centre at Aarhus University Hospital, Denmark, and his research colleagues.

Chronic activation of microglial cells may have a detrimental effect on neurons and contribute to the development of neurodegenerative disorders. Studies have found that uptake of an in vivo marker of microglial activation, 11C-PK11195, is increased in Parkinson’s disease and other neurodegenerative disorders.

To investigate the in vivo occurrence of neuroinflammation in the brains of patients with idiopathic REM sleep behavior disorder and neuroinflammation’s temporal relationship with striatal dopamine dysfunction, Dr. Stokholm and colleagues conducted a multitracer PET study of patients with idiopathic REM sleep behavior disorder.

The investigators enrolled 15 patients with polysomnography-confirmed idiopathic REM sleep behavior disorder at Aarhus University Hospital and Hospital Clínic de Barcelona. They also enrolled 19 matched controls. Participants underwent two PET scans with 18F-DOPA and 11C- PK11195 and a structural T1 MRI scan. Parametric images of specific tracer uptake (ie, F-dopa Ki-values and PK11195 binding potential) were constructed at voxel level using Patlak graphical analysis and a supervised cluster-analysis with compartmental modeling, respectively. A region of interest analysis was performed on a priori defined regions.

Compared with controls, patients with idiopathic REM sleep behavior disorder showed significantly reduced 18F-DOPA tracer uptake in the substantia nigra. Patients with higher substantia nigra11C-PK11195 binding also had increased binding in the ipsilateral putamen. Patients with more severe reductions in putaminal 18F-DOPA uptake had significantly higher 11C-PK11195 binding in the putamen and substantia nigra. 

—Jake Remaly

PORTLAND, OR—In patients with idiopathic REM sleep behavior disorder, microglial activation is increased in the substantia nigra, compared with controls, and microglial activation correlates with putamenal dopaminergic dysfunction, according to research presented at the Fourth World Parkinson Congress. These findings suggest that “anti-inflammatory agents could possibly delay progression to a manifest synucleinopathy in subjects with idiopathic REM sleep behavior disorder,” researchers said.

Longitudinal studies have found that patients with idiopathic REM sleep behavior disorder have an increased risk of Parkinson’s disease and related Lewy body disorders. “This implies that, in idiopathic REM sleep behavior disorder, the underlying pathology of developing neurodegenerative disorders can be investigated years prior to the development of manifest symptoms,” said Morten Gersel Stokholm, MD, a researcher in the Department of Clinical Medicine at Aarhus University and the Department of Nuclear Medicine & PET-Centre at Aarhus University Hospital, Denmark, and his research colleagues.

Chronic activation of microglial cells may have a detrimental effect on neurons and contribute to the development of neurodegenerative disorders. Studies have found that uptake of an in vivo marker of microglial activation, 11C-PK11195, is increased in Parkinson’s disease and other neurodegenerative disorders.

To investigate the in vivo occurrence of neuroinflammation in the brains of patients with idiopathic REM sleep behavior disorder and neuroinflammation’s temporal relationship with striatal dopamine dysfunction, Dr. Stokholm and colleagues conducted a multitracer PET study of patients with idiopathic REM sleep behavior disorder.

The investigators enrolled 15 patients with polysomnography-confirmed idiopathic REM sleep behavior disorder at Aarhus University Hospital and Hospital Clínic de Barcelona. They also enrolled 19 matched controls. Participants underwent two PET scans with 18F-DOPA and 11C- PK11195 and a structural T1 MRI scan. Parametric images of specific tracer uptake (ie, F-dopa Ki-values and PK11195 binding potential) were constructed at voxel level using Patlak graphical analysis and a supervised cluster-analysis with compartmental modeling, respectively. A region of interest analysis was performed on a priori defined regions.

Compared with controls, patients with idiopathic REM sleep behavior disorder showed significantly reduced 18F-DOPA tracer uptake in the substantia nigra. Patients with higher substantia nigra11C-PK11195 binding also had increased binding in the ipsilateral putamen. Patients with more severe reductions in putaminal 18F-DOPA uptake had significantly higher 11C-PK11195 binding in the putamen and substantia nigra. 

—Jake Remaly

PORTLAND, OR—In patients with idiopathic REM sleep behavior disorder, microglial activation is increased in the substantia nigra, compared with controls, and microglial activation correlates with putamenal dopaminergic dysfunction, according to research presented at the Fourth World Parkinson Congress. These findings suggest that “anti-inflammatory agents could possibly delay progression to a manifest synucleinopathy in subjects with idiopathic REM sleep behavior disorder,” researchers said.

Longitudinal studies have found that patients with idiopathic REM sleep behavior disorder have an increased risk of Parkinson’s disease and related Lewy body disorders. “This implies that, in idiopathic REM sleep behavior disorder, the underlying pathology of developing neurodegenerative disorders can be investigated years prior to the development of manifest symptoms,” said Morten Gersel Stokholm, MD, a researcher in the Department of Clinical Medicine at Aarhus University and the Department of Nuclear Medicine & PET-Centre at Aarhus University Hospital, Denmark, and his research colleagues.

Chronic activation of microglial cells may have a detrimental effect on neurons and contribute to the development of neurodegenerative disorders. Studies have found that uptake of an in vivo marker of microglial activation, 11C-PK11195, is increased in Parkinson’s disease and other neurodegenerative disorders.

To investigate the in vivo occurrence of neuroinflammation in the brains of patients with idiopathic REM sleep behavior disorder and neuroinflammation’s temporal relationship with striatal dopamine dysfunction, Dr. Stokholm and colleagues conducted a multitracer PET study of patients with idiopathic REM sleep behavior disorder.

The investigators enrolled 15 patients with polysomnography-confirmed idiopathic REM sleep behavior disorder at Aarhus University Hospital and Hospital Clínic de Barcelona. They also enrolled 19 matched controls. Participants underwent two PET scans with 18F-DOPA and 11C- PK11195 and a structural T1 MRI scan. Parametric images of specific tracer uptake (ie, F-dopa Ki-values and PK11195 binding potential) were constructed at voxel level using Patlak graphical analysis and a supervised cluster-analysis with compartmental modeling, respectively. A region of interest analysis was performed on a priori defined regions.

Compared with controls, patients with idiopathic REM sleep behavior disorder showed significantly reduced 18F-DOPA tracer uptake in the substantia nigra. Patients with higher substantia nigra11C-PK11195 binding also had increased binding in the ipsilateral putamen. Patients with more severe reductions in putaminal 18F-DOPA uptake had significantly higher 11C-PK11195 binding in the putamen and substantia nigra. 

—Jake Remaly