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Strategies for Treating Motor Fluctuations in Parkinson’s Disease
Improved delivery of levodopa and new therapies may help to reduce off time.
MIAMI—Motor fluctuations in Parkinson’s disease can arise from more than one cause, and a clinician needs to consider a range of possibilities. Most commonly, motor fluctuations arise as a consequence of chronic levodopa therapy, though the progression of parkinsonism is a contributing factor, according to an overview presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. The pharmacokinetics of levodopa provide the basis for studying most clinical patterns of motor fluctuations, and new pharmacologic strategies are under development to improve upon existing treatment options. 
“In recent years, there have been some exciting and novel directions of Parkinson’s disease therapeutics for motor fluctuations,” said Peter A. LeWitt, MD, Director of the Parkinson’s Disease and Movement Disorder Program at Henry Ford Hospital in West Bloomfield, Michigan.
A Need to Improve Levodopa Delivery
Beyond irregular effects of levodopa, motor fluctuations may be intrinsic to Parkinson’s disease, said Dr. LeWitt. One problem experienced by some patients is freezing of gait, immobility that is often situation-specific irrespective of medication dosing, he added. The sleep-benefit phenomenon, stress-exacerbated tremors and dyskinesias, and end-of-day medication unresponsiveness are further examples. “But for the most part, most motor fluctuations tend to be closely linked to the variable delivery of levodopa to the brain, where, after a short delay, it undergoes conversion to dopamine. This neurotransmitter does not have long to carry out its intended signaling because enzymes and re-uptake mechanisms quickly dispose of it. So, consistent delivery is the key for averting dose-by-dose motor fluctuations.”
During its 50 years of service to the Parkinson’s disease patient, levodopa has revolutionized the identity of this disorder. It has improved longevity, disability, and overall quality of life, and it inspired
Because the short-duration response pattern is associated with benefits as brief as two to three hours per oral immediate-release dose, the focus for improving levodopa has been the use of extension therapies. Blocking the breakdown of peripheral levodopa metabolism (the mechanism for catechol-O-methyltransferase inhibition) or slowing the central metabolism of dopamine (by inhibiting monoamine oxidase-type B) join extended-release carbidopa-levodopa preparations as ways to improve upon the immediate-release product. “While these strategies do provide some level of effectiveness, the problems of irregular responsiveness and up to several hours of daily ‘off’ time haven’t been solved. ‘Off’ time still imposes a major burden on many patients living with Parkinson’s disease,” said Dr. LeWitt. Like delayed onset of effect and rapid wearing-off, levodopa-induced dyskinesias present another challenge for understanding their origin and optimal control. While new mechanisms of blocking dyskinesia are being sought, a simpler solution can be more continuous levodopa delivery so that drug concentration peaks causing involuntary movements are averted.
Future Therapies Undergoing Trials Today
Several new therapeutic approaches have been developed for dealing with the shortcomings of current therapies, especially levodopa. “The first of these options was a tube inserted through the stomach into the upper small intestine for continuous pumping of a carbidopa-levodopa microsuspension gel –quite effective but not an easy choice for most patients,” said Dr. LeWitt. Less cumbersome ways to extend levodopa effects have been the several sustained-release formulations now under development. One is a gastric-retention product, termed the “Accordion Pill,” which slowly leaches carbidopa and levodopa to enhance their pharmacokinetic absorption profile. Another treatment strategy for motor fluctuations that, like the Accordion Pill, is also in worldwide clinical trials, involves continuous subcutaneous infusion of solubilized levodopa and carbidopa. With the latter approach, the drug is administered by a small pump adjusted to optimized rate of delivery. Dr. LeWitt also described another novel way for administering levodopa for rapid entry into the bloodstream for treating “off” states. This involves an inhalation device for pulmonary uptake of a micro-particulate levodopa formulation. In a recently completed study, “off” states were reversed rapidly with this approach.
Subcutaneous apomorphine infusion has already been used for more than 30 years in treating motor fluctuations. However, just recently, a more complete story of what this adjunctive therapy offers was reported from a large-scale randomized clinical trial in Europe. A similar study is underway in the United States and might lead to availability of apomorphine infusion in the near future, said Dr. LeWitt. Another approach to motor fluctuations can be found in a drug for motor fluctuations that does not act on dopaminergic pathways. This medication is istradefylline, a selective inhibitor of adenosine A2a receptors (which are located in the same pathway targeted by deep brain stimulation). In Japan, istradefylline is marketed for reducing “off” time, and studies with this drug are planned for review in the US, said Dr. LeWitt.
For a nonpharmacologic approach to managing motor fluctuations, neurosurgical targeting of brain circuitry with deep brain electrical stimulation has had several decades of experience. Another direction of neurosurgical intervention is under investigation; this involves gene therapy to improve the efficacy of oral levodopa therapy. “Inserting into the putamen a gene for producing an increase of L-aromatic amino acid decarboxylase appears to offer a way for enhancing dopamine formation. The clinical investigation currently underway is testing whether producing this localized alteration of brain neurochemistry might succeed at attenuating motor fluctuations,” said Dr. LeWitt
“In talking to patients about their experiences with motor fluctuations, my advice is to think both about levodopa pharmacokinetics and how the patient uses levodopa (since schedule compliance, the interaction of meals, and drinking sufficient water with medications commonly contribute to these problems). Fortunately, new treatment options are on their way to help in fighting back against the limitations of levodopa therapy,” Dr. LeWitt concluded.
—Erica Tricarico
Suggested Reading
Anderson E, Nutt J. The long-duration response to levodopa: phenomenology, potential mechanisms and clinical implications. Parkinsonism Relat Disord. 2011;17:587-592.
Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(10);2731-2742.
LeWitt PA. Levodopa therapy for Parkinson’s disease: Pharmacokinetics and pharmacodynamics. Mov Disord. 2015;30(1):64-72.
Improved delivery of levodopa and new therapies may help to reduce off time.
Improved delivery of levodopa and new therapies may help to reduce off time.
MIAMI—Motor fluctuations in Parkinson’s disease can arise from more than one cause, and a clinician needs to consider a range of possibilities. Most commonly, motor fluctuations arise as a consequence of chronic levodopa therapy, though the progression of parkinsonism is a contributing factor, according to an overview presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. The pharmacokinetics of levodopa provide the basis for studying most clinical patterns of motor fluctuations, and new pharmacologic strategies are under development to improve upon existing treatment options.
“In recent years, there have been some exciting and novel directions of Parkinson’s disease therapeutics for motor fluctuations,” said Peter A. LeWitt, MD, Director of the Parkinson’s Disease and Movement Disorder Program at Henry Ford Hospital in West Bloomfield, Michigan.
A Need to Improve Levodopa Delivery
Beyond irregular effects of levodopa, motor fluctuations may be intrinsic to Parkinson’s disease, said Dr. LeWitt. One problem experienced by some patients is freezing of gait, immobility that is often situation-specific irrespective of medication dosing, he added. The sleep-benefit phenomenon, stress-exacerbated tremors and dyskinesias, and end-of-day medication unresponsiveness are further examples. “But for the most part, most motor fluctuations tend to be closely linked to the variable delivery of levodopa to the brain, where, after a short delay, it undergoes conversion to dopamine. This neurotransmitter does not have long to carry out its intended signaling because enzymes and re-uptake mechanisms quickly dispose of it. So, consistent delivery is the key for averting dose-by-dose motor fluctuations.”
During its 50 years of service to the Parkinson’s disease patient, levodopa has revolutionized the identity of this disorder. It has improved longevity, disability, and overall quality of life, and it inspired
Because the short-duration response pattern is associated with benefits as brief as two to three hours per oral immediate-release dose, the focus for improving levodopa has been the use of extension therapies. Blocking the breakdown of peripheral levodopa metabolism (the mechanism for catechol-O-methyltransferase inhibition) or slowing the central metabolism of dopamine (by inhibiting monoamine oxidase-type B) join extended-release carbidopa-levodopa preparations as ways to improve upon the immediate-release product. “While these strategies do provide some level of effectiveness, the problems of irregular responsiveness and up to several hours of daily ‘off’ time haven’t been solved. ‘Off’ time still imposes a major burden on many patients living with Parkinson’s disease,” said Dr. LeWitt. Like delayed onset of effect and rapid wearing-off, levodopa-induced dyskinesias present another challenge for understanding their origin and optimal control. While new mechanisms of blocking dyskinesia are being sought, a simpler solution can be more continuous levodopa delivery so that drug concentration peaks causing involuntary movements are averted.
Future Therapies Undergoing Trials Today
Several new therapeutic approaches have been developed for dealing with the shortcomings of current therapies, especially levodopa. “The first of these options was a tube inserted through the stomach into the upper small intestine for continuous pumping of a carbidopa-levodopa microsuspension gel –quite effective but not an easy choice for most patients,” said Dr. LeWitt. Less cumbersome ways to extend levodopa effects have been the several sustained-release formulations now under development. One is a gastric-retention product, termed the “Accordion Pill,” which slowly leaches carbidopa and levodopa to enhance their pharmacokinetic absorption profile. Another treatment strategy for motor fluctuations that, like the Accordion Pill, is also in worldwide clinical trials, involves continuous subcutaneous infusion of solubilized levodopa and carbidopa. With the latter approach, the drug is administered by a small pump adjusted to optimized rate of delivery. Dr. LeWitt also described another novel way for administering levodopa for rapid entry into the bloodstream for treating “off” states. This involves an inhalation device for pulmonary uptake of a micro-particulate levodopa formulation. In a recently completed study, “off” states were reversed rapidly with this approach.
Subcutaneous apomorphine infusion has already been used for more than 30 years in treating motor fluctuations. However, just recently, a more complete story of what this adjunctive therapy offers was reported from a large-scale randomized clinical trial in Europe. A similar study is underway in the United States and might lead to availability of apomorphine infusion in the near future, said Dr. LeWitt. Another approach to motor fluctuations can be found in a drug for motor fluctuations that does not act on dopaminergic pathways. This medication is istradefylline, a selective inhibitor of adenosine A2a receptors (which are located in the same pathway targeted by deep brain stimulation). In Japan, istradefylline is marketed for reducing “off” time, and studies with this drug are planned for review in the US, said Dr. LeWitt.
For a nonpharmacologic approach to managing motor fluctuations, neurosurgical targeting of brain circuitry with deep brain electrical stimulation has had several decades of experience. Another direction of neurosurgical intervention is under investigation; this involves gene therapy to improve the efficacy of oral levodopa therapy. “Inserting into the putamen a gene for producing an increase of L-aromatic amino acid decarboxylase appears to offer a way for enhancing dopamine formation. The clinical investigation currently underway is testing whether producing this localized alteration of brain neurochemistry might succeed at attenuating motor fluctuations,” said Dr. LeWitt
“In talking to patients about their experiences with motor fluctuations, my advice is to think both about levodopa pharmacokinetics and how the patient uses levodopa (since schedule compliance, the interaction of meals, and drinking sufficient water with medications commonly contribute to these problems). Fortunately, new treatment options are on their way to help in fighting back against the limitations of levodopa therapy,” Dr. LeWitt concluded.
—Erica Tricarico
Suggested Reading
Anderson E, Nutt J. The long-duration response to levodopa: phenomenology, potential mechanisms and clinical implications. Parkinsonism Relat Disord. 2011;17:587-592.
Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(10);2731-2742.
LeWitt PA. Levodopa therapy for Parkinson’s disease: Pharmacokinetics and pharmacodynamics. Mov Disord. 2015;30(1):64-72.
MIAMI—Motor fluctuations in Parkinson’s disease can arise from more than one cause, and a clinician needs to consider a range of possibilities. Most commonly, motor fluctuations arise as a consequence of chronic levodopa therapy, though the progression of parkinsonism is a contributing factor, according to an overview presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. The pharmacokinetics of levodopa provide the basis for studying most clinical patterns of motor fluctuations, and new pharmacologic strategies are under development to improve upon existing treatment options.
“In recent years, there have been some exciting and novel directions of Parkinson’s disease therapeutics for motor fluctuations,” said Peter A. LeWitt, MD, Director of the Parkinson’s Disease and Movement Disorder Program at Henry Ford Hospital in West Bloomfield, Michigan.
A Need to Improve Levodopa Delivery
Beyond irregular effects of levodopa, motor fluctuations may be intrinsic to Parkinson’s disease, said Dr. LeWitt. One problem experienced by some patients is freezing of gait, immobility that is often situation-specific irrespective of medication dosing, he added. The sleep-benefit phenomenon, stress-exacerbated tremors and dyskinesias, and end-of-day medication unresponsiveness are further examples. “But for the most part, most motor fluctuations tend to be closely linked to the variable delivery of levodopa to the brain, where, after a short delay, it undergoes conversion to dopamine. This neurotransmitter does not have long to carry out its intended signaling because enzymes and re-uptake mechanisms quickly dispose of it. So, consistent delivery is the key for averting dose-by-dose motor fluctuations.”
During its 50 years of service to the Parkinson’s disease patient, levodopa has revolutionized the identity of this disorder. It has improved longevity, disability, and overall quality of life, and it inspired
Because the short-duration response pattern is associated with benefits as brief as two to three hours per oral immediate-release dose, the focus for improving levodopa has been the use of extension therapies. Blocking the breakdown of peripheral levodopa metabolism (the mechanism for catechol-O-methyltransferase inhibition) or slowing the central metabolism of dopamine (by inhibiting monoamine oxidase-type B) join extended-release carbidopa-levodopa preparations as ways to improve upon the immediate-release product. “While these strategies do provide some level of effectiveness, the problems of irregular responsiveness and up to several hours of daily ‘off’ time haven’t been solved. ‘Off’ time still imposes a major burden on many patients living with Parkinson’s disease,” said Dr. LeWitt. Like delayed onset of effect and rapid wearing-off, levodopa-induced dyskinesias present another challenge for understanding their origin and optimal control. While new mechanisms of blocking dyskinesia are being sought, a simpler solution can be more continuous levodopa delivery so that drug concentration peaks causing involuntary movements are averted.
Future Therapies Undergoing Trials Today
Several new therapeutic approaches have been developed for dealing with the shortcomings of current therapies, especially levodopa. “The first of these options was a tube inserted through the stomach into the upper small intestine for continuous pumping of a carbidopa-levodopa microsuspension gel –quite effective but not an easy choice for most patients,” said Dr. LeWitt. Less cumbersome ways to extend levodopa effects have been the several sustained-release formulations now under development. One is a gastric-retention product, termed the “Accordion Pill,” which slowly leaches carbidopa and levodopa to enhance their pharmacokinetic absorption profile. Another treatment strategy for motor fluctuations that, like the Accordion Pill, is also in worldwide clinical trials, involves continuous subcutaneous infusion of solubilized levodopa and carbidopa. With the latter approach, the drug is administered by a small pump adjusted to optimized rate of delivery. Dr. LeWitt also described another novel way for administering levodopa for rapid entry into the bloodstream for treating “off” states. This involves an inhalation device for pulmonary uptake of a micro-particulate levodopa formulation. In a recently completed study, “off” states were reversed rapidly with this approach.
