5th International Conference on Parkinson's & Movement Disorders

NEW YORK – A bee-derived supplement known to have anti-inflammatory properties showed promise in potentiating the effect of levodopa in a rodent model of Parkinson’s disease, with biochemical and behavioral improvements seen that exceeded high-dose levodopa alone.

Levodopa (L-dopa) has long been a keystone in treatment for individuals with Parkinson’s disease (PD). However, its effectiveness wanes with time and long-term use is associated with significant undesirable side effects, including dyskinesias.

A dopamine precursor, L-dopa, once converted to dopamine, replaces the dopamine no longer made by the substantia nigra. Increasingly, neuroinflammation and oxidative stress are felt to play a role in the natural history of PD, said Azza Ali, PhD, who presented the findings at a poster session of the International Conference on Parkinson’s Disease and Movement Disorders. Whether mitigating these effects can alter the disease course for individuals with PD has not been well investigated, she added.

Dr. Ali and her research group at Al-Azhar University, Cairo, Egypt, where she heads the department of pharmacology and toxicology, are investigating several nutritional and supplement strategies to dampen inflammation. Among the substances she and her colleagues are investigating is propolis, a plant-derived product produced by bees and distinct from honey or beeswax.

Propolis has been shown to have antioxidant properties in addition to other reported health benefits.

Dr. Ali and her colleagues used a rodent model for PD: Rats were dosed with rotenone, which is known to induce a histologically verifiable parkinsonian syndrome. The investigators used six groups of rats; one group was the normal control, while the others all had rotenone-induced parkinsonism.

Of the remaining groups, one rotenone-dosed group was given neither L-dopa nor propolis. Two groups were treated with oral L-dopa alone, at 10 or 25 mg/kg per day. Another group was given an oral dose of 300 mg/kg per day of propolis, and the last group received propolis at that dose while also receiving the lower dose of L-dopa.

All groups were subject to behavioral assessments including a swim test, an open field test, a maze test, and other tasks designed to assess motor function and other aspects of behavior. Additionally, Dr. Ali and her collaborators assessed a variety of biochemical parameters that looked at oxidative stress and neuroinflammation in all rodent groups.

For most parameters, the rotenone-dosed rats that showed results most like normal controls were those who received both low-dose L-dopa and propolis. In particular, the rats receiving both L-dopa and propolis outperformed the other rotenone groups in the behavioral open field test and a grid test, where their performance neared the control group.

Levels of interleukin-1 beta fell for all treated rodents, but fell the most for those treated with the combination. Tissue dopamine levels were also lower for the rats who received combination treatment, and acetylcholinesterase and malondialdehyde levels also fell to near normal for rats receiving the combination treatment, but not for the other groups.

“Propolis is efficient in protection from PD development and represents a suitable adjuvant therapy, which can be translated to serious reduction of the long-term therapy side effects of the mainstay drug L-dopa,” wrote Dr. Ali and her coauthors. “Consequently, propolis could be recommended as a disease-modifying therapy of PD as well as a promising adjunct therapy with L-dopa especially when given early in the treatment course.”
 

koakes@mdedge.com

NEW YORK – A bee-derived supplement known to have anti-inflammatory properties showed promise in potentiating the effect of levodopa in a rodent model of Parkinson’s disease, with biochemical and behavioral improvements seen that exceeded high-dose levodopa alone.

Levodopa (L-dopa) has long been a keystone in treatment for individuals with Parkinson’s disease (PD). However, its effectiveness wanes with time and long-term use is associated with significant undesirable side effects, including dyskinesias.

A dopamine precursor, L-dopa, once converted to dopamine, replaces the dopamine no longer made by the substantia nigra. Increasingly, neuroinflammation and oxidative stress are felt to play a role in the natural history of PD, said Azza Ali, PhD, who presented the findings at a poster session of the International Conference on Parkinson’s Disease and Movement Disorders. Whether mitigating these effects can alter the disease course for individuals with PD has not been well investigated, she added.

Dr. Ali and her research group at Al-Azhar University, Cairo, Egypt, where she heads the department of pharmacology and toxicology, are investigating several nutritional and supplement strategies to dampen inflammation. Among the substances she and her colleagues are investigating is propolis, a plant-derived product produced by bees and distinct from honey or beeswax.

Propolis has been shown to have antioxidant properties in addition to other reported health benefits.

Dr. Ali and her colleagues used a rodent model for PD: Rats were dosed with rotenone, which is known to induce a histologically verifiable parkinsonian syndrome. The investigators used six groups of rats; one group was the normal control, while the others all had rotenone-induced parkinsonism.

Of the remaining groups, one rotenone-dosed group was given neither L-dopa nor propolis. Two groups were treated with oral L-dopa alone, at 10 or 25 mg/kg per day. Another group was given an oral dose of 300 mg/kg per day of propolis, and the last group received propolis at that dose while also receiving the lower dose of L-dopa.

All groups were subject to behavioral assessments including a swim test, an open field test, a maze test, and other tasks designed to assess motor function and other aspects of behavior. Additionally, Dr. Ali and her collaborators assessed a variety of biochemical parameters that looked at oxidative stress and neuroinflammation in all rodent groups.

For most parameters, the rotenone-dosed rats that showed results most like normal controls were those who received both low-dose L-dopa and propolis. In particular, the rats receiving both L-dopa and propolis outperformed the other rotenone groups in the behavioral open field test and a grid test, where their performance neared the control group.

Levels of interleukin-1 beta fell for all treated rodents, but fell the most for those treated with the combination. Tissue dopamine levels were also lower for the rats who received combination treatment, and acetylcholinesterase and malondialdehyde levels also fell to near normal for rats receiving the combination treatment, but not for the other groups.

“Propolis is efficient in protection from PD development and represents a suitable adjuvant therapy, which can be translated to serious reduction of the long-term therapy side effects of the mainstay drug L-dopa,” wrote Dr. Ali and her coauthors. “Consequently, propolis could be recommended as a disease-modifying therapy of PD as well as a promising adjunct therapy with L-dopa especially when given early in the treatment course.”
 

koakes@mdedge.com

NEW YORK – A bee-derived supplement known to have anti-inflammatory properties showed promise in potentiating the effect of levodopa in a rodent model of Parkinson’s disease, with biochemical and behavioral improvements seen that exceeded high-dose levodopa alone.

Levodopa (L-dopa) has long been a keystone in treatment for individuals with Parkinson’s disease (PD). However, its effectiveness wanes with time and long-term use is associated with significant undesirable side effects, including dyskinesias.

A dopamine precursor, L-dopa, once converted to dopamine, replaces the dopamine no longer made by the substantia nigra. Increasingly, neuroinflammation and oxidative stress are felt to play a role in the natural history of PD, said Azza Ali, PhD, who presented the findings at a poster session of the International Conference on Parkinson’s Disease and Movement Disorders. Whether mitigating these effects can alter the disease course for individuals with PD has not been well investigated, she added.

Dr. Ali and her research group at Al-Azhar University, Cairo, Egypt, where she heads the department of pharmacology and toxicology, are investigating several nutritional and supplement strategies to dampen inflammation. Among the substances she and her colleagues are investigating is propolis, a plant-derived product produced by bees and distinct from honey or beeswax.

Propolis has been shown to have antioxidant properties in addition to other reported health benefits.

Dr. Ali and her colleagues used a rodent model for PD: Rats were dosed with rotenone, which is known to induce a histologically verifiable parkinsonian syndrome. The investigators used six groups of rats; one group was the normal control, while the others all had rotenone-induced parkinsonism.

Of the remaining groups, one rotenone-dosed group was given neither L-dopa nor propolis. Two groups were treated with oral L-dopa alone, at 10 or 25 mg/kg per day. Another group was given an oral dose of 300 mg/kg per day of propolis, and the last group received propolis at that dose while also receiving the lower dose of L-dopa.

All groups were subject to behavioral assessments including a swim test, an open field test, a maze test, and other tasks designed to assess motor function and other aspects of behavior. Additionally, Dr. Ali and her collaborators assessed a variety of biochemical parameters that looked at oxidative stress and neuroinflammation in all rodent groups.

For most parameters, the rotenone-dosed rats that showed results most like normal controls were those who received both low-dose L-dopa and propolis. In particular, the rats receiving both L-dopa and propolis outperformed the other rotenone groups in the behavioral open field test and a grid test, where their performance neared the control group.

Levels of interleukin-1 beta fell for all treated rodents, but fell the most for those treated with the combination. Tissue dopamine levels were also lower for the rats who received combination treatment, and acetylcholinesterase and malondialdehyde levels also fell to near normal for rats receiving the combination treatment, but not for the other groups.

“Propolis is efficient in protection from PD development and represents a suitable adjuvant therapy, which can be translated to serious reduction of the long-term therapy side effects of the mainstay drug L-dopa,” wrote Dr. Ali and her coauthors. “Consequently, propolis could be recommended as a disease-modifying therapy of PD as well as a promising adjunct therapy with L-dopa especially when given early in the treatment course.”
 

koakes@mdedge.com

NEW YORK – Preclinical studies have shown the natural supplements vinpocetine and pomegranate, along with vitamin B complex and vitamin E, may have some effect individually in providing neuroprotection in Parkinson’s disease, but may have a more profound effect when used in combination, a researcher from Egypt reported at the International Conference on Parkinson’s Disease and Movement Disorders.

“We need to carry out a clinical trial to ensure that this multiple direct strategy can provide protection in different stages of neurodegenerative disease – during induction and even during the progression of the disease,” said Azza Ali, PhD, of Al-Azhar University, Cairo. She presented a poster of her research in an unspecified number of rats with manganese-induced Parkinsonian symptoms. The goal of the study was to compare the oral supplements to each other and to evaluate their impact in combinations. Excessive levels of manganese have been associated with movement disorders similar to Parkinson’s disease.

The research involved histologic studies to evaluate the impact of the supplements in the brains, and evaluated biochemical, neuroinflammatory, apoptotic, and oxidative markers. Behavioral tests evaluated cognition, memory, and motor skills.

Histological studies of manganese-induced brains exhibited nuclear pyknosis – clumping of chromosomes, excessive chromatic aberrations, and shrinkage of the nucleus – in the neurons of the cerebral cortex as well as in some areas of the hippocampus, although no alteration was seen in the subiculum, Dr. Ali reported. The stria showed multiple plaque formations with nuclear pyknosis and degeneration in some neurons.

All the studied treatments improved motor, memory, and cognitive decline induced by manganese, with pomegranate and vinpocetine yielding the best results, Dr. Ali said. However, a combination of treatments showed more pronounced improvements in some biochemical markers, as well as the neuroinflammatory, apoptotic, and oxidative markers. “They have a high antioxidant and antiapoptotic effect,” Dr. Ali said. Histopathologic studies confirmed those results, she noted.

Pomegranate (150 mg/kg) had a somewhat positive effect in the subiculum and fascia dentate areas of the hippocampus, although the stria appeared similar to manganese-induced brains. With vinpocetine (20 mg/kg), neurons in the cerebral cortex showed intact histological structure with some degeneration and nuclear pyknosis in the subiculum. There was no alteration in the neurons of the fascia dentate, hilus, and stria of the hippocampus.

Histologic studies of induced brains after treatment with vitamin-B complex (8.5 mg/kg) showed nuclear pyknosis and degeneration in the neurons of the cerebral cortex and hippocampus, including the subiculum. The stria also showed multiple focal eosinophilic plaques with nuclear pyknosis and degeneration in some neurons. Vitamin E (100 mg/kg) resulted in intact neurons in the cerebral cortex but not in the hippocampus.

Histopathologic studies of brains that received combination treatment showed no alteration in the neurons of the cerebral cortex or in the subiculum and fascia dentate of the hippocampus, although a few neurons in the stria showed nuclear pyknosis and degeneration, Dr. Ali said.

She had no financial relationships to disclose.

