Parkinson's Disease

New analyses of both observational and genetic data have provided “convincing evidence” that type 2 diabetes is associated with an increased risk for Parkinson’s disease.

“The fact that we see the same effects in both types of analysis separately makes it more likely that these results are real – that type 2 diabetes really is a driver of Parkinson’s disease risk,” Alastair Noyce, PhD, senior author of the new studies, said in an interview.

The two analyses are reported in one paper published online March 8 in the journal Movement Disorders.

Dr. Noyce, clinical senior lecturer in the preventive neurology unit at the Wolfson Institute of Preventive Medicine, Queen Mary University of London, explained that his group is interested in risk factors for Parkinson’s disease, particularly those relevant at the population level and which might be modifiable.

“Several studies have looked at diabetes as a risk factor for Parkinson’s but very few have focused on type 2 diabetes, and, as this is such a growing health issue, we wanted to look at that in more detail,” he said.

The researchers performed two different analyses: a meta-analysis of observational studies investigating an association between type 2 diabetes and Parkinson’s; and a separate Mendelian randomization analysis of genetic data on the two conditions.

They found similar results in both studies, with the observational data suggesting type 2 diabetes was associated with a 21% increased risk for Parkinson’s disease and the genetic data suggesting an 8% increased risk. There were also hints that type 2 diabetes might also be associated with faster progression of Parkinson’s symptoms.

“I don’t think type 2 diabetes is a major cause of Parkinson’s, but it probably makes some contribution and may increase the risk of a more aggressive form of the condition,” Dr. Noyce said.

“I would say the increased risk of Parkinson’s disease attributable to type 2 diabetes may be similar to that of head injury or pesticide exposure, but it is important, as type 2 diabetes is very prevalent and is increasing,” he added.  “As we see the growth in type 2 diabetes, this could lead to a later increase in Parkinson’s, which is already one of the fastest-growing diseases worldwide.”

For the meta-analysis of observational data, the researchers included nine studies that investigated preceding type 2 diabetes specifically and its effect on the risk for Parkinson’s disease and progression.

The pooled effect estimates showed that type 2 diabetes was associated with an increased risk for Parkinson’s disease (odds ratio, 1.21; 95% confidence interval, 1.07-1.36), and there was some evidence that type 2 diabetes was associated with faster progression of motor symptoms (standardized mean difference [SMD], 0.55) and cognitive decline (SMD, −0.92).

The observational meta-analysis included seven cohort studies and two case-control studies, and these different types of studies showed different results in regard to the association between diabetes and Parkinson’s. While the cohort studies showed a detrimental effect of diabetes on Parkinson’s risk (OR, 1.29), the case-control studies suggested protective effect (OR, 0.51). 

Addressing this, Dr. Noyce noted that the case-control studies may be less reliable as they suffered more from survivor bias. “Diabetes may cause deaths in mid-life before people go on to develop Parkinson’s, and this would cause a protective effect to be seen, but we believe this to be a spurious result. Cohort studies are generally more reliable and are less susceptible to survivor bias,” he said.  

For the genetic analysis, the researchers combined results from two large publicly available genome-wide association studies – one for type 2 diabetes and one for Parkinson’s disease to assess whether individuals with a genetic tendency to type 2 diabetes had a higher risk of developing Parkinson’s.

Results showed an increased risk for Parkinson’s in those individuals with genetic variants associated with type 2 diabetes, with an odds ratio of 1.08 (P = .010). There was also some evidence of an effect on motor progression (OR, 1.10; P = .032) but not on cognitive progression.

On the possible mechanism behind this observation, Dr. Noyce noted type 2 diabetes and Parkinson’s have some similarities in biology, including abnormal protein aggregation.

In the study, the authors also suggest that circulating insulin may have a neuroprotective role, whereas systemic and local insulin resistance can influence pathways known to be important in Parkinson’s pathogenesis, including those that relate to mitochondrial dysfunction, neuroinflammation, synaptic plasticity, and mitochondrial dysfunction.

Dr. Noyce further pointed out that several drugs used for the treatment of type 2 diabetes have been repurposed as possible treatments for Parkinson’s disease and are now being tested for this new indication. “Our results support that approach and raise the idea that some of these drugs may even prevent Parkinson’s in people at risk,” he said.  

Most people who have type 2 diabetes won’t get Parkinson’s disease, he added. Other outcomes such as heart disease, kidney disease, and microvascular complications are far more likely, and the main aim of preventing and treating type 2 diabetes is to prevent these far more common outcomes. “But our data suggests that this could also have a possible benefit in reducing future Parkinson’s risk,” he said.  

Not on the horizon at present is the possibility of screening patients with type 2 diabetes for signs of early Parkinson’s, Dr. Noyce said.

“There isn’t a test for identifying presymptomatic neurodegenerative diseases such as Parkinson’s yet, but perhaps in the future there will be, and type 2 diabetes may be one risk factor to take into account when considering such screening,” he added.

This work was financially supported by grants from The Michael J. Fox Foundation; the Canadian Consortium on Neurodegeneration in Aging (CCNA); the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) initiative; and Parkinson Canada, and the Intramural Research Program of the NIH, National Institute on Aging.

Dr. Noyce reports grants from the Barts Charity, Parkinson’s UK, Aligning Science Across Parkinson’s and Michael J. Fox Foundation, and the Virginia Keiley Benefaction; and personal fees/honoraria from Britannia, BIAL, AbbVie, Global Kinetics Corporation, Profile, Biogen, Roche, and UCB outside of the submitted work.

A version of this article first appeared on Medscape.com.

New analyses of both observational and genetic data have provided “convincing evidence” that type 2 diabetes is associated with an increased risk for Parkinson’s disease.

“The fact that we see the same effects in both types of analysis separately makes it more likely that these results are real – that type 2 diabetes really is a driver of Parkinson’s disease risk,” Alastair Noyce, PhD, senior author of the new studies, said in an interview.

The two analyses are reported in one paper published online March 8 in the journal Movement Disorders.

Dr. Noyce, clinical senior lecturer in the preventive neurology unit at the Wolfson Institute of Preventive Medicine, Queen Mary University of London, explained that his group is interested in risk factors for Parkinson’s disease, particularly those relevant at the population level and which might be modifiable.

“Several studies have looked at diabetes as a risk factor for Parkinson’s but very few have focused on type 2 diabetes, and, as this is such a growing health issue, we wanted to look at that in more detail,” he said.

The researchers performed two different analyses: a meta-analysis of observational studies investigating an association between type 2 diabetes and Parkinson’s; and a separate Mendelian randomization analysis of genetic data on the two conditions.

They found similar results in both studies, with the observational data suggesting type 2 diabetes was associated with a 21% increased risk for Parkinson’s disease and the genetic data suggesting an 8% increased risk. There were also hints that type 2 diabetes might also be associated with faster progression of Parkinson’s symptoms.

“I don’t think type 2 diabetes is a major cause of Parkinson’s, but it probably makes some contribution and may increase the risk of a more aggressive form of the condition,” Dr. Noyce said.

“I would say the increased risk of Parkinson’s disease attributable to type 2 diabetes may be similar to that of head injury or pesticide exposure, but it is important, as type 2 diabetes is very prevalent and is increasing,” he added.  “As we see the growth in type 2 diabetes, this could lead to a later increase in Parkinson’s, which is already one of the fastest-growing diseases worldwide.”

For the meta-analysis of observational data, the researchers included nine studies that investigated preceding type 2 diabetes specifically and its effect on the risk for Parkinson’s disease and progression.

The pooled effect estimates showed that type 2 diabetes was associated with an increased risk for Parkinson’s disease (odds ratio, 1.21; 95% confidence interval, 1.07-1.36), and there was some evidence that type 2 diabetes was associated with faster progression of motor symptoms (standardized mean difference [SMD], 0.55) and cognitive decline (SMD, −0.92).

The observational meta-analysis included seven cohort studies and two case-control studies, and these different types of studies showed different results in regard to the association between diabetes and Parkinson’s. While the cohort studies showed a detrimental effect of diabetes on Parkinson’s risk (OR, 1.29), the case-control studies suggested protective effect (OR, 0.51). 

Addressing this, Dr. Noyce noted that the case-control studies may be less reliable as they suffered more from survivor bias. “Diabetes may cause deaths in mid-life before people go on to develop Parkinson’s, and this would cause a protective effect to be seen, but we believe this to be a spurious result. Cohort studies are generally more reliable and are less susceptible to survivor bias,” he said.  

For the genetic analysis, the researchers combined results from two large publicly available genome-wide association studies – one for type 2 diabetes and one for Parkinson’s disease to assess whether individuals with a genetic tendency to type 2 diabetes had a higher risk of developing Parkinson’s.

Results showed an increased risk for Parkinson’s in those individuals with genetic variants associated with type 2 diabetes, with an odds ratio of 1.08 (P = .010). There was also some evidence of an effect on motor progression (OR, 1.10; P = .032) but not on cognitive progression.

On the possible mechanism behind this observation, Dr. Noyce noted type 2 diabetes and Parkinson’s have some similarities in biology, including abnormal protein aggregation.

In the study, the authors also suggest that circulating insulin may have a neuroprotective role, whereas systemic and local insulin resistance can influence pathways known to be important in Parkinson’s pathogenesis, including those that relate to mitochondrial dysfunction, neuroinflammation, synaptic plasticity, and mitochondrial dysfunction.

Dr. Noyce further pointed out that several drugs used for the treatment of type 2 diabetes have been repurposed as possible treatments for Parkinson’s disease and are now being tested for this new indication. “Our results support that approach and raise the idea that some of these drugs may even prevent Parkinson’s in people at risk,” he said.  

Most people who have type 2 diabetes won’t get Parkinson’s disease, he added. Other outcomes such as heart disease, kidney disease, and microvascular complications are far more likely, and the main aim of preventing and treating type 2 diabetes is to prevent these far more common outcomes. “But our data suggests that this could also have a possible benefit in reducing future Parkinson’s risk,” he said.  

Not on the horizon at present is the possibility of screening patients with type 2 diabetes for signs of early Parkinson’s, Dr. Noyce said.

“There isn’t a test for identifying presymptomatic neurodegenerative diseases such as Parkinson’s yet, but perhaps in the future there will be, and type 2 diabetes may be one risk factor to take into account when considering such screening,” he added.

This work was financially supported by grants from The Michael J. Fox Foundation; the Canadian Consortium on Neurodegeneration in Aging (CCNA); the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) initiative; and Parkinson Canada, and the Intramural Research Program of the NIH, National Institute on Aging.

Dr. Noyce reports grants from the Barts Charity, Parkinson’s UK, Aligning Science Across Parkinson’s and Michael J. Fox Foundation, and the Virginia Keiley Benefaction; and personal fees/honoraria from Britannia, BIAL, AbbVie, Global Kinetics Corporation, Profile, Biogen, Roche, and UCB outside of the submitted work.

A version of this article first appeared on Medscape.com.

New analyses of both observational and genetic data have provided “convincing evidence” that type 2 diabetes is associated with an increased risk for Parkinson’s disease.

“The fact that we see the same effects in both types of analysis separately makes it more likely that these results are real – that type 2 diabetes really is a driver of Parkinson’s disease risk,” Alastair Noyce, PhD, senior author of the new studies, said in an interview.

The two analyses are reported in one paper published online March 8 in the journal Movement Disorders.

Dr. Noyce, clinical senior lecturer in the preventive neurology unit at the Wolfson Institute of Preventive Medicine, Queen Mary University of London, explained that his group is interested in risk factors for Parkinson’s disease, particularly those relevant at the population level and which might be modifiable.

“Several studies have looked at diabetes as a risk factor for Parkinson’s but very few have focused on type 2 diabetes, and, as this is such a growing health issue, we wanted to look at that in more detail,” he said.

The researchers performed two different analyses: a meta-analysis of observational studies investigating an association between type 2 diabetes and Parkinson’s; and a separate Mendelian randomization analysis of genetic data on the two conditions.

They found similar results in both studies, with the observational data suggesting type 2 diabetes was associated with a 21% increased risk for Parkinson’s disease and the genetic data suggesting an 8% increased risk. There were also hints that type 2 diabetes might also be associated with faster progression of Parkinson’s symptoms.

“I don’t think type 2 diabetes is a major cause of Parkinson’s, but it probably makes some contribution and may increase the risk of a more aggressive form of the condition,” Dr. Noyce said.

“I would say the increased risk of Parkinson’s disease attributable to type 2 diabetes may be similar to that of head injury or pesticide exposure, but it is important, as type 2 diabetes is very prevalent and is increasing,” he added.  “As we see the growth in type 2 diabetes, this could lead to a later increase in Parkinson’s, which is already one of the fastest-growing diseases worldwide.”

For the meta-analysis of observational data, the researchers included nine studies that investigated preceding type 2 diabetes specifically and its effect on the risk for Parkinson’s disease and progression.

The pooled effect estimates showed that type 2 diabetes was associated with an increased risk for Parkinson’s disease (odds ratio, 1.21; 95% confidence interval, 1.07-1.36), and there was some evidence that type 2 diabetes was associated with faster progression of motor symptoms (standardized mean difference [SMD], 0.55) and cognitive decline (SMD, −0.92).

The observational meta-analysis included seven cohort studies and two case-control studies, and these different types of studies showed different results in regard to the association between diabetes and Parkinson’s. While the cohort studies showed a detrimental effect of diabetes on Parkinson’s risk (OR, 1.29), the case-control studies suggested protective effect (OR, 0.51). 

Addressing this, Dr. Noyce noted that the case-control studies may be less reliable as they suffered more from survivor bias. “Diabetes may cause deaths in mid-life before people go on to develop Parkinson’s, and this would cause a protective effect to be seen, but we believe this to be a spurious result. Cohort studies are generally more reliable and are less susceptible to survivor bias,” he said.  

For the genetic analysis, the researchers combined results from two large publicly available genome-wide association studies – one for type 2 diabetes and one for Parkinson’s disease to assess whether individuals with a genetic tendency to type 2 diabetes had a higher risk of developing Parkinson’s.

Results showed an increased risk for Parkinson’s in those individuals with genetic variants associated with type 2 diabetes, with an odds ratio of 1.08 (P = .010). There was also some evidence of an effect on motor progression (OR, 1.10; P = .032) but not on cognitive progression.

On the possible mechanism behind this observation, Dr. Noyce noted type 2 diabetes and Parkinson’s have some similarities in biology, including abnormal protein aggregation.

In the study, the authors also suggest that circulating insulin may have a neuroprotective role, whereas systemic and local insulin resistance can influence pathways known to be important in Parkinson’s pathogenesis, including those that relate to mitochondrial dysfunction, neuroinflammation, synaptic plasticity, and mitochondrial dysfunction.

Dr. Noyce further pointed out that several drugs used for the treatment of type 2 diabetes have been repurposed as possible treatments for Parkinson’s disease and are now being tested for this new indication. “Our results support that approach and raise the idea that some of these drugs may even prevent Parkinson’s in people at risk,” he said.  

Most people who have type 2 diabetes won’t get Parkinson’s disease, he added. Other outcomes such as heart disease, kidney disease, and microvascular complications are far more likely, and the main aim of preventing and treating type 2 diabetes is to prevent these far more common outcomes. “But our data suggests that this could also have a possible benefit in reducing future Parkinson’s risk,” he said.  

Not on the horizon at present is the possibility of screening patients with type 2 diabetes for signs of early Parkinson’s, Dr. Noyce said.

“There isn’t a test for identifying presymptomatic neurodegenerative diseases such as Parkinson’s yet, but perhaps in the future there will be, and type 2 diabetes may be one risk factor to take into account when considering such screening,” he added.

This work was financially supported by grants from The Michael J. Fox Foundation; the Canadian Consortium on Neurodegeneration in Aging (CCNA); the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) initiative; and Parkinson Canada, and the Intramural Research Program of the NIH, National Institute on Aging.

Dr. Noyce reports grants from the Barts Charity, Parkinson’s UK, Aligning Science Across Parkinson’s and Michael J. Fox Foundation, and the Virginia Keiley Benefaction; and personal fees/honoraria from Britannia, BIAL, AbbVie, Global Kinetics Corporation, Profile, Biogen, Roche, and UCB outside of the submitted work.

A version of this article first appeared on Medscape.com.

Medicare payments for branded neurologic drugs jumped 50% over a 5-year period, while claims for these medications increased by just 8%, new research shows. Results of the retrospective study also showed that most of the increased costs for these agents were due to rising costs for neuroimmunology drugs, mainly for those used to treat multiple sclerosis (MS).

“The same brand name medication in 2017 cost approximately 50% more than in 2013,” said Adam de Havenon, MD, assistant professor of neurology, University of Utah, Salt Lake City.

“An analogy would be if you bought an iPhone 5 in 2013 for $500, and then in 2017, you were asked to pay $750 for the exact same iPhone 5,” Dr. de Havenon added.

The study findings were published online March 10 in the journal Neurology.
 

$26 billion in payments

Both neurologists and patients are concerned about the high cost of prescription drugs for neurologic diseases, and Medicare Part D data indicate that these drugs are the most expensive component of neurologic care, the researchers noted. In addition, out-of-pocket costs have increased significantly for patients with neurologic disease such as Parkinson’s disease, epilepsy, and MS.

To understand trends in payments for neurologic drugs, Dr. de Havenon and colleagues analyzed Medicare Part D claims filed from 2013 to 2017. The payments include costs paid by Medicare, the patient, government subsidies, and other third-party payers.

In addition to examining more current Medicare Part D data than previous studies, the current analysis examined all medications prescribed by neurologists that consistently remained branded or generic during the 5-year study period, said Dr. de Havenon. This approach resulted in a large number of claims and a large total cost.

To calculate the percentage change in annual payment claims, the researchers used 2013 prices as a reference point. They identified drugs named in 2013 claims and classified them as generic, brand-name only, or brand-name with generic equivalent. Researchers also divided the drugs by neurologic subspecialty.

The analysis included 520 drugs, all of which were available in each year of the study period. Of these drugs, 322 were generic, 61 were brand-name only, and 137 were brand-name with a generic equivalent. There were 90.7 million total claims.

Results showed total payments amounted to $26.65 billion. Yearly total payments increased from $4.05 billion in 2013 to $6.09 billion in 2017, representing a 50.4% increase, even after adjusting for inflation. Total claims increased by 7.6% – from 17.1 million in 2013 to 18.4 million in 2017.

From 2013 to 2017, claim payments increased by 0.6% for generic drugs, 42.4% for brand-name only drugs, and 45% for brand-name drugs with generic equivalents. The proportion of claims increased from 81.9% to 88% for generic drugs and from 4.9% to 6.2% for brand-name only drugs.

However, the proportion of claims for brand-name drugs with generic equivalents decreased from 13.3% to 5.8%.
 

Treatment barrier

Neuroimmunologic drugs, most of which were prescribed for MS, had exceptional cost, the researchers noted. These drugs accounted for more than 50% of payments but only 4.3% of claims. Claim payment for these drugs increased by 46.9% during the study period, from $3,337 to $4,902.

When neuroimmunologic drugs were removed from the analysis there was still significant increase in claim payments for brand-name only drugs (50.4%) and brand-name drugs with generic equivalents (45.6%).