Subcutaneous apomorphine infusion has already been used for more than 30 years in treating motor fluctuations. However, just recently, a more complete story of what this adjunctive therapy offers was reported from a large-scale randomized clinical trial in Europe. A similar study is underway in the United States and might lead to availability of apomorphine infusion in the near future, said Dr. LeWitt. Another approach to motor fluctuations can be found in a drug for motor fluctuations that does not act on dopaminergic pathways. This medication is istradefylline, a selective inhibitor of adenosine A2a receptors (which are located in the same pathway targeted by deep brain stimulation). In Japan, istradefylline is marketed for reducing “off” time, and studies with this drug are planned for review in the US, said Dr. LeWitt.
For a nonpharmacologic approach to managing motor fluctuations, neurosurgical targeting of brain circuitry with deep brain electrical stimulation has had several decades of experience. Another direction of neurosurgical intervention is under investigation; this involves gene therapy to improve the efficacy of oral levodopa therapy. “Inserting into the putamen a gene for producing an increase of L-aromatic amino acid decarboxylase appears to offer a way for enhancing dopamine formation. The clinical investigation currently underway is testing whether producing this localized alteration of brain neurochemistry might succeed at attenuating motor fluctuations,” said Dr. LeWitt
“In talking to patients about their experiences with motor fluctuations, my advice is to think both about levodopa pharmacokinetics and how the patient uses levodopa (since schedule compliance, the interaction of meals, and drinking sufficient water with medications commonly contribute to these problems). Fortunately, new treatment options are on their way to help in fighting back against the limitations of levodopa therapy,” Dr. LeWitt concluded.
—Erica Tricarico
Suggested Reading
Anderson E, Nutt J. The long-duration response to levodopa: phenomenology, potential mechanisms and clinical implications. Parkinsonism Relat Disord. 2011;17:587-592.
Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(10);2731-2742.
LeWitt PA. Levodopa therapy for Parkinson’s disease: Pharmacokinetics and pharmacodynamics. Mov Disord. 2015;30(1):64-72.
Lipid Metabolism May Be a Therapeutic Target in MS
NASHVILLE—Multiple sclerosis (MS) traditionally has been considered a chronic inflammatory autoimmune disease, but inflammation decreases as the disease progresses. Many other biologic processes are dysregulated in MS, such as myelin signal transport, mitochondrial function, and iron metabolism. Lipid metabolism affects all of these processes, including inflammation, and thus could be a valuable therapeutic target, according to research presented at the 2018 CMSC Annual Meeting. 
“MS is not an inflammatory disease,” said John D. Nieland, PhD, Associate Professor of Health Science and Technology at Aalborg University in Denmark. “The inflammatory response is important, but it is not the only component. If you do not focus on the other components, you will never be able to treat the disease.”
The Role of Lipids in the CNS
Healthy brains have a high amount of glucose metabolism, but glucose metabolism is reduced in MS and other neurologic disorders such as Parkinson’s disease and Alzheimer’s disease. “If glucose metabolism is downregulated, something else has to be taking over,” said Dr. Nieland. He and his colleagues hypothesize that lipid metabolism replaces glucose metabolism in MS. They further hypothesize that MS fundamentally is a dysfunction of lipid metabolism.
Lipids have an essential role in the CNS. Proper signal transduction requires lipids to be bound to the myelin sheath. The proteins that compose myelin sheaths are highly immunogenic, and lipids shield them from exposure to the immune system. The half-life of lipids attached to the myelin sheath is three days, so these lipids must be replaced constantly. In addition, lipids are essential for the function of glutamate, cannabinoid, and insulin receptors.
An increase in lipid metabolism decreases glucose metabolism and induces the production of prostaglandin E2, which is a key molecule in the inflammatory response. In the early stages of MS, inflammation attacks the myelin sheath and other brain proteins. Increased lipid metabolism decreases lipid concentrations in the CNS, including around myelin. When lipids are removed from the myelin sheath, they expose the immunogenic proteins that compose it, thus provoking an immune response. Dysregulated lipid metabolism also contributes to oxidative stress, mitochondrial dysfunction, demyelination, and neuronal loss.
Chemical Inhibition of Lipid Metabolism
Dr. Nieland and colleagues hypothesized that blocking lipid metabolism would reverse the inflammatory response and other harmful processes that occur in MS. Previous research by Shriver and colleagues indicated that inhibition of carnitine palmitoyltransferase 1 (CPT1), a molecule essential to lipid metabolism, in encephalitogenic T cells increases apoptosis and reduces the production of inflammatory cytokines. Two of the molecule’s three isoforms, CPT1A and CPT1C, are upregulated in MS. Stress prompts an increase in CPT1 expression, which spurs a shift to lipid metabolism. “If you block CPT1, you jam lipid metabolism,” Dr. Nieland said. “There is no way around it.” Dr. Nieland’s group thus chose CPT1 as its target.
The investigators first conducted studies using etomoxir, which inhibits CPT1 and blocks long-chain fatty acids from entering the mitochondria for beta oxidation. Through these effects, etomoxir causes cells to shift to glucose metabolism.
The researchers immunized 42 mice with myelin oligodendrocyte glycoprotein (MOG35–55) to induce experimental autoimmune encephalopathy (EAE). When the animals first exhibited symptoms at Day 10, they were randomized to receive subcutaneous etomoxir or placebo daily. Disease score decreased significantly in the treated animals, compared with the control animals. On Day 24, more than 50% of the treated mice exhibited normal behavior, compared with approximately 20% of control mice.
In another study, the investigators immunized 47 rats with myelin basic protein to induce EAE. The animals began having symptoms at Day 7, and the investigators randomized them to daily treatment with subcutaneous etomoxir or placebo. At Day 11, disease score was significantly lower among treated animals, compared with control animals. Body weight was significantly higher among rats that received etomoxir, compared with controls, at that time point. Also, 25% of treated animals exhibited normal behavior, but no controls did.
In a third study, the investigators compared etomoxir, interferon beta, and placebo in a rat model of EAE. Each treatment group included 10 rats, and etomoxir had superior effects on disease score and body weight, compared with interferon beta and placebo. When the investigators examined the rats’ serum, they found that levels of antibodies against brain antigens common in EAE were lower in rats treated with etomoxir, compared with those treated with interferon beta or placebo.
Biologic Inhibition of Lipid Metabolism
In addition to pharmacologic treatment, genetic mutations affect CPT1 function. The Hutterites, an ethnoreligious group in Canada, have a mutation in CPT1A that almost completely blocks the molecule’s activity. Similarly, the Inuit have a mutation in CPT1A that reduces its activity to approximately 22%. The prevalence of MS is one in 1,100 among the Hutterites and one in 50,000 among the Inuit, compared with one in 350 in the Canadian population. These observations suggest that gene therapy could be another way to block CPT1.
Dr. Nieland’s group collaborated with the Netherlands Cancer Institute to develop mouse strains with two distinct mutations in CPT1A. The first mutation mimics that found among the Hutterites, and the other mimics that found among the Inuit. In a preliminary study, the investigators induced EAE in three wild-type mice and two mice with the CPT1A mutation similar to that of the Inuit. The mice were 10 weeks old at the time of immunization.
At 24 days, disease score was lower in the CPT1A mutant mice, compared with the wild-type mice. Furthermore, body weight was higher in the mutant mice, compared with the wild-type mice. The investigators also measured the mice’s grip strength at Day 2 and Day 24. Grip strength decreased in the wild-type mice but remained the same in the mutant mice. At Day 24, grip strength was significantly higher among mutant mice than among wild-type mice.
“These results indicate an interaction of the lipid metabolism in the brain and in the immune system, which supports our hypothesis regarding MS pathology,” said Anne Skøttrup Mørkholt, a doctoral student at Aalborg University, who collaborated with Dr. Nieland on these animal studies. “MS is not a disease of the immune system, but a systemic disease with dysregulation of multiple components.” 
Lipid Metabolism in Other Neurologic Diseases
Data suggest that lipid metabolism may contribute to other neurologic diseases such as amyotrophic lateral sclerosis (ALS) as well. Huang et al found a correlation between serum triglyceride levels and the development of ALS. Dupuis et al observed upregulated lipid metabolism and downregulated glucose metabolism in SOD1 mouse models of the disease, as did subsequent researchers. In addition, a 2015 study by Palamiuc et al found that CPT1B was significantly increased in the muscle tissue of SOD1 mice.
To investigate whether suppressing lipid metabolism affected ALS, Dr. Nieland’s group examined a SOD1 mouse model of the disease. The mice developed symptoms at Day 70 and were randomized at Day 100 to etomoxir or placebo. Etomoxir was associated with less weight loss and better neurologic score, compared with placebo. Etomoxir also was associated with better performance on the wire hanging and rotarod tests, compared with placebo. “It seems like etomoxir was able to slow down the disease progression,” said Michael Sloth Trabjerg, MD, a doctoral student at Aalborg University. 
Because research has found increased beta oxidation and decreased glucose metabolism in Parkinson’s disease, Dr. Nieland’s group studied the effect of CPT1 inhibition in a rotenone mouse model of the disease. They induced the disease in the mice for 32 days before randomizing them to placebo or etomoxir. For all mice, treatment alternated between rotenone on one day and placebo or etomoxir on the next day. The investigators observed significantly better sensorimotor performance among treated mice, compared with controls, on Day 47 and Day 56. At Day 60, mice who received etomoxir had significantly more muscle strength and longer latency to fall on the rotarod test, compared with mice that received placebo. These data are being prepared for publication.
The data suggest that dysregulated glucose metabolism and increased lipid metabolism play a role in ALS and Parkinson’s disease. “CPT1 seems to be a prominent target for moderating these diseases,” said Dr. Trabjerg.
—Erik Greb
Suggested Reading
Dodge JC, Treleaven CM, Fidler JA, et al. Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis. Proc Natl Acad Sci U S A. 2013;110(26):10812-10817.
Dupuis L, Oudart H, René F, et al. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004;101(30):11159-11164.
Huang R, Guo X, Chen X, et al. The serum lipid profiles of amyotrophic lateral sclerosis patients: A study from south-west China and a meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):359-365.
Kim SM, Kim H, Kim JE, et al. Amyotrophic lateral sclerosis is associated with hypolipidemia at the presymptomatic stage in mice. PLoS One. 2011;6(3):e17985.
Lieury A, Chanal M, Androdias G, et al. Tissue remodeling in periplaque regions of multiple sclerosis spinal cord lesions. Glia. 2014;62(10):1645-1658.
Mørkholt AS, Kastaniegaard K, Trabjerg MS, et al. Identification of brain antigens recognized by autoantibodies in experimental autoimmune encephalomyelitis-induced animals treated with etomoxir or interferon-β. Sci Rep. 2018;8(1):7092.
Palamiuc L, Schlagowski A, Ngo ST, et al. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Mol Med. 2015;7(5):526-546.
Shriver LP, Manchester M. Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis. Sci Rep. 2011;1:79.
van der Windt GJ, Everts B, Chang CH, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68-78.
NASHVILLE—Multiple sclerosis (MS) traditionally has been considered a chronic inflammatory autoimmune disease, but inflammation decreases as the disease progresses. Many other biologic processes are dysregulated in MS, such as myelin signal transport, mitochondrial function, and iron metabolism. Lipid metabolism affects all of these processes, including inflammation, and thus could be a valuable therapeutic target, according to research presented at the 2018 CMSC Annual Meeting.
“MS is not an inflammatory disease,” said John D. Nieland, PhD, Associate Professor of Health Science and Technology at Aalborg University in Denmark. “The inflammatory response is important, but it is not the only component. If you do not focus on the other components, you will never be able to treat the disease.”
The Role of Lipids in the CNS
Healthy brains have a high amount of glucose metabolism, but glucose metabolism is reduced in MS and other neurologic disorders such as Parkinson’s disease and Alzheimer’s disease. “If glucose metabolism is downregulated, something else has to be taking over,” said Dr. Nieland. He and his colleagues hypothesize that lipid metabolism replaces glucose metabolism in MS. They further hypothesize that MS fundamentally is a dysfunction of lipid metabolism.
Lipids have an essential role in the CNS. Proper signal transduction requires lipids to be bound to the myelin sheath. The proteins that compose myelin sheaths are highly immunogenic, and lipids shield them from exposure to the immune system. The half-life of lipids attached to the myelin sheath is three days, so these lipids must be replaced constantly. In addition, lipids are essential for the function of glutamate, cannabinoid, and insulin receptors.
An increase in lipid metabolism decreases glucose metabolism and induces the production of prostaglandin E2, which is a key molecule in the inflammatory response. In the early stages of MS, inflammation attacks the myelin sheath and other brain proteins. Increased lipid metabolism decreases lipid concentrations in the CNS, including around myelin. When lipids are removed from the myelin sheath, they expose the immunogenic proteins that compose it, thus provoking an immune response. Dysregulated lipid metabolism also contributes to oxidative stress, mitochondrial dysfunction, demyelination, and neuronal loss.
Chemical Inhibition of Lipid Metabolism
Dr. Nieland and colleagues hypothesized that blocking lipid metabolism would reverse the inflammatory response and other harmful processes that occur in MS. Previous research by Shriver and colleagues indicated that inhibition of carnitine palmitoyltransferase 1 (CPT1), a molecule essential to lipid metabolism, in encephalitogenic T cells increases apoptosis and reduces the production of inflammatory cytokines. Two of the molecule’s three isoforms, CPT1A and CPT1C, are upregulated in MS. Stress prompts an increase in CPT1 expression, which spurs a shift to lipid metabolism. “If you block CPT1, you jam lipid metabolism,” Dr. Nieland said. “There is no way around it.” Dr. Nieland’s group thus chose CPT1 as its target.
The investigators first conducted studies using etomoxir, which inhibits CPT1 and blocks long-chain fatty acids from entering the mitochondria for beta oxidation. Through these effects, etomoxir causes cells to shift to glucose metabolism.
The researchers immunized 42 mice with myelin oligodendrocyte glycoprotein (MOG35–55) to induce experimental autoimmune encephalopathy (EAE). When the animals first exhibited symptoms at Day 10, they were randomized to receive subcutaneous etomoxir or placebo daily. Disease score decreased significantly in the treated animals, compared with the control animals. On Day 24, more than 50% of the treated mice exhibited normal behavior, compared with approximately 20% of control mice.
In another study, the investigators immunized 47 rats with myelin basic protein to induce EAE. The animals began having symptoms at Day 7, and the investigators randomized them to daily treatment with subcutaneous etomoxir or placebo. At Day 11, disease score was significantly lower among treated animals, compared with control animals. Body weight was significantly higher among rats that received etomoxir, compared with controls, at that time point. Also, 25% of treated animals exhibited normal behavior, but no controls did.
In a third study, the investigators compared etomoxir, interferon beta, and placebo in a rat model of EAE. Each treatment group included 10 rats, and etomoxir had superior effects on disease score and body weight, compared with interferon beta and placebo. When the investigators examined the rats’ serum, they found that levels of antibodies against brain antigens common in EAE were lower in rats treated with etomoxir, compared with those treated with interferon beta or placebo.
