Movement Disorders

ATLANTA – VY-AADC01, an investigational gene therapy for individuals with medically refractory Parkinson’s disease being developed by Voyager Therapeutics, was well tolerated and decreased the need for antiparkinsonian medications, results from an ongoing phase 1b study showed.

“Prior phase 1 trials also introduced the aromatic l-amino acid decarboxylase (AADC) gene using an adeno-associated virus serotype-2 (AAV2) vector into the putamen of people with Parkinson’s disease (PD),” lead study author Chad Christine, MD, said in an interview in advance of the annual meeting of the American Neurological Association. “Unlike the previous trials, here we increased both vector genome concentration and volume of the AAV2-AADC vector (VY-AADC01) across cohorts and used intraoperative MRI guidance to administer the gene product.”

According to Dr. Christine, a neurologist at the University of California, San Francisco, Parkinson’s Disease Clinic and Research Center, prior trials showed that AAV2-AADC was safe, but there was limited clinical efficacy. This may have been because of the limited volume of putamen treated with the gene therapy. “In our current trial, we admixed VY-AADC01 with gadoteridol (ProHance), an MR imaging agent, which allowed both near real-time MRI monitoring of the location and volume of product infused and postsurgical assessment of the area of the putamen covered by VY-AADC01,” he said. “In addition, we used ¹⁸F-Dopa PET, which allowed us to assess the activity of the AADC enzyme in the putamen.”

The researchers enrolled three cohorts of patients who received bilateral infusions of VY-AADC01, admixed with gadoteridol to facilitate intraoperative MRI monitoring of the infusions. In cohort 1, five patients received up to 450 μL/putamen at a concentration of 8.3 × 10¹¹ vg (viral genomes)/mL and were followed for 36 months. In cohort 2, five patients received up to 900 μL/putamen at 8.3 × 10¹¹ vg/mL and were followed for 18 months. In cohort 3, five patients received up to 900 μL/putamen at 2.6 × 10¹² vg/mL and were followed for 12 months.

At 12 months, Dr. Christine and his associates observed mean levodopa-equivalent dose (LED) reductions of –10.2%, –32.8%, and –39.3% in cohort 1, cohort 2, and cohort 3, respectively; LED reductions were sustained to 18 months in cohorts 1 and 2. “We were impressed by how well the decrease in need for antiparkinsonian medications paralleled the AADC activity we measured in the putamen of our subjects, which is consistent with the proposed mechanism of action of VY-AADC01,” he said.

In addition, subjects in cohort 1 showed a mean 2.3-hour improvement in Parkinson’s diary-“on” time without troublesome dyskinesia at 24 months, which was maintained at 36 months, while subjects in cohort 2 showed a clinically meaningful 3.5-hour improvement at 18 months. Subjects in cohort 3 showed somewhat less improvement than the other cohorts (1.5 hours at 12 months), but they also had more severe baseline dyskinesia on the Unified Dyskinesia Rating Scale (a mean of 30.2 vs. 19.2 and 17.4 in cohorts 1 and 2, respectively). One patient in the trial experienced two surgery-related serious adverse events (pulmonary embolism and related heart arrhythmia) which resolved completely.

“I think we were somewhat surprised by some of the challenges of the surgical administration,” Dr. Christine said. “Our surgeons improved the administration technique throughout the trial and made a major transition from administering VY-AADC01 using a frontal approach to the putamen to using a posterior approach in our second phase 1 trial.”

He concluded that findings of the current trial suggest that AAV2-AADC gene therapy, administered using intraoperative MRI guidance, appears to be safe and well tolerated. “A number of outcomes suggest that it may offer clinical benefit to patients with advancing Parkinson’s disease, but this will have to be tested in a randomized trial which has recently started,” he said.

Dr. Christine acknowledged that the small sample size and the open-label design of the study limits the generalizability of the findings. The trial received support from Voyager Therapeutics and the Michael J. Fox Foundation. Dr. Christine reported having no disclosures.

[email protected]

Source: Christine et al. ANA 2018, Abstract M300.




 

ATLANTA – VY-AADC01, an investigational gene therapy for individuals with medically refractory Parkinson’s disease being developed by Voyager Therapeutics, was well tolerated and decreased the need for antiparkinsonian medications, results from an ongoing phase 1b study showed.