Although neuroimmunologic medicines, including monoclonal antibodies, are more expensive to produce, this factor alone does not explain their exceptional cost, said Dr. de Havenon. “The high cost of brand-name drugs in this speciality is likely because the market bears it,” he added. “In other words, MS is a disabling disease and the medications work, so historically the Centers for Medicare & Medicaid Services have been willing to tolerate the high cost of these primarily brand-name medications.”

Several countries have controlled drug costs by negotiating with pharmaceutical companies and through legislation, Dr. de Havenon noted.

“My intent with this article was to raise awareness on the topic, which I struggle with frequently as a clinician. I know I want my patients to have a medication, but the cost prevents it,” he said.
 

‘Unfettered’ price-setting

Commenting on the findings, Robert J. Fox, MD, vice chair for research at the Neurological Institute of the Cleveland Clinic, said the study “brings into clear light” what neurologists, particularly those who treat MS, have long suspected but did not really know. These neurologists “are typically distanced from the payment aspects of the medications they prescribe,” said Dr. Fox, who was not involved with the research.

Although a particular strength of the study was its comprehensiveness, the researchers excluded infusion claims – which account for a large portion of total patient care costs for many disorders, he noted.

Drugs for MS historically have been expensive, ostensibly because of their high cost of development. In addition, the large and continued price increase that occurs long after these drugs have been approved remains unexplained, said Dr. Fox.

He noted that the study findings might not directly affect clinical practice because neurologists will continue prescribing medications they think are best for their patients. “Instead, I think this is a lesson to lawmakers about the massive error in the Medicare Modernization Act of 2003, where the federal government was prohibited from negotiating drug prices. If the seller is unfettered in setting a price, then no one should be surprised when the price rises,” Dr. Fox said.

Because many new drugs and new generic formulations for treating MS have become available during the past year, “repeating these types of economic studies for the period 2020-2025 will help us understand if generic competition – as well as new laws if they are passed – alter price,” he concluded.

The study was funded by the American Academy of Neurology, which publishes Neurology. Dr. de Havenon has received clinical research funding from AMAG Pharmaceuticals and Regeneron Pharmaceuticals. Dr. Fox receives consulting fees from many pharmaceutical companies involved in the development of therapies for MS.

A version of this article first appeared on Medscape.com.

Medicare payments for branded neurologic drugs jumped 50% over a 5-year period, while claims for these medications increased by just 8%, new research shows. Results of the retrospective study also showed that most of the increased costs for these agents were due to rising costs for neuroimmunology drugs, mainly for those used to treat multiple sclerosis (MS).

“The same brand name medication in 2017 cost approximately 50% more than in 2013,” said Adam de Havenon, MD, assistant professor of neurology, University of Utah, Salt Lake City.

“An analogy would be if you bought an iPhone 5 in 2013 for $500, and then in 2017, you were asked to pay $750 for the exact same iPhone 5,” Dr. de Havenon added.

The study findings were published online March 10 in the journal Neurology.
 

$26 billion in payments

Both neurologists and patients are concerned about the high cost of prescription drugs for neurologic diseases, and Medicare Part D data indicate that these drugs are the most expensive component of neurologic care, the researchers noted. In addition, out-of-pocket costs have increased significantly for patients with neurologic disease such as Parkinson’s disease, epilepsy, and MS.

To understand trends in payments for neurologic drugs, Dr. de Havenon and colleagues analyzed Medicare Part D claims filed from 2013 to 2017. The payments include costs paid by Medicare, the patient, government subsidies, and other third-party payers.

In addition to examining more current Medicare Part D data than previous studies, the current analysis examined all medications prescribed by neurologists that consistently remained branded or generic during the 5-year study period, said Dr. de Havenon. This approach resulted in a large number of claims and a large total cost.

To calculate the percentage change in annual payment claims, the researchers used 2013 prices as a reference point. They identified drugs named in 2013 claims and classified them as generic, brand-name only, or brand-name with generic equivalent. Researchers also divided the drugs by neurologic subspecialty.

The analysis included 520 drugs, all of which were available in each year of the study period. Of these drugs, 322 were generic, 61 were brand-name only, and 137 were brand-name with a generic equivalent. There were 90.7 million total claims.

Results showed total payments amounted to $26.65 billion. Yearly total payments increased from $4.05 billion in 2013 to $6.09 billion in 2017, representing a 50.4% increase, even after adjusting for inflation. Total claims increased by 7.6% – from 17.1 million in 2013 to 18.4 million in 2017.

From 2013 to 2017, claim payments increased by 0.6% for generic drugs, 42.4% for brand-name only drugs, and 45% for brand-name drugs with generic equivalents. The proportion of claims increased from 81.9% to 88% for generic drugs and from 4.9% to 6.2% for brand-name only drugs.

However, the proportion of claims for brand-name drugs with generic equivalents decreased from 13.3% to 5.8%.
 

Treatment barrier

Neuroimmunologic drugs, most of which were prescribed for MS, had exceptional cost, the researchers noted. These drugs accounted for more than 50% of payments but only 4.3% of claims. Claim payment for these drugs increased by 46.9% during the study period, from $3,337 to $4,902.

When neuroimmunologic drugs were removed from the analysis there was still significant increase in claim payments for brand-name only drugs (50.4%) and brand-name drugs with generic equivalents (45.6%).

Although neuroimmunologic medicines, including monoclonal antibodies, are more expensive to produce, this factor alone does not explain their exceptional cost, said Dr. de Havenon. “The high cost of brand-name drugs in this speciality is likely because the market bears it,” he added. “In other words, MS is a disabling disease and the medications work, so historically the Centers for Medicare & Medicaid Services have been willing to tolerate the high cost of these primarily brand-name medications.”

Several countries have controlled drug costs by negotiating with pharmaceutical companies and through legislation, Dr. de Havenon noted.

“My intent with this article was to raise awareness on the topic, which I struggle with frequently as a clinician. I know I want my patients to have a medication, but the cost prevents it,” he said.
 

‘Unfettered’ price-setting

Commenting on the findings, Robert J. Fox, MD, vice chair for research at the Neurological Institute of the Cleveland Clinic, said the study “brings into clear light” what neurologists, particularly those who treat MS, have long suspected but did not really know. These neurologists “are typically distanced from the payment aspects of the medications they prescribe,” said Dr. Fox, who was not involved with the research.

Although a particular strength of the study was its comprehensiveness, the researchers excluded infusion claims – which account for a large portion of total patient care costs for many disorders, he noted.

Drugs for MS historically have been expensive, ostensibly because of their high cost of development. In addition, the large and continued price increase that occurs long after these drugs have been approved remains unexplained, said Dr. Fox.

He noted that the study findings might not directly affect clinical practice because neurologists will continue prescribing medications they think are best for their patients. “Instead, I think this is a lesson to lawmakers about the massive error in the Medicare Modernization Act of 2003, where the federal government was prohibited from negotiating drug prices. If the seller is unfettered in setting a price, then no one should be surprised when the price rises,” Dr. Fox said.

Because many new drugs and new generic formulations for treating MS have become available during the past year, “repeating these types of economic studies for the period 2020-2025 will help us understand if generic competition – as well as new laws if they are passed – alter price,” he concluded.

The study was funded by the American Academy of Neurology, which publishes Neurology. Dr. de Havenon has received clinical research funding from AMAG Pharmaceuticals and Regeneron Pharmaceuticals. Dr. Fox receives consulting fees from many pharmaceutical companies involved in the development of therapies for MS.

A version of this article first appeared on Medscape.com.

Medicare payments for branded neurologic drugs jumped 50% over a 5-year period, while claims for these medications increased by just 8%, new research shows. Results of the retrospective study also showed that most of the increased costs for these agents were due to rising costs for neuroimmunology drugs, mainly for those used to treat multiple sclerosis (MS).

“The same brand name medication in 2017 cost approximately 50% more than in 2013,” said Adam de Havenon, MD, assistant professor of neurology, University of Utah, Salt Lake City.

“An analogy would be if you bought an iPhone 5 in 2013 for $500, and then in 2017, you were asked to pay $750 for the exact same iPhone 5,” Dr. de Havenon added.

The study findings were published online March 10 in the journal Neurology.
 

$26 billion in payments

Both neurologists and patients are concerned about the high cost of prescription drugs for neurologic diseases, and Medicare Part D data indicate that these drugs are the most expensive component of neurologic care, the researchers noted. In addition, out-of-pocket costs have increased significantly for patients with neurologic disease such as Parkinson’s disease, epilepsy, and MS.

To understand trends in payments for neurologic drugs, Dr. de Havenon and colleagues analyzed Medicare Part D claims filed from 2013 to 2017. The payments include costs paid by Medicare, the patient, government subsidies, and other third-party payers.

In addition to examining more current Medicare Part D data than previous studies, the current analysis examined all medications prescribed by neurologists that consistently remained branded or generic during the 5-year study period, said Dr. de Havenon. This approach resulted in a large number of claims and a large total cost.

To calculate the percentage change in annual payment claims, the researchers used 2013 prices as a reference point. They identified drugs named in 2013 claims and classified them as generic, brand-name only, or brand-name with generic equivalent. Researchers also divided the drugs by neurologic subspecialty.

The analysis included 520 drugs, all of which were available in each year of the study period. Of these drugs, 322 were generic, 61 were brand-name only, and 137 were brand-name with a generic equivalent. There were 90.7 million total claims.

Results showed total payments amounted to $26.65 billion. Yearly total payments increased from $4.05 billion in 2013 to $6.09 billion in 2017, representing a 50.4% increase, even after adjusting for inflation. Total claims increased by 7.6% – from 17.1 million in 2013 to 18.4 million in 2017.

From 2013 to 2017, claim payments increased by 0.6% for generic drugs, 42.4% for brand-name only drugs, and 45% for brand-name drugs with generic equivalents. The proportion of claims increased from 81.9% to 88% for generic drugs and from 4.9% to 6.2% for brand-name only drugs.

However, the proportion of claims for brand-name drugs with generic equivalents decreased from 13.3% to 5.8%.
 

Treatment barrier

Neuroimmunologic drugs, most of which were prescribed for MS, had exceptional cost, the researchers noted. These drugs accounted for more than 50% of payments but only 4.3% of claims. Claim payment for these drugs increased by 46.9% during the study period, from $3,337 to $4,902.

When neuroimmunologic drugs were removed from the analysis there was still significant increase in claim payments for brand-name only drugs (50.4%) and brand-name drugs with generic equivalents (45.6%).

Although neuroimmunologic medicines, including monoclonal antibodies, are more expensive to produce, this factor alone does not explain their exceptional cost, said Dr. de Havenon. “The high cost of brand-name drugs in this speciality is likely because the market bears it,” he added. “In other words, MS is a disabling disease and the medications work, so historically the Centers for Medicare & Medicaid Services have been willing to tolerate the high cost of these primarily brand-name medications.”

Several countries have controlled drug costs by negotiating with pharmaceutical companies and through legislation, Dr. de Havenon noted.

“My intent with this article was to raise awareness on the topic, which I struggle with frequently as a clinician. I know I want my patients to have a medication, but the cost prevents it,” he said.
 

‘Unfettered’ price-setting

Commenting on the findings, Robert J. Fox, MD, vice chair for research at the Neurological Institute of the Cleveland Clinic, said the study “brings into clear light” what neurologists, particularly those who treat MS, have long suspected but did not really know. These neurologists “are typically distanced from the payment aspects of the medications they prescribe,” said Dr. Fox, who was not involved with the research.

Although a particular strength of the study was its comprehensiveness, the researchers excluded infusion claims – which account for a large portion of total patient care costs for many disorders, he noted.

Drugs for MS historically have been expensive, ostensibly because of their high cost of development. In addition, the large and continued price increase that occurs long after these drugs have been approved remains unexplained, said Dr. Fox.

He noted that the study findings might not directly affect clinical practice because neurologists will continue prescribing medications they think are best for their patients. “Instead, I think this is a lesson to lawmakers about the massive error in the Medicare Modernization Act of 2003, where the federal government was prohibited from negotiating drug prices. If the seller is unfettered in setting a price, then no one should be surprised when the price rises,” Dr. Fox said.

Because many new drugs and new generic formulations for treating MS have become available during the past year, “repeating these types of economic studies for the period 2020-2025 will help us understand if generic competition – as well as new laws if they are passed – alter price,” he concluded.

The study was funded by the American Academy of Neurology, which publishes Neurology. Dr. de Havenon has received clinical research funding from AMAG Pharmaceuticals and Regeneron Pharmaceuticals. Dr. Fox receives consulting fees from many pharmaceutical companies involved in the development of therapies for MS.

A version of this article first appeared on Medscape.com.

Stroke, dementias, and migraine cause the most disability among neurological disorders in the United States, according to new findings derived from the 2017 Global Burden of Disease study. 

The authors of the analysis, led by Valery Feigin, MD, PhD, of New Zealand’s National Institute for Stroke and Applied Neurosciences, and published in the February 2021 issue of JAMA Neurology, looked at prevalence, incidence, mortality, and disability-adjusted life years for 14 neurological disorders across 50 states between 1990 and 2017. The diseases included in the analysis were stroke, Alzheimer’s disease and other dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, headaches, traumatic brain injury, spinal cord injuries, brain and other nervous system cancers, meningitis, encephalitis, and tetanus.
 

Tracking the burden of neurologic diseases

Dr. Feigin and colleagues estimated that a full 60% of the U.S. population lives with one or more of these disorders, a figure much greater than previous estimates for neurological disease burden nationwide. Tension-type headache and migraine were the most prevalent in the analysis by Dr. Feigin and colleagues. During the study period, they found, prevalence, incidence, and disability burden of nearly all the included disorders increased, with the exception of brain and spinal cord injuries, meningitis, and encephalitis.

The researchers attributed most of the rise in noncommunicable neurological diseases to population aging. An age-standardized analysis found trends for stroke and Alzheimer’s disease and other dementias to be declining or flat. Age-standardized stroke incidence dropped by 16% from 1990 to 2017, while stroke mortality declined by nearly a third, and stroke disability by a quarter. Age-standardized incidence of Alzheimer’s disease and other dementias dropped by 12%, and their prevalence by 13%, during the study period, though dementia mortality and disability were seen increasing.

The authors surmised that the age-standardized declines in stroke and dementias could reflect that “primary prevention of these disorders are beginning to show an influence.” With dementia, which is linked to cognitive reserve and education, “improving educational levels of cohort reaching the age groups at greatest risk of disease may also be contributing to a modest decline over time,” Dr. Feigin and his colleagues wrote.

Parkinson’s disease and multiple sclerosis, meanwhile, were both seen rising in incidence, prevalence, and disability adjusted life years (DALYs) even with age-standardized figures. The United States saw comparatively more disability in 2017 from dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, and headache disorders, which together comprised 6.7% of DALYs, compared with 4.4% globally; these also accounted for a higher share of mortality in the U.S. than worldwide. The authors attributed at least some of the difference to better case ascertainment in the U.S.
 

Regional variations

The researchers also reported variations in disease burden by state and region. While previous studies have identified a “stroke belt” concentrated in North Carolina, South Carolina, and Georgia, the new findings point to stroke disability highest in Alabama, Arkansas, and Mississippi, and mortality highest in Alabama, Mississippi, and South Carolina. The researchers noted increases in dementia mortality in these states, “likely attributable to the reciprocal association between stroke and dementia.”

Northern states saw higher burdens of multiple sclerosis compared with the rest of the country, while eastern states had higher rates of Parkinson’s disease.

Such regional and state-by state variations, Dr. Feigin and colleagues wrote in their analysis, “may be associated with differences in the case ascertainment, as well as access to health care; racial/ethnic, genetic, and socioeconomic diversity; quality and comprehensiveness of preventive strategies; and risk factor distribution.”

The researchers noted as a limitation of their study that the 14 diseases captured were not an exhaustive list of neurological conditions; chronic lower back pain, a condition included in a previous major study of the burden of neurological disease in the United States, was omitted, as were restless legs syndrome and peripheral neuropathy. The researchers cited changes to coding practice in the U.S. and accuracy of medical claims data as potential limitations of their analysis. The Global Burden of Disease study is funded by the Bill and Melinda Gates Foundation, and several of Dr. Feigin’s coauthors reported financial relationships with industry.
 

Time to adjust the stroke belt?

Amelia Boehme, PhD, a stroke epidemiologist at Columbia University Mailman School of Public Health in New York, said in an interview that the current study added to recent findings showing surprising local variability in stroke prevalence, incidence, and mortality. “What we had always conceptually thought of as the ‘stroke belt’ isn’t necessarily the case,” Dr. Boehme said, but is rather subject to local, county-by-county variations. “Looking at the data here in conjunction with what previous authors have found, it raises some questions as to whether or not state-level data is giving a completely accurate picture, and whether we need to start looking at the county level and adjust for populations and age.” Importantly, Dr. Boehme said, data collected in the Global Burden of Disease study tends to be exceptionally rigorous and systematic, adding weight to Dr. Feigin and colleagues’ suggestions that prevention efforts may be making a dent in stroke and dementia. 

“More data is always needed before we start to say we’re seeing things change,” Dr. Boehme noted. “But any glimmer of optimism is welcome, especially with regard to interventions that have been put in place, to allow us to build on those interventions.”

Dr. Boehme disclosed no financial conflicts of interest.

Stroke, dementias, and migraine cause the most disability among neurological disorders in the United States, according to new findings derived from the 2017 Global Burden of Disease study. 

The authors of the analysis, led by Valery Feigin, MD, PhD, of New Zealand’s National Institute for Stroke and Applied Neurosciences, and published in the February 2021 issue of JAMA Neurology, looked at prevalence, incidence, mortality, and disability-adjusted life years for 14 neurological disorders across 50 states between 1990 and 2017. The diseases included in the analysis were stroke, Alzheimer’s disease and other dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, headaches, traumatic brain injury, spinal cord injuries, brain and other nervous system cancers, meningitis, encephalitis, and tetanus.
 

Tracking the burden of neurologic diseases

Dr. Feigin and colleagues estimated that a full 60% of the U.S. population lives with one or more of these disorders, a figure much greater than previous estimates for neurological disease burden nationwide. Tension-type headache and migraine were the most prevalent in the analysis by Dr. Feigin and colleagues. During the study period, they found, prevalence, incidence, and disability burden of nearly all the included disorders increased, with the exception of brain and spinal cord injuries, meningitis, and encephalitis.

The researchers attributed most of the rise in noncommunicable neurological diseases to population aging. An age-standardized analysis found trends for stroke and Alzheimer’s disease and other dementias to be declining or flat. Age-standardized stroke incidence dropped by 16% from 1990 to 2017, while stroke mortality declined by nearly a third, and stroke disability by a quarter. Age-standardized incidence of Alzheimer’s disease and other dementias dropped by 12%, and their prevalence by 13%, during the study period, though dementia mortality and disability were seen increasing.

The authors surmised that the age-standardized declines in stroke and dementias could reflect that “primary prevention of these disorders are beginning to show an influence.” With dementia, which is linked to cognitive reserve and education, “improving educational levels of cohort reaching the age groups at greatest risk of disease may also be contributing to a modest decline over time,” Dr. Feigin and his colleagues wrote.

Parkinson’s disease and multiple sclerosis, meanwhile, were both seen rising in incidence, prevalence, and disability adjusted life years (DALYs) even with age-standardized figures. The United States saw comparatively more disability in 2017 from dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, and headache disorders, which together comprised 6.7% of DALYs, compared with 4.4% globally; these also accounted for a higher share of mortality in the U.S. than worldwide. The authors attributed at least some of the difference to better case ascertainment in the U.S.
 