Biologic Inhibition of Lipid Metabolism
In addition to pharmacologic treatment, genetic mutations affect CPT1 function. The Hutterites, an ethnoreligious group in Canada, have a mutation in CPT1A that almost completely blocks the molecule’s activity. Similarly, the Inuit have a mutation in CPT1A that reduces its activity to approximately 22%. The prevalence of MS is one in 1,100 among the Hutterites and one in 50,000 among the Inuit, compared with one in 350 in the Canadian population. These observations suggest that gene therapy could be another way to block CPT1.
Dr. Nieland’s group collaborated with the Netherlands Cancer Institute to develop mouse strains with two distinct mutations in CPT1A. The first mutation mimics that found among the Hutterites, and the other mimics that found among the Inuit. In a preliminary study, the investigators induced EAE in three wild-type mice and two mice with the CPT1A mutation similar to that of the Inuit. The mice were 10 weeks old at the time of immunization.
At 24 days, disease score was lower in the CPT1A mutant mice, compared with the wild-type mice. Furthermore, body weight was higher in the mutant mice, compared with the wild-type mice. The investigators also measured the mice’s grip strength at Day 2 and Day 24. Grip strength decreased in the wild-type mice but remained the same in the mutant mice. At Day 24, grip strength was significantly higher among mutant mice than among wild-type mice.
“These results indicate an interaction of the lipid metabolism in the brain and in the immune system, which supports our hypothesis regarding MS pathology,” said Anne Skøttrup Mørkholt, a doctoral student at Aalborg University, who collaborated with Dr. Nieland on these animal studies. “MS is not a disease of the immune system, but a systemic disease with dysregulation of multiple components.”
Lipid Metabolism in Other Neurologic Diseases
Data suggest that lipid metabolism may contribute to other neurologic diseases such as amyotrophic lateral sclerosis (ALS) as well. Huang et al found a correlation between serum triglyceride levels and the development of ALS. Dupuis et al observed upregulated lipid metabolism and downregulated glucose metabolism in SOD1 mouse models of the disease, as did subsequent researchers. In addition, a 2015 study by Palamiuc et al found that CPT1B was significantly increased in the muscle tissue of SOD1 mice.
To investigate whether suppressing lipid metabolism affected ALS, Dr. Nieland’s group examined a SOD1 mouse model of the disease. The mice developed symptoms at Day 70 and were randomized at Day 100 to etomoxir or placebo. Etomoxir was associated with less weight loss and better neurologic score, compared with placebo. Etomoxir also was associated with better performance on the wire hanging and rotarod tests, compared with placebo. “It seems like etomoxir was able to slow down the disease progression,” said Michael Sloth Trabjerg, MD, a doctoral student at Aalborg University.
Because research has found increased beta oxidation and decreased glucose metabolism in Parkinson’s disease, Dr. Nieland’s group studied the effect of CPT1 inhibition in a rotenone mouse model of the disease. They induced the disease in the mice for 32 days before randomizing them to placebo or etomoxir. For all mice, treatment alternated between rotenone on one day and placebo or etomoxir on the next day. The investigators observed significantly better sensorimotor performance among treated mice, compared with controls, on Day 47 and Day 56. At Day 60, mice who received etomoxir had significantly more muscle strength and longer latency to fall on the rotarod test, compared with mice that received placebo. These data are being prepared for publication.
The data suggest that dysregulated glucose metabolism and increased lipid metabolism play a role in ALS and Parkinson’s disease. “CPT1 seems to be a prominent target for moderating these diseases,” said Dr. Trabjerg.
—Erik Greb
Suggested Reading
Dodge JC, Treleaven CM, Fidler JA, et al. Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis. Proc Natl Acad Sci U S A. 2013;110(26):10812-10817.
Dupuis L, Oudart H, René F, et al. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004;101(30):11159-11164.
Huang R, Guo X, Chen X, et al. The serum lipid profiles of amyotrophic lateral sclerosis patients: A study from south-west China and a meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):359-365.
Kim SM, Kim H, Kim JE, et al. Amyotrophic lateral sclerosis is associated with hypolipidemia at the presymptomatic stage in mice. PLoS One. 2011;6(3):e17985.
Lieury A, Chanal M, Androdias G, et al. Tissue remodeling in periplaque regions of multiple sclerosis spinal cord lesions. Glia. 2014;62(10):1645-1658.
Mørkholt AS, Kastaniegaard K, Trabjerg MS, et al. Identification of brain antigens recognized by autoantibodies in experimental autoimmune encephalomyelitis-induced animals treated with etomoxir or interferon-β. Sci Rep. 2018;8(1):7092.
Palamiuc L, Schlagowski A, Ngo ST, et al. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Mol Med. 2015;7(5):526-546.
Shriver LP, Manchester M. Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis. Sci Rep. 2011;1:79.
van der Windt GJ, Everts B, Chang CH, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68-78.
NASHVILLE—Multiple sclerosis (MS) traditionally has been considered a chronic inflammatory autoimmune disease, but inflammation decreases as the disease progresses. Many other biologic processes are dysregulated in MS, such as myelin signal transport, mitochondrial function, and iron metabolism. Lipid metabolism affects all of these processes, including inflammation, and thus could be a valuable therapeutic target, according to research presented at the 2018 CMSC Annual Meeting.
“MS is not an inflammatory disease,” said John D. Nieland, PhD, Associate Professor of Health Science and Technology at Aalborg University in Denmark. “The inflammatory response is important, but it is not the only component. If you do not focus on the other components, you will never be able to treat the disease.”
The Role of Lipids in the CNS
Healthy brains have a high amount of glucose metabolism, but glucose metabolism is reduced in MS and other neurologic disorders such as Parkinson’s disease and Alzheimer’s disease. “If glucose metabolism is downregulated, something else has to be taking over,” said Dr. Nieland. He and his colleagues hypothesize that lipid metabolism replaces glucose metabolism in MS. They further hypothesize that MS fundamentally is a dysfunction of lipid metabolism.
Lipids have an essential role in the CNS. Proper signal transduction requires lipids to be bound to the myelin sheath. The proteins that compose myelin sheaths are highly immunogenic, and lipids shield them from exposure to the immune system. The half-life of lipids attached to the myelin sheath is three days, so these lipids must be replaced constantly. In addition, lipids are essential for the function of glutamate, cannabinoid, and insulin receptors.
An increase in lipid metabolism decreases glucose metabolism and induces the production of prostaglandin E2, which is a key molecule in the inflammatory response. In the early stages of MS, inflammation attacks the myelin sheath and other brain proteins. Increased lipid metabolism decreases lipid concentrations in the CNS, including around myelin. When lipids are removed from the myelin sheath, they expose the immunogenic proteins that compose it, thus provoking an immune response. Dysregulated lipid metabolism also contributes to oxidative stress, mitochondrial dysfunction, demyelination, and neuronal loss.
Chemical Inhibition of Lipid Metabolism
Dr. Nieland and colleagues hypothesized that blocking lipid metabolism would reverse the inflammatory response and other harmful processes that occur in MS. Previous research by Shriver and colleagues indicated that inhibition of carnitine palmitoyltransferase 1 (CPT1), a molecule essential to lipid metabolism, in encephalitogenic T cells increases apoptosis and reduces the production of inflammatory cytokines. Two of the molecule’s three isoforms, CPT1A and CPT1C, are upregulated in MS. Stress prompts an increase in CPT1 expression, which spurs a shift to lipid metabolism. “If you block CPT1, you jam lipid metabolism,” Dr. Nieland said. “There is no way around it.” Dr. Nieland’s group thus chose CPT1 as its target.
The investigators first conducted studies using etomoxir, which inhibits CPT1 and blocks long-chain fatty acids from entering the mitochondria for beta oxidation. Through these effects, etomoxir causes cells to shift to glucose metabolism.
The researchers immunized 42 mice with myelin oligodendrocyte glycoprotein (MOG35–55) to induce experimental autoimmune encephalopathy (EAE). When the animals first exhibited symptoms at Day 10, they were randomized to receive subcutaneous etomoxir or placebo daily. Disease score decreased significantly in the treated animals, compared with the control animals. On Day 24, more than 50% of the treated mice exhibited normal behavior, compared with approximately 20% of control mice.
In another study, the investigators immunized 47 rats with myelin basic protein to induce EAE. The animals began having symptoms at Day 7, and the investigators randomized them to daily treatment with subcutaneous etomoxir or placebo. At Day 11, disease score was significantly lower among treated animals, compared with control animals. Body weight was significantly higher among rats that received etomoxir, compared with controls, at that time point. Also, 25% of treated animals exhibited normal behavior, but no controls did.
In a third study, the investigators compared etomoxir, interferon beta, and placebo in a rat model of EAE. Each treatment group included 10 rats, and etomoxir had superior effects on disease score and body weight, compared with interferon beta and placebo. When the investigators examined the rats’ serum, they found that levels of antibodies against brain antigens common in EAE were lower in rats treated with etomoxir, compared with those treated with interferon beta or placebo.
Biologic Inhibition of Lipid Metabolism
In addition to pharmacologic treatment, genetic mutations affect CPT1 function. The Hutterites, an ethnoreligious group in Canada, have a mutation in CPT1A that almost completely blocks the molecule’s activity. Similarly, the Inuit have a mutation in CPT1A that reduces its activity to approximately 22%. The prevalence of MS is one in 1,100 among the Hutterites and one in 50,000 among the Inuit, compared with one in 350 in the Canadian population. These observations suggest that gene therapy could be another way to block CPT1.
Dr. Nieland’s group collaborated with the Netherlands Cancer Institute to develop mouse strains with two distinct mutations in CPT1A. The first mutation mimics that found among the Hutterites, and the other mimics that found among the Inuit. In a preliminary study, the investigators induced EAE in three wild-type mice and two mice with the CPT1A mutation similar to that of the Inuit. The mice were 10 weeks old at the time of immunization.
At 24 days, disease score was lower in the CPT1A mutant mice, compared with the wild-type mice. Furthermore, body weight was higher in the mutant mice, compared with the wild-type mice. The investigators also measured the mice’s grip strength at Day 2 and Day 24. Grip strength decreased in the wild-type mice but remained the same in the mutant mice. At Day 24, grip strength was significantly higher among mutant mice than among wild-type mice.
“These results indicate an interaction of the lipid metabolism in the brain and in the immune system, which supports our hypothesis regarding MS pathology,” said Anne Skøttrup Mørkholt, a doctoral student at Aalborg University, who collaborated with Dr. Nieland on these animal studies. “MS is not a disease of the immune system, but a systemic disease with dysregulation of multiple components.”
Lipid Metabolism in Other Neurologic Diseases
Data suggest that lipid metabolism may contribute to other neurologic diseases such as amyotrophic lateral sclerosis (ALS) as well. Huang et al found a correlation between serum triglyceride levels and the development of ALS. Dupuis et al observed upregulated lipid metabolism and downregulated glucose metabolism in SOD1 mouse models of the disease, as did subsequent researchers. In addition, a 2015 study by Palamiuc et al found that CPT1B was significantly increased in the muscle tissue of SOD1 mice.
To investigate whether suppressing lipid metabolism affected ALS, Dr. Nieland’s group examined a SOD1 mouse model of the disease. The mice developed symptoms at Day 70 and were randomized at Day 100 to etomoxir or placebo. Etomoxir was associated with less weight loss and better neurologic score, compared with placebo. Etomoxir also was associated with better performance on the wire hanging and rotarod tests, compared with placebo. “It seems like etomoxir was able to slow down the disease progression,” said Michael Sloth Trabjerg, MD, a doctoral student at Aalborg University.
Because research has found increased beta oxidation and decreased glucose metabolism in Parkinson’s disease, Dr. Nieland’s group studied the effect of CPT1 inhibition in a rotenone mouse model of the disease. They induced the disease in the mice for 32 days before randomizing them to placebo or etomoxir. For all mice, treatment alternated between rotenone on one day and placebo or etomoxir on the next day. The investigators observed significantly better sensorimotor performance among treated mice, compared with controls, on Day 47 and Day 56. At Day 60, mice who received etomoxir had significantly more muscle strength and longer latency to fall on the rotarod test, compared with mice that received placebo. These data are being prepared for publication.
The data suggest that dysregulated glucose metabolism and increased lipid metabolism play a role in ALS and Parkinson’s disease. “CPT1 seems to be a prominent target for moderating these diseases,” said Dr. Trabjerg.
—Erik Greb
Suggested Reading
Dodge JC, Treleaven CM, Fidler JA, et al. Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis. Proc Natl Acad Sci U S A. 2013;110(26):10812-10817.
Dupuis L, Oudart H, René F, et al. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004;101(30):11159-11164.
Huang R, Guo X, Chen X, et al. The serum lipid profiles of amyotrophic lateral sclerosis patients: A study from south-west China and a meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):359-365.
Kim SM, Kim H, Kim JE, et al. Amyotrophic lateral sclerosis is associated with hypolipidemia at the presymptomatic stage in mice. PLoS One. 2011;6(3):e17985.
Lieury A, Chanal M, Androdias G, et al. Tissue remodeling in periplaque regions of multiple sclerosis spinal cord lesions. Glia. 2014;62(10):1645-1658.
Mørkholt AS, Kastaniegaard K, Trabjerg MS, et al. Identification of brain antigens recognized by autoantibodies in experimental autoimmune encephalomyelitis-induced animals treated with etomoxir or interferon-β. Sci Rep. 2018;8(1):7092.
Palamiuc L, Schlagowski A, Ngo ST, et al. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Mol Med. 2015;7(5):526-546.
Shriver LP, Manchester M. Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis. Sci Rep. 2011;1:79.
van der Windt GJ, Everts B, Chang CH, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68-78.
What Are the Best Therapeutic Options for Parkinson’s Disease?
Levodopa remains the most effective treatment, and techniques for deep brain stimulation are improving.
LOS ANGELES—Physicians who treat patients with Parkinson’s disease have many decisions to make based on therapeutic efficacy and desired outcomes. At the 70th Annual Meeting of the American Academy of Neurology, Melissa J. Nirenberg, MD, PhD, outlined the current landscape of Parkinson’s disease therapeutics, including data about symptom control, timing of treatment, and new therapies.
Initial Therapy: No Benefit to Levodopa Sparing
Levodopa, along with dopamine agonists and monoamine oxidase B (MAO-B) inhibitors, has Level A evidence as initial symptomatic therapy for Parkinson’s disease. “There is no question that levodopa is the most effective treatment for Parkinson’s disease,” said Dr. Nirenberg, Chief Medical Officer of the New York Stem Cell Foundation Research Institute and Adjunct Professor of Neurology at NYU Langone Health in New York City. “However, after people have been taking levodopa for a number of years, its therapeutic effect lasts for shorter periods of time, and patients spend an increasing amount of time in the off state, rather than in the on state.”