NEW YORK – Preclinical studies have shown the natural supplements vinpocetine and pomegranate, along with vitamin B complex and vitamin E, may have some effect individually in providing neuroprotection in Parkinson’s disease, but may have a more profound effect when used in combination, a researcher from Egypt reported at the International Conference on Parkinson’s Disease and Movement Disorders.

“We need to carry out a clinical trial to ensure that this multiple direct strategy can provide protection in different stages of neurodegenerative disease – during induction and even during the progression of the disease,” said Azza Ali, PhD, of Al-Azhar University, Cairo. She presented a poster of her research in an unspecified number of rats with manganese-induced Parkinsonian symptoms. The goal of the study was to compare the oral supplements to each other and to evaluate their impact in combinations. Excessive levels of manganese have been associated with movement disorders similar to Parkinson’s disease.

The research involved histologic studies to evaluate the impact of the supplements in the brains, and evaluated biochemical, neuroinflammatory, apoptotic, and oxidative markers. Behavioral tests evaluated cognition, memory, and motor skills.

Histological studies of manganese-induced brains exhibited nuclear pyknosis – clumping of chromosomes, excessive chromatic aberrations, and shrinkage of the nucleus – in the neurons of the cerebral cortex as well as in some areas of the hippocampus, although no alteration was seen in the subiculum, Dr. Ali reported. The stria showed multiple plaque formations with nuclear pyknosis and degeneration in some neurons.

All the studied treatments improved motor, memory, and cognitive decline induced by manganese, with pomegranate and vinpocetine yielding the best results, Dr. Ali said. However, a combination of treatments showed more pronounced improvements in some biochemical markers, as well as the neuroinflammatory, apoptotic, and oxidative markers. “They have a high antioxidant and antiapoptotic effect,” Dr. Ali said. Histopathologic studies confirmed those results, she noted.

Pomegranate (150 mg/kg) had a somewhat positive effect in the subiculum and fascia dentate areas of the hippocampus, although the stria appeared similar to manganese-induced brains. With vinpocetine (20 mg/kg), neurons in the cerebral cortex showed intact histological structure with some degeneration and nuclear pyknosis in the subiculum. There was no alteration in the neurons of the fascia dentate, hilus, and stria of the hippocampus.

Histologic studies of induced brains after treatment with vitamin-B complex (8.5 mg/kg) showed nuclear pyknosis and degeneration in the neurons of the cerebral cortex and hippocampus, including the subiculum. The stria also showed multiple focal eosinophilic plaques with nuclear pyknosis and degeneration in some neurons. Vitamin E (100 mg/kg) resulted in intact neurons in the cerebral cortex but not in the hippocampus.

Histopathologic studies of brains that received combination treatment showed no alteration in the neurons of the cerebral cortex or in the subiculum and fascia dentate of the hippocampus, although a few neurons in the stria showed nuclear pyknosis and degeneration, Dr. Ali said.

She had no financial relationships to disclose.

NEW YORK – Preclinical studies have shown the natural supplements vinpocetine and pomegranate, along with vitamin B complex and vitamin E, may have some effect individually in providing neuroprotection in Parkinson’s disease, but may have a more profound effect when used in combination, a researcher from Egypt reported at the International Conference on Parkinson’s Disease and Movement Disorders.

“We need to carry out a clinical trial to ensure that this multiple direct strategy can provide protection in different stages of neurodegenerative disease – during induction and even during the progression of the disease,” said Azza Ali, PhD, of Al-Azhar University, Cairo. She presented a poster of her research in an unspecified number of rats with manganese-induced Parkinsonian symptoms. The goal of the study was to compare the oral supplements to each other and to evaluate their impact in combinations. Excessive levels of manganese have been associated with movement disorders similar to Parkinson’s disease.

The research involved histologic studies to evaluate the impact of the supplements in the brains, and evaluated biochemical, neuroinflammatory, apoptotic, and oxidative markers. Behavioral tests evaluated cognition, memory, and motor skills.

Histological studies of manganese-induced brains exhibited nuclear pyknosis – clumping of chromosomes, excessive chromatic aberrations, and shrinkage of the nucleus – in the neurons of the cerebral cortex as well as in some areas of the hippocampus, although no alteration was seen in the subiculum, Dr. Ali reported. The stria showed multiple plaque formations with nuclear pyknosis and degeneration in some neurons.

All the studied treatments improved motor, memory, and cognitive decline induced by manganese, with pomegranate and vinpocetine yielding the best results, Dr. Ali said. However, a combination of treatments showed more pronounced improvements in some biochemical markers, as well as the neuroinflammatory, apoptotic, and oxidative markers. “They have a high antioxidant and antiapoptotic effect,” Dr. Ali said. Histopathologic studies confirmed those results, she noted.

Pomegranate (150 mg/kg) had a somewhat positive effect in the subiculum and fascia dentate areas of the hippocampus, although the stria appeared similar to manganese-induced brains. With vinpocetine (20 mg/kg), neurons in the cerebral cortex showed intact histological structure with some degeneration and nuclear pyknosis in the subiculum. There was no alteration in the neurons of the fascia dentate, hilus, and stria of the hippocampus.

Histologic studies of induced brains after treatment with vitamin-B complex (8.5 mg/kg) showed nuclear pyknosis and degeneration in the neurons of the cerebral cortex and hippocampus, including the subiculum. The stria also showed multiple focal eosinophilic plaques with nuclear pyknosis and degeneration in some neurons. Vitamin E (100 mg/kg) resulted in intact neurons in the cerebral cortex but not in the hippocampus.

Histopathologic studies of brains that received combination treatment showed no alteration in the neurons of the cerebral cortex or in the subiculum and fascia dentate of the hippocampus, although a few neurons in the stria showed nuclear pyknosis and degeneration, Dr. Ali said.

She had no financial relationships to disclose.

NEW YORK – A small pilot study has shown that patients with Parkinson’s disease who participated in the Rock Steady Boxing non-contact training program may have faster reaction times than PD patients who did not participate in the program, according to a poster presented at the International Conference on Parkinson’s Disease and Movement Disorders.

Richard Mark Kirkner/MDedge News

“The novelty of this is that it shows how Rock Steady Boxing and exercise programs that use sequences and the learning of sequences could possibly help slow the decline, or maintain a level of functioning longer, in Parkinson’s disease,” said Christopher McLeod, a second-year medical student at New York Institute of Technology (NYIT) College of Osteopathic Medicine, Old Westbury, N.Y.

Rock Steady Boxing is a non-contact program tailored to Parkinson’s patients founded in 2006 by Scott Newman, an Indiana lawyer who was diagnosed with early onset Parkinson’s at age 40. The regimen involves intense one-on-one training centered around boxing. Rock Steady Boxing offers classes from coast to coast in the United States and in 13 other countries. Mr. McLeod is a volunteer at the NYIT chapter of Rock Steady Boxing in Old Westbury, N.Y.

Mr. McLeod studied 28 PD patients – 14 who had been taking Rock Steady Boxing classes at NYIT for at least 6 months and 14 controls. The goal of the study was to evaluate if the Rock Steady Boxing participants showed any improvement in procedural motor learning. His coauthor was Adena Leder, DO, a faculty neurologist and movement disorder specialist at NYIT,

“What’s new about this research is the procedural memory component and the Rock Steady Boxing program is just more of the vessel, so to speak,” Mr. McLeod said. “This is a pilot study. We wanted to see if Rock Steady Boxing would show benefits in these patients. There are some trends in my research that [indicate] it would; it did not have statistical significance, but we did see trend lines.”

The researchers used a modified Serial Reaction Time Test (SRTT) composed of seven blocks of 10 stimuli each with 30-second breaks between blocks. Blocks consisted of a random familiarization block, four learning blocks repeating the same sequence of stimuli, a transfer block of random stimuli, and a posttransfer block presenting the same sequence of stimuli from the four learning blocks.

They assessed procedural learning by comparing the reduction in response time over the four identical learning blocks as well as by comparing changes in response time when the subjects were subsequently exposed to the random transfer block.

Experienced boxers demonstrated faster reaction time over the four learning blocks, ranging from 795.32 vs. 906.89 ms in the first learning block to 674.79 vs. 787.32 ms in the fourth learning block (P = .19). In the random sequence transfer block, controls showed a 93.5-ms decrease in median reaction time vs. a 27.3-ms increase in reaction time of experienced boxers. One possible explanation the investigators noted is that the controls simply got better at reading the stimuli over time without actually learning the repeated sequence.

Mr. McLeod noted that a typical Rock Steady Boxing session starts with a warmup and stretch, then learning the boxing stance with the nondominant foot back, shoulders over the body and the head over the feet. The boxing moves involve sequences of different punching combinations — jab, jab, cross; left, left, right; jab, cross, hook. Then the class divides into separate circuits for boxing and exercise. The boxing circuit involves punching the speed bag – the small, air-filled, pear-shaped bag attached to a hook at eye level – as well as heavy bag and partner-held focus mitts, all with the aim of reinforcing the learned sequences. The exercise circuit focuses on muscle training and exercise with the goal of improving balance and gait.

“The boxing sequences help not only with cognitive ability but motor control,” Mr. McLeod said. “The program also helps with some of the nonmotor aspects of Parkinson’s disease. Depression is almost synonymous with Parkinson’s disease; this brings people together and builds camaraderie.”

Mr. McLeod said he hopes the research continues. “I’m hoping that this can be a jumping-off point for research going forward with procedural memory, Parkinson’s, and Rock Steady Boxing or programs like it,” he said. Future research should involve more subjects, measure improvement within same subjects who participate in the program, and account for variables such as age and gender.

Mr. McLeod and Dr. Leder reported having no relevant financial disclosures.

NEW YORK – A small pilot study has shown that patients with Parkinson’s disease who participated in the Rock Steady Boxing non-contact training program may have faster reaction times than PD patients who did not participate in the program, according to a poster presented at the International Conference on Parkinson’s Disease and Movement Disorders.

Richard Mark Kirkner/MDedge News

“The novelty of this is that it shows how Rock Steady Boxing and exercise programs that use sequences and the learning of sequences could possibly help slow the decline, or maintain a level of functioning longer, in Parkinson’s disease,” said Christopher McLeod, a second-year medical student at New York Institute of Technology (NYIT) College of Osteopathic Medicine, Old Westbury, N.Y.

Rock Steady Boxing is a non-contact program tailored to Parkinson’s patients founded in 2006 by Scott Newman, an Indiana lawyer who was diagnosed with early onset Parkinson’s at age 40. The regimen involves intense one-on-one training centered around boxing. Rock Steady Boxing offers classes from coast to coast in the United States and in 13 other countries. Mr. McLeod is a volunteer at the NYIT chapter of Rock Steady Boxing in Old Westbury, N.Y.

Mr. McLeod studied 28 PD patients – 14 who had been taking Rock Steady Boxing classes at NYIT for at least 6 months and 14 controls. The goal of the study was to evaluate if the Rock Steady Boxing participants showed any improvement in procedural motor learning. His coauthor was Adena Leder, DO, a faculty neurologist and movement disorder specialist at NYIT,

“What’s new about this research is the procedural memory component and the Rock Steady Boxing program is just more of the vessel, so to speak,” Mr. McLeod said. “This is a pilot study. We wanted to see if Rock Steady Boxing would show benefits in these patients. There are some trends in my research that [indicate] it would; it did not have statistical significance, but we did see trend lines.”

The researchers used a modified Serial Reaction Time Test (SRTT) composed of seven blocks of 10 stimuli each with 30-second breaks between blocks. Blocks consisted of a random familiarization block, four learning blocks repeating the same sequence of stimuli, a transfer block of random stimuli, and a posttransfer block presenting the same sequence of stimuli from the four learning blocks.

They assessed procedural learning by comparing the reduction in response time over the four identical learning blocks as well as by comparing changes in response time when the subjects were subsequently exposed to the random transfer block.