Regional variations

The researchers also reported variations in disease burden by state and region. While previous studies have identified a “stroke belt” concentrated in North Carolina, South Carolina, and Georgia, the new findings point to stroke disability highest in Alabama, Arkansas, and Mississippi, and mortality highest in Alabama, Mississippi, and South Carolina. The researchers noted increases in dementia mortality in these states, “likely attributable to the reciprocal association between stroke and dementia.”

Northern states saw higher burdens of multiple sclerosis compared with the rest of the country, while eastern states had higher rates of Parkinson’s disease.

Such regional and state-by state variations, Dr. Feigin and colleagues wrote in their analysis, “may be associated with differences in the case ascertainment, as well as access to health care; racial/ethnic, genetic, and socioeconomic diversity; quality and comprehensiveness of preventive strategies; and risk factor distribution.”

The researchers noted as a limitation of their study that the 14 diseases captured were not an exhaustive list of neurological conditions; chronic lower back pain, a condition included in a previous major study of the burden of neurological disease in the United States, was omitted, as were restless legs syndrome and peripheral neuropathy. The researchers cited changes to coding practice in the U.S. and accuracy of medical claims data as potential limitations of their analysis. The Global Burden of Disease study is funded by the Bill and Melinda Gates Foundation, and several of Dr. Feigin’s coauthors reported financial relationships with industry.
 

Time to adjust the stroke belt?

Amelia Boehme, PhD, a stroke epidemiologist at Columbia University Mailman School of Public Health in New York, said in an interview that the current study added to recent findings showing surprising local variability in stroke prevalence, incidence, and mortality. “What we had always conceptually thought of as the ‘stroke belt’ isn’t necessarily the case,” Dr. Boehme said, but is rather subject to local, county-by-county variations. “Looking at the data here in conjunction with what previous authors have found, it raises some questions as to whether or not state-level data is giving a completely accurate picture, and whether we need to start looking at the county level and adjust for populations and age.” Importantly, Dr. Boehme said, data collected in the Global Burden of Disease study tends to be exceptionally rigorous and systematic, adding weight to Dr. Feigin and colleagues’ suggestions that prevention efforts may be making a dent in stroke and dementia. 

“More data is always needed before we start to say we’re seeing things change,” Dr. Boehme noted. “But any glimmer of optimism is welcome, especially with regard to interventions that have been put in place, to allow us to build on those interventions.”

Dr. Boehme disclosed no financial conflicts of interest.

Stroke, dementias, and migraine cause the most disability among neurological disorders in the United States, according to new findings derived from the 2017 Global Burden of Disease study. 

The authors of the analysis, led by Valery Feigin, MD, PhD, of New Zealand’s National Institute for Stroke and Applied Neurosciences, and published in the February 2021 issue of JAMA Neurology, looked at prevalence, incidence, mortality, and disability-adjusted life years for 14 neurological disorders across 50 states between 1990 and 2017. The diseases included in the analysis were stroke, Alzheimer’s disease and other dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, headaches, traumatic brain injury, spinal cord injuries, brain and other nervous system cancers, meningitis, encephalitis, and tetanus.
 

Tracking the burden of neurologic diseases

Dr. Feigin and colleagues estimated that a full 60% of the U.S. population lives with one or more of these disorders, a figure much greater than previous estimates for neurological disease burden nationwide. Tension-type headache and migraine were the most prevalent in the analysis by Dr. Feigin and colleagues. During the study period, they found, prevalence, incidence, and disability burden of nearly all the included disorders increased, with the exception of brain and spinal cord injuries, meningitis, and encephalitis.

The researchers attributed most of the rise in noncommunicable neurological diseases to population aging. An age-standardized analysis found trends for stroke and Alzheimer’s disease and other dementias to be declining or flat. Age-standardized stroke incidence dropped by 16% from 1990 to 2017, while stroke mortality declined by nearly a third, and stroke disability by a quarter. Age-standardized incidence of Alzheimer’s disease and other dementias dropped by 12%, and their prevalence by 13%, during the study period, though dementia mortality and disability were seen increasing.

The authors surmised that the age-standardized declines in stroke and dementias could reflect that “primary prevention of these disorders are beginning to show an influence.” With dementia, which is linked to cognitive reserve and education, “improving educational levels of cohort reaching the age groups at greatest risk of disease may also be contributing to a modest decline over time,” Dr. Feigin and his colleagues wrote.

Parkinson’s disease and multiple sclerosis, meanwhile, were both seen rising in incidence, prevalence, and disability adjusted life years (DALYs) even with age-standardized figures. The United States saw comparatively more disability in 2017 from dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, and headache disorders, which together comprised 6.7% of DALYs, compared with 4.4% globally; these also accounted for a higher share of mortality in the U.S. than worldwide. The authors attributed at least some of the difference to better case ascertainment in the U.S.
 

Regional variations

The researchers also reported variations in disease burden by state and region. While previous studies have identified a “stroke belt” concentrated in North Carolina, South Carolina, and Georgia, the new findings point to stroke disability highest in Alabama, Arkansas, and Mississippi, and mortality highest in Alabama, Mississippi, and South Carolina. The researchers noted increases in dementia mortality in these states, “likely attributable to the reciprocal association between stroke and dementia.”

Northern states saw higher burdens of multiple sclerosis compared with the rest of the country, while eastern states had higher rates of Parkinson’s disease.

Such regional and state-by state variations, Dr. Feigin and colleagues wrote in their analysis, “may be associated with differences in the case ascertainment, as well as access to health care; racial/ethnic, genetic, and socioeconomic diversity; quality and comprehensiveness of preventive strategies; and risk factor distribution.”

The researchers noted as a limitation of their study that the 14 diseases captured were not an exhaustive list of neurological conditions; chronic lower back pain, a condition included in a previous major study of the burden of neurological disease in the United States, was omitted, as were restless legs syndrome and peripheral neuropathy. The researchers cited changes to coding practice in the U.S. and accuracy of medical claims data as potential limitations of their analysis. The Global Burden of Disease study is funded by the Bill and Melinda Gates Foundation, and several of Dr. Feigin’s coauthors reported financial relationships with industry.
 

Time to adjust the stroke belt?

Amelia Boehme, PhD, a stroke epidemiologist at Columbia University Mailman School of Public Health in New York, said in an interview that the current study added to recent findings showing surprising local variability in stroke prevalence, incidence, and mortality. “What we had always conceptually thought of as the ‘stroke belt’ isn’t necessarily the case,” Dr. Boehme said, but is rather subject to local, county-by-county variations. “Looking at the data here in conjunction with what previous authors have found, it raises some questions as to whether or not state-level data is giving a completely accurate picture, and whether we need to start looking at the county level and adjust for populations and age.” Importantly, Dr. Boehme said, data collected in the Global Burden of Disease study tends to be exceptionally rigorous and systematic, adding weight to Dr. Feigin and colleagues’ suggestions that prevention efforts may be making a dent in stroke and dementia. 

“More data is always needed before we start to say we’re seeing things change,” Dr. Boehme noted. “But any glimmer of optimism is welcome, especially with regard to interventions that have been put in place, to allow us to build on those interventions.”

Dr. Boehme disclosed no financial conflicts of interest.

Certain drugs currently used to treat benign prostatic hyperplasia (BPH) may provide neuroprotection and delay or prevent the onset of Parkinson’s disease, new research suggests. Treatment of BPH with terazosin (Hytrin), doxazosin (Cardura), or alfuzosin (Uroxatral), all of which enhance glycolysis, was associated with a lower risk of developing Parkinson’s disease than patients taking a drug used for the same indication, tamsulosin (Flomax), which does not affect glycolysis.

“If giving someone terazosin or similar medications truly reduces their risk of disease, these results could have significant clinical implications for neurologists,” said lead author Jacob E. Simmering, PhD, assistant professor of internal medicine at the University of Iowa, Iowa City.

There are few reliable neuroprotective treatments for Parkinson’s disease, he said. “We can manage some of the symptoms, but we can’t stop it from progressing. If a randomized trial finds the same result, this will provide a new option to slow progression of Parkinson’s disease.”

The pathogenesis of Parkinson’s disease is heterogeneous, however, and not all patients may benefit from glycolysis-enhancing drugs, the investigators noted. Future research will be needed to identify potential candidates for this treatment, and clarify the effects of these drugs, they wrote.

The findings were published online Feb. 1, 2021, in JAMA Neurology.
 

Time-dependent effects

The major risk factor for Parkinson’s disease is age, which is associated with impaired energy metabolism. Glycolysis is decreased among patients with Parkinson’s disease, yet impaired energy metabolism has not been investigated widely as a pathogenic factor in the disease, the authors wrote.

Studies have indicated that terazosin increases the activity of an enzyme important in glycolysis. Doxazosin and alfuzosin have a similar mechanism of action and enhance energy metabolism. Tamsulosin, a structurally unrelated drug, has the same mechanism of action as the other three drugs, but does not enhance energy metabolism.

In this report, the researchers investigated the hypothesis that patients who received therapy with terazosin, doxazosin, or alfuzosin would have a lower risk of developing Parkinson’s disease than patients receiving tamsulosin. To do that, they used health care utilization data from Denmark and the United States, including the Danish National Prescription Registry, the Danish National Patient Registry, the Danish Civil Registration System, and the Truven Health Analytics MarketScan database.

The investigators searched the records for patients who filled prescriptions for any of the four drugs of interest. They excluded any patients who developed Parkinson’s disease within 1 year of starting medication. Because use of these drugs is rare among women, they included only men in their analysis.

They looked at patient outcomes beginning at 1 year after the initiation of treatment. They also required patients to fill at least two prescriptions before the beginning of follow-up. Patients who switched from tamsulosin to any of the other drugs, or vice versa, were excluded from analysis.

The investigators used propensity-score matching to ensure that patients in the tamsulosin and terazosin/doxazosin/alfuzosin groups were similar in terms of their other potential risk factors. The primary outcome was the development of Parkinson’s disease.

They identified 52,365 propensity score–matched pairs in the Danish registries and 94,883 pairs in the Truven database. The mean age was 67.9 years in the Danish registries and 63.8 years in the Truven database, and follow-up was approximately 5 years and 3 years respectively. Baseline covariates were well balanced between cohorts.

Among Danish patients, those who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease versus those who took tamsulosin (hazard ratio, 0.88). Similarly, patients in the Truven database who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease than those who took tamsulosin (HR, 0.63).

In both cohorts, the risk for Parkinson’s disease among patients receiving terazosin, doxazosin, or alfuzosin, compared with those receiving tamsulosin, decreased with increasing numbers of prescriptions filled. Long-term treatment with any of the three glycolysis-enhancing drugs was associated with greater risk reduction in the Danish (HR, 0.79) and Truven (HR, 0.46) cohorts versus tamsulosin.

Differences in case definitions, which may reflect how Parkinson’s disease was managed, complicate comparisons between the Danish and Truven cohorts, said Dr. Simmering. Another challenge is the source of the data. “The Truven data set was derived from insurance claims from people with private insurance or Medicare supplemental plans,” he said. “This group is quite large but may not be representative of everyone in the United States. We would also only be able to follow people while they were on one insurance plan. If they switched coverage to a company that doesn’t contribute data, we would lose them.”

The Danish database, however, includes all residents of Denmark. Only people who left the country were lost to follow-up.

The results support the hypothesis that increasing energy in cells slows disease progression, Dr. Simmering added. “There are a few conditions, mostly REM sleep disorders, that are associated with future diagnosis of Parkinson’s disease. Right now, we don’t have anything to offer people at elevated risk of Parkinson’s disease that might prevent the disease. If a controlled trial finds that terazosin slows or prevents Parkinson’s disease, we would have something truly protective to offer these patients.”
 

Biomarker needed

Commenting on the results, Alberto J. Espay, MD, MSc, professor of neurology at the University of Cincinnati Academic Health Center, was cautious. “These findings are of unclear applicability to any particular patient without a biomarker for a deficit of glycolysis that these drugs are presumed to affect,” Dr. Espay said. “Hence, there is no feasible or warranted change in practice as a result of this study.”

Pathogenic mechanisms are heterogeneous among patients with Parkinson’s disease, Dr. Espay added. “We will need to understand who among the large biological universe of Parkinson’s patients may have impaired energy metabolism as a pathogenic mechanism to be selected for a future clinical trial evaluating terazosin, doxazosin, or alfuzosin as a potential disease-modifying intervention.”

Parkinson’s disease is not one disease, but a group of disorders with unique biological abnormalities, said Dr. Espay. “We know so much about ‘Parkinson’s disease’ and next to nothing about the biology of individuals with Parkinson’s disease.”

This situation has enabled the development of symptomatic treatments, such as dopaminergic therapies, but failed to yield disease-modifying treatments, he said.

The University of Iowa contributed funds for this study. Dr. Simmering has received pilot funding from the University of Iowa Institute for Clinical and Translational Science. He had no conflicts of interest to disclose. Dr. Espay disclosed no relevant financial relationships.  

A version of this article first appeared on Medscape.com.

Certain drugs currently used to treat benign prostatic hyperplasia (BPH) may provide neuroprotection and delay or prevent the onset of Parkinson’s disease, new research suggests. Treatment of BPH with terazosin (Hytrin), doxazosin (Cardura), or alfuzosin (Uroxatral), all of which enhance glycolysis, was associated with a lower risk of developing Parkinson’s disease than patients taking a drug used for the same indication, tamsulosin (Flomax), which does not affect glycolysis.

“If giving someone terazosin or similar medications truly reduces their risk of disease, these results could have significant clinical implications for neurologists,” said lead author Jacob E. Simmering, PhD, assistant professor of internal medicine at the University of Iowa, Iowa City.

There are few reliable neuroprotective treatments for Parkinson’s disease, he said. “We can manage some of the symptoms, but we can’t stop it from progressing. If a randomized trial finds the same result, this will provide a new option to slow progression of Parkinson’s disease.”

The pathogenesis of Parkinson’s disease is heterogeneous, however, and not all patients may benefit from glycolysis-enhancing drugs, the investigators noted. Future research will be needed to identify potential candidates for this treatment, and clarify the effects of these drugs, they wrote.

The findings were published online Feb. 1, 2021, in JAMA Neurology.
 

Time-dependent effects

The major risk factor for Parkinson’s disease is age, which is associated with impaired energy metabolism. Glycolysis is decreased among patients with Parkinson’s disease, yet impaired energy metabolism has not been investigated widely as a pathogenic factor in the disease, the authors wrote.

Studies have indicated that terazosin increases the activity of an enzyme important in glycolysis. Doxazosin and alfuzosin have a similar mechanism of action and enhance energy metabolism. Tamsulosin, a structurally unrelated drug, has the same mechanism of action as the other three drugs, but does not enhance energy metabolism.

In this report, the researchers investigated the hypothesis that patients who received therapy with terazosin, doxazosin, or alfuzosin would have a lower risk of developing Parkinson’s disease than patients receiving tamsulosin. To do that, they used health care utilization data from Denmark and the United States, including the Danish National Prescription Registry, the Danish National Patient Registry, the Danish Civil Registration System, and the Truven Health Analytics MarketScan database.

The investigators searched the records for patients who filled prescriptions for any of the four drugs of interest. They excluded any patients who developed Parkinson’s disease within 1 year of starting medication. Because use of these drugs is rare among women, they included only men in their analysis.

They looked at patient outcomes beginning at 1 year after the initiation of treatment. They also required patients to fill at least two prescriptions before the beginning of follow-up. Patients who switched from tamsulosin to any of the other drugs, or vice versa, were excluded from analysis.

The investigators used propensity-score matching to ensure that patients in the tamsulosin and terazosin/doxazosin/alfuzosin groups were similar in terms of their other potential risk factors. The primary outcome was the development of Parkinson’s disease.

They identified 52,365 propensity score–matched pairs in the Danish registries and 94,883 pairs in the Truven database. The mean age was 67.9 years in the Danish registries and 63.8 years in the Truven database, and follow-up was approximately 5 years and 3 years respectively. Baseline covariates were well balanced between cohorts.

Among Danish patients, those who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease versus those who took tamsulosin (hazard ratio, 0.88). Similarly, patients in the Truven database who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease than those who took tamsulosin (HR, 0.63).

In both cohorts, the risk for Parkinson’s disease among patients receiving terazosin, doxazosin, or alfuzosin, compared with those receiving tamsulosin, decreased with increasing numbers of prescriptions filled. Long-term treatment with any of the three glycolysis-enhancing drugs was associated with greater risk reduction in the Danish (HR, 0.79) and Truven (HR, 0.46) cohorts versus tamsulosin.

Differences in case definitions, which may reflect how Parkinson’s disease was managed, complicate comparisons between the Danish and Truven cohorts, said Dr. Simmering. Another challenge is the source of the data. “The Truven data set was derived from insurance claims from people with private insurance or Medicare supplemental plans,” he said. “This group is quite large but may not be representative of everyone in the United States. We would also only be able to follow people while they were on one insurance plan. If they switched coverage to a company that doesn’t contribute data, we would lose them.”

The Danish database, however, includes all residents of Denmark. Only people who left the country were lost to follow-up.

The results support the hypothesis that increasing energy in cells slows disease progression, Dr. Simmering added. “There are a few conditions, mostly REM sleep disorders, that are associated with future diagnosis of Parkinson’s disease. Right now, we don’t have anything to offer people at elevated risk of Parkinson’s disease that might prevent the disease. If a controlled trial finds that terazosin slows or prevents Parkinson’s disease, we would have something truly protective to offer these patients.”
 

Biomarker needed

Commenting on the results, Alberto J. Espay, MD, MSc, professor of neurology at the University of Cincinnati Academic Health Center, was cautious. “These findings are of unclear applicability to any particular patient without a biomarker for a deficit of glycolysis that these drugs are presumed to affect,” Dr. Espay said. “Hence, there is no feasible or warranted change in practice as a result of this study.”

Pathogenic mechanisms are heterogeneous among patients with Parkinson’s disease, Dr. Espay added. “We will need to understand who among the large biological universe of Parkinson’s patients may have impaired energy metabolism as a pathogenic mechanism to be selected for a future clinical trial evaluating terazosin, doxazosin, or alfuzosin as a potential disease-modifying intervention.”

Parkinson’s disease is not one disease, but a group of disorders with unique biological abnormalities, said Dr. Espay. “We know so much about ‘Parkinson’s disease’ and next to nothing about the biology of individuals with Parkinson’s disease.”

This situation has enabled the development of symptomatic treatments, such as dopaminergic therapies, but failed to yield disease-modifying treatments, he said.

The University of Iowa contributed funds for this study. Dr. Simmering has received pilot funding from the University of Iowa Institute for Clinical and Translational Science. He had no conflicts of interest to disclose. Dr. Espay disclosed no relevant financial relationships.  

A version of this article first appeared on Medscape.com.

Certain drugs currently used to treat benign prostatic hyperplasia (BPH) may provide neuroprotection and delay or prevent the onset of Parkinson’s disease, new research suggests. Treatment of BPH with terazosin (Hytrin), doxazosin (Cardura), or alfuzosin (Uroxatral), all of which enhance glycolysis, was associated with a lower risk of developing Parkinson’s disease than patients taking a drug used for the same indication, tamsulosin (Flomax), which does not affect glycolysis.