In addition to this wearing-off effect, levodopa treatment is associated with dyskinesias. This association and the wearing-off effect have prompted many physicians to adopt levodopa-sparing strategies, such as using dopamine agonists as initial treatment. However, dopamine agonists have other serious side effects, and research shows that in the long run, starting with a dopamine agonist does not improve outcomes.
In one study, data were compared between a large cohort of patients with Parkinson’s disease in Ghana, where levodopa therapy was initiated after a mean of 4.2 years’ disease duration, and patients with Parkinson’s disease in Italy, where levodopa was initiated at a mean of 2.4 years’ disease duration. “Disease duration and medication dosage, rather than the duration of levodopa therapy, affected the likelihood of dyskinesia,” Dr. Nirenberg said. “When you start levodopa late, you miss the honeymoon period,” she said, referring to the period during which patients experience the benefits of levodopa therapy before developing motor complications. “Simply put, levodopa as initial treatment works better [and] has fewer short- and long-term adverse effects [than dopamine agonists].”
Other Therapies
Dopamine agonists are highly efficacious as add-on treatment, but they also can have serious adverse effects. “Neurogenic orthostatic hypotension, psychosis, and sleepiness are adverse effects that are worse with dopamine agonists than with levodopa,” Dr. Nirenberg noted. “Another common adverse effect associated with dopamine agonists is impulse control disorders—pathologic gambling, compulsive eating, compulsive shopping, and hypersexuality.”
MAO-B inhibitors are also commonly used, well-tolerated medications that can be administered alone or in combination with levodopa or other medications. Of these drugs, selegiline and rasagiline can be used as monotherapy, Dr. Nirenberg noted, but a newer MAO-B inhibitor, safinamide, is not effective as monotherapy and should only be used as an adjunctive therapy with levodopa.
Extended release (ER) carbidopa–levodopa capsules, which contain immediate-release and ER beads to provide initial and extended levodopa plasma concentrations, have been effective in reducing wearing off between doses of levodopa, but conversion to this formulation from immediate-release levodopa is not straightforward. Rather than using the suggested conversion table in the package insert, neurologists might try the approach suggested by investigators who participated in the original clinical trials, said Dr. Nirenberg. Extended-release “capsules can be twisted open, and the beads poured into applesauce for people who have trouble swallowing,” she added.
Amantadine and anticholinergics are second-line medications that can be used as initial or adjunctive therapy. “They are weaker than the first-line drugs and have unfavorable adverse-effect profiles,” said Dr. Nirenberg. Amantadine, of which a newly approved extended-release formulation is available, can reduce dyskinesias.
New and Investigational Treatments
Deep brain stimulation (DBS) techniques are advancing, said Dr. Nirenberg. With DBS, a device implanted in the chest sends electrical pulses to electrodes inserted into targeted areas of the brain. “Recent studies are looking at closed-loop systems that provide direct feedback from the brain to the pacemaker so that stimulation is adjusted in real time.”
Continuous enteral infusion of carbidopa–levodopa intestinal gel over 16 hours via percutaneous endoscopic gastrojejunostomy is an option for people for whom DBS is being considered, but who have contraindications such as cognitive impairment or psychosis. “This [treatment] should only be prescribed to someone who has a good caregiver, because the pump has to be flushed often, removed before bathing, and checked to make sure there are no hardware problems or infections associated with its use.”
Droxidopa, a synthetic amino acid precursor of noradrenaline, received orphan-product designation for treatment of
Pimavanserin, a first-in-class drug approved in 2016 to treat hallucinations and delusions associated with Parkinson’s disease psychosis, is an atypical antipsychotic with a serotonergic mechanism of action. While the prospect of having such a treatment option initially generated excitement in the medical community, there have been recent concerns about adverse events in patients taking pimavanserin, including deaths, falls, insomnia, and nausea, in addition to continued hallucinations.
Focused ultrasound is approved for essential tremor and is investigational for Parkinson’s disease, Dr. Nirenberg noted. During the procedure, which can be performed on an outpatient basis, focused beams of ultrasonic energy are trained on targets deep in the brain to destroy diseased tissue without damaging surrounding normal tissue. Because of the lack of long-term follow-up of these patients, neurologists “do not know where this ultimately will fit in with Parkinson’s disease management,” said Dr. Nirenberg. Focused ultrasound is mainly being investigated as unilateral treatment because of concerns about the safety of bilateral ablative therapy.
To date, research on oral cannabinoids has not shown evidence of benefit for Parkinson’s disease, said Dr. Nirenberg. Neurologists have concerns about potential drug interactions and side effects such as imbalance, falls, cognitive impairment, and psychosis, which are of particular concern in people with Parkinson’s disease.
—Adriene Marshall
Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(Pt 10):2731-2742.
Tetrud J, Nausieda P, Kreitzman D, et al. Conversion to carbidopa and levodopa extended-release (IPX066) followed by its extended use in patients previously taking controlled-release carbidopa-levodopa for advanced Parkinson’s disease. J Neurol Sci. 2017;373:116-123.
Levodopa remains the most effective treatment, and techniques for deep brain stimulation are improving.
Levodopa remains the most effective treatment, and techniques for deep brain stimulation are improving.
LOS ANGELES—Physicians who treat patients with Parkinson’s disease have many decisions to make based on therapeutic efficacy and desired outcomes. At the 70th Annual Meeting of the American Academy of Neurology, Melissa J. Nirenberg, MD, PhD, outlined the current landscape of Parkinson’s disease therapeutics, including data about symptom control, timing of treatment, and new therapies.
Initial Therapy: No Benefit to Levodopa Sparing
Levodopa, along with dopamine agonists and monoamine oxidase B (MAO-B) inhibitors, has Level A evidence as initial symptomatic therapy for Parkinson’s disease. “There is no question that levodopa is the most effective treatment for Parkinson’s disease,” said Dr. Nirenberg, Chief Medical Officer of the New York Stem Cell Foundation Research Institute and Adjunct Professor of Neurology at NYU Langone Health in New York City. “However, after people have been taking levodopa for a number of years, its therapeutic effect lasts for shorter periods of time, and patients spend an increasing amount of time in the off state, rather than in the on state.”
In addition to this wearing-off effect, levodopa treatment is associated with dyskinesias. This association and the wearing-off effect have prompted many physicians to adopt levodopa-sparing strategies, such as using dopamine agonists as initial treatment. However, dopamine agonists have other serious side effects, and research shows that in the long run, starting with a dopamine agonist does not improve outcomes.
In one study, data were compared between a large cohort of patients with Parkinson’s disease in Ghana, where levodopa therapy was initiated after a mean of 4.2 years’ disease duration, and patients with Parkinson’s disease in Italy, where levodopa was initiated at a mean of 2.4 years’ disease duration. “Disease duration and medication dosage, rather than the duration of levodopa therapy, affected the likelihood of dyskinesia,” Dr. Nirenberg said. “When you start levodopa late, you miss the honeymoon period,” she said, referring to the period during which patients experience the benefits of levodopa therapy before developing motor complications. “Simply put, levodopa as initial treatment works better [and] has fewer short- and long-term adverse effects [than dopamine agonists].”
Other Therapies
Dopamine agonists are highly efficacious as add-on treatment, but they also can have serious adverse effects. “Neurogenic orthostatic hypotension, psychosis, and sleepiness are adverse effects that are worse with dopamine agonists than with levodopa,” Dr. Nirenberg noted. “Another common adverse effect associated with dopamine agonists is impulse control disorders—pathologic gambling, compulsive eating, compulsive shopping, and hypersexuality.”
MAO-B inhibitors are also commonly used, well-tolerated medications that can be administered alone or in combination with levodopa or other medications. Of these drugs, selegiline and rasagiline can be used as monotherapy, Dr. Nirenberg noted, but a newer MAO-B inhibitor, safinamide, is not effective as monotherapy and should only be used as an adjunctive therapy with levodopa.
Extended release (ER) carbidopa–levodopa capsules, which contain immediate-release and ER beads to provide initial and extended levodopa plasma concentrations, have been effective in reducing wearing off between doses of levodopa, but conversion to this formulation from immediate-release levodopa is not straightforward. Rather than using the suggested conversion table in the package insert, neurologists might try the approach suggested by investigators who participated in the original clinical trials, said Dr. Nirenberg. Extended-release “capsules can be twisted open, and the beads poured into applesauce for people who have trouble swallowing,” she added.
Amantadine and anticholinergics are second-line medications that can be used as initial or adjunctive therapy. “They are weaker than the first-line drugs and have unfavorable adverse-effect profiles,” said Dr. Nirenberg. Amantadine, of which a newly approved extended-release formulation is available, can reduce dyskinesias.
New and Investigational Treatments
Deep brain stimulation (DBS) techniques are advancing, said Dr. Nirenberg. With DBS, a device implanted in the chest sends electrical pulses to electrodes inserted into targeted areas of the brain. “Recent studies are looking at closed-loop systems that provide direct feedback from the brain to the pacemaker so that stimulation is adjusted in real time.”
Continuous enteral infusion of carbidopa–levodopa intestinal gel over 16 hours via percutaneous endoscopic gastrojejunostomy is an option for people for whom DBS is being considered, but who have contraindications such as cognitive impairment or psychosis. “This [treatment] should only be prescribed to someone who has a good caregiver, because the pump has to be flushed often, removed before bathing, and checked to make sure there are no hardware problems or infections associated with its use.”
Droxidopa, a synthetic amino acid precursor of noradrenaline, received orphan-product designation for treatment of
Pimavanserin, a first-in-class drug approved in 2016 to treat hallucinations and delusions associated with Parkinson’s disease psychosis, is an atypical antipsychotic with a serotonergic mechanism of action. While the prospect of having such a treatment option initially generated excitement in the medical community, there have been recent concerns about adverse events in patients taking pimavanserin, including deaths, falls, insomnia, and nausea, in addition to continued hallucinations.
Focused ultrasound is approved for essential tremor and is investigational for Parkinson’s disease, Dr. Nirenberg noted. During the procedure, which can be performed on an outpatient basis, focused beams of ultrasonic energy are trained on targets deep in the brain to destroy diseased tissue without damaging surrounding normal tissue. Because of the lack of long-term follow-up of these patients, neurologists “do not know where this ultimately will fit in with Parkinson’s disease management,” said Dr. Nirenberg. Focused ultrasound is mainly being investigated as unilateral treatment because of concerns about the safety of bilateral ablative therapy.
To date, research on oral cannabinoids has not shown evidence of benefit for Parkinson’s disease, said Dr. Nirenberg. Neurologists have concerns about potential drug interactions and side effects such as imbalance, falls, cognitive impairment, and psychosis, which are of particular concern in people with Parkinson’s disease.
—Adriene Marshall
Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(Pt 10):2731-2742.
Tetrud J, Nausieda P, Kreitzman D, et al. Conversion to carbidopa and levodopa extended-release (IPX066) followed by its extended use in patients previously taking controlled-release carbidopa-levodopa for advanced Parkinson’s disease. J Neurol Sci. 2017;373:116-123.
LOS ANGELES—Physicians who treat patients with Parkinson’s disease have many decisions to make based on therapeutic efficacy and desired outcomes. At the 70th Annual Meeting of the American Academy of Neurology, Melissa J. Nirenberg, MD, PhD, outlined the current landscape of Parkinson’s disease therapeutics, including data about symptom control, timing of treatment, and new therapies.
Initial Therapy: No Benefit to Levodopa Sparing
Levodopa, along with dopamine agonists and monoamine oxidase B (MAO-B) inhibitors, has Level A evidence as initial symptomatic therapy for Parkinson’s disease. “There is no question that levodopa is the most effective treatment for Parkinson’s disease,” said Dr. Nirenberg, Chief Medical Officer of the New York Stem Cell Foundation Research Institute and Adjunct Professor of Neurology at NYU Langone Health in New York City. “However, after people have been taking levodopa for a number of years, its therapeutic effect lasts for shorter periods of time, and patients spend an increasing amount of time in the off state, rather than in the on state.”
In addition to this wearing-off effect, levodopa treatment is associated with dyskinesias. This association and the wearing-off effect have prompted many physicians to adopt levodopa-sparing strategies, such as using dopamine agonists as initial treatment. However, dopamine agonists have other serious side effects, and research shows that in the long run, starting with a dopamine agonist does not improve outcomes.
In one study, data were compared between a large cohort of patients with Parkinson’s disease in Ghana, where levodopa therapy was initiated after a mean of 4.2 years’ disease duration, and patients with Parkinson’s disease in Italy, where levodopa was initiated at a mean of 2.4 years’ disease duration. “Disease duration and medication dosage, rather than the duration of levodopa therapy, affected the likelihood of dyskinesia,” Dr. Nirenberg said. “When you start levodopa late, you miss the honeymoon period,” she said, referring to the period during which patients experience the benefits of levodopa therapy before developing motor complications. “Simply put, levodopa as initial treatment works better [and] has fewer short- and long-term adverse effects [than dopamine agonists].”
Other Therapies
Dopamine agonists are highly efficacious as add-on treatment, but they also can have serious adverse effects. “Neurogenic orthostatic hypotension, psychosis, and sleepiness are adverse effects that are worse with dopamine agonists than with levodopa,” Dr. Nirenberg noted. “Another common adverse effect associated with dopamine agonists is impulse control disorders—pathologic gambling, compulsive eating, compulsive shopping, and hypersexuality.”
MAO-B inhibitors are also commonly used, well-tolerated medications that can be administered alone or in combination with levodopa or other medications. Of these drugs, selegiline and rasagiline can be used as monotherapy, Dr. Nirenberg noted, but a newer MAO-B inhibitor, safinamide, is not effective as monotherapy and should only be used as an adjunctive therapy with levodopa.
Extended release (ER) carbidopa–levodopa capsules, which contain immediate-release and ER beads to provide initial and extended levodopa plasma concentrations, have been effective in reducing wearing off between doses of levodopa, but conversion to this formulation from immediate-release levodopa is not straightforward. Rather than using the suggested conversion table in the package insert, neurologists might try the approach suggested by investigators who participated in the original clinical trials, said Dr. Nirenberg. Extended-release “capsules can be twisted open, and the beads poured into applesauce for people who have trouble swallowing,” she added.
Amantadine and anticholinergics are second-line medications that can be used as initial or adjunctive therapy. “They are weaker than the first-line drugs and have unfavorable adverse-effect profiles,” said Dr. Nirenberg. Amantadine, of which a newly approved extended-release formulation is available, can reduce dyskinesias.
New and Investigational Treatments
Deep brain stimulation (DBS) techniques are advancing, said Dr. Nirenberg. With DBS, a device implanted in the chest sends electrical pulses to electrodes inserted into targeted areas of the brain. “Recent studies are looking at closed-loop systems that provide direct feedback from the brain to the pacemaker so that stimulation is adjusted in real time.”
Continuous enteral infusion of carbidopa–levodopa intestinal gel over 16 hours via percutaneous endoscopic gastrojejunostomy is an option for people for whom DBS is being considered, but who have contraindications such as cognitive impairment or psychosis. “This [treatment] should only be prescribed to someone who has a good caregiver, because the pump has to be flushed often, removed before bathing, and checked to make sure there are no hardware problems or infections associated with its use.”