“Prior phase 1 trials also introduced the aromatic l-amino acid decarboxylase (AADC) gene using an adeno-associated virus serotype-2 (AAV2) vector into the putamen of people with Parkinson’s disease (PD),” lead study author Chad Christine, MD, said in an interview in advance of the annual meeting of the American Neurological Association. “Unlike the previous trials, here we increased both vector genome concentration and volume of the AAV2-AADC vector (VY-AADC01) across cohorts and used intraoperative MRI guidance to administer the gene product.”

According to Dr. Christine, a neurologist at the University of California, San Francisco, Parkinson’s Disease Clinic and Research Center, prior trials showed that AAV2-AADC was safe, but there was limited clinical efficacy. This may have been because of the limited volume of putamen treated with the gene therapy. “In our current trial, we admixed VY-AADC01 with gadoteridol (ProHance), an MR imaging agent, which allowed both near real-time MRI monitoring of the location and volume of product infused and postsurgical assessment of the area of the putamen covered by VY-AADC01,” he said. “In addition, we used ¹⁸F-Dopa PET, which allowed us to assess the activity of the AADC enzyme in the putamen.”

The researchers enrolled three cohorts of patients who received bilateral infusions of VY-AADC01, admixed with gadoteridol to facilitate intraoperative MRI monitoring of the infusions. In cohort 1, five patients received up to 450 μL/putamen at a concentration of 8.3 × 10¹¹ vg (viral genomes)/mL and were followed for 36 months. In cohort 2, five patients received up to 900 μL/putamen at 8.3 × 10¹¹ vg/mL and were followed for 18 months. In cohort 3, five patients received up to 900 μL/putamen at 2.6 × 10¹² vg/mL and were followed for 12 months.

At 12 months, Dr. Christine and his associates observed mean levodopa-equivalent dose (LED) reductions of –10.2%, –32.8%, and –39.3% in cohort 1, cohort 2, and cohort 3, respectively; LED reductions were sustained to 18 months in cohorts 1 and 2. “We were impressed by how well the decrease in need for antiparkinsonian medications paralleled the AADC activity we measured in the putamen of our subjects, which is consistent with the proposed mechanism of action of VY-AADC01,” he said.

In addition, subjects in cohort 1 showed a mean 2.3-hour improvement in Parkinson’s diary-“on” time without troublesome dyskinesia at 24 months, which was maintained at 36 months, while subjects in cohort 2 showed a clinically meaningful 3.5-hour improvement at 18 months. Subjects in cohort 3 showed somewhat less improvement than the other cohorts (1.5 hours at 12 months), but they also had more severe baseline dyskinesia on the Unified Dyskinesia Rating Scale (a mean of 30.2 vs. 19.2 and 17.4 in cohorts 1 and 2, respectively). One patient in the trial experienced two surgery-related serious adverse events (pulmonary embolism and related heart arrhythmia) which resolved completely.

“I think we were somewhat surprised by some of the challenges of the surgical administration,” Dr. Christine said. “Our surgeons improved the administration technique throughout the trial and made a major transition from administering VY-AADC01 using a frontal approach to the putamen to using a posterior approach in our second phase 1 trial.”

He concluded that findings of the current trial suggest that AAV2-AADC gene therapy, administered using intraoperative MRI guidance, appears to be safe and well tolerated. “A number of outcomes suggest that it may offer clinical benefit to patients with advancing Parkinson’s disease, but this will have to be tested in a randomized trial which has recently started,” he said.

Dr. Christine acknowledged that the small sample size and the open-label design of the study limits the generalizability of the findings. The trial received support from Voyager Therapeutics and the Michael J. Fox Foundation. Dr. Christine reported having no disclosures.

[email protected]

Source: Christine et al. ANA 2018, Abstract M300.




 

ATLANTA – VY-AADC01, an investigational gene therapy for individuals with medically refractory Parkinson’s disease being developed by Voyager Therapeutics, was well tolerated and decreased the need for antiparkinsonian medications, results from an ongoing phase 1b study showed.

“Prior phase 1 trials also introduced the aromatic l-amino acid decarboxylase (AADC) gene using an adeno-associated virus serotype-2 (AAV2) vector into the putamen of people with Parkinson’s disease (PD),” lead study author Chad Christine, MD, said in an interview in advance of the annual meeting of the American Neurological Association. “Unlike the previous trials, here we increased both vector genome concentration and volume of the AAV2-AADC vector (VY-AADC01) across cohorts and used intraoperative MRI guidance to administer the gene product.”