“If giving someone terazosin or similar medications truly reduces their risk of disease, these results could have significant clinical implications for neurologists,” said lead author Jacob E. Simmering, PhD, assistant professor of internal medicine at the University of Iowa, Iowa City.

There are few reliable neuroprotective treatments for Parkinson’s disease, he said. “We can manage some of the symptoms, but we can’t stop it from progressing. If a randomized trial finds the same result, this will provide a new option to slow progression of Parkinson’s disease.”

The pathogenesis of Parkinson’s disease is heterogeneous, however, and not all patients may benefit from glycolysis-enhancing drugs, the investigators noted. Future research will be needed to identify potential candidates for this treatment, and clarify the effects of these drugs, they wrote.

The findings were published online Feb. 1, 2021, in JAMA Neurology.
 

Time-dependent effects

The major risk factor for Parkinson’s disease is age, which is associated with impaired energy metabolism. Glycolysis is decreased among patients with Parkinson’s disease, yet impaired energy metabolism has not been investigated widely as a pathogenic factor in the disease, the authors wrote.

Studies have indicated that terazosin increases the activity of an enzyme important in glycolysis. Doxazosin and alfuzosin have a similar mechanism of action and enhance energy metabolism. Tamsulosin, a structurally unrelated drug, has the same mechanism of action as the other three drugs, but does not enhance energy metabolism.

In this report, the researchers investigated the hypothesis that patients who received therapy with terazosin, doxazosin, or alfuzosin would have a lower risk of developing Parkinson’s disease than patients receiving tamsulosin. To do that, they used health care utilization data from Denmark and the United States, including the Danish National Prescription Registry, the Danish National Patient Registry, the Danish Civil Registration System, and the Truven Health Analytics MarketScan database.

The investigators searched the records for patients who filled prescriptions for any of the four drugs of interest. They excluded any patients who developed Parkinson’s disease within 1 year of starting medication. Because use of these drugs is rare among women, they included only men in their analysis.

They looked at patient outcomes beginning at 1 year after the initiation of treatment. They also required patients to fill at least two prescriptions before the beginning of follow-up. Patients who switched from tamsulosin to any of the other drugs, or vice versa, were excluded from analysis.

The investigators used propensity-score matching to ensure that patients in the tamsulosin and terazosin/doxazosin/alfuzosin groups were similar in terms of their other potential risk factors. The primary outcome was the development of Parkinson’s disease.

They identified 52,365 propensity score–matched pairs in the Danish registries and 94,883 pairs in the Truven database. The mean age was 67.9 years in the Danish registries and 63.8 years in the Truven database, and follow-up was approximately 5 years and 3 years respectively. Baseline covariates were well balanced between cohorts.

Among Danish patients, those who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease versus those who took tamsulosin (hazard ratio, 0.88). Similarly, patients in the Truven database who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease than those who took tamsulosin (HR, 0.63).

In both cohorts, the risk for Parkinson’s disease among patients receiving terazosin, doxazosin, or alfuzosin, compared with those receiving tamsulosin, decreased with increasing numbers of prescriptions filled. Long-term treatment with any of the three glycolysis-enhancing drugs was associated with greater risk reduction in the Danish (HR, 0.79) and Truven (HR, 0.46) cohorts versus tamsulosin.

Differences in case definitions, which may reflect how Parkinson’s disease was managed, complicate comparisons between the Danish and Truven cohorts, said Dr. Simmering. Another challenge is the source of the data. “The Truven data set was derived from insurance claims from people with private insurance or Medicare supplemental plans,” he said. “This group is quite large but may not be representative of everyone in the United States. We would also only be able to follow people while they were on one insurance plan. If they switched coverage to a company that doesn’t contribute data, we would lose them.”

The Danish database, however, includes all residents of Denmark. Only people who left the country were lost to follow-up.

The results support the hypothesis that increasing energy in cells slows disease progression, Dr. Simmering added. “There are a few conditions, mostly REM sleep disorders, that are associated with future diagnosis of Parkinson’s disease. Right now, we don’t have anything to offer people at elevated risk of Parkinson’s disease that might prevent the disease. If a controlled trial finds that terazosin slows or prevents Parkinson’s disease, we would have something truly protective to offer these patients.”
 

Biomarker needed

Commenting on the results, Alberto J. Espay, MD, MSc, professor of neurology at the University of Cincinnati Academic Health Center, was cautious. “These findings are of unclear applicability to any particular patient without a biomarker for a deficit of glycolysis that these drugs are presumed to affect,” Dr. Espay said. “Hence, there is no feasible or warranted change in practice as a result of this study.”

Pathogenic mechanisms are heterogeneous among patients with Parkinson’s disease, Dr. Espay added. “We will need to understand who among the large biological universe of Parkinson’s patients may have impaired energy metabolism as a pathogenic mechanism to be selected for a future clinical trial evaluating terazosin, doxazosin, or alfuzosin as a potential disease-modifying intervention.”

Parkinson’s disease is not one disease, but a group of disorders with unique biological abnormalities, said Dr. Espay. “We know so much about ‘Parkinson’s disease’ and next to nothing about the biology of individuals with Parkinson’s disease.”

This situation has enabled the development of symptomatic treatments, such as dopaminergic therapies, but failed to yield disease-modifying treatments, he said.

The University of Iowa contributed funds for this study. Dr. Simmering has received pilot funding from the University of Iowa Institute for Clinical and Translational Science. He had no conflicts of interest to disclose. Dr. Espay disclosed no relevant financial relationships.  

A version of this article first appeared on Medscape.com.

Focused ultrasound for ablation of the subthalamic nucleus in one hemisphere improved motor features in a selected group of patients with markedly asymmetric Parkinson’s disease, but was associated with a high rate of adverse events, including dyskinesias and other neurologic complications, in a new randomized, sham-controlled trial.

“Longer-term and larger trials are needed to determine the role of focused ultrasound subthalamotomy in the management of Parkinson’s disease and its effect as compared with other available treatments, including deep-brain stimulation,” the authors concluded.

The trial was published online Dec.24, 2020, in the New England Journal of Medicine.

An accompanying editorial concluded that the high rate of adverse events and the lack of ability to modulate treatment over time to treat prominent tremor “raise questions about the appropriate implementation of focused ultrasound–produced lesions for the treatment of Parkinson’s disease.”
 

A scalpel-free alternative to brain surgery

The study authors, led by Raul Martinez-Fernandez, MD, PhD, University Hospital HM Puerta del Sur, Mostoles, Spain, explained that, in severe cases of refractory motor manifestations such as tremor and motor complications, a neurosurgical approach using deep-brain stimulation of the subthalamic nucleus can be used. But to avoid craniotomy and electrode penetration, MRI-guided focused ultrasound for the ablation of deep-brain structures, including the subthalamic nucleus, is being investigated as a treatment for Parkinson’s disease.

Patients are potential candidates for ultrasound ablation if they have prominently asymmetric parkinsonism, if they are not considered to be clinically suitable candidates for surgery because of contraindications, or if they are reluctant to undergo a brain operation or to have an implanted device.

The current trial involved 40 patients with markedly asymmetric Parkinson’s disease who had motor signs not fully controlled by medication or who were ineligible for deep-brain stimulation surgery. They were randomly assigned in a 2:1 ratio to undergo focused ultrasound subthalamotomy on the side opposite their main motor signs or a sham procedure.

Results showed that the mean Movement Disorder Society–Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS III) motor score for the more affected side – which was the primary endpoint – decreased from 19.9 at baseline to 9.9 at 4 months in the active-treatment group (least-squares mean difference, 9.8 points); and from 18.7 to 17.1 in the control group (least-squares mean difference, 1.7 points). The between-group difference was 8.1 points (P < .001).

The change from baseline in the MDS-UPDRS III score for the more affected side in patients who underwent active treatment varied, ranging from 5% to 95%; the changes were qualitatively more evident for reduction of tremor and rigidity than for bradykinesia.

Adverse events in the active-treatment group were the following:

• Dyskinesia in the off-medication state in six patients and in the on-medication state in six, which persisted in three and one, respectively, at 4 months.
• Weakness on the treated side in five patients, which persisted in two at 4 months.
• Speech disturbance in 15 patients, which persisted in 3 at 4 months.
• Facial weakness in three patients, which persisted in one at 4 months.
• in 13 patients, which persisted in two at 4 months.

In six patients in the active-treatment group, some of these deficits were present at 12 months.

The researchers noted that an approach that has been suggested to reduce the risk of dyskinesias has been to extend ablations dorsal to the subthalamic nucleus in order to interrupt the pallidothalamic-projecting neurons.

The study also showed a greater reduction in the use of dopaminergic medication in the active-treatment group versus the control group, but the researchers noted that the 95% confidence intervals for this and other secondary outcomes were not adjusted for multiple comparisons, so no definite conclusions can be drawn from these data.

They also pointed out that subthalamotomy was performed in one hemisphere, and the natural evolution of Parkinson’s disease eventually leads to motor impairment on both sides of the body in most patients.

“The likely need for an increase in the daily dose of levodopa equivalent to maintain function on the untreated side of the body could lead to the development of dyskinesias on the treated side. However, the few open-label studies of long-term (≥36 months) follow-up of radiofrequency subthalamotomy performed in one hemisphere do not provide support for this concern,” they said.
 

An important step, but improvements are needed

In an accompanying editorial, Joel S. Perlmutter, MD, and Mwiza Ushe, MD, Washington University, St. Louis, noted that surgical deep brain stimulation of the left and right subthalamic nuclei has shown a reduction in the severity of motor signs of 40%-60% and a reduction in medication use of up to 50%. But this technique involves a small craniotomy with implantation of stimulating electrodes, which has a 1%-5% risk of major adverse events such as hemorrhage, stroke, or infection.

Less severe complications include dystonia, dysarthria, gait impairment, dyskinesia, swallowing dysfunction, or change in verbal fluency; however, modification of the device programming may alleviate these effects. Nevertheless, some patients are wary of the implantation surgery and hardware and therefore decline to undergo deep-brain stimulation, the editorialists explained.

“The development of alternative procedures to deep-brain stimulation is important to the field of Parkinson’s disease treatment. The current trial begins the path to that goal, and improvements in targeting may improve the risk-benefit ratio and permit the use of lesions in both hemispheres, which would widen the population of eligible patients,” Dr. Perlmutter and Dr. Ushe wrote.

They pointed out that limiting the treatment to one side of the brain by ultrasound-produced lesioning constrains the application, since most patients with Parkinson’s disease have progression of symptoms on both sides of the body.

“The potential advantages and limitations of focused ultrasound–produced lesioning should be discussed with patients. We hope that improved technique will reduce the associated risks and increase the applicability of this provocative procedure,” the editorialists concluded.

This study was supported by Insightec, the Focused Ultrasound Foundation, Fundacion MAPFRE, Fundacion Hospitales de Madrid, and the University of Virginia Center of Excellence. Dr. Martinez-Fernandez reported receiving for consultancy fees for Insightec. Dr. Ushe reported non-financial support for Abbott outside the submitted work. Dr. Perlmutter disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Focused ultrasound for ablation of the subthalamic nucleus in one hemisphere improved motor features in a selected group of patients with markedly asymmetric Parkinson’s disease, but was associated with a high rate of adverse events, including dyskinesias and other neurologic complications, in a new randomized, sham-controlled trial.

“Longer-term and larger trials are needed to determine the role of focused ultrasound subthalamotomy in the management of Parkinson’s disease and its effect as compared with other available treatments, including deep-brain stimulation,” the authors concluded.

The trial was published online Dec.24, 2020, in the New England Journal of Medicine.

An accompanying editorial concluded that the high rate of adverse events and the lack of ability to modulate treatment over time to treat prominent tremor “raise questions about the appropriate implementation of focused ultrasound–produced lesions for the treatment of Parkinson’s disease.”
 

A scalpel-free alternative to brain surgery

The study authors, led by Raul Martinez-Fernandez, MD, PhD, University Hospital HM Puerta del Sur, Mostoles, Spain, explained that, in severe cases of refractory motor manifestations such as tremor and motor complications, a neurosurgical approach using deep-brain stimulation of the subthalamic nucleus can be used. But to avoid craniotomy and electrode penetration, MRI-guided focused ultrasound for the ablation of deep-brain structures, including the subthalamic nucleus, is being investigated as a treatment for Parkinson’s disease.

Patients are potential candidates for ultrasound ablation if they have prominently asymmetric parkinsonism, if they are not considered to be clinically suitable candidates for surgery because of contraindications, or if they are reluctant to undergo a brain operation or to have an implanted device.

The current trial involved 40 patients with markedly asymmetric Parkinson’s disease who had motor signs not fully controlled by medication or who were ineligible for deep-brain stimulation surgery. They were randomly assigned in a 2:1 ratio to undergo focused ultrasound subthalamotomy on the side opposite their main motor signs or a sham procedure.

Results showed that the mean Movement Disorder Society–Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS III) motor score for the more affected side – which was the primary endpoint – decreased from 19.9 at baseline to 9.9 at 4 months in the active-treatment group (least-squares mean difference, 9.8 points); and from 18.7 to 17.1 in the control group (least-squares mean difference, 1.7 points). The between-group difference was 8.1 points (P < .001).

The change from baseline in the MDS-UPDRS III score for the more affected side in patients who underwent active treatment varied, ranging from 5% to 95%; the changes were qualitatively more evident for reduction of tremor and rigidity than for bradykinesia.

Adverse events in the active-treatment group were the following:

• Dyskinesia in the off-medication state in six patients and in the on-medication state in six, which persisted in three and one, respectively, at 4 months.
• Weakness on the treated side in five patients, which persisted in two at 4 months.
• Speech disturbance in 15 patients, which persisted in 3 at 4 months.
• Facial weakness in three patients, which persisted in one at 4 months.
• in 13 patients, which persisted in two at 4 months.

In six patients in the active-treatment group, some of these deficits were present at 12 months.

The researchers noted that an approach that has been suggested to reduce the risk of dyskinesias has been to extend ablations dorsal to the subthalamic nucleus in order to interrupt the pallidothalamic-projecting neurons.

The study also showed a greater reduction in the use of dopaminergic medication in the active-treatment group versus the control group, but the researchers noted that the 95% confidence intervals for this and other secondary outcomes were not adjusted for multiple comparisons, so no definite conclusions can be drawn from these data.

They also pointed out that subthalamotomy was performed in one hemisphere, and the natural evolution of Parkinson’s disease eventually leads to motor impairment on both sides of the body in most patients.

“The likely need for an increase in the daily dose of levodopa equivalent to maintain function on the untreated side of the body could lead to the development of dyskinesias on the treated side. However, the few open-label studies of long-term (≥36 months) follow-up of radiofrequency subthalamotomy performed in one hemisphere do not provide support for this concern,” they said.
 

An important step, but improvements are needed

In an accompanying editorial, Joel S. Perlmutter, MD, and Mwiza Ushe, MD, Washington University, St. Louis, noted that surgical deep brain stimulation of the left and right subthalamic nuclei has shown a reduction in the severity of motor signs of 40%-60% and a reduction in medication use of up to 50%. But this technique involves a small craniotomy with implantation of stimulating electrodes, which has a 1%-5% risk of major adverse events such as hemorrhage, stroke, or infection.

Less severe complications include dystonia, dysarthria, gait impairment, dyskinesia, swallowing dysfunction, or change in verbal fluency; however, modification of the device programming may alleviate these effects. Nevertheless, some patients are wary of the implantation surgery and hardware and therefore decline to undergo deep-brain stimulation, the editorialists explained.

“The development of alternative procedures to deep-brain stimulation is important to the field of Parkinson’s disease treatment. The current trial begins the path to that goal, and improvements in targeting may improve the risk-benefit ratio and permit the use of lesions in both hemispheres, which would widen the population of eligible patients,” Dr. Perlmutter and Dr. Ushe wrote.

They pointed out that limiting the treatment to one side of the brain by ultrasound-produced lesioning constrains the application, since most patients with Parkinson’s disease have progression of symptoms on both sides of the body.

“The potential advantages and limitations of focused ultrasound–produced lesioning should be discussed with patients. We hope that improved technique will reduce the associated risks and increase the applicability of this provocative procedure,” the editorialists concluded.

This study was supported by Insightec, the Focused Ultrasound Foundation, Fundacion MAPFRE, Fundacion Hospitales de Madrid, and the University of Virginia Center of Excellence. Dr. Martinez-Fernandez reported receiving for consultancy fees for Insightec. Dr. Ushe reported non-financial support for Abbott outside the submitted work. Dr. Perlmutter disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Focused ultrasound for ablation of the subthalamic nucleus in one hemisphere improved motor features in a selected group of patients with markedly asymmetric Parkinson’s disease, but was associated with a high rate of adverse events, including dyskinesias and other neurologic complications, in a new randomized, sham-controlled trial.

“Longer-term and larger trials are needed to determine the role of focused ultrasound subthalamotomy in the management of Parkinson’s disease and its effect as compared with other available treatments, including deep-brain stimulation,” the authors concluded.

The trial was published online Dec.24, 2020, in the New England Journal of Medicine.

An accompanying editorial concluded that the high rate of adverse events and the lack of ability to modulate treatment over time to treat prominent tremor “raise questions about the appropriate implementation of focused ultrasound–produced lesions for the treatment of Parkinson’s disease.”
 

A scalpel-free alternative to brain surgery

The study authors, led by Raul Martinez-Fernandez, MD, PhD, University Hospital HM Puerta del Sur, Mostoles, Spain, explained that, in severe cases of refractory motor manifestations such as tremor and motor complications, a neurosurgical approach using deep-brain stimulation of the subthalamic nucleus can be used. But to avoid craniotomy and electrode penetration, MRI-guided focused ultrasound for the ablation of deep-brain structures, including the subthalamic nucleus, is being investigated as a treatment for Parkinson’s disease.

Patients are potential candidates for ultrasound ablation if they have prominently asymmetric parkinsonism, if they are not considered to be clinically suitable candidates for surgery because of contraindications, or if they are reluctant to undergo a brain operation or to have an implanted device.

The current trial involved 40 patients with markedly asymmetric Parkinson’s disease who had motor signs not fully controlled by medication or who were ineligible for deep-brain stimulation surgery. They were randomly assigned in a 2:1 ratio to undergo focused ultrasound subthalamotomy on the side opposite their main motor signs or a sham procedure.

Results showed that the mean Movement Disorder Society–Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS III) motor score for the more affected side – which was the primary endpoint – decreased from 19.9 at baseline to 9.9 at 4 months in the active-treatment group (least-squares mean difference, 9.8 points); and from 18.7 to 17.1 in the control group (least-squares mean difference, 1.7 points). The between-group difference was 8.1 points (P < .001).

The change from baseline in the MDS-UPDRS III score for the more affected side in patients who underwent active treatment varied, ranging from 5% to 95%; the changes were qualitatively more evident for reduction of tremor and rigidity than for bradykinesia.

Adverse events in the active-treatment group were the following:

• Dyskinesia in the off-medication state in six patients and in the on-medication state in six, which persisted in three and one, respectively, at 4 months.
• Weakness on the treated side in five patients, which persisted in two at 4 months.
• Speech disturbance in 15 patients, which persisted in 3 at 4 months.
• Facial weakness in three patients, which persisted in one at 4 months.
• in 13 patients, which persisted in two at 4 months.

In six patients in the active-treatment group, some of these deficits were present at 12 months.