Droxidopa, a synthetic amino acid precursor of noradrenaline, received orphan-product designation for treatment of
Pimavanserin, a first-in-class drug approved in 2016 to treat hallucinations and delusions associated with Parkinson’s disease psychosis, is an atypical antipsychotic with a serotonergic mechanism of action. While the prospect of having such a treatment option initially generated excitement in the medical community, there have been recent concerns about adverse events in patients taking pimavanserin, including deaths, falls, insomnia, and nausea, in addition to continued hallucinations.
Focused ultrasound is approved for essential tremor and is investigational for Parkinson’s disease, Dr. Nirenberg noted. During the procedure, which can be performed on an outpatient basis, focused beams of ultrasonic energy are trained on targets deep in the brain to destroy diseased tissue without damaging surrounding normal tissue. Because of the lack of long-term follow-up of these patients, neurologists “do not know where this ultimately will fit in with Parkinson’s disease management,” said Dr. Nirenberg. Focused ultrasound is mainly being investigated as unilateral treatment because of concerns about the safety of bilateral ablative therapy.
To date, research on oral cannabinoids has not shown evidence of benefit for Parkinson’s disease, said Dr. Nirenberg. Neurologists have concerns about potential drug interactions and side effects such as imbalance, falls, cognitive impairment, and psychosis, which are of particular concern in people with Parkinson’s disease.
—Adriene Marshall
Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(Pt 10):2731-2742.
Tetrud J, Nausieda P, Kreitzman D, et al. Conversion to carbidopa and levodopa extended-release (IPX066) followed by its extended use in patients previously taking controlled-release carbidopa-levodopa for advanced Parkinson’s disease. J Neurol Sci. 2017;373:116-123.
Type 2 Diabetes Increases the Risk of Parkinson’s Disease
The risk is particularly high among younger patients and those with complications from diabetes.
Patients with type 2 diabetes mellitus have an increased risk of developing Parkinson’s disease later in life, according to an investigation published online ahead of print June 13 in Neurology. The magnitude of risk is greater in younger patients and in patients with complications from diabetes.
Investigators have hypothesized an association between diabetes and the risk of Parkinson’s disease, but studies of the potential link have had conflicting results. Thomas T. Warner, MD, PhD, Professor of Clinical Neurology at University College London (UCL), and colleagues conducted a retrospective cohort study to examine this question anew. 
Analyzing a Nationwide Hospital Database
The researchers reviewed English national Hospital Episode Statistics and mortality data collected between 1999 and 2011 and created a cohort of 2,017,115 patients who had been admitted for hospital care with a diagnosis of type 2 diabetes. They created a reference cohort of 6,173,208 patients without diabetes who were admitted for minor medical and surgical procedures. Conditions in this cohort included sprains, inguinal hernia, bruising, and hip replacement. People with Parkinson’s disease, ischemic cerebral infarction, vascular parkinsonism, drug-induced secondary parkinsonism, and normal pressure hydrocephalus were excluded from the study. Dr. Warner and colleagues created multivariable Cox proportional hazard regression models to estimate the risk of subsequent Parkinson’s disease.
Participants with diabetes had a greater risk of a subsequent diagnosis of Parkinson’s disease than patients in the reference cohort (adjusted hazard ratio [HR], 1.32). In subgroup analyses, the researchers found that the risk was substantially higher among patients between ages 25 and 44 (adjusted HR, 3.81) and those with complicated diabetes (adjusted HR, 1.49). Genetic factors may exert a relatively greater effect on younger people, and this difference may account for the increased risk among younger participants with diabetes, said the authors.
The adjusted HR of Parkinson’s disease was 1.40 in patients with diabetes between ages 65 and 74 and 1.18 in those age 75 or older. “The association in elderly patients may be the consequence of disrupted insulin signaling secondary to additional lifestyle and environmental factors causing cumulative pathogenic brain changes,” said Dr. Warner and colleagues.
No Adjustment for Potential Confounders
The large size of the database and the ability to exclude people with cerebrovascular disease and drug-induced and vascular parkinsonisms were among the study’s main strengths, according to the authors. Its weaknesses included an inability to adjust for potential confounders and the lack of clinical information about Parkinson’s disease ascertainment beyond routinely collected data.
The results could help researchers identify “new ways to treat or prevent the development of Parkinson’s disease, such as use of antidiabetes drugs to restore the brain’s insulin signaling,” said Dr. Warner. “A UCL-led study published last year found that a drug commonly used to treat diabetes shows promise in not only relieving Parkinson’s disease symptoms, but potentially altering the course of the disease itself. What we do not know is whether trying to treat people with type 2 diabetes better would reduce the risk of developing Parkinson’s disease.”
—Erik Greb
Suggested Reading
De Pablo-Fernandez E, Goldacre R, Pakpoor J, et al. Association between diabetes and subsequent Parkinson disease: a record-linkage cohort study. Neurology. 2018 Jun 13 [Epub ahead of print].
The risk is particularly high among younger patients and those with complications from diabetes.
The risk is particularly high among younger patients and those with complications from diabetes.
Patients with type 2 diabetes mellitus have an increased risk of developing Parkinson’s disease later in life, according to an investigation published online ahead of print June 13 in Neurology. The magnitude of risk is greater in younger patients and in patients with complications from diabetes.
Investigators have hypothesized an association between diabetes and the risk of Parkinson’s disease, but studies of the potential link have had conflicting results. Thomas T. Warner, MD, PhD, Professor of Clinical Neurology at University College London (UCL), and colleagues conducted a retrospective cohort study to examine this question anew.
Analyzing a Nationwide Hospital Database
The researchers reviewed English national Hospital Episode Statistics and mortality data collected between 1999 and 2011 and created a cohort of 2,017,115 patients who had been admitted for hospital care with a diagnosis of type 2 diabetes. They created a reference cohort of 6,173,208 patients without diabetes who were admitted for minor medical and surgical procedures. Conditions in this cohort included sprains, inguinal hernia, bruising, and hip replacement. People with Parkinson’s disease, ischemic cerebral infarction, vascular parkinsonism, drug-induced secondary parkinsonism, and normal pressure hydrocephalus were excluded from the study. Dr. Warner and colleagues created multivariable Cox proportional hazard regression models to estimate the risk of subsequent Parkinson’s disease.
Participants with diabetes had a greater risk of a subsequent diagnosis of Parkinson’s disease than patients in the reference cohort (adjusted hazard ratio [HR], 1.32). In subgroup analyses, the researchers found that the risk was substantially higher among patients between ages 25 and 44 (adjusted HR, 3.81) and those with complicated diabetes (adjusted HR, 1.49). Genetic factors may exert a relatively greater effect on younger people, and this difference may account for the increased risk among younger participants with diabetes, said the authors.
The adjusted HR of Parkinson’s disease was 1.40 in patients with diabetes between ages 65 and 74 and 1.18 in those age 75 or older. “The association in elderly patients may be the consequence of disrupted insulin signaling secondary to additional lifestyle and environmental factors causing cumulative pathogenic brain changes,” said Dr. Warner and colleagues.
No Adjustment for Potential Confounders
The large size of the database and the ability to exclude people with cerebrovascular disease and drug-induced and vascular parkinsonisms were among the study’s main strengths, according to the authors. Its weaknesses included an inability to adjust for potential confounders and the lack of clinical information about Parkinson’s disease ascertainment beyond routinely collected data.
The results could help researchers identify “new ways to treat or prevent the development of Parkinson’s disease, such as use of antidiabetes drugs to restore the brain’s insulin signaling,” said Dr. Warner. “A UCL-led study published last year found that a drug commonly used to treat diabetes shows promise in not only relieving Parkinson’s disease symptoms, but potentially altering the course of the disease itself. What we do not know is whether trying to treat people with type 2 diabetes better would reduce the risk of developing Parkinson’s disease.”
—Erik Greb
Suggested Reading
De Pablo-Fernandez E, Goldacre R, Pakpoor J, et al. Association between diabetes and subsequent Parkinson disease: a record-linkage cohort study. Neurology. 2018 Jun 13 [Epub ahead of print].
Patients with type 2 diabetes mellitus have an increased risk of developing Parkinson’s disease later in life, according to an investigation published online ahead of print June 13 in Neurology. The magnitude of risk is greater in younger patients and in patients with complications from diabetes.
Investigators have hypothesized an association between diabetes and the risk of Parkinson’s disease, but studies of the potential link have had conflicting results. Thomas T. Warner, MD, PhD, Professor of Clinical Neurology at University College London (UCL), and colleagues conducted a retrospective cohort study to examine this question anew.
Analyzing a Nationwide Hospital Database
The researchers reviewed English national Hospital Episode Statistics and mortality data collected between 1999 and 2011 and created a cohort of 2,017,115 patients who had been admitted for hospital care with a diagnosis of type 2 diabetes. They created a reference cohort of 6,173,208 patients without diabetes who were admitted for minor medical and surgical procedures. Conditions in this cohort included sprains, inguinal hernia, bruising, and hip replacement. People with Parkinson’s disease, ischemic cerebral infarction, vascular parkinsonism, drug-induced secondary parkinsonism, and normal pressure hydrocephalus were excluded from the study. Dr. Warner and colleagues created multivariable Cox proportional hazard regression models to estimate the risk of subsequent Parkinson’s disease.
Participants with diabetes had a greater risk of a subsequent diagnosis of Parkinson’s disease than patients in the reference cohort (adjusted hazard ratio [HR], 1.32). In subgroup analyses, the researchers found that the risk was substantially higher among patients between ages 25 and 44 (adjusted HR, 3.81) and those with complicated diabetes (adjusted HR, 1.49). Genetic factors may exert a relatively greater effect on younger people, and this difference may account for the increased risk among younger participants with diabetes, said the authors.
The adjusted HR of Parkinson’s disease was 1.40 in patients with diabetes between ages 65 and 74 and 1.18 in those age 75 or older. “The association in elderly patients may be the consequence of disrupted insulin signaling secondary to additional lifestyle and environmental factors causing cumulative pathogenic brain changes,” said Dr. Warner and colleagues.
No Adjustment for Potential Confounders
The large size of the database and the ability to exclude people with cerebrovascular disease and drug-induced and vascular parkinsonisms were among the study’s main strengths, according to the authors. Its weaknesses included an inability to adjust for potential confounders and the lack of clinical information about Parkinson’s disease ascertainment beyond routinely collected data.
The results could help researchers identify “new ways to treat or prevent the development of Parkinson’s disease, such as use of antidiabetes drugs to restore the brain’s insulin signaling,” said Dr. Warner. “A UCL-led study published last year found that a drug commonly used to treat diabetes shows promise in not only relieving Parkinson’s disease symptoms, but potentially altering the course of the disease itself. What we do not know is whether trying to treat people with type 2 diabetes better would reduce the risk of developing Parkinson’s disease.”
—Erik Greb
Suggested Reading
De Pablo-Fernandez E, Goldacre R, Pakpoor J, et al. Association between diabetes and subsequent Parkinson disease: a record-linkage cohort study. Neurology. 2018 Jun 13 [Epub ahead of print].
Type 2 diabetes may promote Parkinson development
Type 2 diabetes mellitus may be associated with an increased risk of Parkinson’s disease, according to a large retrospective cohort study published online June 13 in Neurology.
Researchers accessed the linked English national Hospital Episode Statistics and mortality data from 1999-2011 to compare data from 2,017,115 individuals admitted to hospital who had a diagnostic code for type 2 diabetes with data from a reference cohort of 6,173,208 individuals admitted for a range of other minor procedures.
They found a significant 32% higher incidence of Parkinson’s disease among individuals with type 2 diabetes, compared with the reference cohort (95% confidence interval, 1.29-1.35; P less than .001).
The incidence was particularly high among younger individuals with type 2 diabetes; those aged 25-44 years at the time of admission had a 3.8-fold higher rate of Parkinson’s disease, compared with the reference group (P less than .001). Individuals aged 45-64 years with type 2 diabetes had 71% greater rate of Parkinson, those aged 65-74 years had a 40% higher incidence, and those aged 75 years or over had an 18% higher rate.
Individuals with complicated type 2 diabetes, defined as the presence of diabetic neuropathy, nephropathy, or retinopathy, had a 49% higher incidence of Parkinson disease than did the reference cohort.
Eduardo De Pablo-Fernandez, MD, from the University College London Institute of Neurology, and his coauthors suggested that the interaction between the two, apparently unconnected, diseases may be a function of both genetics and shared pathogenic pathways.
“The magnitude of risk in our study was greater in younger individuals, whereby genetic factors may relatively exert more of an effect, and more than 400 genes, previously identified through genome-wide association studies, have been closely linked to both conditions using integrative network analysis,” the authors wrote.
“However, the association in elderly patients may be the consequence of disrupted insulin signaling secondary to additional lifestyle and environmental factors causing cumulative pathogenic brain changes.”
They proposed that disrupted brain insulin signaling could lead to neuroinflammation, mitochondrial dysfunction, and increased oxidative stress that could contribute to the development of Parkinson’s disease.
The findings were similar to those seen in a previous meta-analysis of five studies, although the authors commented that there was significant heterogeneity among the studies included in that analysis.
The authors of this study also noted that their study did not adjust for potential confounders such as smoking or antidiabetic medication use.
The study was supported by the National Institute for Health Research Biomedical Research Centre at the University of Oxford, England, and the NIHR Biomedical Research Centre at University College London. Two authors declared funding and payments from private industry outside the submitted work, but no other conflicts of interest were declared.
SOURCE: De Pablo Fernandez E et al. Neurology. 2018 June 13. doi: 10.1212/WNL.0000000000005771.
Type 2 diabetes mellitus may be associated with an increased risk of Parkinson’s disease, according to a large retrospective cohort study published online June 13 in Neurology.
Researchers accessed the linked English national Hospital Episode Statistics and mortality data from 1999-2011 to compare data from 2,017,115 individuals admitted to hospital who had a diagnostic code for type 2 diabetes with data from a reference cohort of 6,173,208 individuals admitted for a range of other minor procedures.
They found a significant 32% higher incidence of Parkinson’s disease among individuals with type 2 diabetes, compared with the reference cohort (95% confidence interval, 1.29-1.35; P less than .001).
The incidence was particularly high among younger individuals with type 2 diabetes; those aged 25-44 years at the time of admission had a 3.8-fold higher rate of Parkinson’s disease, compared with the reference group (P less than .001). Individuals aged 45-64 years with type 2 diabetes had 71% greater rate of Parkinson, those aged 65-74 years had a 40% higher incidence, and those aged 75 years or over had an 18% higher rate.
Individuals with complicated type 2 diabetes, defined as the presence of diabetic neuropathy, nephropathy, or retinopathy, had a 49% higher incidence of Parkinson disease than did the reference cohort.
Eduardo De Pablo-Fernandez, MD, from the University College London Institute of Neurology, and his coauthors suggested that the interaction between the two, apparently unconnected, diseases may be a function of both genetics and shared pathogenic pathways.