Experienced boxers demonstrated faster reaction time over the four learning blocks, ranging from 795.32 vs. 906.89 ms in the first learning block to 674.79 vs. 787.32 ms in the fourth learning block (P = .19). In the random sequence transfer block, controls showed a 93.5-ms decrease in median reaction time vs. a 27.3-ms increase in reaction time of experienced boxers. One possible explanation the investigators noted is that the controls simply got better at reading the stimuli over time without actually learning the repeated sequence.

Mr. McLeod noted that a typical Rock Steady Boxing session starts with a warmup and stretch, then learning the boxing stance with the nondominant foot back, shoulders over the body and the head over the feet. The boxing moves involve sequences of different punching combinations — jab, jab, cross; left, left, right; jab, cross, hook. Then the class divides into separate circuits for boxing and exercise. The boxing circuit involves punching the speed bag – the small, air-filled, pear-shaped bag attached to a hook at eye level – as well as heavy bag and partner-held focus mitts, all with the aim of reinforcing the learned sequences. The exercise circuit focuses on muscle training and exercise with the goal of improving balance and gait.

“The boxing sequences help not only with cognitive ability but motor control,” Mr. McLeod said. “The program also helps with some of the nonmotor aspects of Parkinson’s disease. Depression is almost synonymous with Parkinson’s disease; this brings people together and builds camaraderie.”

Mr. McLeod said he hopes the research continues. “I’m hoping that this can be a jumping-off point for research going forward with procedural memory, Parkinson’s, and Rock Steady Boxing or programs like it,” he said. Future research should involve more subjects, measure improvement within same subjects who participate in the program, and account for variables such as age and gender.

Mr. McLeod and Dr. Leder reported having no relevant financial disclosures.

NEW YORK – A small pilot study has shown that patients with Parkinson’s disease who participated in the Rock Steady Boxing non-contact training program may have faster reaction times than PD patients who did not participate in the program, according to a poster presented at the International Conference on Parkinson’s Disease and Movement Disorders.

Richard Mark Kirkner/MDedge News

“The novelty of this is that it shows how Rock Steady Boxing and exercise programs that use sequences and the learning of sequences could possibly help slow the decline, or maintain a level of functioning longer, in Parkinson’s disease,” said Christopher McLeod, a second-year medical student at New York Institute of Technology (NYIT) College of Osteopathic Medicine, Old Westbury, N.Y.

Rock Steady Boxing is a non-contact program tailored to Parkinson’s patients founded in 2006 by Scott Newman, an Indiana lawyer who was diagnosed with early onset Parkinson’s at age 40. The regimen involves intense one-on-one training centered around boxing. Rock Steady Boxing offers classes from coast to coast in the United States and in 13 other countries. Mr. McLeod is a volunteer at the NYIT chapter of Rock Steady Boxing in Old Westbury, N.Y.

Mr. McLeod studied 28 PD patients – 14 who had been taking Rock Steady Boxing classes at NYIT for at least 6 months and 14 controls. The goal of the study was to evaluate if the Rock Steady Boxing participants showed any improvement in procedural motor learning. His coauthor was Adena Leder, DO, a faculty neurologist and movement disorder specialist at NYIT,

“What’s new about this research is the procedural memory component and the Rock Steady Boxing program is just more of the vessel, so to speak,” Mr. McLeod said. “This is a pilot study. We wanted to see if Rock Steady Boxing would show benefits in these patients. There are some trends in my research that [indicate] it would; it did not have statistical significance, but we did see trend lines.”

The researchers used a modified Serial Reaction Time Test (SRTT) composed of seven blocks of 10 stimuli each with 30-second breaks between blocks. Blocks consisted of a random familiarization block, four learning blocks repeating the same sequence of stimuli, a transfer block of random stimuli, and a posttransfer block presenting the same sequence of stimuli from the four learning blocks.

They assessed procedural learning by comparing the reduction in response time over the four identical learning blocks as well as by comparing changes in response time when the subjects were subsequently exposed to the random transfer block.

Experienced boxers demonstrated faster reaction time over the four learning blocks, ranging from 795.32 vs. 906.89 ms in the first learning block to 674.79 vs. 787.32 ms in the fourth learning block (P = .19). In the random sequence transfer block, controls showed a 93.5-ms decrease in median reaction time vs. a 27.3-ms increase in reaction time of experienced boxers. One possible explanation the investigators noted is that the controls simply got better at reading the stimuli over time without actually learning the repeated sequence.

Mr. McLeod noted that a typical Rock Steady Boxing session starts with a warmup and stretch, then learning the boxing stance with the nondominant foot back, shoulders over the body and the head over the feet. The boxing moves involve sequences of different punching combinations — jab, jab, cross; left, left, right; jab, cross, hook. Then the class divides into separate circuits for boxing and exercise. The boxing circuit involves punching the speed bag – the small, air-filled, pear-shaped bag attached to a hook at eye level – as well as heavy bag and partner-held focus mitts, all with the aim of reinforcing the learned sequences. The exercise circuit focuses on muscle training and exercise with the goal of improving balance and gait.

“The boxing sequences help not only with cognitive ability but motor control,” Mr. McLeod said. “The program also helps with some of the nonmotor aspects of Parkinson’s disease. Depression is almost synonymous with Parkinson’s disease; this brings people together and builds camaraderie.”

Mr. McLeod said he hopes the research continues. “I’m hoping that this can be a jumping-off point for research going forward with procedural memory, Parkinson’s, and Rock Steady Boxing or programs like it,” he said. Future research should involve more subjects, measure improvement within same subjects who participate in the program, and account for variables such as age and gender.

Mr. McLeod and Dr. Leder reported having no relevant financial disclosures.

NEW YORK – As part of a comprehensive support program, a computer program administered to patients with cognitive impairment, including those with Alzheimer’s disease, has been associated with preserved cognitive function.

“Based on this series of cases, we believe that the brain in patients with dementia can maintain cognitive function for up to 8 years when an integrative rehabilitation program is employed,” reported Valentin I. Bragin, MD, PhD, of the Stress and Pain Relief Memory Training Center, New York.

While the integrative program involves other types of supportive care, including physical exercises and pharmacologic treatments, the focus of this case series was on the contribution of a computer program for cognitive training. As described by Dr. Bragin, it consists of tasks aimed at training working memory, selective attention, visual field expansion, and eye-hand coordination.

The computer program is designed to improve or maintain motor speed and reaction time. The aim is a rehabilitation process to activate the brain via sensory motor and other bodily systems to prevent patients with Alzheimer’s disease from decline, according to Dr. Bragin. He explained that the computer program is augmented with pen and paper tasks, such as clock drawing, that also stimulate cognitive function.

“The theory behind this treatment is the notion that increased cerebral blood flow is a highly modifiable factor in the risk of cognitive decline,” Dr. Bragin explained at the International Conference on Parkinson’s Disease and Movement Disorders. This premise is supported by a case series of four patients. The shortest duration of treatment was 4 years, but two patients were treated for 7 years and one for 8 years. In this series, motor speed has remained stable in all four patients throughout follow-up. Reaction time remained stable over the period of study in three of four patients, while working memory remained stable in two of the four. Although there was no control group, this persistence of cognitive function is longer than that expected in patients with progressive dementia, according to Dr. Bragin.

“Previously, we demonstrated an improvement and stabilization of cognitive functions in people with mild dementia and depression for periods of up to 6 years by using pen and paper tests,” Dr. Bragin reported. He explained that the computer program expands on this approach.

“We believe that cerebral blood flow is a highly modifiable factor that is a crucial element for reducing hypoxia, improving energy production, and increasing protein synthesis to prevent dementia,” Dr. Bragin said.

Although Dr. Bragin acknowledged that the findings from this case series are preliminary and need to be replicated in a large and controlled trial, he considers it a reasonable empirical strategy, particularly when employed as part of an integrative rehabilitation program like the one now in place at his center.

“This could be a feasible treatment option for dementia patients to stabilize their cognition and improve their quality of life until newer effective approaches become available,” Dr. Bragin said. He noted in the absence of a clear understanding of the pathology of Alzheimer’s disease and other progressive disorders involving cognitive decline, “the most successful treatment model is integrative care.”

NEW YORK – As part of a comprehensive support program, a computer program administered to patients with cognitive impairment, including those with Alzheimer’s disease, has been associated with preserved cognitive function.

“Based on this series of cases, we believe that the brain in patients with dementia can maintain cognitive function for up to 8 years when an integrative rehabilitation program is employed,” reported Valentin I. Bragin, MD, PhD, of the Stress and Pain Relief Memory Training Center, New York.

While the integrative program involves other types of supportive care, including physical exercises and pharmacologic treatments, the focus of this case series was on the contribution of a computer program for cognitive training. As described by Dr. Bragin, it consists of tasks aimed at training working memory, selective attention, visual field expansion, and eye-hand coordination.

The computer program is designed to improve or maintain motor speed and reaction time. The aim is a rehabilitation process to activate the brain via sensory motor and other bodily systems to prevent patients with Alzheimer’s disease from decline, according to Dr. Bragin. He explained that the computer program is augmented with pen and paper tasks, such as clock drawing, that also stimulate cognitive function.

“The theory behind this treatment is the notion that increased cerebral blood flow is a highly modifiable factor in the risk of cognitive decline,” Dr. Bragin explained at the International Conference on Parkinson’s Disease and Movement Disorders. This premise is supported by a case series of four patients. The shortest duration of treatment was 4 years, but two patients were treated for 7 years and one for 8 years. In this series, motor speed has remained stable in all four patients throughout follow-up. Reaction time remained stable over the period of study in three of four patients, while working memory remained stable in two of the four. Although there was no control group, this persistence of cognitive function is longer than that expected in patients with progressive dementia, according to Dr. Bragin.

“Previously, we demonstrated an improvement and stabilization of cognitive functions in people with mild dementia and depression for periods of up to 6 years by using pen and paper tests,” Dr. Bragin reported. He explained that the computer program expands on this approach.

“We believe that cerebral blood flow is a highly modifiable factor that is a crucial element for reducing hypoxia, improving energy production, and increasing protein synthesis to prevent dementia,” Dr. Bragin said.

Although Dr. Bragin acknowledged that the findings from this case series are preliminary and need to be replicated in a large and controlled trial, he considers it a reasonable empirical strategy, particularly when employed as part of an integrative rehabilitation program like the one now in place at his center.

“This could be a feasible treatment option for dementia patients to stabilize their cognition and improve their quality of life until newer effective approaches become available,” Dr. Bragin said. He noted in the absence of a clear understanding of the pathology of Alzheimer’s disease and other progressive disorders involving cognitive decline, “the most successful treatment model is integrative care.”

NEW YORK – As part of a comprehensive support program, a computer program administered to patients with cognitive impairment, including those with Alzheimer’s disease, has been associated with preserved cognitive function.

“Based on this series of cases, we believe that the brain in patients with dementia can maintain cognitive function for up to 8 years when an integrative rehabilitation program is employed,” reported Valentin I. Bragin, MD, PhD, of the Stress and Pain Relief Memory Training Center, New York.

While the integrative program involves other types of supportive care, including physical exercises and pharmacologic treatments, the focus of this case series was on the contribution of a computer program for cognitive training. As described by Dr. Bragin, it consists of tasks aimed at training working memory, selective attention, visual field expansion, and eye-hand coordination.

The computer program is designed to improve or maintain motor speed and reaction time. The aim is a rehabilitation process to activate the brain via sensory motor and other bodily systems to prevent patients with Alzheimer’s disease from decline, according to Dr. Bragin. He explained that the computer program is augmented with pen and paper tasks, such as clock drawing, that also stimulate cognitive function.

“The theory behind this treatment is the notion that increased cerebral blood flow is a highly modifiable factor in the risk of cognitive decline,” Dr. Bragin explained at the International Conference on Parkinson’s Disease and Movement Disorders. This premise is supported by a case series of four patients. The shortest duration of treatment was 4 years, but two patients were treated for 7 years and one for 8 years. In this series, motor speed has remained stable in all four patients throughout follow-up. Reaction time remained stable over the period of study in three of four patients, while working memory remained stable in two of the four. Although there was no control group, this persistence of cognitive function is longer than that expected in patients with progressive dementia, according to Dr. Bragin.