According to Dr. Christine, a neurologist at the University of California, San Francisco, Parkinson’s Disease Clinic and Research Center, prior trials showed that AAV2-AADC was safe, but there was limited clinical efficacy. This may have been because of the limited volume of putamen treated with the gene therapy. “In our current trial, we admixed VY-AADC01 with gadoteridol (ProHance), an MR imaging agent, which allowed both near real-time MRI monitoring of the location and volume of product infused and postsurgical assessment of the area of the putamen covered by VY-AADC01,” he said. “In addition, we used ¹⁸F-Dopa PET, which allowed us to assess the activity of the AADC enzyme in the putamen.”

The researchers enrolled three cohorts of patients who received bilateral infusions of VY-AADC01, admixed with gadoteridol to facilitate intraoperative MRI monitoring of the infusions. In cohort 1, five patients received up to 450 μL/putamen at a concentration of 8.3 × 10¹¹ vg (viral genomes)/mL and were followed for 36 months. In cohort 2, five patients received up to 900 μL/putamen at 8.3 × 10¹¹ vg/mL and were followed for 18 months. In cohort 3, five patients received up to 900 μL/putamen at 2.6 × 10¹² vg/mL and were followed for 12 months.

At 12 months, Dr. Christine and his associates observed mean levodopa-equivalent dose (LED) reductions of –10.2%, –32.8%, and –39.3% in cohort 1, cohort 2, and cohort 3, respectively; LED reductions were sustained to 18 months in cohorts 1 and 2. “We were impressed by how well the decrease in need for antiparkinsonian medications paralleled the AADC activity we measured in the putamen of our subjects, which is consistent with the proposed mechanism of action of VY-AADC01,” he said.

In addition, subjects in cohort 1 showed a mean 2.3-hour improvement in Parkinson’s diary-“on” time without troublesome dyskinesia at 24 months, which was maintained at 36 months, while subjects in cohort 2 showed a clinically meaningful 3.5-hour improvement at 18 months. Subjects in cohort 3 showed somewhat less improvement than the other cohorts (1.5 hours at 12 months), but they also had more severe baseline dyskinesia on the Unified Dyskinesia Rating Scale (a mean of 30.2 vs. 19.2 and 17.4 in cohorts 1 and 2, respectively). One patient in the trial experienced two surgery-related serious adverse events (pulmonary embolism and related heart arrhythmia) which resolved completely.

“I think we were somewhat surprised by some of the challenges of the surgical administration,” Dr. Christine said. “Our surgeons improved the administration technique throughout the trial and made a major transition from administering VY-AADC01 using a frontal approach to the putamen to using a posterior approach in our second phase 1 trial.”

He concluded that findings of the current trial suggest that AAV2-AADC gene therapy, administered using intraoperative MRI guidance, appears to be safe and well tolerated. “A number of outcomes suggest that it may offer clinical benefit to patients with advancing Parkinson’s disease, but this will have to be tested in a randomized trial which has recently started,” he said.

Dr. Christine acknowledged that the small sample size and the open-label design of the study limits the generalizability of the findings. The trial received support from Voyager Therapeutics and the Michael J. Fox Foundation. Dr. Christine reported having no disclosures.

[email protected]

Source: Christine et al. ANA 2018, Abstract M300.




 

ATLANTA – A majority of oromandibular dystonia patients treated with botulinum toxin injections reported improvement in symptoms in the largest cohort of patients to date.

Doug Brunk/MDedge News

Improvements in the range of 50%-100% occurred in 78% of oromandibular dystonia (OMD) patients who received botulinum toxin injections in the retrospective, multicenter analysis, which was presented by Laura Scorr, MD, at the annual meeting of the American Neurological Association.

In an effort to better describe the clinical characteristics of patients with OMD, Dr. Scorr, a movement disorders specialist at Emory University, Atlanta, and her colleagues analyzed data collected from 164 OMD patients enrolled at 26 international sites in the Dystonia Coalition and 37 additional patients who were evaluated at the Emory University within the last year. Subjects enrolled at Dystonia Coalition centers underwent evaluation by a movement disorders specialist to determine distribution of dystonia, areas affected, and severity as measured by the Global Dystonia Rating Scale. A subgroup of patients also completed the SF 36-item Health Survey, the Beck Depression Scale, and the Liebowitz social anxiety scale. Meanwhile, the charts of patients seen at Emory underwent review for data on clinical characteristics, treatment type, botulinum toxin doses, and response.