“The magnitude of risk in our study was greater in younger individuals, whereby genetic factors may relatively exert more of an effect, and more than 400 genes, previously identified through genome-wide association studies, have been closely linked to both conditions using integrative network analysis,” the authors wrote.
“However, the association in elderly patients may be the consequence of disrupted insulin signaling secondary to additional lifestyle and environmental factors causing cumulative pathogenic brain changes.”
They proposed that disrupted brain insulin signaling could lead to neuroinflammation, mitochondrial dysfunction, and increased oxidative stress that could contribute to the development of Parkinson’s disease.
The findings were similar to those seen in a previous meta-analysis of five studies, although the authors commented that there was significant heterogeneity among the studies included in that analysis.
The authors of this study also noted that their study did not adjust for potential confounders such as smoking or antidiabetic medication use.
The study was supported by the National Institute for Health Research Biomedical Research Centre at the University of Oxford, England, and the NIHR Biomedical Research Centre at University College London. Two authors declared funding and payments from private industry outside the submitted work, but no other conflicts of interest were declared.
SOURCE: De Pablo Fernandez E et al. Neurology. 2018 June 13. doi: 10.1212/WNL.0000000000005771.
Type 2 diabetes mellitus may be associated with an increased risk of Parkinson’s disease, according to a large retrospective cohort study published online June 13 in Neurology.
Researchers accessed the linked English national Hospital Episode Statistics and mortality data from 1999-2011 to compare data from 2,017,115 individuals admitted to hospital who had a diagnostic code for type 2 diabetes with data from a reference cohort of 6,173,208 individuals admitted for a range of other minor procedures.
They found a significant 32% higher incidence of Parkinson’s disease among individuals with type 2 diabetes, compared with the reference cohort (95% confidence interval, 1.29-1.35; P less than .001).
The incidence was particularly high among younger individuals with type 2 diabetes; those aged 25-44 years at the time of admission had a 3.8-fold higher rate of Parkinson’s disease, compared with the reference group (P less than .001). Individuals aged 45-64 years with type 2 diabetes had 71% greater rate of Parkinson, those aged 65-74 years had a 40% higher incidence, and those aged 75 years or over had an 18% higher rate.
Individuals with complicated type 2 diabetes, defined as the presence of diabetic neuropathy, nephropathy, or retinopathy, had a 49% higher incidence of Parkinson disease than did the reference cohort.
Eduardo De Pablo-Fernandez, MD, from the University College London Institute of Neurology, and his coauthors suggested that the interaction between the two, apparently unconnected, diseases may be a function of both genetics and shared pathogenic pathways.
“The magnitude of risk in our study was greater in younger individuals, whereby genetic factors may relatively exert more of an effect, and more than 400 genes, previously identified through genome-wide association studies, have been closely linked to both conditions using integrative network analysis,” the authors wrote.
“However, the association in elderly patients may be the consequence of disrupted insulin signaling secondary to additional lifestyle and environmental factors causing cumulative pathogenic brain changes.”
They proposed that disrupted brain insulin signaling could lead to neuroinflammation, mitochondrial dysfunction, and increased oxidative stress that could contribute to the development of Parkinson’s disease.
The findings were similar to those seen in a previous meta-analysis of five studies, although the authors commented that there was significant heterogeneity among the studies included in that analysis.
The authors of this study also noted that their study did not adjust for potential confounders such as smoking or antidiabetic medication use.
The study was supported by the National Institute for Health Research Biomedical Research Centre at the University of Oxford, England, and the NIHR Biomedical Research Centre at University College London. Two authors declared funding and payments from private industry outside the submitted work, but no other conflicts of interest were declared.
SOURCE: De Pablo Fernandez E et al. Neurology. 2018 June 13. doi: 10.1212/WNL.0000000000005771.
FROM NEUROLOGY
Key clinical point: Type 2 diabetes may be associated with an increased risk of Parkinson’s disease.
Major finding: The incidence of Parkinson’s disease is 32% higher in people with type 2 diabetes.
Study details: Retrospective cohort study including 2,017,115 individuals with type 2 diabetes and 6,173,208 controls.
Disclosures: The study was supported by the National Institute for Health Research Biomedical Research Centre at the University of Oxford, England, and the NIHR Biomedical Research Centre at University College London. Two authors declared funding and payments from private industry outside the submitted work, but no other conflicts of interest were declared.
Source: De Pablo-Fernandez E et al. Neurology. 2018 June 13. doi: 10.1212/WNL.0000000000005771.
Can a Finger Displacement Test Help Assess Parkinson’s Disease Dementia?
LOS ANGELES—A simple test of finger displacement may distinguish between Parkinson’s disease dementia and Alzheimer’s disease and help neurologists assess the progression of dementia in Parkinson’s disease, according to a study presented at the 70th Annual Meeting of the American Academy of Neurology.
Parkinson’s disease dementia is one of the most disabling nonmotor complications of Parkinson’s disease, but “there is no simple bedside test available that can measure the progression of dementia,” said Aman Deep, MD, a neurology resident at the University of Tennessee Health Science Center in Memphis, and colleagues. 
To study the clinical utility of finger displacement in patients with dementia, Dr. Deep and colleagues examined 56 patients with Parkinson’s disease dementia and 35 patients with Alzheimer’s disease. The patients pointed their index fingers toward a grid ruler. After maintaining the pointing position for 15 seconds, patients were asked to close their eyes for another 15 seconds while maintaining the same position. A positive result was downward index finger displacement of 5 cm or greater while patients had their eyes closed.
The patients with Parkinson’s disease dementia (42 male; mean age, 75) had a mean Parkinson’s disease duration of 9.1 years, a mean dementia duration of 3.1 years, and a mean Unified Parkinson’s Disease Rating Scale score of 37. The group’s mean Mini-Mental State Examination (MMSE) score was 17.5. Fifty-three patients out of 56 (95%) exhibited bilateral downward drift of 5 cm or greater, and three patients exhibited less than 5 cm of downward drift. The mean bilateral downward finger drift was 6.8 cm for the group.
Among patients with Alzheimer’s disease (21 male; mean age, 77.4), the mean dementia duration was 3.9 years. The group’s mean MMSE score was 17.8. In the Alzheimer’s disease group, only one patient had minimal drift, and the group’s mean bilateral downward drift was 0.2 cm.
According to the researchers, the finger displacement test has a sensitivity of 100% and a specificity of 92.1%. “Downward finger displacement, especially bilateral downward displacement, may signal extensive disruption of subcortical–cortical circuits,” Dr. Deep and colleagues said. “The simple and inexpensive bedside test of finger displacement may be used to help distinguish Parkinson’s disease dementia from Alzheimer’s disease.”
—Jake Remaly
Suggested Reading
Lieberman A, Deep A, Shi J, et al. Downward finger displacement distinguishes Parkinson disease dementia from Alzheimer disease. Int J Neurosci. 2018;128(2):151-154.
LOS ANGELES—A simple test of finger displacement may distinguish between Parkinson’s disease dementia and Alzheimer’s disease and help neurologists assess the progression of dementia in Parkinson’s disease, according to a study presented at the 70th Annual Meeting of the American Academy of Neurology.
Parkinson’s disease dementia is one of the most disabling nonmotor complications of Parkinson’s disease, but “there is no simple bedside test available that can measure the progression of dementia,” said Aman Deep, MD, a neurology resident at the University of Tennessee Health Science Center in Memphis, and colleagues.
To study the clinical utility of finger displacement in patients with dementia, Dr. Deep and colleagues examined 56 patients with Parkinson’s disease dementia and 35 patients with Alzheimer’s disease. The patients pointed their index fingers toward a grid ruler. After maintaining the pointing position for 15 seconds, patients were asked to close their eyes for another 15 seconds while maintaining the same position. A positive result was downward index finger displacement of 5 cm or greater while patients had their eyes closed.
The patients with Parkinson’s disease dementia (42 male; mean age, 75) had a mean Parkinson’s disease duration of 9.1 years, a mean dementia duration of 3.1 years, and a mean Unified Parkinson’s Disease Rating Scale score of 37. The group’s mean Mini-Mental State Examination (MMSE) score was 17.5. Fifty-three patients out of 56 (95%) exhibited bilateral downward drift of 5 cm or greater, and three patients exhibited less than 5 cm of downward drift. The mean bilateral downward finger drift was 6.8 cm for the group.
Among patients with Alzheimer’s disease (21 male; mean age, 77.4), the mean dementia duration was 3.9 years. The group’s mean MMSE score was 17.8. In the Alzheimer’s disease group, only one patient had minimal drift, and the group’s mean bilateral downward drift was 0.2 cm.
According to the researchers, the finger displacement test has a sensitivity of 100% and a specificity of 92.1%. “Downward finger displacement, especially bilateral downward displacement, may signal extensive disruption of subcortical–cortical circuits,” Dr. Deep and colleagues said. “The simple and inexpensive bedside test of finger displacement may be used to help distinguish Parkinson’s disease dementia from Alzheimer’s disease.”
—Jake Remaly
Suggested Reading
Lieberman A, Deep A, Shi J, et al. Downward finger displacement distinguishes Parkinson disease dementia from Alzheimer disease. Int J Neurosci. 2018;128(2):151-154.
LOS ANGELES—A simple test of finger displacement may distinguish between Parkinson’s disease dementia and Alzheimer’s disease and help neurologists assess the progression of dementia in Parkinson’s disease, according to a study presented at the 70th Annual Meeting of the American Academy of Neurology.
Parkinson’s disease dementia is one of the most disabling nonmotor complications of Parkinson’s disease, but “there is no simple bedside test available that can measure the progression of dementia,” said Aman Deep, MD, a neurology resident at the University of Tennessee Health Science Center in Memphis, and colleagues.
To study the clinical utility of finger displacement in patients with dementia, Dr. Deep and colleagues examined 56 patients with Parkinson’s disease dementia and 35 patients with Alzheimer’s disease. The patients pointed their index fingers toward a grid ruler. After maintaining the pointing position for 15 seconds, patients were asked to close their eyes for another 15 seconds while maintaining the same position. A positive result was downward index finger displacement of 5 cm or greater while patients had their eyes closed.
The patients with Parkinson’s disease dementia (42 male; mean age, 75) had a mean Parkinson’s disease duration of 9.1 years, a mean dementia duration of 3.1 years, and a mean Unified Parkinson’s Disease Rating Scale score of 37. The group’s mean Mini-Mental State Examination (MMSE) score was 17.5. Fifty-three patients out of 56 (95%) exhibited bilateral downward drift of 5 cm or greater, and three patients exhibited less than 5 cm of downward drift. The mean bilateral downward finger drift was 6.8 cm for the group.
Among patients with Alzheimer’s disease (21 male; mean age, 77.4), the mean dementia duration was 3.9 years. The group’s mean MMSE score was 17.8. In the Alzheimer’s disease group, only one patient had minimal drift, and the group’s mean bilateral downward drift was 0.2 cm.
According to the researchers, the finger displacement test has a sensitivity of 100% and a specificity of 92.1%. “Downward finger displacement, especially bilateral downward displacement, may signal extensive disruption of subcortical–cortical circuits,” Dr. Deep and colleagues said. “The simple and inexpensive bedside test of finger displacement may be used to help distinguish Parkinson’s disease dementia from Alzheimer’s disease.”
—Jake Remaly
Suggested Reading
Lieberman A, Deep A, Shi J, et al. Downward finger displacement distinguishes Parkinson disease dementia from Alzheimer disease. Int J Neurosci. 2018;128(2):151-154.
Tear Proteins May Be Biomarkers for Parkinson’s Disease
LOS ANGELES—Tears may hold diagnostic clues as to whether someone has Parkinson’s disease, according to a preliminary study presented at the American Academy of Neurology’s 70th Annual Meeting. “We believe our research is the first to show that tears may be a reliable, inexpensive, and noninvasive biologic marker of Parkinson’s disease,” said study author Mark Floyd Lew, MD, Professor of Clinical Neurology, and Joseph P. Van Der Meulen, MD, Chair in Parkinson’s Disease Research in Honor of Robert J. Pasarow, and Vice Chair, in the Department of Neurology at the Keck School of Medicine of the University of Southern California in Los Angeles.
Nonmotor features of Parkinson’s disease occur years prior to motor dysfunction and represent a well-suited platform to investigate for a possible biomarker. Lacrimal glands are highly innervated by cholinergic neurons, and tear fluid secreted by lacrimal glands is greatly stimulated by cholinergic neurons. The production, packaging, and secretion of specific proteins into tears may be regulated by changes in nerve function to lacrimal glands. According to the researchers, analysis of any alteration in the secretion of proteins into tears may identify a reliable and noninvasive biomarker for Parkinson’s disease.
For the study, tear samples were collected from 55 patients with Parkinson’s disease of varying severity and 27 age- and gender-matched controls without Parkinson’s disease. In addition, tears were analyzed for the levels of four proteins—total alpha synuclein, CC chemokine ligand 2 (CCL-2), DJ-1 (Parkinson’s disease protein 7), and oligomeric alpha synuclein.
The researchers found differences in the levels of a total alpha-synuclein in the tears of patients with Parkinson’s disease, compared with those of controls. Additionally, levels of oligomeric alpha-synuclein, which is alpha-synuclein that has formed aggregates that are implicated in nerve damage in Parkinson’s disease, were also significantly different, compared with controls. It is also possible that the tear gland secretory cells themselves produce these different forms of alpha-synuclein that can be directly secreted into tears, the researchers said.
Total levels of alpha-synuclein were decreased in patients with Parkinson’s disease, with an average of 423 picograms of that protein per milligram (pg/mg) compared with 704 pg/mg in healthy controls. However, levels of oligomeric alpha-synuclein were increased in patients with Parkinson’s disease, with an average of 1.45 nanograms per milligram of tear protein (ng/mg), compared with 0.27 ng/mg in controls. While detectable in tears, neither CCL-2 nor DJ-1 varied between patients with Parkinson’s disease and controls.
“Knowing that something as simple as tears could help neurologists differentiate between people who have Parkinson’s disease and those who do not in a noninvasive manner is exciting,” said Dr. Lew. “And because the Parkinson’s disease process can begin years or decades before symptoms appear, a biologic marker like this could be useful in diagnosing, or even treating, the disease earlier.”
More research needs to be done in larger groups of people to investigate whether these protein changes can be detected in tears in the earliest presymptomatic stages of the disease, said the researchers.
The study was supported by the Michael J. Fox Foundation for Parkinson’s Research and the Plotkin Foundation.
LOS ANGELES—Tears may hold diagnostic clues as to whether someone has Parkinson’s disease, according to a preliminary study presented at the American Academy of Neurology’s 70th Annual Meeting. “We believe our research is the first to show that tears may be a reliable, inexpensive, and noninvasive biologic marker of Parkinson’s disease,” said study author Mark Floyd Lew, MD, Professor of Clinical Neurology, and Joseph P. Van Der Meulen, MD, Chair in Parkinson’s Disease Research in Honor of Robert J. Pasarow, and Vice Chair, in the Department of Neurology at the Keck School of Medicine of the University of Southern California in Los Angeles.