The researchers noted that an approach that has been suggested to reduce the risk of dyskinesias has been to extend ablations dorsal to the subthalamic nucleus in order to interrupt the pallidothalamic-projecting neurons.

The study also showed a greater reduction in the use of dopaminergic medication in the active-treatment group versus the control group, but the researchers noted that the 95% confidence intervals for this and other secondary outcomes were not adjusted for multiple comparisons, so no definite conclusions can be drawn from these data.

They also pointed out that subthalamotomy was performed in one hemisphere, and the natural evolution of Parkinson’s disease eventually leads to motor impairment on both sides of the body in most patients.

“The likely need for an increase in the daily dose of levodopa equivalent to maintain function on the untreated side of the body could lead to the development of dyskinesias on the treated side. However, the few open-label studies of long-term (≥36 months) follow-up of radiofrequency subthalamotomy performed in one hemisphere do not provide support for this concern,” they said.
 

An important step, but improvements are needed

In an accompanying editorial, Joel S. Perlmutter, MD, and Mwiza Ushe, MD, Washington University, St. Louis, noted that surgical deep brain stimulation of the left and right subthalamic nuclei has shown a reduction in the severity of motor signs of 40%-60% and a reduction in medication use of up to 50%. But this technique involves a small craniotomy with implantation of stimulating electrodes, which has a 1%-5% risk of major adverse events such as hemorrhage, stroke, or infection.

Less severe complications include dystonia, dysarthria, gait impairment, dyskinesia, swallowing dysfunction, or change in verbal fluency; however, modification of the device programming may alleviate these effects. Nevertheless, some patients are wary of the implantation surgery and hardware and therefore decline to undergo deep-brain stimulation, the editorialists explained.

“The development of alternative procedures to deep-brain stimulation is important to the field of Parkinson’s disease treatment. The current trial begins the path to that goal, and improvements in targeting may improve the risk-benefit ratio and permit the use of lesions in both hemispheres, which would widen the population of eligible patients,” Dr. Perlmutter and Dr. Ushe wrote.

They pointed out that limiting the treatment to one side of the brain by ultrasound-produced lesioning constrains the application, since most patients with Parkinson’s disease have progression of symptoms on both sides of the body.

“The potential advantages and limitations of focused ultrasound–produced lesioning should be discussed with patients. We hope that improved technique will reduce the associated risks and increase the applicability of this provocative procedure,” the editorialists concluded.

This study was supported by Insightec, the Focused Ultrasound Foundation, Fundacion MAPFRE, Fundacion Hospitales de Madrid, and the University of Virginia Center of Excellence. Dr. Martinez-Fernandez reported receiving for consultancy fees for Insightec. Dr. Ushe reported non-financial support for Abbott outside the submitted work. Dr. Perlmutter disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

An eye exam may be all that is needed to diagnose Parkinson’s disease, new research shows. Using an advanced machine-learning algorithm and fundus eye images, which depict the small blood vessels and more at the back of the eye, investigators are able to classify patients with Parkinson’s disease compared against a control group. “We discovered that micro blood vessels decreased in both size and number in patients with Parkinson’s disease,” said Maximillian Diaz, a PhD student at the University of Florida, Gainesville.

The simple eye examination may offer a way to diagnose Parkinson’s early in the disease progression.

Mr. Diaz said the test could be incorporated to a patient’s annual physical examination not only to look for Parkinson’s disease but also for other neurological diseases. Researchers at the University of Florida are also looking at whether the same technique can diagnose Alzheimer’s disease.

The beauty of this is that “the technique is simple,” he said. “What surprised us is that we can do this with fundus images, which can be taken in a clinical setting with a lens that attaches to your smartphone. It’s affordable and portable and it takes less than a minute.”
 

Machine learning on fundus eye images

Researchers, under the direction of Ruogu Fang, PhD, director of the J. Crayton Pruitt Department of Biomedical Engineering’s Smart Medical Informatics Learning and Evaluation Lab (SMILE) at the University of Florida, Gainesville, collected fundus eye images from 476 age- and gender-matched individuals, 238 diagnosed with Parkinson’s disease and 238 control group images. Another set of 100 images were collected from the University of Florida database using green color channels (UKB-Green and UF-UKB Green) and used to improve vessel segmentation. Of these, 28 were controls and 72 from patients with Parkinson’s disease. Researchers added 44 more control images from the U.K. Biobank to complete the second age- and gender-matched dataset.

“We used 80% of the images to develop the machine-learning network,” Mr. Diaz said. The other 20% of images, which were new to the algorithm, were used to test it, to determine true or false, Parkinson’s disease or control?

“We were able to achieve an accuracy of 85%,” Mr. Diaz said. Currently, there are no biomarkers to diagnose Parkinson’s disease. The disease is only recognizable once 80% of dopaminergic cells have already decayed. “Clinically, there’s no way to tell how long someone has had it,” Mr. Diaz said. He hopes that by doing additional research and testing earlier – with a longitudinal study of images – a pattern may be detected to better predict disease.
 

Eye vasculature reveals disease

“This concept [studying eye vasculature] is getting a lot of interest right now,” said Anant Madabhushi, PhD, Case Western Reserve University, Cleveland. “The eye is the proverbial window to the soul, and in this case, shows what’s happening in rest of the body.”

Dr. Madabhushi, who was not involved in the Parkinson’s research, has also been working with a team in Cleveland to look at how vessels in the eye predict response to drug therapies in diabetic macular edema, including treatment durability. “What we’ve found is the more twisted the vessels, the more constricted, and the less likely the person would respond to therapy,” he said, adding that studying the pathology of the eye makes a lot of sense. “The arrangement of vessels in the eye are likely to have implications in all kinds of diseases.”

Since Parkinson’s disease does not have any biomarkers, this technology could be very useful in diagnosis. “With specific quantitative measurements, we could have computational imaging biomarkers to predict the risk of onset of Parkinson’s, and the prognosis of disease. That’s the true utility of this approach,” he said.

Mr. Diaz disclosed no relevant financial relationships. Dr. Madabhushi has consulted for Aiforia and has had research sponsored by AstraZeneca, Bristol-Myers Squibb, and Boehringer Ingelheim.

A version of this article originally appeared on Medscape.com.

An eye exam may be all that is needed to diagnose Parkinson’s disease, new research shows. Using an advanced machine-learning algorithm and fundus eye images, which depict the small blood vessels and more at the back of the eye, investigators are able to classify patients with Parkinson’s disease compared against a control group. “We discovered that micro blood vessels decreased in both size and number in patients with Parkinson’s disease,” said Maximillian Diaz, a PhD student at the University of Florida, Gainesville.

The simple eye examination may offer a way to diagnose Parkinson’s early in the disease progression.

Mr. Diaz said the test could be incorporated to a patient’s annual physical examination not only to look for Parkinson’s disease but also for other neurological diseases. Researchers at the University of Florida are also looking at whether the same technique can diagnose Alzheimer’s disease.

The beauty of this is that “the technique is simple,” he said. “What surprised us is that we can do this with fundus images, which can be taken in a clinical setting with a lens that attaches to your smartphone. It’s affordable and portable and it takes less than a minute.”
 

Machine learning on fundus eye images

Researchers, under the direction of Ruogu Fang, PhD, director of the J. Crayton Pruitt Department of Biomedical Engineering’s Smart Medical Informatics Learning and Evaluation Lab (SMILE) at the University of Florida, Gainesville, collected fundus eye images from 476 age- and gender-matched individuals, 238 diagnosed with Parkinson’s disease and 238 control group images. Another set of 100 images were collected from the University of Florida database using green color channels (UKB-Green and UF-UKB Green) and used to improve vessel segmentation. Of these, 28 were controls and 72 from patients with Parkinson’s disease. Researchers added 44 more control images from the U.K. Biobank to complete the second age- and gender-matched dataset.

“We used 80% of the images to develop the machine-learning network,” Mr. Diaz said. The other 20% of images, which were new to the algorithm, were used to test it, to determine true or false, Parkinson’s disease or control?

“We were able to achieve an accuracy of 85%,” Mr. Diaz said. Currently, there are no biomarkers to diagnose Parkinson’s disease. The disease is only recognizable once 80% of dopaminergic cells have already decayed. “Clinically, there’s no way to tell how long someone has had it,” Mr. Diaz said. He hopes that by doing additional research and testing earlier – with a longitudinal study of images – a pattern may be detected to better predict disease.
 

Eye vasculature reveals disease

“This concept [studying eye vasculature] is getting a lot of interest right now,” said Anant Madabhushi, PhD, Case Western Reserve University, Cleveland. “The eye is the proverbial window to the soul, and in this case, shows what’s happening in rest of the body.”

Dr. Madabhushi, who was not involved in the Parkinson’s research, has also been working with a team in Cleveland to look at how vessels in the eye predict response to drug therapies in diabetic macular edema, including treatment durability. “What we’ve found is the more twisted the vessels, the more constricted, and the less likely the person would respond to therapy,” he said, adding that studying the pathology of the eye makes a lot of sense. “The arrangement of vessels in the eye are likely to have implications in all kinds of diseases.”

Since Parkinson’s disease does not have any biomarkers, this technology could be very useful in diagnosis. “With specific quantitative measurements, we could have computational imaging biomarkers to predict the risk of onset of Parkinson’s, and the prognosis of disease. That’s the true utility of this approach,” he said.

Mr. Diaz disclosed no relevant financial relationships. Dr. Madabhushi has consulted for Aiforia and has had research sponsored by AstraZeneca, Bristol-Myers Squibb, and Boehringer Ingelheim.

A version of this article originally appeared on Medscape.com.

An eye exam may be all that is needed to diagnose Parkinson’s disease, new research shows. Using an advanced machine-learning algorithm and fundus eye images, which depict the small blood vessels and more at the back of the eye, investigators are able to classify patients with Parkinson’s disease compared against a control group. “We discovered that micro blood vessels decreased in both size and number in patients with Parkinson’s disease,” said Maximillian Diaz, a PhD student at the University of Florida, Gainesville.

The simple eye examination may offer a way to diagnose Parkinson’s early in the disease progression.

Mr. Diaz said the test could be incorporated to a patient’s annual physical examination not only to look for Parkinson’s disease but also for other neurological diseases. Researchers at the University of Florida are also looking at whether the same technique can diagnose Alzheimer’s disease.

The beauty of this is that “the technique is simple,” he said. “What surprised us is that we can do this with fundus images, which can be taken in a clinical setting with a lens that attaches to your smartphone. It’s affordable and portable and it takes less than a minute.”
 

Machine learning on fundus eye images

Researchers, under the direction of Ruogu Fang, PhD, director of the J. Crayton Pruitt Department of Biomedical Engineering’s Smart Medical Informatics Learning and Evaluation Lab (SMILE) at the University of Florida, Gainesville, collected fundus eye images from 476 age- and gender-matched individuals, 238 diagnosed with Parkinson’s disease and 238 control group images. Another set of 100 images were collected from the University of Florida database using green color channels (UKB-Green and UF-UKB Green) and used to improve vessel segmentation. Of these, 28 were controls and 72 from patients with Parkinson’s disease. Researchers added 44 more control images from the U.K. Biobank to complete the second age- and gender-matched dataset.

“We used 80% of the images to develop the machine-learning network,” Mr. Diaz said. The other 20% of images, which were new to the algorithm, were used to test it, to determine true or false, Parkinson’s disease or control?

“We were able to achieve an accuracy of 85%,” Mr. Diaz said. Currently, there are no biomarkers to diagnose Parkinson’s disease. The disease is only recognizable once 80% of dopaminergic cells have already decayed. “Clinically, there’s no way to tell how long someone has had it,” Mr. Diaz said. He hopes that by doing additional research and testing earlier – with a longitudinal study of images – a pattern may be detected to better predict disease.
 

Eye vasculature reveals disease

“This concept [studying eye vasculature] is getting a lot of interest right now,” said Anant Madabhushi, PhD, Case Western Reserve University, Cleveland. “The eye is the proverbial window to the soul, and in this case, shows what’s happening in rest of the body.”

Dr. Madabhushi, who was not involved in the Parkinson’s research, has also been working with a team in Cleveland to look at how vessels in the eye predict response to drug therapies in diabetic macular edema, including treatment durability. “What we’ve found is the more twisted the vessels, the more constricted, and the less likely the person would respond to therapy,” he said, adding that studying the pathology of the eye makes a lot of sense. “The arrangement of vessels in the eye are likely to have implications in all kinds of diseases.”

Since Parkinson’s disease does not have any biomarkers, this technology could be very useful in diagnosis. “With specific quantitative measurements, we could have computational imaging biomarkers to predict the risk of onset of Parkinson’s, and the prognosis of disease. That’s the true utility of this approach,” he said.

Mr. Diaz disclosed no relevant financial relationships. Dr. Madabhushi has consulted for Aiforia and has had research sponsored by AstraZeneca, Bristol-Myers Squibb, and Boehringer Ingelheim.

A version of this article originally appeared on Medscape.com.

Concussion is associated with increased risk for subsequent development of attention-deficit/hyperactivity disorder (ADHD), as well as dementia and Parkinson’s disease, new research suggests. Results from a retrospective, population-based cohort study showed that controlling for socioeconomic status and overall health did not significantly affect this association.

The link between concussion and risk for ADHD and for mood and anxiety disorder was stronger in the women than in the men. In addition, having a history of multiple concussions strengthened the association between concussion and subsequent mood and anxiety disorder, dementia, and Parkinson’s disease compared with experiencing just one concussion.

The findings are similar to those of previous studies, noted lead author Marc P. Morissette, PhD, research assistant at the Pan Am Clinic Foundation in Winnipeg, Manitoba, Canada. “The main methodological differences separating our study from previous studies in this area is a focus on concussion-specific injuries identified from medical records and the potential for study participants to have up to 25 years of follow-up data,” said Dr. Morissette.

The findings were published online July 27 in Family Medicine and Community Health, a BMJ journal.
 

Almost 190,000 participants

Several studies have shown associations between head injury and increased risk for ADHD, depression, anxiety, Alzheimer’s disease, and Parkinson’s disease. However, many of these studies relied on self-reported medical history, included all forms of traumatic brain injury, and failed to adjust for preexisting health conditions.

An improved understanding of concussion and the risks associated with it could help physicians manage their patients’ long-term needs, the investigators noted.

In the current study, the researchers examined anonymized administrative health data collected between the periods of 1990–1991 and 2014–2015 in the Manitoba Population Research Data Repository at the Manitoba Center for Health Policy.

Eligible patients had been diagnosed with concussion in accordance with standard criteria. Participants were excluded if they had been diagnosed with dementia or Parkinson’s disease before the incident concussion during the study period. The investigators matched three control participants to each included patient on the basis of age, sex, and location.

Study outcome was time from index date (date of first concussion) to diagnosis of ADHD, mood and anxiety disorder, dementia, or Parkinson’s disease. The researchers controlled for socioeconomic status using the Socioeconomic Factor Index, version 2 (SEFI2), and for preexisting medical conditions using the Charlson Comorbidity Index (CCI).

The study included 28,021 men (mean age, 25 years) and 19,462 women (mean age, 30 years) in the concussion group and 81,871 men (mean age, 25 years) and 57,159 women (mean age, 30 years) in the control group. Mean SEFI2 score was approximately −0.05, and mean CCI score was approximately 0.2.
 

Dose effect?

Results showed that concussion was associated with an increased risk for ADHD (hazard ratio [HR], 1.39), mood and anxiety disorder (HR, 1.72), dementia (HR, 1.72), and Parkinson’s disease (HR, 1.57).

After a concussion, the risk of developing ADHD was 28% higher and the risk of developing mood and anxiety disorder was 7% higher among women than among men. Gender was not associated with risk for dementia or Parkinson’s disease after concussion.

Sustaining a second concussion increased the strength of the association with risk for dementia compared with sustaining a single concussion (HR, 1.62). Similarly, sustaining more than three concussions increased the strength of the association with the risk for mood and anxiety disorders (HR for more than three vs one concussion, 1.22) and Parkinson›s disease (HR, 3.27).

A sensitivity analysis found similar associations between concussion and risk for mood and anxiety disorder among all age groups. Younger participants were at greater risk for ADHD, however, and older participants were at greater risk for dementia and Parkinson’s disease.

Increased awareness of concussion and the outcomes of interest, along with improved diagnostic tools, may have influenced the study’s findings, Dr. Morissette noted. “The sex-based differences may be due to either pathophysiological differences in response to concussive injuries or potentially a difference in willingness to seek medical care or share symptoms, concussion-related or otherwise, with a medical professional,” he said.

“We are hopeful that our findings will encourage practitioners to be cognizant of various conditions that may present in individuals who have previously experienced a concussion,” Dr. Morissette added. “If physicians are aware of the various associations identified following a concussion, it may lead to more thorough clinical examination at initial presentation, along with more dedicated care throughout the patient’s life.”
 

Association versus causation

Commenting on the research, Steven Erickson, MD, sports medicine specialist at Banner–University Medicine Neuroscience Institute, Phoenix, Ariz., noted that although the study showed an association between concussion and subsequent diagnosis of ADHD, anxiety, and Parkinson’s disease, “this association should not be misconstrued as causation.” He added that the study’s conclusions “are just as likely to be due to labeling theory” or a self-fulfilling prophecy.

“Patients diagnosed with ADHD, anxiety, or Parkinson’s disease may recall concussion and associate the two diagnoses; but patients who have not previously been diagnosed with a concussion cannot draw that conclusion,” said Dr. Erickson, who was not involved with the research.

Citing the apparent gender difference in the strength of the association between concussion and the outcomes of interest, Dr. Erickson noted that women are more likely to report symptoms in general “and therefore are more likely to be diagnosed with ADHD and anxiety disorders” because of differences in reporting rather than incidence of disease.

“Further research needs to be done to definitively determine a causal relationship between concussion and any psychiatric or neurologic diagnosis,” Dr. Erickson concluded.

The study was funded by the Pan Am Clinic Foundation. Dr. Morissette and Dr. Erickson have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Concussion is associated with increased risk for subsequent development of attention-deficit/hyperactivity disorder (ADHD), as well as dementia and Parkinson’s disease, new research suggests. Results from a retrospective, population-based cohort study showed that controlling for socioeconomic status and overall health did not significantly affect this association.

The link between concussion and risk for ADHD and for mood and anxiety disorder was stronger in the women than in the men. In addition, having a history of multiple concussions strengthened the association between concussion and subsequent mood and anxiety disorder, dementia, and Parkinson’s disease compared with experiencing just one concussion.

The findings are similar to those of previous studies, noted lead author Marc P. Morissette, PhD, research assistant at the Pan Am Clinic Foundation in Winnipeg, Manitoba, Canada. “The main methodological differences separating our study from previous studies in this area is a focus on concussion-specific injuries identified from medical records and the potential for study participants to have up to 25 years of follow-up data,” said Dr. Morissette.

The findings were published online July 27 in Family Medicine and Community Health, a BMJ journal.
 

Almost 190,000 participants

Several studies have shown associations between head injury and increased risk for ADHD, depression, anxiety, Alzheimer’s disease, and Parkinson’s disease. However, many of these studies relied on self-reported medical history, included all forms of traumatic brain injury, and failed to adjust for preexisting health conditions.

An improved understanding of concussion and the risks associated with it could help physicians manage their patients’ long-term needs, the investigators noted.