Among all 201 patients, the average age of onset was 54 years and 65% were female. About 45% were determined to have focal dystonia, 36% had segmental dystonia, and 19% had generalized dystonia. Among a cohort of 47 patients evaluated in the Dystonia Coalition biorepository, the researchers observed significantly increased social anxiety and impaired quality of life on the Liebowitz social anxiety scale and the SF-36 Health Survey.

Of the 37 Emory patients, 31 (84%) received botulinum toxin injections. Of these, 39% reported symptom improvement that ranged from 75%-100% while 39% reported symptom improvement that ranged from 50%-74%. Only 13% had a minimal response, defined as improvement that ranged from 1%-24%.

“Oromandibular dystonia is particularly disabling,” Dr. Scorr said. “There have been a few reports in the literature that say it does not respond to botulinum toxin injections. But in our retrospective review, the majority of patients not only have a response, but a response that’s greater than 50% improvement, which is significant.” She acknowledged that the study’s retrospective design is a limitation. “I think we need more prospective studies, specifically on response to treatment with botulinum toxin,” she said.

The study was funded in part by the Dystonia Medical Research Foundation. Dr. Scorr reported having no financial disclosures.

[email protected]

SOURCE: Scorr L et al. Ann Neurol. 2018;84[S22]:S90, Abstract S216.

ATLANTA – A majority of oromandibular dystonia patients treated with botulinum toxin injections reported improvement in symptoms in the largest cohort of patients to date.

Doug Brunk/MDedge News

Improvements in the range of 50%-100% occurred in 78% of oromandibular dystonia (OMD) patients who received botulinum toxin injections in the retrospective, multicenter analysis, which was presented by Laura Scorr, MD, at the annual meeting of the American Neurological Association.

In an effort to better describe the clinical characteristics of patients with OMD, Dr. Scorr, a movement disorders specialist at Emory University, Atlanta, and her colleagues analyzed data collected from 164 OMD patients enrolled at 26 international sites in the Dystonia Coalition and 37 additional patients who were evaluated at the Emory University within the last year. Subjects enrolled at Dystonia Coalition centers underwent evaluation by a movement disorders specialist to determine distribution of dystonia, areas affected, and severity as measured by the Global Dystonia Rating Scale. A subgroup of patients also completed the SF 36-item Health Survey, the Beck Depression Scale, and the Liebowitz social anxiety scale. Meanwhile, the charts of patients seen at Emory underwent review for data on clinical characteristics, treatment type, botulinum toxin doses, and response.

Among all 201 patients, the average age of onset was 54 years and 65% were female. About 45% were determined to have focal dystonia, 36% had segmental dystonia, and 19% had generalized dystonia. Among a cohort of 47 patients evaluated in the Dystonia Coalition biorepository, the researchers observed significantly increased social anxiety and impaired quality of life on the Liebowitz social anxiety scale and the SF-36 Health Survey.

Of the 37 Emory patients, 31 (84%) received botulinum toxin injections. Of these, 39% reported symptom improvement that ranged from 75%-100% while 39% reported symptom improvement that ranged from 50%-74%. Only 13% had a minimal response, defined as improvement that ranged from 1%-24%.

“Oromandibular dystonia is particularly disabling,” Dr. Scorr said. “There have been a few reports in the literature that say it does not respond to botulinum toxin injections. But in our retrospective review, the majority of patients not only have a response, but a response that’s greater than 50% improvement, which is significant.” She acknowledged that the study’s retrospective design is a limitation. “I think we need more prospective studies, specifically on response to treatment with botulinum toxin,” she said.

The study was funded in part by the Dystonia Medical Research Foundation. Dr. Scorr reported having no financial disclosures.

[email protected]

SOURCE: Scorr L et al. Ann Neurol. 2018;84[S22]:S90, Abstract S216.

ATLANTA – A majority of oromandibular dystonia patients treated with botulinum toxin injections reported improvement in symptoms in the largest cohort of patients to date.

Doug Brunk/MDedge News

Improvements in the range of 50%-100% occurred in 78% of oromandibular dystonia (OMD) patients who received botulinum toxin injections in the retrospective, multicenter analysis, which was presented by Laura Scorr, MD, at the annual meeting of the American Neurological Association.