Nonmotor features of Parkinson’s disease occur years prior to motor dysfunction and represent a well-suited platform to investigate for a possible biomarker. Lacrimal glands are highly innervated by cholinergic neurons, and tear fluid secreted by lacrimal glands is greatly stimulated by cholinergic neurons. The production, packaging, and secretion of specific proteins into tears may be regulated by changes in nerve function to lacrimal glands. According to the researchers, analysis of any alteration in the secretion of proteins into tears may identify a reliable and noninvasive biomarker for Parkinson’s disease.
For the study, tear samples were collected from 55 patients with Parkinson’s disease of varying severity and 27 age- and gender-matched controls without Parkinson’s disease. In addition, tears were analyzed for the levels of four proteins—total alpha synuclein, CC chemokine ligand 2 (CCL-2), DJ-1 (Parkinson’s disease protein 7), and oligomeric alpha synuclein.
The researchers found differences in the levels of a total alpha-synuclein in the tears of patients with Parkinson’s disease, compared with those of controls. Additionally, levels of oligomeric alpha-synuclein, which is alpha-synuclein that has formed aggregates that are implicated in nerve damage in Parkinson’s disease, were also significantly different, compared with controls. It is also possible that the tear gland secretory cells themselves produce these different forms of alpha-synuclein that can be directly secreted into tears, the researchers said.
Total levels of alpha-synuclein were decreased in patients with Parkinson’s disease, with an average of 423 picograms of that protein per milligram (pg/mg) compared with 704 pg/mg in healthy controls. However, levels of oligomeric alpha-synuclein were increased in patients with Parkinson’s disease, with an average of 1.45 nanograms per milligram of tear protein (ng/mg), compared with 0.27 ng/mg in controls. While detectable in tears, neither CCL-2 nor DJ-1 varied between patients with Parkinson’s disease and controls.
“Knowing that something as simple as tears could help neurologists differentiate between people who have Parkinson’s disease and those who do not in a noninvasive manner is exciting,” said Dr. Lew. “And because the Parkinson’s disease process can begin years or decades before symptoms appear, a biologic marker like this could be useful in diagnosing, or even treating, the disease earlier.”
More research needs to be done in larger groups of people to investigate whether these protein changes can be detected in tears in the earliest presymptomatic stages of the disease, said the researchers.
The study was supported by the Michael J. Fox Foundation for Parkinson’s Research and the Plotkin Foundation.
LOS ANGELES—Tears may hold diagnostic clues as to whether someone has Parkinson’s disease, according to a preliminary study presented at the American Academy of Neurology’s 70th Annual Meeting. “We believe our research is the first to show that tears may be a reliable, inexpensive, and noninvasive biologic marker of Parkinson’s disease,” said study author Mark Floyd Lew, MD, Professor of Clinical Neurology, and Joseph P. Van Der Meulen, MD, Chair in Parkinson’s Disease Research in Honor of Robert J. Pasarow, and Vice Chair, in the Department of Neurology at the Keck School of Medicine of the University of Southern California in Los Angeles.
Nonmotor features of Parkinson’s disease occur years prior to motor dysfunction and represent a well-suited platform to investigate for a possible biomarker. Lacrimal glands are highly innervated by cholinergic neurons, and tear fluid secreted by lacrimal glands is greatly stimulated by cholinergic neurons. The production, packaging, and secretion of specific proteins into tears may be regulated by changes in nerve function to lacrimal glands. According to the researchers, analysis of any alteration in the secretion of proteins into tears may identify a reliable and noninvasive biomarker for Parkinson’s disease.
For the study, tear samples were collected from 55 patients with Parkinson’s disease of varying severity and 27 age- and gender-matched controls without Parkinson’s disease. In addition, tears were analyzed for the levels of four proteins—total alpha synuclein, CC chemokine ligand 2 (CCL-2), DJ-1 (Parkinson’s disease protein 7), and oligomeric alpha synuclein.
The researchers found differences in the levels of a total alpha-synuclein in the tears of patients with Parkinson’s disease, compared with those of controls. Additionally, levels of oligomeric alpha-synuclein, which is alpha-synuclein that has formed aggregates that are implicated in nerve damage in Parkinson’s disease, were also significantly different, compared with controls. It is also possible that the tear gland secretory cells themselves produce these different forms of alpha-synuclein that can be directly secreted into tears, the researchers said.
Total levels of alpha-synuclein were decreased in patients with Parkinson’s disease, with an average of 423 picograms of that protein per milligram (pg/mg) compared with 704 pg/mg in healthy controls. However, levels of oligomeric alpha-synuclein were increased in patients with Parkinson’s disease, with an average of 1.45 nanograms per milligram of tear protein (ng/mg), compared with 0.27 ng/mg in controls. While detectable in tears, neither CCL-2 nor DJ-1 varied between patients with Parkinson’s disease and controls.
“Knowing that something as simple as tears could help neurologists differentiate between people who have Parkinson’s disease and those who do not in a noninvasive manner is exciting,” said Dr. Lew. “And because the Parkinson’s disease process can begin years or decades before symptoms appear, a biologic marker like this could be useful in diagnosing, or even treating, the disease earlier.”
More research needs to be done in larger groups of people to investigate whether these protein changes can be detected in tears in the earliest presymptomatic stages of the disease, said the researchers.
The study was supported by the Michael J. Fox Foundation for Parkinson’s Research and the Plotkin Foundation.
Staging System Classifies Nearly All Patients With Lewy Body Synucleinopathy
LOS ANGELES—The Unified Staging System for Lewy Body Disorders (USSLB) enables the categorization of almost all brains with Lewy body synucleinopathy, according to research described at the 70th Annual Meeting of the American Academy of Neurology. The USSLB’s stages correlate significantly with motor and nonmotor findings. “Wider use of the USSLB would help standardize research in synucleinopathies,” said Charles H. Adler, MD, PhD, Professor of Neurology at Mayo Clinic in Scottsdale, Arizona. 
Investigators have developed several neuropathologic staging systems for Lewy body disorders, but many focus on specific diseases, such as Parkinson’s disease or dementia with Lewy bodies. They thus do not allow the classification of all patients with Lewy body disorders. In addition, the literature contains few data about how well these systems’ stages correlate with clinical and pathologic findings.
The Emergence of the USSLB
Dr. Adler and colleagues proposed the USSLB in research published in Acta Neuropathologica in 2009. Their goal was to enable the classification of patients with Lewy body disorders, regardless of their specific diagnoses. The USSLB includes four stages. Stage I denotes pathology limited to the olfactory bulb. Stage IIa denotes predominantly brainstem involvement. Stage IIb refers to pathology predominantly in the limbic system, rather than the brainstem. Stage III denotes pathology in the brainstem and limbic system. Stage IV represents neocortical pathology.
To examine the correlation between patients’ motor and nonmotor findings, including cognitive measures, and the extent of Lewy-type synucleinopathy, as categorized by the USSLB, Dr. Adler and others examined data from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). That study includes participants in the Banner Sun Health Research Institute brain and body donation program. Participants undergo annual clinical exams that include movement testing, cognitive testing, sleep and autonomic questionnaires, and a smell test.
The investigators searched the AZSAND database for patients who presented from January 1997 through December 2015. They identified 641 autopsies. Clinical data and information on Lewy-type synucleinopathy were available for 280 of the cases. The population included cases with Lewy bodies and those with synuclein pathology within the neuropil and fibers. The population’s mean age at death was 83. Greater severity of synucleinopathy was associated with younger age at death.
Braak Staging Could Not Characterize Some Patients
The researchers classified 8.6% of cases as Stage I, 15.4% as Stage IIa, 13.6% as Stage IIb, 31.8% as Stage III, and 30.7% as Stage IV. Cognition was normal in 25.7% of the cases, 8.6% had mild cognitive impairment, and 65.7% had dementia.
Multiple measures of motor parkinsonism and cognitive impairment, as well as of hyposmia and probable REM sleep behavior disorder, correlated significantly with increasing USSLB stage. A few clinical features had no correlation with USSLB stage.
Dr. Adler and colleagues also applied the Braak staging criteria to the cases. To classify all cases, the investigators added an olfactory-bulb-only stage to the Braak criteria. Of the initial cohort, 70 cases could not be assigned a Braak stage. When the researchers removed cases with Alzheimer’s disease, 21% of cases could not be staged.
—Erik Greb
LOS ANGELES—The Unified Staging System for Lewy Body Disorders (USSLB) enables the categorization of almost all brains with Lewy body synucleinopathy, according to research described at the 70th Annual Meeting of the American Academy of Neurology. The USSLB’s stages correlate significantly with motor and nonmotor findings. “Wider use of the USSLB would help standardize research in synucleinopathies,” said Charles H. Adler, MD, PhD, Professor of Neurology at Mayo Clinic in Scottsdale, Arizona.
Investigators have developed several neuropathologic staging systems for Lewy body disorders, but many focus on specific diseases, such as Parkinson’s disease or dementia with Lewy bodies. They thus do not allow the classification of all patients with Lewy body disorders. In addition, the literature contains few data about how well these systems’ stages correlate with clinical and pathologic findings.
The Emergence of the USSLB
Dr. Adler and colleagues proposed the USSLB in research published in Acta Neuropathologica in 2009. Their goal was to enable the classification of patients with Lewy body disorders, regardless of their specific diagnoses. The USSLB includes four stages. Stage I denotes pathology limited to the olfactory bulb. Stage IIa denotes predominantly brainstem involvement. Stage IIb refers to pathology predominantly in the limbic system, rather than the brainstem. Stage III denotes pathology in the brainstem and limbic system. Stage IV represents neocortical pathology.
To examine the correlation between patients’ motor and nonmotor findings, including cognitive measures, and the extent of Lewy-type synucleinopathy, as categorized by the USSLB, Dr. Adler and others examined data from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). That study includes participants in the Banner Sun Health Research Institute brain and body donation program. Participants undergo annual clinical exams that include movement testing, cognitive testing, sleep and autonomic questionnaires, and a smell test.
The investigators searched the AZSAND database for patients who presented from January 1997 through December 2015. They identified 641 autopsies. Clinical data and information on Lewy-type synucleinopathy were available for 280 of the cases. The population included cases with Lewy bodies and those with synuclein pathology within the neuropil and fibers. The population’s mean age at death was 83. Greater severity of synucleinopathy was associated with younger age at death.
Braak Staging Could Not Characterize Some Patients
The researchers classified 8.6% of cases as Stage I, 15.4% as Stage IIa, 13.6% as Stage IIb, 31.8% as Stage III, and 30.7% as Stage IV. Cognition was normal in 25.7% of the cases, 8.6% had mild cognitive impairment, and 65.7% had dementia.
Multiple measures of motor parkinsonism and cognitive impairment, as well as of hyposmia and probable REM sleep behavior disorder, correlated significantly with increasing USSLB stage. A few clinical features had no correlation with USSLB stage.
Dr. Adler and colleagues also applied the Braak staging criteria to the cases. To classify all cases, the investigators added an olfactory-bulb-only stage to the Braak criteria. Of the initial cohort, 70 cases could not be assigned a Braak stage. When the researchers removed cases with Alzheimer’s disease, 21% of cases could not be staged.
—Erik Greb
LOS ANGELES—The Unified Staging System for Lewy Body Disorders (USSLB) enables the categorization of almost all brains with Lewy body synucleinopathy, according to research described at the 70th Annual Meeting of the American Academy of Neurology. The USSLB’s stages correlate significantly with motor and nonmotor findings. “Wider use of the USSLB would help standardize research in synucleinopathies,” said Charles H. Adler, MD, PhD, Professor of Neurology at Mayo Clinic in Scottsdale, Arizona.
Investigators have developed several neuropathologic staging systems for Lewy body disorders, but many focus on specific diseases, such as Parkinson’s disease or dementia with Lewy bodies. They thus do not allow the classification of all patients with Lewy body disorders. In addition, the literature contains few data about how well these systems’ stages correlate with clinical and pathologic findings.
The Emergence of the USSLB
Dr. Adler and colleagues proposed the USSLB in research published in Acta Neuropathologica in 2009. Their goal was to enable the classification of patients with Lewy body disorders, regardless of their specific diagnoses. The USSLB includes four stages. Stage I denotes pathology limited to the olfactory bulb. Stage IIa denotes predominantly brainstem involvement. Stage IIb refers to pathology predominantly in the limbic system, rather than the brainstem. Stage III denotes pathology in the brainstem and limbic system. Stage IV represents neocortical pathology.
To examine the correlation between patients’ motor and nonmotor findings, including cognitive measures, and the extent of Lewy-type synucleinopathy, as categorized by the USSLB, Dr. Adler and others examined data from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). That study includes participants in the Banner Sun Health Research Institute brain and body donation program. Participants undergo annual clinical exams that include movement testing, cognitive testing, sleep and autonomic questionnaires, and a smell test.
The investigators searched the AZSAND database for patients who presented from January 1997 through December 2015. They identified 641 autopsies. Clinical data and information on Lewy-type synucleinopathy were available for 280 of the cases. The population included cases with Lewy bodies and those with synuclein pathology within the neuropil and fibers. The population’s mean age at death was 83. Greater severity of synucleinopathy was associated with younger age at death.
Braak Staging Could Not Characterize Some Patients
The researchers classified 8.6% of cases as Stage I, 15.4% as Stage IIa, 13.6% as Stage IIb, 31.8% as Stage III, and 30.7% as Stage IV. Cognition was normal in 25.7% of the cases, 8.6% had mild cognitive impairment, and 65.7% had dementia.
Multiple measures of motor parkinsonism and cognitive impairment, as well as of hyposmia and probable REM sleep behavior disorder, correlated significantly with increasing USSLB stage. A few clinical features had no correlation with USSLB stage.
Dr. Adler and colleagues also applied the Braak staging criteria to the cases. To classify all cases, the investigators added an olfactory-bulb-only stage to the Braak criteria. Of the initial cohort, 70 cases could not be assigned a Braak stage. When the researchers removed cases with Alzheimer’s disease, 21% of cases could not be staged.
—Erik Greb
IncobotulinumtoxinA May Reduce Sialorrhea in Parkinson’s Disease
LOS ANGELES—IncobotulinumtoxinA may treat sialorrhea in Parkinson’s disease and other neurologic disorders effectively, according to a trial described at the 70th Annual Meeting of the American Academy of Neurology. The treatment effect may persist for as long as 16 weeks.
Various neurologic disorders, such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS), may cause troublesome sialorrhea. Olaf Michel, PhD, Vice Chair of the Department of Otorhinolaryngology at the University Hospital Brussels, and colleagues conducted a phase III trial to investigate the safety and efficacy of incobotulinumtoxinA as a treatment for sialorrhea.