“Previously, we demonstrated an improvement and stabilization of cognitive functions in people with mild dementia and depression for periods of up to 6 years by using pen and paper tests,” Dr. Bragin reported. He explained that the computer program expands on this approach.

“We believe that cerebral blood flow is a highly modifiable factor that is a crucial element for reducing hypoxia, improving energy production, and increasing protein synthesis to prevent dementia,” Dr. Bragin said.

Although Dr. Bragin acknowledged that the findings from this case series are preliminary and need to be replicated in a large and controlled trial, he considers it a reasonable empirical strategy, particularly when employed as part of an integrative rehabilitation program like the one now in place at his center.

“This could be a feasible treatment option for dementia patients to stabilize their cognition and improve their quality of life until newer effective approaches become available,” Dr. Bragin said. He noted in the absence of a clear understanding of the pathology of Alzheimer’s disease and other progressive disorders involving cognitive decline, “the most successful treatment model is integrative care.”

NEW YORK – There are numerous clinical factors and objective tools for identifying patients with Parkinson’s disease who have an increased risk of falls, according to data from a prospective study and an overview of this topic that was presented at the International Conference on Parkinson’s Disease and Movement Disorders

Ted Bosworth/MDedge News

“Identifying risk of falls, which can produce complications beyond the acute injury, is one of the most important unmet needs in Parkinson’s disease,” reported A.V. Srinivasan, MD, PhD, DSc, of the Tamil Nadu Dr. MGR Medial University, Chennai, India.

Falls pose a risk of complications beyond acute injury because of the potential domino effect, according to Dr. Srinivasan. He maintained that when aging Parkinson’s disease patients are confined to bed for an extended period of recovery, a host of adverse health consequences can follow, including such life-threatening events as aspiration pneumonia.

“A serious fall can be the start of a downward clinical slope,” according to Dr. Srinivasan, who cited data suggesting that 40%-70% of Parkinson’s disease patients will have a serious fall at advanced stages of disease.

To identify those at greatest risk, a number of objective studies were shown to be useful in a study undertaken at the Institute of Neurology of Madras (India) Medical College, according to Dr. Srinivasan, where he was a professor when the study was conducted. In this study, 112 patients were evaluated with more than 15 months of follow-up. The 57 (51%) who experienced a fall were compared with the 55 who did not.

Between these groups, there was no difference in mean age (approximately 57 years in both) or in gender (approximately 70% male in both), according to Dr. Srinivasan. However, those who fell were significantly more likely to be obese (P = .009), to be on two or more anti-Parkinson’s medication (P = .01), and to be hypertensive (P = .018). Disease duration was significantly longer and disease severity significantly greater in those who fell relative to those who did not, according to Dr. Srinivasan.

However, Dr. Srinivasan placed particular emphasis on the objective studies that predicted risk of falls.

“When we compared baseline characteristics, Tinetti balance score, episodes of freezing gait, and the Get-Up-And-Go Test [GAGT], were all significant predictors of falls [all P less than .001],” Dr. Srinivasan said.

Of clinical studies, he suggested that GAGT is particularly simple and helpful. In GAGT, the time for a patient to rise from a chair, walk 10 feet, and return to their original sitting position, is timed. According to Dr. Srinivasan, an interval of 12 seconds or greater is a measure of impaired mobility and a signal for increased risk of falls.

Other patient characteristics or disease features that predicted increased risk of falls included the presence of dyskinesias and treatment with relatively high doses of levodopa. All of these factors should be considered when conducting a comprehensive risk assessment.

“A formal evaluation should be conducted routinely in all patients because there are a number of simple and effective strategies to reduce falls in patients at high risk,” Dr. Srinivasan said. These include teaching patients to avoid abrupt movements and modifying therapies to avoid gait freezing and other symptoms associated with falls. He cited a 2014 review article by Canning et al. (Neurodegen Dis Manag. 2014;4:203-21) as one source of clinically useful approaches.

“Early prevention is important. One of the most significant risks of falls is a previous fall. Control of disease symptoms lowers risk, but motor symptoms are not the only concern,” Dr. Srinivasan said. He suggested nonmotor issues, including inadequate sleep, impaired cognitive function, and attention deficits, can all be addressed in order to prevent falls and the risks they pose to quality of life and outcome.

NEW YORK – There are numerous clinical factors and objective tools for identifying patients with Parkinson’s disease who have an increased risk of falls, according to data from a prospective study and an overview of this topic that was presented at the International Conference on Parkinson’s Disease and Movement Disorders

Ted Bosworth/MDedge News

“Identifying risk of falls, which can produce complications beyond the acute injury, is one of the most important unmet needs in Parkinson’s disease,” reported A.V. Srinivasan, MD, PhD, DSc, of the Tamil Nadu Dr. MGR Medial University, Chennai, India.

Falls pose a risk of complications beyond acute injury because of the potential domino effect, according to Dr. Srinivasan. He maintained that when aging Parkinson’s disease patients are confined to bed for an extended period of recovery, a host of adverse health consequences can follow, including such life-threatening events as aspiration pneumonia.

“A serious fall can be the start of a downward clinical slope,” according to Dr. Srinivasan, who cited data suggesting that 40%-70% of Parkinson’s disease patients will have a serious fall at advanced stages of disease.

To identify those at greatest risk, a number of objective studies were shown to be useful in a study undertaken at the Institute of Neurology of Madras (India) Medical College, according to Dr. Srinivasan, where he was a professor when the study was conducted. In this study, 112 patients were evaluated with more than 15 months of follow-up. The 57 (51%) who experienced a fall were compared with the 55 who did not.

Between these groups, there was no difference in mean age (approximately 57 years in both) or in gender (approximately 70% male in both), according to Dr. Srinivasan. However, those who fell were significantly more likely to be obese (P = .009), to be on two or more anti-Parkinson’s medication (P = .01), and to be hypertensive (P = .018). Disease duration was significantly longer and disease severity significantly greater in those who fell relative to those who did not, according to Dr. Srinivasan.

However, Dr. Srinivasan placed particular emphasis on the objective studies that predicted risk of falls.

“When we compared baseline characteristics, Tinetti balance score, episodes of freezing gait, and the Get-Up-And-Go Test [GAGT], were all significant predictors of falls [all P less than .001],” Dr. Srinivasan said.

Of clinical studies, he suggested that GAGT is particularly simple and helpful. In GAGT, the time for a patient to rise from a chair, walk 10 feet, and return to their original sitting position, is timed. According to Dr. Srinivasan, an interval of 12 seconds or greater is a measure of impaired mobility and a signal for increased risk of falls.

Other patient characteristics or disease features that predicted increased risk of falls included the presence of dyskinesias and treatment with relatively high doses of levodopa. All of these factors should be considered when conducting a comprehensive risk assessment.

“A formal evaluation should be conducted routinely in all patients because there are a number of simple and effective strategies to reduce falls in patients at high risk,” Dr. Srinivasan said. These include teaching patients to avoid abrupt movements and modifying therapies to avoid gait freezing and other symptoms associated with falls. He cited a 2014 review article by Canning et al. (Neurodegen Dis Manag. 2014;4:203-21) as one source of clinically useful approaches.

“Early prevention is important. One of the most significant risks of falls is a previous fall. Control of disease symptoms lowers risk, but motor symptoms are not the only concern,” Dr. Srinivasan said. He suggested nonmotor issues, including inadequate sleep, impaired cognitive function, and attention deficits, can all be addressed in order to prevent falls and the risks they pose to quality of life and outcome.

NEW YORK – There are numerous clinical factors and objective tools for identifying patients with Parkinson’s disease who have an increased risk of falls, according to data from a prospective study and an overview of this topic that was presented at the International Conference on Parkinson’s Disease and Movement Disorders

Ted Bosworth/MDedge News

“Identifying risk of falls, which can produce complications beyond the acute injury, is one of the most important unmet needs in Parkinson’s disease,” reported A.V. Srinivasan, MD, PhD, DSc, of the Tamil Nadu Dr. MGR Medial University, Chennai, India.

Falls pose a risk of complications beyond acute injury because of the potential domino effect, according to Dr. Srinivasan. He maintained that when aging Parkinson’s disease patients are confined to bed for an extended period of recovery, a host of adverse health consequences can follow, including such life-threatening events as aspiration pneumonia.

“A serious fall can be the start of a downward clinical slope,” according to Dr. Srinivasan, who cited data suggesting that 40%-70% of Parkinson’s disease patients will have a serious fall at advanced stages of disease.

To identify those at greatest risk, a number of objective studies were shown to be useful in a study undertaken at the Institute of Neurology of Madras (India) Medical College, according to Dr. Srinivasan, where he was a professor when the study was conducted. In this study, 112 patients were evaluated with more than 15 months of follow-up. The 57 (51%) who experienced a fall were compared with the 55 who did not.

Between these groups, there was no difference in mean age (approximately 57 years in both) or in gender (approximately 70% male in both), according to Dr. Srinivasan. However, those who fell were significantly more likely to be obese (P = .009), to be on two or more anti-Parkinson’s medication (P = .01), and to be hypertensive (P = .018). Disease duration was significantly longer and disease severity significantly greater in those who fell relative to those who did not, according to Dr. Srinivasan.

However, Dr. Srinivasan placed particular emphasis on the objective studies that predicted risk of falls.

“When we compared baseline characteristics, Tinetti balance score, episodes of freezing gait, and the Get-Up-And-Go Test [GAGT], were all significant predictors of falls [all P less than .001],” Dr. Srinivasan said.

Of clinical studies, he suggested that GAGT is particularly simple and helpful. In GAGT, the time for a patient to rise from a chair, walk 10 feet, and return to their original sitting position, is timed. According to Dr. Srinivasan, an interval of 12 seconds or greater is a measure of impaired mobility and a signal for increased risk of falls.

Other patient characteristics or disease features that predicted increased risk of falls included the presence of dyskinesias and treatment with relatively high doses of levodopa. All of these factors should be considered when conducting a comprehensive risk assessment.

“A formal evaluation should be conducted routinely in all patients because there are a number of simple and effective strategies to reduce falls in patients at high risk,” Dr. Srinivasan said. These include teaching patients to avoid abrupt movements and modifying therapies to avoid gait freezing and other symptoms associated with falls. He cited a 2014 review article by Canning et al. (Neurodegen Dis Manag. 2014;4:203-21) as one source of clinically useful approaches.

“Early prevention is important. One of the most significant risks of falls is a previous fall. Control of disease symptoms lowers risk, but motor symptoms are not the only concern,” Dr. Srinivasan said. He suggested nonmotor issues, including inadequate sleep, impaired cognitive function, and attention deficits, can all be addressed in order to prevent falls and the risks they pose to quality of life and outcome.

NEW YORK – A self-assembling model brain neurovascular unit showed that it emulated in vivo behavior of the human blood-brain barrier under a variety of conditions, including hypoxia and histamine exposure.

Goodwell Nzou, a doctoral student at Wake Forest University, Winston-Salem, N.C., discussed findings published earlier this year in Scientific Reports showing that the three-dimensional brain organoid has promise for rapid in vitro testing of central nervous system drugs.

The model contains all the primary cell types in the human brain cortex, said Mr. Nzou, speaking at the International Conference for Parkinson’s Disease and Movement Disorders. These include human brain microvascular endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes, and neurons. Human endothelial cells enclose the parenchymal cells in the model.

The human neurovascular unit (NVU) organoid model was developed using induced pluripotent stem cells for the microglial, oligodendrocyte, and neuron cell components. Human primary cells were used for the remaining components.