In an effort to better describe the clinical characteristics of patients with OMD, Dr. Scorr, a movement disorders specialist at Emory University, Atlanta, and her colleagues analyzed data collected from 164 OMD patients enrolled at 26 international sites in the Dystonia Coalition and 37 additional patients who were evaluated at the Emory University within the last year. Subjects enrolled at Dystonia Coalition centers underwent evaluation by a movement disorders specialist to determine distribution of dystonia, areas affected, and severity as measured by the Global Dystonia Rating Scale. A subgroup of patients also completed the SF 36-item Health Survey, the Beck Depression Scale, and the Liebowitz social anxiety scale. Meanwhile, the charts of patients seen at Emory underwent review for data on clinical characteristics, treatment type, botulinum toxin doses, and response.

Among all 201 patients, the average age of onset was 54 years and 65% were female. About 45% were determined to have focal dystonia, 36% had segmental dystonia, and 19% had generalized dystonia. Among a cohort of 47 patients evaluated in the Dystonia Coalition biorepository, the researchers observed significantly increased social anxiety and impaired quality of life on the Liebowitz social anxiety scale and the SF-36 Health Survey.

Of the 37 Emory patients, 31 (84%) received botulinum toxin injections. Of these, 39% reported symptom improvement that ranged from 75%-100% while 39% reported symptom improvement that ranged from 50%-74%. Only 13% had a minimal response, defined as improvement that ranged from 1%-24%.

“Oromandibular dystonia is particularly disabling,” Dr. Scorr said. “There have been a few reports in the literature that say it does not respond to botulinum toxin injections. But in our retrospective review, the majority of patients not only have a response, but a response that’s greater than 50% improvement, which is significant.” She acknowledged that the study’s retrospective design is a limitation. “I think we need more prospective studies, specifically on response to treatment with botulinum toxin,” she said.

The study was funded in part by the Dystonia Medical Research Foundation. Dr. Scorr reported having no financial disclosures.

[email protected]

SOURCE: Scorr L et al. Ann Neurol. 2018;84[S22]:S90, Abstract S216.

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.

[email protected]

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.

[email protected]

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.

[email protected]

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.

[email protected]
 

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.

[email protected]
 

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.

[email protected]
 

NEW YORK – One reason to pursue a multimodality strategy to control the symptoms as well as the underlying pathophysiology of Parkinson’s disease (PD) is that a small but substantial proportion of patients with PD-like symptoms have a different diagnosis, according to an expert overview at the International Conference on Parkinson’s Disease and Movement Disorders.

Ted Bosworth/MDedge News

“Fifteen to 20% of patients treated for Parkinson’s disease, even in the most established centers of excellence, do not have Parkinson’s disease on necropsy,” said A.V. Srinivasan, MD, PhD, DSc, of The Tamil Nadu Dr. M.G.R. Medical University, Chennai, India.

This does not preclude benefit from antiparkinson drugs in those patients with PD-like symptoms but a different etiology. Many can benefit from increased dopamine availability, even in the absence of PD, but it emphasizes the complexity of clinical diseases associated with diminished dopamine function, according to Dr. Srinivasan. He characterized this complexity as a reason to avoid a regimented approach to PD management.

“You can just imagine how much this influences our data analysis,” said Dr. Srinivasan, referring to clinical trials designed to generate evidence-based treatment. “We should remember that we should not be too statistically oriented,” he added, citing the adage that “statistics can cause paralysis in your analysis.”

PD is associated with a vast array of neurologic and physical symptoms attributable to PD that overlap with other neurologic disorders, which is the reason that a definitive diagnosis is challenging, according to Dr. Srinivasan. Listing symptoms that should prompt consideration of an alternative diagnosis, Dr. Srinivasan said hallucinations suggest diffuse Lewy body disease, myoclonus suggests corticobasal degeneration, and amyotrophy suggests multiple system atrophy.

“These are only clues, however,” said Dr. Srinivasan, suggesting their presence should prompt consideration of alternative diagnoses, but their absence does not confirm PD.

In some cases, further work-up with one or more of the array of increasingly sophisticated imaging strategies, such as the combination of SPECT and PET, might help clinicians reach a more definitive diagnosis of the underlying pathology, a step that might guide use of dopaminergic therapies. However, effective treatment of PD symptoms does not depend on a definitive diagnosis.