The researchers enrolled 184 participants (age 18 to 80) with chronic troublesome sialorrhea resulting from Parkinson’s disease or atypical parkinsonism, stroke, or traumatic brain injury (TBI) into the trial. They randomized participants in a double-blinded fashion to 75 U of incobotulinumtoxinA (ie, the low-dose group), 100 U of incobotulinumtoxinA (ie, the high-dose group), or placebo. The low-dose group received 15 U in each submandibular gland and 22.5, in each parotid gland. The high-dose group received 20 U in each submandibular gland and 30 U in each parotid gland. Follow-up lasted for 16 weeks after injection. The study’s primary outcomes were unstimulated salivary flow rate (uSFR) at week four, compared with baseline, and Global Impression of Change Scale (GICS) at week four.
In all, 74 participants were randomized to the low dose, 74 to the high dose, and 36 to placebo. The three groups were well balanced, but the proportion of women in the placebo group was lower than that in the treatment groups. Sialorrhea was associated with Parkinson’s disease in 70.6% of patients, atypical Parkinson syndromes in 8.7%, stroke in 17.9%, and TBI in 2.7%.
The investigators localized injection sites using anatomical landmarks in 39.2% of the low-dose group, 44.6% of the high-dose group, and 50% of the placebo group. They used ultrasound guidance to localize injection sites in 60.8% of the low-dose group, 55.4% of the high-dose group, and 50% of the placebo group.
At week four, changes in uSFR and GICS were similar in the placebo and low-dose groups. Improvements in these measures reached statistical significance in the high-dose group at week four, however. At weeks eight through 12, the improvements in uSFR and GICS in both active treatment groups were significant. Improvements in the uSFR and GICS in both dose groups were maintained at week 16, but were lower in the low-dose group than in the high-dose group. Dr. Michel and colleagues observed no relevant differences in outcomes according to the technique used to localize injection sites. They also observed no unexpected side effects.
At the end of the 16-week study, all patients entered a 48-week extension period during which they received three additional injections of dose-blinded incobotulinumtoxinA at 16-week intervals. The treatment effect stabilized and did not decline during the extension, and the investigators observed no accumulation of adverse events.
LOS ANGELES—IncobotulinumtoxinA may treat sialorrhea in Parkinson’s disease and other neurologic disorders effectively, according to a trial described at the 70th Annual Meeting of the American Academy of Neurology. The treatment effect may persist for as long as 16 weeks.
Various neurologic disorders, such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS), may cause troublesome sialorrhea. Olaf Michel, PhD, Vice Chair of the Department of Otorhinolaryngology at the University Hospital Brussels, and colleagues conducted a phase III trial to investigate the safety and efficacy of incobotulinumtoxinA as a treatment for sialorrhea.
The researchers enrolled 184 participants (age 18 to 80) with chronic troublesome sialorrhea resulting from Parkinson’s disease or atypical parkinsonism, stroke, or traumatic brain injury (TBI) into the trial. They randomized participants in a double-blinded fashion to 75 U of incobotulinumtoxinA (ie, the low-dose group), 100 U of incobotulinumtoxinA (ie, the high-dose group), or placebo. The low-dose group received 15 U in each submandibular gland and 22.5, in each parotid gland. The high-dose group received 20 U in each submandibular gland and 30 U in each parotid gland. Follow-up lasted for 16 weeks after injection. The study’s primary outcomes were unstimulated salivary flow rate (uSFR) at week four, compared with baseline, and Global Impression of Change Scale (GICS) at week four.
In all, 74 participants were randomized to the low dose, 74 to the high dose, and 36 to placebo. The three groups were well balanced, but the proportion of women in the placebo group was lower than that in the treatment groups. Sialorrhea was associated with Parkinson’s disease in 70.6% of patients, atypical Parkinson syndromes in 8.7%, stroke in 17.9%, and TBI in 2.7%.
The investigators localized injection sites using anatomical landmarks in 39.2% of the low-dose group, 44.6% of the high-dose group, and 50% of the placebo group. They used ultrasound guidance to localize injection sites in 60.8% of the low-dose group, 55.4% of the high-dose group, and 50% of the placebo group.
At week four, changes in uSFR and GICS were similar in the placebo and low-dose groups. Improvements in these measures reached statistical significance in the high-dose group at week four, however. At weeks eight through 12, the improvements in uSFR and GICS in both active treatment groups were significant. Improvements in the uSFR and GICS in both dose groups were maintained at week 16, but were lower in the low-dose group than in the high-dose group. Dr. Michel and colleagues observed no relevant differences in outcomes according to the technique used to localize injection sites. They also observed no unexpected side effects.
At the end of the 16-week study, all patients entered a 48-week extension period during which they received three additional injections of dose-blinded incobotulinumtoxinA at 16-week intervals. The treatment effect stabilized and did not decline during the extension, and the investigators observed no accumulation of adverse events.
LOS ANGELES—IncobotulinumtoxinA may treat sialorrhea in Parkinson’s disease and other neurologic disorders effectively, according to a trial described at the 70th Annual Meeting of the American Academy of Neurology. The treatment effect may persist for as long as 16 weeks.
Various neurologic disorders, such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS), may cause troublesome sialorrhea. Olaf Michel, PhD, Vice Chair of the Department of Otorhinolaryngology at the University Hospital Brussels, and colleagues conducted a phase III trial to investigate the safety and efficacy of incobotulinumtoxinA as a treatment for sialorrhea.
The researchers enrolled 184 participants (age 18 to 80) with chronic troublesome sialorrhea resulting from Parkinson’s disease or atypical parkinsonism, stroke, or traumatic brain injury (TBI) into the trial. They randomized participants in a double-blinded fashion to 75 U of incobotulinumtoxinA (ie, the low-dose group), 100 U of incobotulinumtoxinA (ie, the high-dose group), or placebo. The low-dose group received 15 U in each submandibular gland and 22.5, in each parotid gland. The high-dose group received 20 U in each submandibular gland and 30 U in each parotid gland. Follow-up lasted for 16 weeks after injection. The study’s primary outcomes were unstimulated salivary flow rate (uSFR) at week four, compared with baseline, and Global Impression of Change Scale (GICS) at week four.
In all, 74 participants were randomized to the low dose, 74 to the high dose, and 36 to placebo. The three groups were well balanced, but the proportion of women in the placebo group was lower than that in the treatment groups. Sialorrhea was associated with Parkinson’s disease in 70.6% of patients, atypical Parkinson syndromes in 8.7%, stroke in 17.9%, and TBI in 2.7%.
The investigators localized injection sites using anatomical landmarks in 39.2% of the low-dose group, 44.6% of the high-dose group, and 50% of the placebo group. They used ultrasound guidance to localize injection sites in 60.8% of the low-dose group, 55.4% of the high-dose group, and 50% of the placebo group.
At week four, changes in uSFR and GICS were similar in the placebo and low-dose groups. Improvements in these measures reached statistical significance in the high-dose group at week four, however. At weeks eight through 12, the improvements in uSFR and GICS in both active treatment groups were significant. Improvements in the uSFR and GICS in both dose groups were maintained at week 16, but were lower in the low-dose group than in the high-dose group. Dr. Michel and colleagues observed no relevant differences in outcomes according to the technique used to localize injection sites. They also observed no unexpected side effects.
At the end of the 16-week study, all patients entered a 48-week extension period during which they received three additional injections of dose-blinded incobotulinumtoxinA at 16-week intervals. The treatment effect stabilized and did not decline during the extension, and the investigators observed no accumulation of adverse events.
Retinal Changes Indicate Parkinson’s Disease Pathology Severity
The accumulation of phosphorylated α-synuclein in the retina may serve as a biomarker of brain pathology severity and aid in diagnosis and monitoring of Parkinson’s disease, according to data published online ahead of print May 8 in Movement Disorders.
“These data suggest that phosphorylated α-synuclein accumulates in the retina in parallel with that in the brain, including in early stages preceding development of clinical signs of parkinsonism or dementia,” said Nicolás Cuenca, PhD, Assistant Professor of Physiology, Genetics, and Microbiology at the University of Alicante in Spain, and colleagues. 
Parkinson’s disease pathology is mainly characterized by the accumulation of pathologic α-synuclein deposits in the brain, but little is known about how synucleinopathy affects the retina.
Dr. Cuenca and colleagues used immunohistochemistry to evaluate the presence of phosphorylated α-synuclein deposits in the retina of nine autopsied subjects with Parkinson’s disease, four with incidental Lewy body disease, and six controls. Eligible subjects had motor parkinsonism, Lewy body pathology, and pigmented neuron loss in the substantia nigra at autopsy. For each subject, the researchers compared the amount of retinal synucleinopathy with indicators of brain disease severity.
All subjects with Parkinson’s disease and three subjects with incidental Lewy body disease had phosphorylated α-synuclein deposits in ganglion cell perikarya, dendrites, and axons. Some of the deposits resembled brain Lewy bodies and Lewy neurites. Cells that contained phosphorylated α-synuclein had different morphologies, soma sizes (ie, from 15 µm to 30 µm), dendritic lengths (ie, from 570 µm to 1,620 µm), and receptive fields. Control subjects did not show any phosphorylated α-synuclein immunoreactivity in their retinas, however.
The Lewy-type synucleinopathy density in the retina significantly correlated with Lewy-type synucleinopathy density in the brain, with the Unified Parkinson’s disease pathology stage, and with the motor subscale of the Unifed Parkinson’s Disease Rating Scale. Confirmation of disease by autopsy partly compensated for the small number of subjects, according to the authors.
“Further investigations of the eye in Parkinson’s disease are desirable, given that ocular structures are involved in the pathology of several neurodegenerative diseases,” said Dr. Cuenca and colleagues.
—Erica Tricarico
Suggested Reading
Ortuño-Lizarán I, Beach TG, Serrano GE, et al. Phosphorylated α-synuclein in the retina is a biomarker of Parkinson’s disease pathology severity. Mov Disord. 2018 May 8 [Epub ahead of print].
Ma LJ, Xu LL, Mao CJ, et al. Progressive changes in the retinal structure of patients with Parkinson’s disease. J Parkinsons Dis. 2018;8(1):85-92.
The accumulation of phosphorylated α-synuclein in the retina may serve as a biomarker of brain pathology severity and aid in diagnosis and monitoring of Parkinson’s disease, according to data published online ahead of print May 8 in Movement Disorders.
“These data suggest that phosphorylated α-synuclein accumulates in the retina in parallel with that in the brain, including in early stages preceding development of clinical signs of parkinsonism or dementia,” said Nicolás Cuenca, PhD, Assistant Professor of Physiology, Genetics, and Microbiology at the University of Alicante in Spain, and colleagues.
Parkinson’s disease pathology is mainly characterized by the accumulation of pathologic α-synuclein deposits in the brain, but little is known about how synucleinopathy affects the retina.
Dr. Cuenca and colleagues used immunohistochemistry to evaluate the presence of phosphorylated α-synuclein deposits in the retina of nine autopsied subjects with Parkinson’s disease, four with incidental Lewy body disease, and six controls. Eligible subjects had motor parkinsonism, Lewy body pathology, and pigmented neuron loss in the substantia nigra at autopsy. For each subject, the researchers compared the amount of retinal synucleinopathy with indicators of brain disease severity.
All subjects with Parkinson’s disease and three subjects with incidental Lewy body disease had phosphorylated α-synuclein deposits in ganglion cell perikarya, dendrites, and axons. Some of the deposits resembled brain Lewy bodies and Lewy neurites. Cells that contained phosphorylated α-synuclein had different morphologies, soma sizes (ie, from 15 µm to 30 µm), dendritic lengths (ie, from 570 µm to 1,620 µm), and receptive fields. Control subjects did not show any phosphorylated α-synuclein immunoreactivity in their retinas, however.
The Lewy-type synucleinopathy density in the retina significantly correlated with Lewy-type synucleinopathy density in the brain, with the Unified Parkinson’s disease pathology stage, and with the motor subscale of the Unifed Parkinson’s Disease Rating Scale. Confirmation of disease by autopsy partly compensated for the small number of subjects, according to the authors.
“Further investigations of the eye in Parkinson’s disease are desirable, given that ocular structures are involved in the pathology of several neurodegenerative diseases,” said Dr. Cuenca and colleagues.
—Erica Tricarico
Suggested Reading
Ortuño-Lizarán I, Beach TG, Serrano GE, et al. Phosphorylated α-synuclein in the retina is a biomarker of Parkinson’s disease pathology severity. Mov Disord. 2018 May 8 [Epub ahead of print].
Ma LJ, Xu LL, Mao CJ, et al. Progressive changes in the retinal structure of patients with Parkinson’s disease. J Parkinsons Dis. 2018;8(1):85-92.
The accumulation of phosphorylated α-synuclein in the retina may serve as a biomarker of brain pathology severity and aid in diagnosis and monitoring of Parkinson’s disease, according to data published online ahead of print May 8 in Movement Disorders.
“These data suggest that phosphorylated α-synuclein accumulates in the retina in parallel with that in the brain, including in early stages preceding development of clinical signs of parkinsonism or dementia,” said Nicolás Cuenca, PhD, Assistant Professor of Physiology, Genetics, and Microbiology at the University of Alicante in Spain, and colleagues.
Parkinson’s disease pathology is mainly characterized by the accumulation of pathologic α-synuclein deposits in the brain, but little is known about how synucleinopathy affects the retina.
Dr. Cuenca and colleagues used immunohistochemistry to evaluate the presence of phosphorylated α-synuclein deposits in the retina of nine autopsied subjects with Parkinson’s disease, four with incidental Lewy body disease, and six controls. Eligible subjects had motor parkinsonism, Lewy body pathology, and pigmented neuron loss in the substantia nigra at autopsy. For each subject, the researchers compared the amount of retinal synucleinopathy with indicators of brain disease severity.
All subjects with Parkinson’s disease and three subjects with incidental Lewy body disease had phosphorylated α-synuclein deposits in ganglion cell perikarya, dendrites, and axons. Some of the deposits resembled brain Lewy bodies and Lewy neurites. Cells that contained phosphorylated α-synuclein had different morphologies, soma sizes (ie, from 15 µm to 30 µm), dendritic lengths (ie, from 570 µm to 1,620 µm), and receptive fields. Control subjects did not show any phosphorylated α-synuclein immunoreactivity in their retinas, however.
The Lewy-type synucleinopathy density in the retina significantly correlated with Lewy-type synucleinopathy density in the brain, with the Unified Parkinson’s disease pathology stage, and with the motor subscale of the Unifed Parkinson’s Disease Rating Scale. Confirmation of disease by autopsy partly compensated for the small number of subjects, according to the authors.
“Further investigations of the eye in Parkinson’s disease are desirable, given that ocular structures are involved in the pathology of several neurodegenerative diseases,” said Dr. Cuenca and colleagues.
—Erica Tricarico
Suggested Reading
Ortuño-Lizarán I, Beach TG, Serrano GE, et al. Phosphorylated α-synuclein in the retina is a biomarker of Parkinson’s disease pathology severity. Mov Disord. 2018 May 8 [Epub ahead of print].
Ma LJ, Xu LL, Mao CJ, et al. Progressive changes in the retinal structure of patients with Parkinson’s disease. J Parkinsons Dis. 2018;8(1):85-92.