First, Mr. Nzou and his collaborators constructed a four-cell model. By placing the cells in a hanging drop culture environment and culturing for 96 hours, the investigators were able to induce assembly of the organoids. Since the cells had been pretreated with a durable labeling dye, the investigators could confirm anatomically appropriate self-assembly using confocal microscopy. Blood-brain barrier (BBB) tight junctions were confirmed by testing for the tight junction protein ZO-1 via immunofluorescent labeling, said Mr. Nzou.

From this experience, they were able to conduct a staged assembly using all six cell types, yielding a neurovascular unit that was durable, maintaining “very high cell viability for up to 21 days in vitro,” Mr. Nzou said, with both core and outer cells showing good viability.

Mr. Nzou and his colleagues at the Wake Forest Institute for Regenerative Medicine tested the model’s function against several emulated physical states: In one, they flooded the field with histamine, finding that the junctions lost integrity, accurately mimicking the “leaky” tissue state that occurs in vivo with histamine release.

The histamine-treated organoids allowed IgG permeability that was largely absent in the control organoids. “In the control system we did not see much of the IgG going in. We did see a lot more going in after we treated the organoids with histamine,” said Mr. Nzou.

However, IgG is a large molecule, and much CNS drug discovery right now is focused on small molecules, so Mr. Nzou and his colleagues also wanted to see whether the NVU’s BBB integrity would hold up against a small molecule.

Using exposure to a molecule called MPTP, Mr. Nzou and his collaborators compared how much MPTP entered two different types of organoids: One was the six-cell organoid, and the other was made up of neurons only.

The neuron-only organoid would not be expected to prevent influx of MPTP since it lacked the BBB-like composition of the full organoid, explained Mr. Nzou. Once past the BBB, MPTP is converted to an active substance that interferes with adenosine triphosphate (ATP) production . The investigators did see a significant drop in APT production with MPTP exposure in the neuron-only, but not the full, organoid, said Mr. Nzou.

In another trial, they exposed the model to an atmosphere with lowered oxygen tension and saw resultant changes consistent with ischemia. The model “showed normal physiologic responses under hypoxic conditions,” they said. These included increased proinflammatory cytokine production and decreased integrity of the BBB.

The in vitro hypoxia was profound – oxygen exposure was dropped to 1% from normal atmospheric composition of 21%. Still, the organoids maintained good viability despite the hypoxia-induced changes in physiology, making them appropriate candidates for testing such hypoxic conditions as ischemic stroke and conditions that elevate intracranial pressure, Mr. Nzou said.

In addition to drug discovery uses, the model could allow for rapid and safe toxicology research and for accelerated investigation of neurologic diseases, including Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis. The research group, said Mr. Nzou, has largely achieved its model of “forming a better blood-brain barrier–equivalent model through the concerted interactions of all cell types with the endothelial layer,” he said.

koakes@mdedge.com

NEW YORK – A self-assembling model brain neurovascular unit showed that it emulated in vivo behavior of the human blood-brain barrier under a variety of conditions, including hypoxia and histamine exposure.

Goodwell Nzou, a doctoral student at Wake Forest University, Winston-Salem, N.C., discussed findings published earlier this year in Scientific Reports showing that the three-dimensional brain organoid has promise for rapid in vitro testing of central nervous system drugs.

The model contains all the primary cell types in the human brain cortex, said Mr. Nzou, speaking at the International Conference for Parkinson’s Disease and Movement Disorders. These include human brain microvascular endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes, and neurons. Human endothelial cells enclose the parenchymal cells in the model.

The human neurovascular unit (NVU) organoid model was developed using induced pluripotent stem cells for the microglial, oligodendrocyte, and neuron cell components. Human primary cells were used for the remaining components.

First, Mr. Nzou and his collaborators constructed a four-cell model. By placing the cells in a hanging drop culture environment and culturing for 96 hours, the investigators were able to induce assembly of the organoids. Since the cells had been pretreated with a durable labeling dye, the investigators could confirm anatomically appropriate self-assembly using confocal microscopy. Blood-brain barrier (BBB) tight junctions were confirmed by testing for the tight junction protein ZO-1 via immunofluorescent labeling, said Mr. Nzou.

From this experience, they were able to conduct a staged assembly using all six cell types, yielding a neurovascular unit that was durable, maintaining “very high cell viability for up to 21 days in vitro,” Mr. Nzou said, with both core and outer cells showing good viability.

Mr. Nzou and his colleagues at the Wake Forest Institute for Regenerative Medicine tested the model’s function against several emulated physical states: In one, they flooded the field with histamine, finding that the junctions lost integrity, accurately mimicking the “leaky” tissue state that occurs in vivo with histamine release.

The histamine-treated organoids allowed IgG permeability that was largely absent in the control organoids. “In the control system we did not see much of the IgG going in. We did see a lot more going in after we treated the organoids with histamine,” said Mr. Nzou.

However, IgG is a large molecule, and much CNS drug discovery right now is focused on small molecules, so Mr. Nzou and his colleagues also wanted to see whether the NVU’s BBB integrity would hold up against a small molecule.

Using exposure to a molecule called MPTP, Mr. Nzou and his collaborators compared how much MPTP entered two different types of organoids: One was the six-cell organoid, and the other was made up of neurons only.

The neuron-only organoid would not be expected to prevent influx of MPTP since it lacked the BBB-like composition of the full organoid, explained Mr. Nzou. Once past the BBB, MPTP is converted to an active substance that interferes with adenosine triphosphate (ATP) production . The investigators did see a significant drop in APT production with MPTP exposure in the neuron-only, but not the full, organoid, said Mr. Nzou.

In another trial, they exposed the model to an atmosphere with lowered oxygen tension and saw resultant changes consistent with ischemia. The model “showed normal physiologic responses under hypoxic conditions,” they said. These included increased proinflammatory cytokine production and decreased integrity of the BBB.

The in vitro hypoxia was profound – oxygen exposure was dropped to 1% from normal atmospheric composition of 21%. Still, the organoids maintained good viability despite the hypoxia-induced changes in physiology, making them appropriate candidates for testing such hypoxic conditions as ischemic stroke and conditions that elevate intracranial pressure, Mr. Nzou said.

In addition to drug discovery uses, the model could allow for rapid and safe toxicology research and for accelerated investigation of neurologic diseases, including Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis. The research group, said Mr. Nzou, has largely achieved its model of “forming a better blood-brain barrier–equivalent model through the concerted interactions of all cell types with the endothelial layer,” he said.

koakes@mdedge.com

NEW YORK – A self-assembling model brain neurovascular unit showed that it emulated in vivo behavior of the human blood-brain barrier under a variety of conditions, including hypoxia and histamine exposure.

Goodwell Nzou, a doctoral student at Wake Forest University, Winston-Salem, N.C., discussed findings published earlier this year in Scientific Reports showing that the three-dimensional brain organoid has promise for rapid in vitro testing of central nervous system drugs.

The model contains all the primary cell types in the human brain cortex, said Mr. Nzou, speaking at the International Conference for Parkinson’s Disease and Movement Disorders. These include human brain microvascular endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes, and neurons. Human endothelial cells enclose the parenchymal cells in the model.

The human neurovascular unit (NVU) organoid model was developed using induced pluripotent stem cells for the microglial, oligodendrocyte, and neuron cell components. Human primary cells were used for the remaining components.

First, Mr. Nzou and his collaborators constructed a four-cell model. By placing the cells in a hanging drop culture environment and culturing for 96 hours, the investigators were able to induce assembly of the organoids. Since the cells had been pretreated with a durable labeling dye, the investigators could confirm anatomically appropriate self-assembly using confocal microscopy. Blood-brain barrier (BBB) tight junctions were confirmed by testing for the tight junction protein ZO-1 via immunofluorescent labeling, said Mr. Nzou.

From this experience, they were able to conduct a staged assembly using all six cell types, yielding a neurovascular unit that was durable, maintaining “very high cell viability for up to 21 days in vitro,” Mr. Nzou said, with both core and outer cells showing good viability.

Mr. Nzou and his colleagues at the Wake Forest Institute for Regenerative Medicine tested the model’s function against several emulated physical states: In one, they flooded the field with histamine, finding that the junctions lost integrity, accurately mimicking the “leaky” tissue state that occurs in vivo with histamine release.

The histamine-treated organoids allowed IgG permeability that was largely absent in the control organoids. “In the control system we did not see much of the IgG going in. We did see a lot more going in after we treated the organoids with histamine,” said Mr. Nzou.

However, IgG is a large molecule, and much CNS drug discovery right now is focused on small molecules, so Mr. Nzou and his colleagues also wanted to see whether the NVU’s BBB integrity would hold up against a small molecule.

Using exposure to a molecule called MPTP, Mr. Nzou and his collaborators compared how much MPTP entered two different types of organoids: One was the six-cell organoid, and the other was made up of neurons only.

The neuron-only organoid would not be expected to prevent influx of MPTP since it lacked the BBB-like composition of the full organoid, explained Mr. Nzou. Once past the BBB, MPTP is converted to an active substance that interferes with adenosine triphosphate (ATP) production . The investigators did see a significant drop in APT production with MPTP exposure in the neuron-only, but not the full, organoid, said Mr. Nzou.

In another trial, they exposed the model to an atmosphere with lowered oxygen tension and saw resultant changes consistent with ischemia. The model “showed normal physiologic responses under hypoxic conditions,” they said. These included increased proinflammatory cytokine production and decreased integrity of the BBB.

The in vitro hypoxia was profound – oxygen exposure was dropped to 1% from normal atmospheric composition of 21%. Still, the organoids maintained good viability despite the hypoxia-induced changes in physiology, making them appropriate candidates for testing such hypoxic conditions as ischemic stroke and conditions that elevate intracranial pressure, Mr. Nzou said.

In addition to drug discovery uses, the model could allow for rapid and safe toxicology research and for accelerated investigation of neurologic diseases, including Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis. The research group, said Mr. Nzou, has largely achieved its model of “forming a better blood-brain barrier–equivalent model through the concerted interactions of all cell types with the endothelial layer,” he said.

koakes@mdedge.com

NEW YORK – When paraganglionic lesions are compared with isolated basal ganglionic lesions in children, important differences in clinical manifestations were identified, according to imaging-based findings presented at the International Conference on Parkinson’s Disease and Movement Disorders.

Ted Bosworth/MDedge News

“The percentage of children with impaired cognitive function, motor weakness, and disturbed level of consciousness were all significantly higher among the paraganglionic group,” reported Hamada I. Zehry, MD, of Al-Azhar University, Cairo, Egypt.

Conversely, “the incidence of abnormal movements and rigidity were significantly higher among the group with basal ganglion lesions alone,” he said.

The findings were based on comparisons made after MRI imaging differentiated the 23 children with basal ganglionic lesions alone (IG) from 11 children with paraganglionic lesions (PG). About half of the PG group also had lesions involving the basal ganglion as well. All patients were 18 years of age or younger. The mean ages were 9 years in the IG group and 5.7 years in the PG group (P less than .04). Both groups contained approximately 55% males.

Both the IG and PG groups were stratified by ischemic, infectious, metabolic, and toxic etiologies. For the IG relative to the PG group, the ischemic (34.8% vs. 36.4%), infectious (26.1% vs. 36.4%), and metabolic (30.4% vs. 27.2%) etiologies had a relatively similar distribution. However, there was no patient in the PG group with a toxic etiology versus 8.7% (P = .003) in the IG group.

Neurologic symptoms by lesion site differed. Cognitive dysfunction (55% vs. 26%), seizures (64% vs. 43%), muscle weakness (45% vs. 30%), and changes in level of consciousness (82% vs. 22%) were all more common in the PG than the IG group according to Dr. Zehry. However, abnormal movements (30% vs. 9%) and rigidity (17% vs. 0%) were more common in the IG group.

These differences were all significant by conventional statistical analysis (P less than .05), according to Dr. Zehry, although he did not provide the specific P values for each of the comparisons.