In the current study, the researchers examined anonymized administrative health data collected between the periods of 1990–1991 and 2014–2015 in the Manitoba Population Research Data Repository at the Manitoba Center for Health Policy.

Eligible patients had been diagnosed with concussion in accordance with standard criteria. Participants were excluded if they had been diagnosed with dementia or Parkinson’s disease before the incident concussion during the study period. The investigators matched three control participants to each included patient on the basis of age, sex, and location.

Study outcome was time from index date (date of first concussion) to diagnosis of ADHD, mood and anxiety disorder, dementia, or Parkinson’s disease. The researchers controlled for socioeconomic status using the Socioeconomic Factor Index, version 2 (SEFI2), and for preexisting medical conditions using the Charlson Comorbidity Index (CCI).

The study included 28,021 men (mean age, 25 years) and 19,462 women (mean age, 30 years) in the concussion group and 81,871 men (mean age, 25 years) and 57,159 women (mean age, 30 years) in the control group. Mean SEFI2 score was approximately −0.05, and mean CCI score was approximately 0.2.
 

Dose effect?

Results showed that concussion was associated with an increased risk for ADHD (hazard ratio [HR], 1.39), mood and anxiety disorder (HR, 1.72), dementia (HR, 1.72), and Parkinson’s disease (HR, 1.57).

After a concussion, the risk of developing ADHD was 28% higher and the risk of developing mood and anxiety disorder was 7% higher among women than among men. Gender was not associated with risk for dementia or Parkinson’s disease after concussion.

Sustaining a second concussion increased the strength of the association with risk for dementia compared with sustaining a single concussion (HR, 1.62). Similarly, sustaining more than three concussions increased the strength of the association with the risk for mood and anxiety disorders (HR for more than three vs one concussion, 1.22) and Parkinson›s disease (HR, 3.27).

A sensitivity analysis found similar associations between concussion and risk for mood and anxiety disorder among all age groups. Younger participants were at greater risk for ADHD, however, and older participants were at greater risk for dementia and Parkinson’s disease.

Increased awareness of concussion and the outcomes of interest, along with improved diagnostic tools, may have influenced the study’s findings, Dr. Morissette noted. “The sex-based differences may be due to either pathophysiological differences in response to concussive injuries or potentially a difference in willingness to seek medical care or share symptoms, concussion-related or otherwise, with a medical professional,” he said.

“We are hopeful that our findings will encourage practitioners to be cognizant of various conditions that may present in individuals who have previously experienced a concussion,” Dr. Morissette added. “If physicians are aware of the various associations identified following a concussion, it may lead to more thorough clinical examination at initial presentation, along with more dedicated care throughout the patient’s life.”
 

Association versus causation

Commenting on the research, Steven Erickson, MD, sports medicine specialist at Banner–University Medicine Neuroscience Institute, Phoenix, Ariz., noted that although the study showed an association between concussion and subsequent diagnosis of ADHD, anxiety, and Parkinson’s disease, “this association should not be misconstrued as causation.” He added that the study’s conclusions “are just as likely to be due to labeling theory” or a self-fulfilling prophecy.

“Patients diagnosed with ADHD, anxiety, or Parkinson’s disease may recall concussion and associate the two diagnoses; but patients who have not previously been diagnosed with a concussion cannot draw that conclusion,” said Dr. Erickson, who was not involved with the research.

Citing the apparent gender difference in the strength of the association between concussion and the outcomes of interest, Dr. Erickson noted that women are more likely to report symptoms in general “and therefore are more likely to be diagnosed with ADHD and anxiety disorders” because of differences in reporting rather than incidence of disease.

“Further research needs to be done to definitively determine a causal relationship between concussion and any psychiatric or neurologic diagnosis,” Dr. Erickson concluded.

The study was funded by the Pan Am Clinic Foundation. Dr. Morissette and Dr. Erickson have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Concussion is associated with increased risk for subsequent development of attention-deficit/hyperactivity disorder (ADHD), as well as dementia and Parkinson’s disease, new research suggests. Results from a retrospective, population-based cohort study showed that controlling for socioeconomic status and overall health did not significantly affect this association.

The link between concussion and risk for ADHD and for mood and anxiety disorder was stronger in the women than in the men. In addition, having a history of multiple concussions strengthened the association between concussion and subsequent mood and anxiety disorder, dementia, and Parkinson’s disease compared with experiencing just one concussion.

The findings are similar to those of previous studies, noted lead author Marc P. Morissette, PhD, research assistant at the Pan Am Clinic Foundation in Winnipeg, Manitoba, Canada. “The main methodological differences separating our study from previous studies in this area is a focus on concussion-specific injuries identified from medical records and the potential for study participants to have up to 25 years of follow-up data,” said Dr. Morissette.

The findings were published online July 27 in Family Medicine and Community Health, a BMJ journal.
 

Almost 190,000 participants

Several studies have shown associations between head injury and increased risk for ADHD, depression, anxiety, Alzheimer’s disease, and Parkinson’s disease. However, many of these studies relied on self-reported medical history, included all forms of traumatic brain injury, and failed to adjust for preexisting health conditions.

An improved understanding of concussion and the risks associated with it could help physicians manage their patients’ long-term needs, the investigators noted.

In the current study, the researchers examined anonymized administrative health data collected between the periods of 1990–1991 and 2014–2015 in the Manitoba Population Research Data Repository at the Manitoba Center for Health Policy.

Eligible patients had been diagnosed with concussion in accordance with standard criteria. Participants were excluded if they had been diagnosed with dementia or Parkinson’s disease before the incident concussion during the study period. The investigators matched three control participants to each included patient on the basis of age, sex, and location.

Study outcome was time from index date (date of first concussion) to diagnosis of ADHD, mood and anxiety disorder, dementia, or Parkinson’s disease. The researchers controlled for socioeconomic status using the Socioeconomic Factor Index, version 2 (SEFI2), and for preexisting medical conditions using the Charlson Comorbidity Index (CCI).

The study included 28,021 men (mean age, 25 years) and 19,462 women (mean age, 30 years) in the concussion group and 81,871 men (mean age, 25 years) and 57,159 women (mean age, 30 years) in the control group. Mean SEFI2 score was approximately −0.05, and mean CCI score was approximately 0.2.
 

Dose effect?

Results showed that concussion was associated with an increased risk for ADHD (hazard ratio [HR], 1.39), mood and anxiety disorder (HR, 1.72), dementia (HR, 1.72), and Parkinson’s disease (HR, 1.57).

After a concussion, the risk of developing ADHD was 28% higher and the risk of developing mood and anxiety disorder was 7% higher among women than among men. Gender was not associated with risk for dementia or Parkinson’s disease after concussion.

Sustaining a second concussion increased the strength of the association with risk for dementia compared with sustaining a single concussion (HR, 1.62). Similarly, sustaining more than three concussions increased the strength of the association with the risk for mood and anxiety disorders (HR for more than three vs one concussion, 1.22) and Parkinson›s disease (HR, 3.27).

A sensitivity analysis found similar associations between concussion and risk for mood and anxiety disorder among all age groups. Younger participants were at greater risk for ADHD, however, and older participants were at greater risk for dementia and Parkinson’s disease.

Increased awareness of concussion and the outcomes of interest, along with improved diagnostic tools, may have influenced the study’s findings, Dr. Morissette noted. “The sex-based differences may be due to either pathophysiological differences in response to concussive injuries or potentially a difference in willingness to seek medical care or share symptoms, concussion-related or otherwise, with a medical professional,” he said.

“We are hopeful that our findings will encourage practitioners to be cognizant of various conditions that may present in individuals who have previously experienced a concussion,” Dr. Morissette added. “If physicians are aware of the various associations identified following a concussion, it may lead to more thorough clinical examination at initial presentation, along with more dedicated care throughout the patient’s life.”
 

Association versus causation

Commenting on the research, Steven Erickson, MD, sports medicine specialist at Banner–University Medicine Neuroscience Institute, Phoenix, Ariz., noted that although the study showed an association between concussion and subsequent diagnosis of ADHD, anxiety, and Parkinson’s disease, “this association should not be misconstrued as causation.” He added that the study’s conclusions “are just as likely to be due to labeling theory” or a self-fulfilling prophecy.

“Patients diagnosed with ADHD, anxiety, or Parkinson’s disease may recall concussion and associate the two diagnoses; but patients who have not previously been diagnosed with a concussion cannot draw that conclusion,” said Dr. Erickson, who was not involved with the research.

Citing the apparent gender difference in the strength of the association between concussion and the outcomes of interest, Dr. Erickson noted that women are more likely to report symptoms in general “and therefore are more likely to be diagnosed with ADHD and anxiety disorders” because of differences in reporting rather than incidence of disease.

“Further research needs to be done to definitively determine a causal relationship between concussion and any psychiatric or neurologic diagnosis,” Dr. Erickson concluded.

The study was funded by the Pan Am Clinic Foundation. Dr. Morissette and Dr. Erickson have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Apomorphine sublingual film (Kynmobi, Sunovion Pharmaceuticals) was efficacious and generally safe and well tolerated for the on-demand treatment of off episodes in Parkinson’s disease, long-term follow-up of a phase 3 study has shown. Besides the usual adverse effects with apomorphine, the sublingual film was associated with more oral adverse effects than seen with the injectable drug. However, it may have some advantages over subcutaneous apomorphine injections in terms of administration during off episodes.

The study was presented at the Movement Disorder Society 23rd International Congress of Parkinson’s Disease and Movement Disorders (Virtual) 2020.

For example, the new formulation is more convenient than carrying an injection. It comes in a small, tear-open packet that contains a medication strip patients place under their tongues.

“When a patient is in the off state, depending on how off they are, they could have a little difficulty opening the strip [packet], but anyone can open the strip for them,” said lead author Rajesh Pahwa, MD, professor of neurology and chief of the Parkinson and Movement Disorder Division at the University of Kansas Medical Center in Kansas City. “On the other hand with the subcutaneous, they have to give the injection themselves and a stranger or someone is not going to help them with that.”
 

Open-label safety and efficacy study

The aims of this open-label, 48-week follow-up were to add new patients to assess safety and tolerability over the long term and to see if continued benefit from a previous 12-week double-blind study was still present at 1 year for patients in the earlier study.

This multicenter study (NCT02542696) included “rollover” patients (n = 78 for safety; n = 70 for efficacy) from the previous phase 2/3 double-blind trial, as well as new patients with no prior exposure to apomorphine sublingual film (n = 347 for safety; n = 275 for efficacy).

New patients experienced one or more off episodes per day with a daily off time of 2 hours or more per day while on stable doses of levodopa/carbidopa. All had clinically meaningful responses to levodopa/carbidopa and were judged by the investigator to be Stage 1-3 by modified Hoehn and Yahr scale rating during ON periods.

Rollover patients completed the prior study and had no major changes in their anti-Parkinson’s medications since then. Mouth cankers or sores were exclusion criteria for either group. New subjects could not have received subcutaneous apomorphine within 7 days of a screening visit.

The demographics and baseline characteristics of the new and rollover groups were similar (approximately 64 years; 65%-71% male; 96% White; 8.3-9.6 years since diagnosis; 3.9 to 4.1 off episodes/day, and total mean daily levodopa dose of 1120 to 1478 mg).

Assessing only the group of new patients, the investigators reported that 80% had a Hoehn and Yahr score of 2 or 2.5 when in the ON state and a Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III predose score of 41.8.

At the beginning of this study, patients in an off period received titrated doses of 10-35 mg of sublingual apomorphine in 5 mg increments during sequential office visits until they achieved a tolerable full ON within 45 minutes of a dose. They then entered a 48-week safety and efficacy phase, during which they self-administered the drug at home up to five times daily for off episodes with a minimum of 2 hours between doses. The investigators could adjust the doses for safety or lack of efficacy.

Two-thirds of new patients and three-quarters of rollovers received doses in the 10-20 mg range. The highest dose in the study of 35 mg was used by only 8%-9% of patients, but the highest approved and marketed dose is 30 mg.
 

Long-term benefits

Onset of efficacy was achieved by 15 minutes after dose for both new and rollover patients, and maximal efficacy occurred by 30 minutes. Results were very similar at 24, 36, and 48 weeks. The investigators did not perform statistical analyses.

Across study weeks 1, 12, 24, 36, and 48, between 77% and 92% of new patients and between 65% and 77% of rollover patients self-reported full ON within 30 minutes. “The long-term benefits are maintained over a year as far as the speed of onset and the duration,” Dr. Pahwa said.

Treatment-emergent adverse events occurred in about half of the new and the rollover patient groups in the titration phase and in 71%-81% of patients during the long-term safety phase. Nearly all were mild to moderate in severity.

A large number of participants withdrew from this long-term safety phase because of adverse events – 90 (33%) of new enrollees and 16 (23%) of rollover patients. Only 4% dropped out for lack of efficacy, all in the new enrollee group. Because the sublingual formulation is delivered under the tongue, patients in that group had more oral side effects, Dr. Pahwa said. Otherwise, “the side effects were very similar to the subcutaneous delivery.”

Treatment-emergent adverse events specific to sublingual apomorphine included oral mucosal erythema, lip or tongue swelling, and mouth ulceration (6% to 7% of patients each). Occurring less often were glossodynia, oral candidiasis, stomatitis, and tongue ulceration (2% each).

These were in addition to adverse events typically occurring with subcutaneous apomorphine, which are nausea, falls, dizziness, somnolence, dyskinesia, syncope, and yawning.

There are no head-to-head comparisons of sublingual versus subcutaneous delivery of apomorphine. But based on experience, Dr. Pahwa said, “With the subcutaneous, you have a slightly faster onset of action compared to the sublingual. However, sublingual has a slightly longer duration of benefit.”

He predicted that patients may prefer using an injection for a faster benefit or a sublingual for a slightly longer benefit.
 

More therapeutic options are welcome

Commenting on the study, Ray Dorsey, MD, professor of neurology at the University of Rochester (N.Y.), said that, for people with more advanced Parkinson’s disease “there’s usually a caregiver who’s injecting someone with an off period, as opposed to sublingual, which seems like a much easier way of administering a drug, especially for people with motor fluctuations.”

He noted that adverse events that led to premature discontinuation from the study “are concerning about the overall tolerability of the drug, which also will be determined in clinical practice, and will likely influence its overall utility.”

However, more therapeutic options are welcome because “the number of people with advanced Parkinson’s disease is going to grow and grow substantially,” he said. “So having therapies that help people with more advanced Parkinson’s disease ... many of whom don’t reach the clinic ... are going to be increasingly important.”

The study was supported by Sunovion. Dr. Pahwa and Dr. Dorsey reported conflicts of interest with numerous sources in industry.
 

A version of this article originally appeared on Medscape.com.

Apomorphine sublingual film (Kynmobi, Sunovion Pharmaceuticals) was efficacious and generally safe and well tolerated for the on-demand treatment of off episodes in Parkinson’s disease, long-term follow-up of a phase 3 study has shown. Besides the usual adverse effects with apomorphine, the sublingual film was associated with more oral adverse effects than seen with the injectable drug. However, it may have some advantages over subcutaneous apomorphine injections in terms of administration during off episodes.

The study was presented at the Movement Disorder Society 23rd International Congress of Parkinson’s Disease and Movement Disorders (Virtual) 2020.

For example, the new formulation is more convenient than carrying an injection. It comes in a small, tear-open packet that contains a medication strip patients place under their tongues.

“When a patient is in the off state, depending on how off they are, they could have a little difficulty opening the strip [packet], but anyone can open the strip for them,” said lead author Rajesh Pahwa, MD, professor of neurology and chief of the Parkinson and Movement Disorder Division at the University of Kansas Medical Center in Kansas City. “On the other hand with the subcutaneous, they have to give the injection themselves and a stranger or someone is not going to help them with that.”
 

Open-label safety and efficacy study

The aims of this open-label, 48-week follow-up were to add new patients to assess safety and tolerability over the long term and to see if continued benefit from a previous 12-week double-blind study was still present at 1 year for patients in the earlier study.

This multicenter study (NCT02542696) included “rollover” patients (n = 78 for safety; n = 70 for efficacy) from the previous phase 2/3 double-blind trial, as well as new patients with no prior exposure to apomorphine sublingual film (n = 347 for safety; n = 275 for efficacy).

New patients experienced one or more off episodes per day with a daily off time of 2 hours or more per day while on stable doses of levodopa/carbidopa. All had clinically meaningful responses to levodopa/carbidopa and were judged by the investigator to be Stage 1-3 by modified Hoehn and Yahr scale rating during ON periods.

Rollover patients completed the prior study and had no major changes in their anti-Parkinson’s medications since then. Mouth cankers or sores were exclusion criteria for either group. New subjects could not have received subcutaneous apomorphine within 7 days of a screening visit.

The demographics and baseline characteristics of the new and rollover groups were similar (approximately 64 years; 65%-71% male; 96% White; 8.3-9.6 years since diagnosis; 3.9 to 4.1 off episodes/day, and total mean daily levodopa dose of 1120 to 1478 mg).

Assessing only the group of new patients, the investigators reported that 80% had a Hoehn and Yahr score of 2 or 2.5 when in the ON state and a Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III predose score of 41.8.

At the beginning of this study, patients in an off period received titrated doses of 10-35 mg of sublingual apomorphine in 5 mg increments during sequential office visits until they achieved a tolerable full ON within 45 minutes of a dose. They then entered a 48-week safety and efficacy phase, during which they self-administered the drug at home up to five times daily for off episodes with a minimum of 2 hours between doses. The investigators could adjust the doses for safety or lack of efficacy.

Two-thirds of new patients and three-quarters of rollovers received doses in the 10-20 mg range. The highest dose in the study of 35 mg was used by only 8%-9% of patients, but the highest approved and marketed dose is 30 mg.
 

Long-term benefits

Onset of efficacy was achieved by 15 minutes after dose for both new and rollover patients, and maximal efficacy occurred by 30 minutes. Results were very similar at 24, 36, and 48 weeks. The investigators did not perform statistical analyses.

Across study weeks 1, 12, 24, 36, and 48, between 77% and 92% of new patients and between 65% and 77% of rollover patients self-reported full ON within 30 minutes. “The long-term benefits are maintained over a year as far as the speed of onset and the duration,” Dr. Pahwa said.

Treatment-emergent adverse events occurred in about half of the new and the rollover patient groups in the titration phase and in 71%-81% of patients during the long-term safety phase. Nearly all were mild to moderate in severity.

A large number of participants withdrew from this long-term safety phase because of adverse events – 90 (33%) of new enrollees and 16 (23%) of rollover patients. Only 4% dropped out for lack of efficacy, all in the new enrollee group. Because the sublingual formulation is delivered under the tongue, patients in that group had more oral side effects, Dr. Pahwa said. Otherwise, “the side effects were very similar to the subcutaneous delivery.”

Treatment-emergent adverse events specific to sublingual apomorphine included oral mucosal erythema, lip or tongue swelling, and mouth ulceration (6% to 7% of patients each). Occurring less often were glossodynia, oral candidiasis, stomatitis, and tongue ulceration (2% each).

These were in addition to adverse events typically occurring with subcutaneous apomorphine, which are nausea, falls, dizziness, somnolence, dyskinesia, syncope, and yawning.

There are no head-to-head comparisons of sublingual versus subcutaneous delivery of apomorphine. But based on experience, Dr. Pahwa said, “With the subcutaneous, you have a slightly faster onset of action compared to the sublingual. However, sublingual has a slightly longer duration of benefit.”

He predicted that patients may prefer using an injection for a faster benefit or a sublingual for a slightly longer benefit.
 

More therapeutic options are welcome

Commenting on the study, Ray Dorsey, MD, professor of neurology at the University of Rochester (N.Y.), said that, for people with more advanced Parkinson’s disease “there’s usually a caregiver who’s injecting someone with an off period, as opposed to sublingual, which seems like a much easier way of administering a drug, especially for people with motor fluctuations.”

He noted that adverse events that led to premature discontinuation from the study “are concerning about the overall tolerability of the drug, which also will be determined in clinical practice, and will likely influence its overall utility.”

However, more therapeutic options are welcome because “the number of people with advanced Parkinson’s disease is going to grow and grow substantially,” he said. “So having therapies that help people with more advanced Parkinson’s disease ... many of whom don’t reach the clinic ... are going to be increasingly important.”

The study was supported by Sunovion. Dr. Pahwa and Dr. Dorsey reported conflicts of interest with numerous sources in industry.
 

A version of this article originally appeared on Medscape.com.

Apomorphine sublingual film (Kynmobi, Sunovion Pharmaceuticals) was efficacious and generally safe and well tolerated for the on-demand treatment of off episodes in Parkinson’s disease, long-term follow-up of a phase 3 study has shown. Besides the usual adverse effects with apomorphine, the sublingual film was associated with more oral adverse effects than seen with the injectable drug. However, it may have some advantages over subcutaneous apomorphine injections in terms of administration during off episodes.

The study was presented at the Movement Disorder Society 23rd International Congress of Parkinson’s Disease and Movement Disorders (Virtual) 2020.

For example, the new formulation is more convenient than carrying an injection. It comes in a small, tear-open packet that contains a medication strip patients place under their tongues.

“When a patient is in the off state, depending on how off they are, they could have a little difficulty opening the strip [packet], but anyone can open the strip for them,” said lead author Rajesh Pahwa, MD, professor of neurology and chief of the Parkinson and Movement Disorder Division at the University of Kansas Medical Center in Kansas City. “On the other hand with the subcutaneous, they have to give the injection themselves and a stranger or someone is not going to help them with that.”
 

Open-label safety and efficacy study

The aims of this open-label, 48-week follow-up were to add new patients to assess safety and tolerability over the long term and to see if continued benefit from a previous 12-week double-blind study was still present at 1 year for patients in the earlier study.

This multicenter study (NCT02542696) included “rollover” patients (n = 78 for safety; n = 70 for efficacy) from the previous phase 2/3 double-blind trial, as well as new patients with no prior exposure to apomorphine sublingual film (n = 347 for safety; n = 275 for efficacy).

New patients experienced one or more off episodes per day with a daily off time of 2 hours or more per day while on stable doses of levodopa/carbidopa. All had clinically meaningful responses to levodopa/carbidopa and were judged by the investigator to be Stage 1-3 by modified Hoehn and Yahr scale rating during ON periods.

Rollover patients completed the prior study and had no major changes in their anti-Parkinson’s medications since then. Mouth cankers or sores were exclusion criteria for either group. New subjects could not have received subcutaneous apomorphine within 7 days of a screening visit.

The demographics and baseline characteristics of the new and rollover groups were similar (approximately 64 years; 65%-71% male; 96% White; 8.3-9.6 years since diagnosis; 3.9 to 4.1 off episodes/day, and total mean daily levodopa dose of 1120 to 1478 mg).

Assessing only the group of new patients, the investigators reported that 80% had a Hoehn and Yahr score of 2 or 2.5 when in the ON state and a Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III predose score of 41.8.

At the beginning of this study, patients in an off period received titrated doses of 10-35 mg of sublingual apomorphine in 5 mg increments during sequential office visits until they achieved a tolerable full ON within 45 minutes of a dose. They then entered a 48-week safety and efficacy phase, during which they self-administered the drug at home up to five times daily for off episodes with a minimum of 2 hours between doses. The investigators could adjust the doses for safety or lack of efficacy.

Two-thirds of new patients and three-quarters of rollovers received doses in the 10-20 mg range. The highest dose in the study of 35 mg was used by only 8%-9% of patients, but the highest approved and marketed dose is 30 mg.
 

Long-term benefits

Onset of efficacy was achieved by 15 minutes after dose for both new and rollover patients, and maximal efficacy occurred by 30 minutes. Results were very similar at 24, 36, and 48 weeks. The investigators did not perform statistical analyses.

Across study weeks 1, 12, 24, 36, and 48, between 77% and 92% of new patients and between 65% and 77% of rollover patients self-reported full ON within 30 minutes. “The long-term benefits are maintained over a year as far as the speed of onset and the duration,” Dr. Pahwa said.

Treatment-emergent adverse events occurred in about half of the new and the rollover patient groups in the titration phase and in 71%-81% of patients during the long-term safety phase. Nearly all were mild to moderate in severity.

A large number of participants withdrew from this long-term safety phase because of adverse events – 90 (33%) of new enrollees and 16 (23%) of rollover patients. Only 4% dropped out for lack of efficacy, all in the new enrollee group. Because the sublingual formulation is delivered under the tongue, patients in that group had more oral side effects, Dr. Pahwa said. Otherwise, “the side effects were very similar to the subcutaneous delivery.”

Treatment-emergent adverse events specific to sublingual apomorphine included oral mucosal erythema, lip or tongue swelling, and mouth ulceration (6% to 7% of patients each). Occurring less often were glossodynia, oral candidiasis, stomatitis, and tongue ulceration (2% each).

These were in addition to adverse events typically occurring with subcutaneous apomorphine, which are nausea, falls, dizziness, somnolence, dyskinesia, syncope, and yawning.

There are no head-to-head comparisons of sublingual versus subcutaneous delivery of apomorphine. But based on experience, Dr. Pahwa said, “With the subcutaneous, you have a slightly faster onset of action compared to the sublingual. However, sublingual has a slightly longer duration of benefit.”

He predicted that patients may prefer using an injection for a faster benefit or a sublingual for a slightly longer benefit.
 

More therapeutic options are welcome

Commenting on the study, Ray Dorsey, MD, professor of neurology at the University of Rochester (N.Y.), said that, for people with more advanced Parkinson’s disease “there’s usually a caregiver who’s injecting someone with an off period, as opposed to sublingual, which seems like a much easier way of administering a drug, especially for people with motor fluctuations.”

He noted that adverse events that led to premature discontinuation from the study “are concerning about the overall tolerability of the drug, which also will be determined in clinical practice, and will likely influence its overall utility.”

However, more therapeutic options are welcome because “the number of people with advanced Parkinson’s disease is going to grow and grow substantially,” he said. “So having therapies that help people with more advanced Parkinson’s disease ... many of whom don’t reach the clinic ... are going to be increasingly important.”

The study was supported by Sunovion. Dr. Pahwa and Dr. Dorsey reported conflicts of interest with numerous sources in industry.
 

A version of this article originally appeared on Medscape.com.

It may be possible to diagnose Parkinson’s disease with a skin test, a new study suggests. For the study, researchers used a chemical assay to detect clumping of the protein alpha-synuclein, a hallmark of Parkinson’s disease, in autopsy skin samples taken from patients who had Parkinson’s disease confirmed by brain pathology and from controls without the disease. The test showed a high degree of sensitivity and specificity for the diagnosis of Parkinson’s disease.

The study was published online in Movement Disorders.

“This test has a lot of promise,” said senior author Anumantha Kanthasamy, PhD, professor of biomedical sciences at Iowa State University in Ames. “At present there are no peripheral biomarkers for Parkinson’s disease. The current diagnosis is just based on symptoms, and the symptoms can be similar to many other neurological diseases,” he added. “It can take many years to establish a correct diagnosis and the accuracy is low even with experienced neurologists.”

If the current results can be replicated in samples from live patients and in those with very early stages of Parkinson’s disease, a skin test could allow early diagnosis and the possibility of starting preventive treatments to slow disease progression before symptoms develop too severely, the researchers suggest.
 

Sensitive and specific test

The blinded study used a seeding assay – used previously to detect misfolded proteins in prion diseases – to analyze 50 skin samples provided by the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program based at Banner Sun Health Research Institute in Sun City.

Half of the skin samples came from patients with Parkinson’s disease and half came from people without neurologic disease. The protein assay correctly diagnosed 24 out of 25 patients with Parkinson’s disease and only one of the 25 controls had the protein clumping.

“At present, the only way to definitely diagnose Parkinson’s disease is on autopsy – by the detection of alpha-synuclein clumps [Lewy bodies] in the brain,” commented Charles Adler, MD, professor of neurology at Mayo Clinic Arizona in Scottsdale and a coinvestigator of the study. “In our research, we have also seen clumping of alpha-synuclein in many other organs including submandibular gland, colon, skin, heart, and stomach, but in terms of access, the skin is probably the easiest source.”

In this study, “we found this seeding assay for alpha-synuclein clumps to be extremely sensitive and specific in the diagnosis of Parkinson’s disease,” he added. “This is very valuable data as we have samples from patients with autopsy-validated Parkinson’s disease.”
 

A reliable biomarker?

The researchers are now starting a study in living patients with funding from the National Institutes of Health in which they will repeat the process comparing skin samples from patients with clinically diagnosed Parkinson’s disease and controls.

“We need to know whether analyzing alpha-synuclein clumping in skin biopsies from live patients with Parkinson’s disease would serve as a reliable biomarker for disease progression. Will clumping of this protein in skin samples increase over time and does it correspond with disease progression?” Dr. Adler said.

In future they are also hoping to test individuals who have not yet developed Parkinson’s disease but may have some prodromal type symptoms and to test whether this assay could measure a treatment effect of drug therapy.

Dr. Adler noted that they are currently conducting an autopsy study of skin samples from individuals who did not have clinical Parkinson’s disease when alive but in whom Lewy bodies have been found postmortem.

“This suggests that the disease pathology starts before Parkinson’s symptoms develop, and in the future, if we can diagnose Parkinson’s disease earlier then we may be able to stop progression,” he said.

“There is a long list of compounds that have been studied to try and slow progression but haven’t shown benefits, but by the time patients develop symptoms they already have significant disease and [have] lost most of their dopamine neurons,” he added. “If we could backtrack by 10 years, then these drugs may well make a difference.”

Dr. Adler also noted that currently more advanced patients may undergo invasive procedures such as deep brain stimulation or surgery. “It is of utmost importance that they have an accurate diagnosis before being subjected to such procedures.”

In addition, he pointed out that an accurate test would help the drug development process. “It is vitally important to enroll patients with an accurate diagnosis in clinical trials of new drugs. At present, a large percentage of patients in these trials may not actually have Parkinson’s disease, which makes it very difficult to show a treatment effect.”
 

Important step, but preliminary

Commenting on the research, James Beck, PhD, chief scientific officer of the Parkinson’s Foundation, said the study “is an important step toward the creation of a new way to potentially diagnose Parkinson’s disease.”

But he cautioned that this is a preliminary study. “To really confirm the possibility of using this approach for diagnosing Parkinson’s disease, a larger study will be necessary. And it will be important to test this in a population with early disease – the most difficult group to accurately diagnose.”

Also commenting on the findings, Beate Ritz, MD, PhD, an epidemiologist at UCLA Fielding School of Public Health in Los Angeles, who is part of a team also working on ways to measure abnormal alpha-synuclein to diagnose Parkinson’s disease, described the current study of skin samples as “pretty nifty.”

“Their research shows clearly that they can distinguish between patients with Parkinson’s disease and controls in this way,” she said. “The big advantage of this study is that they have brain pathology, so they know exactly which individuals had Parkinson’s disease.”

Dr. Ritz is working with Gal Bitan, PhD, from the UCLA Brain Research Institute on a potential blood test to measure abnormal alpha-synuclein.

Dr. Ritz explained that it is not possible to measure alpha-synuclein pathology in regular blood samples as it is expressed normally in red blood cells, but they are measuring the protein and its more toxic phosphorylated form from exosomes, which contain the waste discarded by cells using technology that determines the origin of these exosomes.

“Alpha-synuclein itself is not a problem. It is the way it misfolds that causes toxicity and disrupts the workings of the cell,” Dr. Ritz added. “In Parkinson’s disease, it is particularly toxic to dopaminergic neurons, and in multiple system atrophy, it is toxic to glial cells, so if we can identify the source of the protein then that could be helpful.”

The study was funded by the National Institutes of Health and the US Army Medical Research Materiel Command. The study authors, Dr. Beck, and Dr. Ritz have disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

It may be possible to diagnose Parkinson’s disease with a skin test, a new study suggests. For the study, researchers used a chemical assay to detect clumping of the protein alpha-synuclein, a hallmark of Parkinson’s disease, in autopsy skin samples taken from patients who had Parkinson’s disease confirmed by brain pathology and from controls without the disease. The test showed a high degree of sensitivity and specificity for the diagnosis of Parkinson’s disease.

The study was published online in Movement Disorders.

“This test has a lot of promise,” said senior author Anumantha Kanthasamy, PhD, professor of biomedical sciences at Iowa State University in Ames. “At present there are no peripheral biomarkers for Parkinson’s disease. The current diagnosis is just based on symptoms, and the symptoms can be similar to many other neurological diseases,” he added. “It can take many years to establish a correct diagnosis and the accuracy is low even with experienced neurologists.”

If the current results can be replicated in samples from live patients and in those with very early stages of Parkinson’s disease, a skin test could allow early diagnosis and the possibility of starting preventive treatments to slow disease progression before symptoms develop too severely, the researchers suggest.
 

Sensitive and specific test

The blinded study used a seeding assay – used previously to detect misfolded proteins in prion diseases – to analyze 50 skin samples provided by the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program based at Banner Sun Health Research Institute in Sun City.

Half of the skin samples came from patients with Parkinson’s disease and half came from people without neurologic disease. The protein assay correctly diagnosed 24 out of 25 patients with Parkinson’s disease and only one of the 25 controls had the protein clumping.

“At present, the only way to definitely diagnose Parkinson’s disease is on autopsy – by the detection of alpha-synuclein clumps [Lewy bodies] in the brain,” commented Charles Adler, MD, professor of neurology at Mayo Clinic Arizona in Scottsdale and a coinvestigator of the study. “In our research, we have also seen clumping of alpha-synuclein in many other organs including submandibular gland, colon, skin, heart, and stomach, but in terms of access, the skin is probably the easiest source.”

In this study, “we found this seeding assay for alpha-synuclein clumps to be extremely sensitive and specific in the diagnosis of Parkinson’s disease,” he added. “This is very valuable data as we have samples from patients with autopsy-validated Parkinson’s disease.”
 

A reliable biomarker?

The researchers are now starting a study in living patients with funding from the National Institutes of Health in which they will repeat the process comparing skin samples from patients with clinically diagnosed Parkinson’s disease and controls.

“We need to know whether analyzing alpha-synuclein clumping in skin biopsies from live patients with Parkinson’s disease would serve as a reliable biomarker for disease progression. Will clumping of this protein in skin samples increase over time and does it correspond with disease progression?” Dr. Adler said.

In future they are also hoping to test individuals who have not yet developed Parkinson’s disease but may have some prodromal type symptoms and to test whether this assay could measure a treatment effect of drug therapy.

Dr. Adler noted that they are currently conducting an autopsy study of skin samples from individuals who did not have clinical Parkinson’s disease when alive but in whom Lewy bodies have been found postmortem.

“This suggests that the disease pathology starts before Parkinson’s symptoms develop, and in the future, if we can diagnose Parkinson’s disease earlier then we may be able to stop progression,” he said.

“There is a long list of compounds that have been studied to try and slow progression but haven’t shown benefits, but by the time patients develop symptoms they already have significant disease and [have] lost most of their dopamine neurons,” he added. “If we could backtrack by 10 years, then these drugs may well make a difference.”

Dr. Adler also noted that currently more advanced patients may undergo invasive procedures such as deep brain stimulation or surgery. “It is of utmost importance that they have an accurate diagnosis before being subjected to such procedures.”

In addition, he pointed out that an accurate test would help the drug development process. “It is vitally important to enroll patients with an accurate diagnosis in clinical trials of new drugs. At present, a large percentage of patients in these trials may not actually have Parkinson’s disease, which makes it very difficult to show a treatment effect.”
 

Important step, but preliminary

Commenting on the research, James Beck, PhD, chief scientific officer of the Parkinson’s Foundation, said the study “is an important step toward the creation of a new way to potentially diagnose Parkinson’s disease.”

But he cautioned that this is a preliminary study. “To really confirm the possibility of using this approach for diagnosing Parkinson’s disease, a larger study will be necessary. And it will be important to test this in a population with early disease – the most difficult group to accurately diagnose.”

Also commenting on the findings, Beate Ritz, MD, PhD, an epidemiologist at UCLA Fielding School of Public Health in Los Angeles, who is part of a team also working on ways to measure abnormal alpha-synuclein to diagnose Parkinson’s disease, described the current study of skin samples as “pretty nifty.”

“Their research shows clearly that they can distinguish between patients with Parkinson’s disease and controls in this way,” she said. “The big advantage of this study is that they have brain pathology, so they know exactly which individuals had Parkinson’s disease.”

Dr. Ritz is working with Gal Bitan, PhD, from the UCLA Brain Research Institute on a potential blood test to measure abnormal alpha-synuclein.

Dr. Ritz explained that it is not possible to measure alpha-synuclein pathology in regular blood samples as it is expressed normally in red blood cells, but they are measuring the protein and its more toxic phosphorylated form from exosomes, which contain the waste discarded by cells using technology that determines the origin of these exosomes.

“Alpha-synuclein itself is not a problem. It is the way it misfolds that causes toxicity and disrupts the workings of the cell,” Dr. Ritz added. “In Parkinson’s disease, it is particularly toxic to dopaminergic neurons, and in multiple system atrophy, it is toxic to glial cells, so if we can identify the source of the protein then that could be helpful.”

The study was funded by the National Institutes of Health and the US Army Medical Research Materiel Command. The study authors, Dr. Beck, and Dr. Ritz have disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

It may be possible to diagnose Parkinson’s disease with a skin test, a new study suggests. For the study, researchers used a chemical assay to detect clumping of the protein alpha-synuclein, a hallmark of Parkinson’s disease, in autopsy skin samples taken from patients who had Parkinson’s disease confirmed by brain pathology and from controls without the disease. The test showed a high degree of sensitivity and specificity for the diagnosis of Parkinson’s disease.

The study was published online in Movement Disorders.

“This test has a lot of promise,” said senior author Anumantha Kanthasamy, PhD, professor of biomedical sciences at Iowa State University in Ames. “At present there are no peripheral biomarkers for Parkinson’s disease. The current diagnosis is just based on symptoms, and the symptoms can be similar to many other neurological diseases,” he added. “It can take many years to establish a correct diagnosis and the accuracy is low even with experienced neurologists.”

If the current results can be replicated in samples from live patients and in those with very early stages of Parkinson’s disease, a skin test could allow early diagnosis and the possibility of starting preventive treatments to slow disease progression before symptoms develop too severely, the researchers suggest.
 

Sensitive and specific test

The blinded study used a seeding assay – used previously to detect misfolded proteins in prion diseases – to analyze 50 skin samples provided by the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program based at Banner Sun Health Research Institute in Sun City.