There were also differences in the frequency of neurologic symptoms within groups when stratified by etiology. Of the biggest differences in the IG group, cognitive dysfunction was observed in 57% of those with a metabolic etiology but only 17% of those with an infectious etiology and 13% of those with an ischemic etiology. None of those with a toxic etiology had cognitive dysfunction.

In the PG group, the rates of cognitive dysfunction were 25%, 50%, and 100% for the ischemic, infectious, and metabolic etiologies, respectively. Changed levels of consciousness were observed in 75%, 100%, and 67% of these etiologies, respectively, in the PG group, but in only 13%, 33%, and 0%, respectively, in the IG group. In those with a toxic etiology in the IG group, a changed level of consciousness was observed in 100%.

Laboratory findings also were compared between groups and between etiologies within groups. It is notable that liver dysfunction and cytopenias were confined to those with metabolic infectious etiologies in both the IG and PG patients. However, Dr. Zehry suggested that the significance of these and other differences in laboratory findings deserve confirmation and further study in a larger study.

In this series, which excluded patients with a history of trauma or tumors, Dr. Zehry emphasized that bilateral lesions were commonly found in both groups. Overall, he cautioned that distinguishing IG and PG “is not straightforward.” In addition to MRI, he suggested additional imaging tools – such as MR angiography, MR venography, and CT scans – might be useful for evaluating children suspected of pathology in the basal ganglion.

Because there is often bilateral involvement, “the careful assessment of imaging abnormalities occurring simultaneously with bilateral ganglionic injury is recommended,” he said. He added that the diagnosis can also be facilitated by correlating imaging features with clinical and laboratory data.”

NEW YORK – When paraganglionic lesions are compared with isolated basal ganglionic lesions in children, important differences in clinical manifestations were identified, according to imaging-based findings presented at the International Conference on Parkinson’s Disease and Movement Disorders.

Ted Bosworth/MDedge News

“The percentage of children with impaired cognitive function, motor weakness, and disturbed level of consciousness were all significantly higher among the paraganglionic group,” reported Hamada I. Zehry, MD, of Al-Azhar University, Cairo, Egypt.

Conversely, “the incidence of abnormal movements and rigidity were significantly higher among the group with basal ganglion lesions alone,” he said.

The findings were based on comparisons made after MRI imaging differentiated the 23 children with basal ganglionic lesions alone (IG) from 11 children with paraganglionic lesions (PG). About half of the PG group also had lesions involving the basal ganglion as well. All patients were 18 years of age or younger. The mean ages were 9 years in the IG group and 5.7 years in the PG group (P less than .04). Both groups contained approximately 55% males.

Both the IG and PG groups were stratified by ischemic, infectious, metabolic, and toxic etiologies. For the IG relative to the PG group, the ischemic (34.8% vs. 36.4%), infectious (26.1% vs. 36.4%), and metabolic (30.4% vs. 27.2%) etiologies had a relatively similar distribution. However, there was no patient in the PG group with a toxic etiology versus 8.7% (P = .003) in the IG group.

Neurologic symptoms by lesion site differed. Cognitive dysfunction (55% vs. 26%), seizures (64% vs. 43%), muscle weakness (45% vs. 30%), and changes in level of consciousness (82% vs. 22%) were all more common in the PG than the IG group according to Dr. Zehry. However, abnormal movements (30% vs. 9%) and rigidity (17% vs. 0%) were more common in the IG group.

These differences were all significant by conventional statistical analysis (P less than .05), according to Dr. Zehry, although he did not provide the specific P values for each of the comparisons.

There were also differences in the frequency of neurologic symptoms within groups when stratified by etiology. Of the biggest differences in the IG group, cognitive dysfunction was observed in 57% of those with a metabolic etiology but only 17% of those with an infectious etiology and 13% of those with an ischemic etiology. None of those with a toxic etiology had cognitive dysfunction.

In the PG group, the rates of cognitive dysfunction were 25%, 50%, and 100% for the ischemic, infectious, and metabolic etiologies, respectively. Changed levels of consciousness were observed in 75%, 100%, and 67% of these etiologies, respectively, in the PG group, but in only 13%, 33%, and 0%, respectively, in the IG group. In those with a toxic etiology in the IG group, a changed level of consciousness was observed in 100%.

Laboratory findings also were compared between groups and between etiologies within groups. It is notable that liver dysfunction and cytopenias were confined to those with metabolic infectious etiologies in both the IG and PG patients. However, Dr. Zehry suggested that the significance of these and other differences in laboratory findings deserve confirmation and further study in a larger study.

In this series, which excluded patients with a history of trauma or tumors, Dr. Zehry emphasized that bilateral lesions were commonly found in both groups. Overall, he cautioned that distinguishing IG and PG “is not straightforward.” In addition to MRI, he suggested additional imaging tools – such as MR angiography, MR venography, and CT scans – might be useful for evaluating children suspected of pathology in the basal ganglion.

Because there is often bilateral involvement, “the careful assessment of imaging abnormalities occurring simultaneously with bilateral ganglionic injury is recommended,” he said. He added that the diagnosis can also be facilitated by correlating imaging features with clinical and laboratory data.”

NEW YORK – When paraganglionic lesions are compared with isolated basal ganglionic lesions in children, important differences in clinical manifestations were identified, according to imaging-based findings presented at the International Conference on Parkinson’s Disease and Movement Disorders.

Ted Bosworth/MDedge News

“The percentage of children with impaired cognitive function, motor weakness, and disturbed level of consciousness were all significantly higher among the paraganglionic group,” reported Hamada I. Zehry, MD, of Al-Azhar University, Cairo, Egypt.

Conversely, “the incidence of abnormal movements and rigidity were significantly higher among the group with basal ganglion lesions alone,” he said.

The findings were based on comparisons made after MRI imaging differentiated the 23 children with basal ganglionic lesions alone (IG) from 11 children with paraganglionic lesions (PG). About half of the PG group also had lesions involving the basal ganglion as well. All patients were 18 years of age or younger. The mean ages were 9 years in the IG group and 5.7 years in the PG group (P less than .04). Both groups contained approximately 55% males.

Both the IG and PG groups were stratified by ischemic, infectious, metabolic, and toxic etiologies. For the IG relative to the PG group, the ischemic (34.8% vs. 36.4%), infectious (26.1% vs. 36.4%), and metabolic (30.4% vs. 27.2%) etiologies had a relatively similar distribution. However, there was no patient in the PG group with a toxic etiology versus 8.7% (P = .003) in the IG group.

Neurologic symptoms by lesion site differed. Cognitive dysfunction (55% vs. 26%), seizures (64% vs. 43%), muscle weakness (45% vs. 30%), and changes in level of consciousness (82% vs. 22%) were all more common in the PG than the IG group according to Dr. Zehry. However, abnormal movements (30% vs. 9%) and rigidity (17% vs. 0%) were more common in the IG group.

These differences were all significant by conventional statistical analysis (P less than .05), according to Dr. Zehry, although he did not provide the specific P values for each of the comparisons.

There were also differences in the frequency of neurologic symptoms within groups when stratified by etiology. Of the biggest differences in the IG group, cognitive dysfunction was observed in 57% of those with a metabolic etiology but only 17% of those with an infectious etiology and 13% of those with an ischemic etiology. None of those with a toxic etiology had cognitive dysfunction.

In the PG group, the rates of cognitive dysfunction were 25%, 50%, and 100% for the ischemic, infectious, and metabolic etiologies, respectively. Changed levels of consciousness were observed in 75%, 100%, and 67% of these etiologies, respectively, in the PG group, but in only 13%, 33%, and 0%, respectively, in the IG group. In those with a toxic etiology in the IG group, a changed level of consciousness was observed in 100%.

Laboratory findings also were compared between groups and between etiologies within groups. It is notable that liver dysfunction and cytopenias were confined to those with metabolic infectious etiologies in both the IG and PG patients. However, Dr. Zehry suggested that the significance of these and other differences in laboratory findings deserve confirmation and further study in a larger study.

In this series, which excluded patients with a history of trauma or tumors, Dr. Zehry emphasized that bilateral lesions were commonly found in both groups. Overall, he cautioned that distinguishing IG and PG “is not straightforward.” In addition to MRI, he suggested additional imaging tools – such as MR angiography, MR venography, and CT scans – might be useful for evaluating children suspected of pathology in the basal ganglion.

Because there is often bilateral involvement, “the careful assessment of imaging abnormalities occurring simultaneously with bilateral ganglionic injury is recommended,” he said. He added that the diagnosis can also be facilitated by correlating imaging features with clinical and laboratory data.”

NEW YORK – Making the clinical diagnosis of dementia in Parkinson’s patients has been confounding because of the difficulty of differentiating it from dementia in Alzheimer’s disease, but researchers have developed a novel imaging technique, known as single-scan dynamic molecular imaging, which uses positron emission tomography to identify the key differentiating factor between the two types of dementia, as reported at the International Conference on Parkinson’s Disease and Movement Disorders.

Richard Mark Kirkner/MDedge News

“We have a technique with which we can detect neurotransmitters in the brain, particularly in patients with dementia,” said Rajendra D. Badgaiyan, PhD, professor of psychiatry at the Icahn School of Medicine at Mount Sinai in New York. “This is important to not only understand the type of dementia you’re dealing with but also to understand the underlying neurocognitive problem.”

The technique is called single-scan dynamic molecular imaging technique (SDMIT) and uses PET to detect and measure dopamine release activity in the brain during cognitive or behavioral functioning, he said. After patients are placed in the PET scanner, they receive an IV injection of the radio-labeled ligand fallypride. While in the PET scanner, patients are asked to perform a cognitive task, and PET measures the ligand concentration before and after the task in the dorsal striatum of the brain. The rate of ligand displacement before and after the task are compared to determine the levels of dopamine activity in the brain.

A significant dysregulation of dopaminergic neurotransmission would indicate a diagnosis of Parkinson’s dementia, while dysregulation of acetylcholine neurotransmission is characteristic of Alzheimer’s dementia, Dr. Badgaiyan said.

He described the experimentation that went into developing SDMIT, including its use in patients with ADHD and how the technique evolved from obtaining two PET scans to measure dopamine levels. His research also found that fallypride was the most effective ligand because it has a high affinity for the dopamine-2 receptor.

“The bottom line is that this technique can be used to study those conditions that are dopamine dependent” Dr. Badgaiyan said. “We can also use this technique to study the neurocognitive basis of the clinical symptoms in dementia and other cognitive deficits.”

SDMIT can also help to identify novel therapeutics targets for dementia, he said. “Today there is no medication that can reverse dementia; all the drugs that we use can only reduce the progression,” he said. “But this technique can help us identify which area of the brain should be targeted and what symptoms should be targeted to reverse dementia, treat dementia, or to cure dementia.”

Dr. Badgaiyan disclosed receiving funding for his research from the National Institutes of Mental Health, Department of Veterans Affairs, the Dana Foundation and Shriners Foundation.

NEW YORK – Making the clinical diagnosis of dementia in Parkinson’s patients has been confounding because of the difficulty of differentiating it from dementia in Alzheimer’s disease, but researchers have developed a novel imaging technique, known as single-scan dynamic molecular imaging, which uses positron emission tomography to identify the key differentiating factor between the two types of dementia, as reported at the International Conference on Parkinson’s Disease and Movement Disorders.

Richard Mark Kirkner/MDedge News

“We have a technique with which we can detect neurotransmitters in the brain, particularly in patients with dementia,” said Rajendra D. Badgaiyan, PhD, professor of psychiatry at the Icahn School of Medicine at Mount Sinai in New York. “This is important to not only understand the type of dementia you’re dealing with but also to understand the underlying neurocognitive problem.”

The technique is called single-scan dynamic molecular imaging technique (SDMIT) and uses PET to detect and measure dopamine release activity in the brain during cognitive or behavioral functioning, he said. After patients are placed in the PET scanner, they receive an IV injection of the radio-labeled ligand fallypride. While in the PET scanner, patients are asked to perform a cognitive task, and PET measures the ligand concentration before and after the task in the dorsal striatum of the brain. The rate of ligand displacement before and after the task are compared to determine the levels of dopamine activity in the brain.

A significant dysregulation of dopaminergic neurotransmission would indicate a diagnosis of Parkinson’s dementia, while dysregulation of acetylcholine neurotransmission is characteristic of Alzheimer’s dementia, Dr. Badgaiyan said.

He described the experimentation that went into developing SDMIT, including its use in patients with ADHD and how the technique evolved from obtaining two PET scans to measure dopamine levels. His research also found that fallypride was the most effective ligand because it has a high affinity for the dopamine-2 receptor.

“The bottom line is that this technique can be used to study those conditions that are dopamine dependent” Dr. Badgaiyan said. “We can also use this technique to study the neurocognitive basis of the clinical symptoms in dementia and other cognitive deficits.”

SDMIT can also help to identify novel therapeutics targets for dementia, he said. “Today there is no medication that can reverse dementia; all the drugs that we use can only reduce the progression,” he said. “But this technique can help us identify which area of the brain should be targeted and what symptoms should be targeted to reverse dementia, treat dementia, or to cure dementia.”

Dr. Badgaiyan disclosed receiving funding for his research from the National Institutes of Mental Health, Department of Veterans Affairs, the Dana Foundation and Shriners Foundation.

NEW YORK – Making the clinical diagnosis of dementia in Parkinson’s patients has been confounding because of the difficulty of differentiating it from dementia in Alzheimer’s disease, but researchers have developed a novel imaging technique, known as single-scan dynamic molecular imaging, which uses positron emission tomography to identify the key differentiating factor between the two types of dementia, as reported at the International Conference on Parkinson’s Disease and Movement Disorders.

Richard Mark Kirkner/MDedge News

“We have a technique with which we can detect neurotransmitters in the brain, particularly in patients with dementia,” said Rajendra D. Badgaiyan, PhD, professor of psychiatry at the Icahn School of Medicine at Mount Sinai in New York. “This is important to not only understand the type of dementia you’re dealing with but also to understand the underlying neurocognitive problem.”

The technique is called single-scan dynamic molecular imaging technique (SDMIT) and uses PET to detect and measure dopamine release activity in the brain during cognitive or behavioral functioning, he said. After patients are placed in the PET scanner, they receive an IV injection of the radio-labeled ligand fallypride. While in the PET scanner, patients are asked to perform a cognitive task, and PET measures the ligand concentration before and after the task in the dorsal striatum of the brain. The rate of ligand displacement before and after the task are compared to determine the levels of dopamine activity in the brain.

A significant dysregulation of dopaminergic neurotransmission would indicate a diagnosis of Parkinson’s dementia, while dysregulation of acetylcholine neurotransmission is characteristic of Alzheimer’s dementia, Dr. Badgaiyan said.

He described the experimentation that went into developing SDMIT, including its use in patients with ADHD and how the technique evolved from obtaining two PET scans to measure dopamine levels. His research also found that fallypride was the most effective ligand because it has a high affinity for the dopamine-2 receptor.

“The bottom line is that this technique can be used to study those conditions that are dopamine dependent” Dr. Badgaiyan said. “We can also use this technique to study the neurocognitive basis of the clinical symptoms in dementia and other cognitive deficits.”

SDMIT can also help to identify novel therapeutics targets for dementia, he said. “Today there is no medication that can reverse dementia; all the drugs that we use can only reduce the progression,” he said. “But this technique can help us identify which area of the brain should be targeted and what symptoms should be targeted to reverse dementia, treat dementia, or to cure dementia.”

Dr. Badgaiyan disclosed receiving funding for his research from the National Institutes of Mental Health, Department of Veterans Affairs, the Dana Foundation and Shriners Foundation.

NEW YORK – The loss of dopaminergic neurons is known to be a pivotal mechanism in Parkinson’s disease (PD), but early research into the anticonvulsant drug valproic acid has found it may produce antioxidant and neuroprotective actions that enhance the effects of levodopa, as reported at the International Conference on Parkinson’s Disease and Movement Disorders.

RIchard Mark Kirkner/MDedge News

“Levodopa had better activity than valproic aside, but when they are used together, they have really very effective results,” said Ece Genç, PhD, of Yeditepe University in Istanbul, who reported on the research conducted in her laboratory.

Dr. Genç noted her research in rats has focused on the possible mechanisms of neurodegeneration in Parkinson’s disease: mitochondrial dysfunction, oxidative stress and tissue damage, disruption in protein organization, and cell death caused by inflammatory changes. “Dopamine metabolism can itself be a toxic compound for the neurons,” she said, explaining that dopamine is critical for stabilizing nerve synapses, but its dysregulation can cause oxidative stress of the neurons, leading to cell death.

A key mechanism in the tremors PD patients experience is histone deacetylase, Dr. Genç said. “Histone acetylation and deacetylation are extremely important in these processes,” she said (Neurosci Lett. 2018 Feb 14;666:48-57). “Valproic acid is an antiepileptic drug; it is used in bipolar disorder and migraine complexes, but one of the major actions of valproic acid is that it caused histone deacetylase in the patients.”

Previous research that has shown the rotenone model of valproic acid provided neuroprotection helped drive her research, she said (Neurotox Res. 2010;17:130-41).

Future directions in her research would aim to synchronize cell cultures and in-vivo studies, and try to develop a method to measure alpha-synucleinopathy – abnormal levels of alpha-synuclein protein in the nerves of people with neurodegenerative diseases. “I think that alpha-synucleinopathy is the key word here,” Dr. Genç said. “We have to be very careful with alpha-synuclein proteins and their presence in individuals and, of course, with the successful use of valproic acid and histone deacetylase in patients, we can look for new drugs with less adverse effects.”

One of the drawbacks of valproic acid is that it affects so many different channels in the body. “We have to find some drugs with more targeted action.” Dr. Genç said.

Dr. Genç did not report any relevant disclosures.

NEW YORK – The loss of dopaminergic neurons is known to be a pivotal mechanism in Parkinson’s disease (PD), but early research into the anticonvulsant drug valproic acid has found it may produce antioxidant and neuroprotective actions that enhance the effects of levodopa, as reported at the International Conference on Parkinson’s Disease and Movement Disorders.

RIchard Mark Kirkner/MDedge News

“Levodopa had better activity than valproic aside, but when they are used together, they have really very effective results,” said Ece Genç, PhD, of Yeditepe University in Istanbul, who reported on the research conducted in her laboratory.

Dr. Genç noted her research in rats has focused on the possible mechanisms of neurodegeneration in Parkinson’s disease: mitochondrial dysfunction, oxidative stress and tissue damage, disruption in protein organization, and cell death caused by inflammatory changes. “Dopamine metabolism can itself be a toxic compound for the neurons,” she said, explaining that dopamine is critical for stabilizing nerve synapses, but its dysregulation can cause oxidative stress of the neurons, leading to cell death.

A key mechanism in the tremors PD patients experience is histone deacetylase, Dr. Genç said. “Histone acetylation and deacetylation are extremely important in these processes,” she said (Neurosci Lett. 2018 Feb 14;666:48-57). “Valproic acid is an antiepileptic drug; it is used in bipolar disorder and migraine complexes, but one of the major actions of valproic acid is that it caused histone deacetylase in the patients.”

Previous research that has shown the rotenone model of valproic acid provided neuroprotection helped drive her research, she said (Neurotox Res. 2010;17:130-41).

Future directions in her research would aim to synchronize cell cultures and in-vivo studies, and try to develop a method to measure alpha-synucleinopathy – abnormal levels of alpha-synuclein protein in the nerves of people with neurodegenerative diseases. “I think that alpha-synucleinopathy is the key word here,” Dr. Genç said. “We have to be very careful with alpha-synuclein proteins and their presence in individuals and, of course, with the successful use of valproic acid and histone deacetylase in patients, we can look for new drugs with less adverse effects.”

One of the drawbacks of valproic acid is that it affects so many different channels in the body. “We have to find some drugs with more targeted action.” Dr. Genç said.

Dr. Genç did not report any relevant disclosures.

NEW YORK – The loss of dopaminergic neurons is known to be a pivotal mechanism in Parkinson’s disease (PD), but early research into the anticonvulsant drug valproic acid has found it may produce antioxidant and neuroprotective actions that enhance the effects of levodopa, as reported at the International Conference on Parkinson’s Disease and Movement Disorders.

RIchard Mark Kirkner/MDedge News

“Levodopa had better activity than valproic aside, but when they are used together, they have really very effective results,” said Ece Genç, PhD, of Yeditepe University in Istanbul, who reported on the research conducted in her laboratory.

Dr. Genç noted her research in rats has focused on the possible mechanisms of neurodegeneration in Parkinson’s disease: mitochondrial dysfunction, oxidative stress and tissue damage, disruption in protein organization, and cell death caused by inflammatory changes. “Dopamine metabolism can itself be a toxic compound for the neurons,” she said, explaining that dopamine is critical for stabilizing nerve synapses, but its dysregulation can cause oxidative stress of the neurons, leading to cell death.

A key mechanism in the tremors PD patients experience is histone deacetylase, Dr. Genç said. “Histone acetylation and deacetylation are extremely important in these processes,” she said (Neurosci Lett. 2018 Feb 14;666:48-57). “Valproic acid is an antiepileptic drug; it is used in bipolar disorder and migraine complexes, but one of the major actions of valproic acid is that it caused histone deacetylase in the patients.”

Previous research that has shown the rotenone model of valproic acid provided neuroprotection helped drive her research, she said (Neurotox Res. 2010;17:130-41).

Future directions in her research would aim to synchronize cell cultures and in-vivo studies, and try to develop a method to measure alpha-synucleinopathy – abnormal levels of alpha-synuclein protein in the nerves of people with neurodegenerative diseases. “I think that alpha-synucleinopathy is the key word here,” Dr. Genç said. “We have to be very careful with alpha-synuclein proteins and their presence in individuals and, of course, with the successful use of valproic acid and histone deacetylase in patients, we can look for new drugs with less adverse effects.”

One of the drawbacks of valproic acid is that it affects so many different channels in the body. “We have to find some drugs with more targeted action.” Dr. Genç said.

Dr. Genç did not report any relevant disclosures.

NEW YORK – A combination of nutrients offered protection against neurodegeneration in a rodent model of parkinsonism, according to a new study.

Kari Oakes/MDedge News

The findings pave the way for human studies to explore whether nutritional supplementation in early Parkinson’s disease (PD) can modify the disease course, said Azza Ali, PhD, speaking at the International Conference on Parkinson’s Disease and Movement Disorders.

The rodent study found improvement in a broad array of behavioral, biochemical, and histopathologic measures in rats who were dosed with a combination of whole foods known to have constituents beneficial in other disease states.

Dr. Ali, who is head of the department of pharmacology and toxicology at Al-Azzah University, Cairo, said that the element manganese ingested in excessive amounts is neurotoxic to both humans and rodents. Many elements of manganism, or manganese poisoning, she said, mimic PD in both species. She added that, in humans, “Chronic exposures to low levels of manganese may progressively extend the site of manganese deposition and toxicity to the entire area of the basal ganglia,” and that this chronic exposure can be a risk factor for PD.

Manganese-induced oxidative stress, with subsequent neuroinflammation, DNA damage, and cell apoptosis and necrosis, is a logical target for therapy by means of nutritional supplementation, said Dr. Ali.

Dr. Ali and her collaborators selected several supplements to test against both control rats fed a usual diet and those in whom manganism had been induced via a 17-day run-in period of manganese supplementation.

Wheatgrass has active constituents, including chlorophyll, vitamins, minerals, enzymes, and amino acids, and has been studied in a variety of inflammatory conditions, said Dr. Ali. Cocoa is a natural source of flavonoids and was another nutrient selected for study.