Half of the skin samples came from patients with Parkinson’s disease and half came from people without neurologic disease. The protein assay correctly diagnosed 24 out of 25 patients with Parkinson’s disease and only one of the 25 controls had the protein clumping.

“At present, the only way to definitely diagnose Parkinson’s disease is on autopsy – by the detection of alpha-synuclein clumps [Lewy bodies] in the brain,” commented Charles Adler, MD, professor of neurology at Mayo Clinic Arizona in Scottsdale and a coinvestigator of the study. “In our research, we have also seen clumping of alpha-synuclein in many other organs including submandibular gland, colon, skin, heart, and stomach, but in terms of access, the skin is probably the easiest source.”

In this study, “we found this seeding assay for alpha-synuclein clumps to be extremely sensitive and specific in the diagnosis of Parkinson’s disease,” he added. “This is very valuable data as we have samples from patients with autopsy-validated Parkinson’s disease.”
 

A reliable biomarker?

The researchers are now starting a study in living patients with funding from the National Institutes of Health in which they will repeat the process comparing skin samples from patients with clinically diagnosed Parkinson’s disease and controls.

“We need to know whether analyzing alpha-synuclein clumping in skin biopsies from live patients with Parkinson’s disease would serve as a reliable biomarker for disease progression. Will clumping of this protein in skin samples increase over time and does it correspond with disease progression?” Dr. Adler said.

In future they are also hoping to test individuals who have not yet developed Parkinson’s disease but may have some prodromal type symptoms and to test whether this assay could measure a treatment effect of drug therapy.

Dr. Adler noted that they are currently conducting an autopsy study of skin samples from individuals who did not have clinical Parkinson’s disease when alive but in whom Lewy bodies have been found postmortem.

“This suggests that the disease pathology starts before Parkinson’s symptoms develop, and in the future, if we can diagnose Parkinson’s disease earlier then we may be able to stop progression,” he said.

“There is a long list of compounds that have been studied to try and slow progression but haven’t shown benefits, but by the time patients develop symptoms they already have significant disease and [have] lost most of their dopamine neurons,” he added. “If we could backtrack by 10 years, then these drugs may well make a difference.”

Dr. Adler also noted that currently more advanced patients may undergo invasive procedures such as deep brain stimulation or surgery. “It is of utmost importance that they have an accurate diagnosis before being subjected to such procedures.”

In addition, he pointed out that an accurate test would help the drug development process. “It is vitally important to enroll patients with an accurate diagnosis in clinical trials of new drugs. At present, a large percentage of patients in these trials may not actually have Parkinson’s disease, which makes it very difficult to show a treatment effect.”
 

Important step, but preliminary

Commenting on the research, James Beck, PhD, chief scientific officer of the Parkinson’s Foundation, said the study “is an important step toward the creation of a new way to potentially diagnose Parkinson’s disease.”

But he cautioned that this is a preliminary study. “To really confirm the possibility of using this approach for diagnosing Parkinson’s disease, a larger study will be necessary. And it will be important to test this in a population with early disease – the most difficult group to accurately diagnose.”

Also commenting on the findings, Beate Ritz, MD, PhD, an epidemiologist at UCLA Fielding School of Public Health in Los Angeles, who is part of a team also working on ways to measure abnormal alpha-synuclein to diagnose Parkinson’s disease, described the current study of skin samples as “pretty nifty.”

“Their research shows clearly that they can distinguish between patients with Parkinson’s disease and controls in this way,” she said. “The big advantage of this study is that they have brain pathology, so they know exactly which individuals had Parkinson’s disease.”

Dr. Ritz is working with Gal Bitan, PhD, from the UCLA Brain Research Institute on a potential blood test to measure abnormal alpha-synuclein.

Dr. Ritz explained that it is not possible to measure alpha-synuclein pathology in regular blood samples as it is expressed normally in red blood cells, but they are measuring the protein and its more toxic phosphorylated form from exosomes, which contain the waste discarded by cells using technology that determines the origin of these exosomes.

“Alpha-synuclein itself is not a problem. It is the way it misfolds that causes toxicity and disrupts the workings of the cell,” Dr. Ritz added. “In Parkinson’s disease, it is particularly toxic to dopaminergic neurons, and in multiple system atrophy, it is toxic to glial cells, so if we can identify the source of the protein then that could be helpful.”

The study was funded by the National Institutes of Health and the US Army Medical Research Materiel Command. The study authors, Dr. Beck, and Dr. Ritz have disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

A 24-hour continuous subcutaneous infusion of foslevodopa/foscarbidopa improved Parkinson’s disease (PD) motor symptoms during all waking hours for patients with advanced disease, according to a new study. The beneficial effects of these phosphate prodrugs of levodopa and carbidopa were most noticeable in the early morning, results of the phase 1B study showed.

As Parkinson’s disease progresses and dosing of oral levodopa/carbidopa (LD/CD) increases, its therapeutic window narrows, resulting in troublesome dyskinesia at peak drug levels and tremors and rigidity when levels fall.

“Foslevodopa/foscarbidopa shows lower ‘off’ time than oral levodopa/carbidopa, and this was statistically significant. Also, foslevodopa/foscarbidopa (fosL/fosC) showed more ‘on’ time without dyskinesia, compared with oral levodopa/carbidopa. This was also statistically significant,” lead author Sven Stodtmann, PhD, of AbbVie GmbH, Ludwigshafen, Germany, reported in his recorded presentation at the Movement Disorders Society’s 23rd International Congress of Parkinson’s Disease and Movement Disorder (Virtual) 2020.
 

Continuous infusion versus oral therapy

The analysis included 20 patients, and all data from these individuals were collected between 4:30 a.m. and 9:30 p.m.

Participants were 12 men and 8 women, aged 30-80 years, with advanced, idiopathic Parkinson’s disease responsive to levodopa but inadequately controlled on their current stable therapy, having a minimum of 2.5 off hours/day. Mean age was 61.3 plus or minus 10.5 years (range 35-77 years).

In this single-arm, open-label study, they received subcutaneous infusions of personalized therapeutic doses of fosL/fosC 24 hours/day for 28 days after a 10- to 30-day screening period during which they recorded LD/CD doses in a diary and had motor symptoms monitored using a wearable device.

Following the screening period, fosL/fosC doses were titrated over up to 5 days, with subsequent weekly study visits, for a total time on fosL/fosC of 28 days. Drug titration was aimed at maximizing functional on time and minimizing the number of off episodes while minimizing troublesome dyskinesia.

Continuous infusion of fosL/fosC performed better than oral LD/CD on all counts.

“The off time is much lower in the morning for people on foslevodopa/foscarbidopa [compared with oral LD/CD] because this is a 24-hour infusion product,” Dr. Stodtmann explained.

The effect was maintained over the course of the day with little fluctuation with fosL/fosC, off periods never exceeding about 25% between 4:30 a.m. and 9 p.m. For LD/CD, off periods were highest in the early morning and peaked at about 50% on a 3- to 4-hour cycle during the course of the day.

Increased on time without dyskinesia varied between about 60% and 80% during the day with fosL/fosC, showing the greatest difference between fosL/fosC and oral LD/CD in the early morning hours.

“On time with nontroublesome dyskinesia was lower for foscarbidopa/foslevodopa, compared to oral levodopa/carbidopa, but this was not statistically significant,” Dr. Stodtmann said. On time with troublesome dyskinesia followed the same pattern, again, not statistically significant.

Looking at the data another way, the investigators calculated the odds ratios of motor symptoms using fosL/fosC, compared with oral LD/CD. Use of fosL/fosC was associated with a 59% lower risk of being in the off state during the day, compared with oral LD/CD (odds ratio, 0.4; 95% confidence interval, 0.2-0.7; P < .01). Similarly, the probability of being in the on state without dyskinesia was much greater with fosL/fosC (OR, 2.75; 95% CI, 1.08-6.99; P < .05).
 

Encouraging, but more data needed

Indu Subramanian, MD, of the department of neurology at the University of California, Los Angeles, and director of the Parkinson’s Disease Research, Education, and Clinical Center at the West Los Angeles Veterans Affairs Hospital, commented that the field has been waiting to see data on fosL/fosC.

“It seems like it’s pretty reasonable in terms of what the goals were, which is to improve stability of Parkinson’s symptoms, to improve off time and give on time without troublesome dyskinesia,” she said. “So I think those [goals] have been met.”

Dr. Subramanian, who was not involved with the research, said she would have liked to have seen results concerning safety of this drug formulation, which the presentation lacked, “because historically, there have been issues with nodule formation and skin breakdown, things like that, due to the stability of the product in the subcutaneous form. … So, always to my understanding, there has been this search for things that are tolerated in the subcutaneous delivery.”

If this formulation proves safe and tolerable, Dr. Subramanian sees a potential place for it for some patients with advanced Parkinson’s disease.

“Certainly a subcutaneous formulation will be better than something that requires … deep brain surgery or even a pump insertion like Duopa [carbidopa/levodopa enteral suspension, AbbVie] or something like that,” she said. “I think [it] would be beneficial over something with the gut because the gut historically has been a problem to rely on in advanced Parkinson’s patients due to slower transit times, and the gut itself is affected with Parkinson’s disease.”

Dr. Stodtmann and all coauthors are employees of AbbVie, which was the sponsor of the study and was responsible for all aspects of it. Dr. Subramanian has given talks for Acadia Pharmaceuticals and Acorda Therapeutics in the past.

A version of this article originally appeared on Medscape.com.

A 24-hour continuous subcutaneous infusion of foslevodopa/foscarbidopa improved Parkinson’s disease (PD) motor symptoms during all waking hours for patients with advanced disease, according to a new study. The beneficial effects of these phosphate prodrugs of levodopa and carbidopa were most noticeable in the early morning, results of the phase 1B study showed.

As Parkinson’s disease progresses and dosing of oral levodopa/carbidopa (LD/CD) increases, its therapeutic window narrows, resulting in troublesome dyskinesia at peak drug levels and tremors and rigidity when levels fall.

“Foslevodopa/foscarbidopa shows lower ‘off’ time than oral levodopa/carbidopa, and this was statistically significant. Also, foslevodopa/foscarbidopa (fosL/fosC) showed more ‘on’ time without dyskinesia, compared with oral levodopa/carbidopa. This was also statistically significant,” lead author Sven Stodtmann, PhD, of AbbVie GmbH, Ludwigshafen, Germany, reported in his recorded presentation at the Movement Disorders Society’s 23rd International Congress of Parkinson’s Disease and Movement Disorder (Virtual) 2020.
 

Continuous infusion versus oral therapy

The analysis included 20 patients, and all data from these individuals were collected between 4:30 a.m. and 9:30 p.m.

Participants were 12 men and 8 women, aged 30-80 years, with advanced, idiopathic Parkinson’s disease responsive to levodopa but inadequately controlled on their current stable therapy, having a minimum of 2.5 off hours/day. Mean age was 61.3 plus or minus 10.5 years (range 35-77 years).

In this single-arm, open-label study, they received subcutaneous infusions of personalized therapeutic doses of fosL/fosC 24 hours/day for 28 days after a 10- to 30-day screening period during which they recorded LD/CD doses in a diary and had motor symptoms monitored using a wearable device.

Following the screening period, fosL/fosC doses were titrated over up to 5 days, with subsequent weekly study visits, for a total time on fosL/fosC of 28 days. Drug titration was aimed at maximizing functional on time and minimizing the number of off episodes while minimizing troublesome dyskinesia.

Continuous infusion of fosL/fosC performed better than oral LD/CD on all counts.

“The off time is much lower in the morning for people on foslevodopa/foscarbidopa [compared with oral LD/CD] because this is a 24-hour infusion product,” Dr. Stodtmann explained.

The effect was maintained over the course of the day with little fluctuation with fosL/fosC, off periods never exceeding about 25% between 4:30 a.m. and 9 p.m. For LD/CD, off periods were highest in the early morning and peaked at about 50% on a 3- to 4-hour cycle during the course of the day.

Increased on time without dyskinesia varied between about 60% and 80% during the day with fosL/fosC, showing the greatest difference between fosL/fosC and oral LD/CD in the early morning hours.

“On time with nontroublesome dyskinesia was lower for foscarbidopa/foslevodopa, compared to oral levodopa/carbidopa, but this was not statistically significant,” Dr. Stodtmann said. On time with troublesome dyskinesia followed the same pattern, again, not statistically significant.

Looking at the data another way, the investigators calculated the odds ratios of motor symptoms using fosL/fosC, compared with oral LD/CD. Use of fosL/fosC was associated with a 59% lower risk of being in the off state during the day, compared with oral LD/CD (odds ratio, 0.4; 95% confidence interval, 0.2-0.7; P < .01). Similarly, the probability of being in the on state without dyskinesia was much greater with fosL/fosC (OR, 2.75; 95% CI, 1.08-6.99; P < .05).
 

Encouraging, but more data needed

Indu Subramanian, MD, of the department of neurology at the University of California, Los Angeles, and director of the Parkinson’s Disease Research, Education, and Clinical Center at the West Los Angeles Veterans Affairs Hospital, commented that the field has been waiting to see data on fosL/fosC.

“It seems like it’s pretty reasonable in terms of what the goals were, which is to improve stability of Parkinson’s symptoms, to improve off time and give on time without troublesome dyskinesia,” she said. “So I think those [goals] have been met.”

Dr. Subramanian, who was not involved with the research, said she would have liked to have seen results concerning safety of this drug formulation, which the presentation lacked, “because historically, there have been issues with nodule formation and skin breakdown, things like that, due to the stability of the product in the subcutaneous form. … So, always to my understanding, there has been this search for things that are tolerated in the subcutaneous delivery.”

If this formulation proves safe and tolerable, Dr. Subramanian sees a potential place for it for some patients with advanced Parkinson’s disease.

“Certainly a subcutaneous formulation will be better than something that requires … deep brain surgery or even a pump insertion like Duopa [carbidopa/levodopa enteral suspension, AbbVie] or something like that,” she said. “I think [it] would be beneficial over something with the gut because the gut historically has been a problem to rely on in advanced Parkinson’s patients due to slower transit times, and the gut itself is affected with Parkinson’s disease.”

Dr. Stodtmann and all coauthors are employees of AbbVie, which was the sponsor of the study and was responsible for all aspects of it. Dr. Subramanian has given talks for Acadia Pharmaceuticals and Acorda Therapeutics in the past.

A version of this article originally appeared on Medscape.com.

A 24-hour continuous subcutaneous infusion of foslevodopa/foscarbidopa improved Parkinson’s disease (PD) motor symptoms during all waking hours for patients with advanced disease, according to a new study. The beneficial effects of these phosphate prodrugs of levodopa and carbidopa were most noticeable in the early morning, results of the phase 1B study showed.

As Parkinson’s disease progresses and dosing of oral levodopa/carbidopa (LD/CD) increases, its therapeutic window narrows, resulting in troublesome dyskinesia at peak drug levels and tremors and rigidity when levels fall.

“Foslevodopa/foscarbidopa shows lower ‘off’ time than oral levodopa/carbidopa, and this was statistically significant. Also, foslevodopa/foscarbidopa (fosL/fosC) showed more ‘on’ time without dyskinesia, compared with oral levodopa/carbidopa. This was also statistically significant,” lead author Sven Stodtmann, PhD, of AbbVie GmbH, Ludwigshafen, Germany, reported in his recorded presentation at the Movement Disorders Society’s 23rd International Congress of Parkinson’s Disease and Movement Disorder (Virtual) 2020.
 

Continuous infusion versus oral therapy

The analysis included 20 patients, and all data from these individuals were collected between 4:30 a.m. and 9:30 p.m.

Participants were 12 men and 8 women, aged 30-80 years, with advanced, idiopathic Parkinson’s disease responsive to levodopa but inadequately controlled on their current stable therapy, having a minimum of 2.5 off hours/day. Mean age was 61.3 plus or minus 10.5 years (range 35-77 years).

In this single-arm, open-label study, they received subcutaneous infusions of personalized therapeutic doses of fosL/fosC 24 hours/day for 28 days after a 10- to 30-day screening period during which they recorded LD/CD doses in a diary and had motor symptoms monitored using a wearable device.

Following the screening period, fosL/fosC doses were titrated over up to 5 days, with subsequent weekly study visits, for a total time on fosL/fosC of 28 days. Drug titration was aimed at maximizing functional on time and minimizing the number of off episodes while minimizing troublesome dyskinesia.

Continuous infusion of fosL/fosC performed better than oral LD/CD on all counts.

“The off time is much lower in the morning for people on foslevodopa/foscarbidopa [compared with oral LD/CD] because this is a 24-hour infusion product,” Dr. Stodtmann explained.

The effect was maintained over the course of the day with little fluctuation with fosL/fosC, off periods never exceeding about 25% between 4:30 a.m. and 9 p.m. For LD/CD, off periods were highest in the early morning and peaked at about 50% on a 3- to 4-hour cycle during the course of the day.

Increased on time without dyskinesia varied between about 60% and 80% during the day with fosL/fosC, showing the greatest difference between fosL/fosC and oral LD/CD in the early morning hours.

“On time with nontroublesome dyskinesia was lower for foscarbidopa/foslevodopa, compared to oral levodopa/carbidopa, but this was not statistically significant,” Dr. Stodtmann said. On time with troublesome dyskinesia followed the same pattern, again, not statistically significant.

Looking at the data another way, the investigators calculated the odds ratios of motor symptoms using fosL/fosC, compared with oral LD/CD. Use of fosL/fosC was associated with a 59% lower risk of being in the off state during the day, compared with oral LD/CD (odds ratio, 0.4; 95% confidence interval, 0.2-0.7; P < .01). Similarly, the probability of being in the on state without dyskinesia was much greater with fosL/fosC (OR, 2.75; 95% CI, 1.08-6.99; P < .05).
 

Encouraging, but more data needed

Indu Subramanian, MD, of the department of neurology at the University of California, Los Angeles, and director of the Parkinson’s Disease Research, Education, and Clinical Center at the West Los Angeles Veterans Affairs Hospital, commented that the field has been waiting to see data on fosL/fosC.

“It seems like it’s pretty reasonable in terms of what the goals were, which is to improve stability of Parkinson’s symptoms, to improve off time and give on time without troublesome dyskinesia,” she said. “So I think those [goals] have been met.”

Dr. Subramanian, who was not involved with the research, said she would have liked to have seen results concerning safety of this drug formulation, which the presentation lacked, “because historically, there have been issues with nodule formation and skin breakdown, things like that, due to the stability of the product in the subcutaneous form. … So, always to my understanding, there has been this search for things that are tolerated in the subcutaneous delivery.”

If this formulation proves safe and tolerable, Dr. Subramanian sees a potential place for it for some patients with advanced Parkinson’s disease.

“Certainly a subcutaneous formulation will be better than something that requires … deep brain surgery or even a pump insertion like Duopa [carbidopa/levodopa enteral suspension, AbbVie] or something like that,” she said. “I think [it] would be beneficial over something with the gut because the gut historically has been a problem to rely on in advanced Parkinson’s patients due to slower transit times, and the gut itself is affected with Parkinson’s disease.”

Dr. Stodtmann and all coauthors are employees of AbbVie, which was the sponsor of the study and was responsible for all aspects of it. Dr. Subramanian has given talks for Acadia Pharmaceuticals and Acorda Therapeutics in the past.

A version of this article originally appeared on Medscape.com.