Coenzyme Q10 (CoQ10) “acts as an antioxidant that scavenges free radicals and ... protects the stability of cell membranes,” and is key to mitochondrial bioenergetics, Dr. Ali said. Finally, pomegranate contains vitamins and minerals, as well as phenolic compounds that have been studied in diabetes and Alzheimer’s disease, she said.

The study’s primary aim was to assess the neuroprotective effects of each of these four supplements singly and in combination against manganese-induced parkinsonism in rats, with a secondary aim of comparing the efficacy of each substance against the others and against the combination taken together.

The PD rats were divided into five groups, with four groups each receiving one of the supplements, and one group receiving all four in combination. The normal controls – who were dosed with saline rather than manganese – made up the sixth group of rodents studied.

After 28 days, all groups were put through a series of behavioral tests. The investigators also drew blood to assess levels of a variety of neurotransmitters, inflammatory markers, and hormones. Finally, the animals were sacrificed for histopathologic examination of the cerebral cortex, the hippocampus, and the striatum, all areas where PD-related neurodegeneration are seen.

Compared with the control rats, the manganese-dosed rats showed significantly abnormal behavior, with longer latency shown on the classic swimming test and worse working memory performance in a maze test. In most cases, though, giving a PD model rat each supplement individually resulted in significant improvements in the behavioral tests. The PD model rats given the full combination of supplements showed performance essentially equal to the control rats, Dr. Ali said. Turning to the many biochemical parameters measured in the rodent study, Dr. Ali said that the supplements all ameliorated, but did not normalize, the proinflammatory effects of manganese. Tumor necrosis factor–alpha and interleukin 1–beta levels fell by about one half with all kinds of supplementation – a significant effect – but levels still far exceeded those seen in the control rats, she said.

Dopamine and norepinephrine levels rose markedly with supplement administration as well, though serotonin levels did not. With combination therapy, both dopamine and norepinephrine values, as well as those of gamma-aminobutyric acid and glutamate, approached those of controls, said Dr. Ali.

Histology of the control rats’ brains, as expected, showed no abnormal changes in the areas examined. The manganese-dosed rats showed a variety of degenerative changes, including diffuse nuclear pyknosis, and eosinophilic plaque formation within the striatum. The brains of the rats fed the individual supplements showed essentially the same amount of degeneration. However, Dr. Ali noted, rats fed the combination therapy had brain tissue that essentially looked like that of the control rats, with “no histopathological alteration” in any area examined.

A more fine-grained examination of the data showed that overall, “Cocoa and pomegranate showed more pronounced protection against neuronal degeneration and behavioral impairments induced by manganese than wheatgrass or CoQ10,” Dr. Ali said.

Still, the combination of nutrients offered “maximum protection” against manganese-induced parkinsonism, she said. “This combination of nutrients could be a meaningful approach to reduce motor and nonmotor symptoms of Parkinson’s disease, and warrants further study in human subjects.”

Dr. Ali reported no relevant financial disclosures.

koakes@mdedge.com
 

NEW YORK – A combination of nutrients offered protection against neurodegeneration in a rodent model of parkinsonism, according to a new study.

Kari Oakes/MDedge News

The findings pave the way for human studies to explore whether nutritional supplementation in early Parkinson’s disease (PD) can modify the disease course, said Azza Ali, PhD, speaking at the International Conference on Parkinson’s Disease and Movement Disorders.

The rodent study found improvement in a broad array of behavioral, biochemical, and histopathologic measures in rats who were dosed with a combination of whole foods known to have constituents beneficial in other disease states.

Dr. Ali, who is head of the department of pharmacology and toxicology at Al-Azzah University, Cairo, said that the element manganese ingested in excessive amounts is neurotoxic to both humans and rodents. Many elements of manganism, or manganese poisoning, she said, mimic PD in both species. She added that, in humans, “Chronic exposures to low levels of manganese may progressively extend the site of manganese deposition and toxicity to the entire area of the basal ganglia,” and that this chronic exposure can be a risk factor for PD.

Manganese-induced oxidative stress, with subsequent neuroinflammation, DNA damage, and cell apoptosis and necrosis, is a logical target for therapy by means of nutritional supplementation, said Dr. Ali.

Dr. Ali and her collaborators selected several supplements to test against both control rats fed a usual diet and those in whom manganism had been induced via a 17-day run-in period of manganese supplementation.

Wheatgrass has active constituents, including chlorophyll, vitamins, minerals, enzymes, and amino acids, and has been studied in a variety of inflammatory conditions, said Dr. Ali. Cocoa is a natural source of flavonoids and was another nutrient selected for study.

Coenzyme Q10 (CoQ10) “acts as an antioxidant that scavenges free radicals and ... protects the stability of cell membranes,” and is key to mitochondrial bioenergetics, Dr. Ali said. Finally, pomegranate contains vitamins and minerals, as well as phenolic compounds that have been studied in diabetes and Alzheimer’s disease, she said.

The study’s primary aim was to assess the neuroprotective effects of each of these four supplements singly and in combination against manganese-induced parkinsonism in rats, with a secondary aim of comparing the efficacy of each substance against the others and against the combination taken together.

The PD rats were divided into five groups, with four groups each receiving one of the supplements, and one group receiving all four in combination. The normal controls – who were dosed with saline rather than manganese – made up the sixth group of rodents studied.

After 28 days, all groups were put through a series of behavioral tests. The investigators also drew blood to assess levels of a variety of neurotransmitters, inflammatory markers, and hormones. Finally, the animals were sacrificed for histopathologic examination of the cerebral cortex, the hippocampus, and the striatum, all areas where PD-related neurodegeneration are seen.

Compared with the control rats, the manganese-dosed rats showed significantly abnormal behavior, with longer latency shown on the classic swimming test and worse working memory performance in a maze test. In most cases, though, giving a PD model rat each supplement individually resulted in significant improvements in the behavioral tests. The PD model rats given the full combination of supplements showed performance essentially equal to the control rats, Dr. Ali said. Turning to the many biochemical parameters measured in the rodent study, Dr. Ali said that the supplements all ameliorated, but did not normalize, the proinflammatory effects of manganese. Tumor necrosis factor–alpha and interleukin 1–beta levels fell by about one half with all kinds of supplementation – a significant effect – but levels still far exceeded those seen in the control rats, she said.

Dopamine and norepinephrine levels rose markedly with supplement administration as well, though serotonin levels did not. With combination therapy, both dopamine and norepinephrine values, as well as those of gamma-aminobutyric acid and glutamate, approached those of controls, said Dr. Ali.

Histology of the control rats’ brains, as expected, showed no abnormal changes in the areas examined. The manganese-dosed rats showed a variety of degenerative changes, including diffuse nuclear pyknosis, and eosinophilic plaque formation within the striatum. The brains of the rats fed the individual supplements showed essentially the same amount of degeneration. However, Dr. Ali noted, rats fed the combination therapy had brain tissue that essentially looked like that of the control rats, with “no histopathological alteration” in any area examined.

A more fine-grained examination of the data showed that overall, “Cocoa and pomegranate showed more pronounced protection against neuronal degeneration and behavioral impairments induced by manganese than wheatgrass or CoQ10,” Dr. Ali said.

Still, the combination of nutrients offered “maximum protection” against manganese-induced parkinsonism, she said. “This combination of nutrients could be a meaningful approach to reduce motor and nonmotor symptoms of Parkinson’s disease, and warrants further study in human subjects.”

Dr. Ali reported no relevant financial disclosures.

koakes@mdedge.com
 

NEW YORK – A combination of nutrients offered protection against neurodegeneration in a rodent model of parkinsonism, according to a new study.

Kari Oakes/MDedge News

The findings pave the way for human studies to explore whether nutritional supplementation in early Parkinson’s disease (PD) can modify the disease course, said Azza Ali, PhD, speaking at the International Conference on Parkinson’s Disease and Movement Disorders.

The rodent study found improvement in a broad array of behavioral, biochemical, and histopathologic measures in rats who were dosed with a combination of whole foods known to have constituents beneficial in other disease states.

Dr. Ali, who is head of the department of pharmacology and toxicology at Al-Azzah University, Cairo, said that the element manganese ingested in excessive amounts is neurotoxic to both humans and rodents. Many elements of manganism, or manganese poisoning, she said, mimic PD in both species. She added that, in humans, “Chronic exposures to low levels of manganese may progressively extend the site of manganese deposition and toxicity to the entire area of the basal ganglia,” and that this chronic exposure can be a risk factor for PD.

Manganese-induced oxidative stress, with subsequent neuroinflammation, DNA damage, and cell apoptosis and necrosis, is a logical target for therapy by means of nutritional supplementation, said Dr. Ali.

Dr. Ali and her collaborators selected several supplements to test against both control rats fed a usual diet and those in whom manganism had been induced via a 17-day run-in period of manganese supplementation.

Wheatgrass has active constituents, including chlorophyll, vitamins, minerals, enzymes, and amino acids, and has been studied in a variety of inflammatory conditions, said Dr. Ali. Cocoa is a natural source of flavonoids and was another nutrient selected for study.

Coenzyme Q10 (CoQ10) “acts as an antioxidant that scavenges free radicals and ... protects the stability of cell membranes,” and is key to mitochondrial bioenergetics, Dr. Ali said. Finally, pomegranate contains vitamins and minerals, as well as phenolic compounds that have been studied in diabetes and Alzheimer’s disease, she said.

The study’s primary aim was to assess the neuroprotective effects of each of these four supplements singly and in combination against manganese-induced parkinsonism in rats, with a secondary aim of comparing the efficacy of each substance against the others and against the combination taken together.

The PD rats were divided into five groups, with four groups each receiving one of the supplements, and one group receiving all four in combination. The normal controls – who were dosed with saline rather than manganese – made up the sixth group of rodents studied.

After 28 days, all groups were put through a series of behavioral tests. The investigators also drew blood to assess levels of a variety of neurotransmitters, inflammatory markers, and hormones. Finally, the animals were sacrificed for histopathologic examination of the cerebral cortex, the hippocampus, and the striatum, all areas where PD-related neurodegeneration are seen.

Compared with the control rats, the manganese-dosed rats showed significantly abnormal behavior, with longer latency shown on the classic swimming test and worse working memory performance in a maze test. In most cases, though, giving a PD model rat each supplement individually resulted in significant improvements in the behavioral tests. The PD model rats given the full combination of supplements showed performance essentially equal to the control rats, Dr. Ali said. Turning to the many biochemical parameters measured in the rodent study, Dr. Ali said that the supplements all ameliorated, but did not normalize, the proinflammatory effects of manganese. Tumor necrosis factor–alpha and interleukin 1–beta levels fell by about one half with all kinds of supplementation – a significant effect – but levels still far exceeded those seen in the control rats, she said.

Dopamine and norepinephrine levels rose markedly with supplement administration as well, though serotonin levels did not. With combination therapy, both dopamine and norepinephrine values, as well as those of gamma-aminobutyric acid and glutamate, approached those of controls, said Dr. Ali.

Histology of the control rats’ brains, as expected, showed no abnormal changes in the areas examined. The manganese-dosed rats showed a variety of degenerative changes, including diffuse nuclear pyknosis, and eosinophilic plaque formation within the striatum. The brains of the rats fed the individual supplements showed essentially the same amount of degeneration. However, Dr. Ali noted, rats fed the combination therapy had brain tissue that essentially looked like that of the control rats, with “no histopathological alteration” in any area examined.

A more fine-grained examination of the data showed that overall, “Cocoa and pomegranate showed more pronounced protection against neuronal degeneration and behavioral impairments induced by manganese than wheatgrass or CoQ10,” Dr. Ali said.

Still, the combination of nutrients offered “maximum protection” against manganese-induced parkinsonism, she said. “This combination of nutrients could be a meaningful approach to reduce motor and nonmotor symptoms of Parkinson’s disease, and warrants further study in human subjects.”

Dr. Ali reported no relevant financial disclosures.

koakes@mdedge.com