Rather, Dr. Srinivasan advocated an open mind to the management of symptoms, which he indicated are best addressed empirically. As PD or other progressive movement disorders advance, the goal is to keep patients functional and comfortable.

This includes managing patients beyond prescription drugs to address such complications as dysphagia or impaired balance. He advocated practical solutions for causes of impaired quality of life such as soft foods to facilitate swallowing or walkers to keep patients ambulatory. No option that leads to symptom relief should be discounted, including alternative therapies.

“Some clinicians are strongly opposed to nontraditional therapies, such as naturopathy and homeopathy, but these have all been used in Parkinson’s,” Dr. Srinivasan said. Although he did not present data to show efficacy, he indicated that relief of symptoms and improvement of quality of life is the point of any treatment, which should be individualized by response in every patient.

And individualized therapy – in relationship to patient age – is particularly important, according to Dr. Srinivasan. While younger patients typically tolerate relatively aggressive therapies aimed at both PD and its specific symptoms, older patients may accept less ambitious functional improvements to achieve an adequate quality of life.

“After 70 years of age, every additional year is a bonus. After 80 years, every week is a bonus. After 90 years, every minute is a bonus,” said Dr. Srinivasan, in emphasizing an appropriate clinical perspective.

NEW YORK – One reason to pursue a multimodality strategy to control the symptoms as well as the underlying pathophysiology of Parkinson’s disease (PD) is that a small but substantial proportion of patients with PD-like symptoms have a different diagnosis, according to an expert overview at the International Conference on Parkinson’s Disease and Movement Disorders.

Ted Bosworth/MDedge News

“Fifteen to 20% of patients treated for Parkinson’s disease, even in the most established centers of excellence, do not have Parkinson’s disease on necropsy,” said A.V. Srinivasan, MD, PhD, DSc, of The Tamil Nadu Dr. M.G.R. Medical University, Chennai, India.

This does not preclude benefit from antiparkinson drugs in those patients with PD-like symptoms but a different etiology. Many can benefit from increased dopamine availability, even in the absence of PD, but it emphasizes the complexity of clinical diseases associated with diminished dopamine function, according to Dr. Srinivasan. He characterized this complexity as a reason to avoid a regimented approach to PD management.

“You can just imagine how much this influences our data analysis,” said Dr. Srinivasan, referring to clinical trials designed to generate evidence-based treatment. “We should remember that we should not be too statistically oriented,” he added, citing the adage that “statistics can cause paralysis in your analysis.”

PD is associated with a vast array of neurologic and physical symptoms attributable to PD that overlap with other neurologic disorders, which is the reason that a definitive diagnosis is challenging, according to Dr. Srinivasan. Listing symptoms that should prompt consideration of an alternative diagnosis, Dr. Srinivasan said hallucinations suggest diffuse Lewy body disease, myoclonus suggests corticobasal degeneration, and amyotrophy suggests multiple system atrophy.

“These are only clues, however,” said Dr. Srinivasan, suggesting their presence should prompt consideration of alternative diagnoses, but their absence does not confirm PD.

In some cases, further work-up with one or more of the array of increasingly sophisticated imaging strategies, such as the combination of SPECT and PET, might help clinicians reach a more definitive diagnosis of the underlying pathology, a step that might guide use of dopaminergic therapies. However, effective treatment of PD symptoms does not depend on a definitive diagnosis.

Rather, Dr. Srinivasan advocated an open mind to the management of symptoms, which he indicated are best addressed empirically. As PD or other progressive movement disorders advance, the goal is to keep patients functional and comfortable.

This includes managing patients beyond prescription drugs to address such complications as dysphagia or impaired balance. He advocated practical solutions for causes of impaired quality of life such as soft foods to facilitate swallowing or walkers to keep patients ambulatory. No option that leads to symptom relief should be discounted, including alternative therapies.

“Some clinicians are strongly opposed to nontraditional therapies, such as naturopathy and homeopathy, but these have all been used in Parkinson’s,” Dr. Srinivasan said. Although he did not present data to show efficacy, he indicated that relief of symptoms and improvement of quality of life is the point of any treatment, which should be individualized by response in every patient.

And individualized therapy – in relationship to patient age – is particularly important, according to Dr. Srinivasan. While younger patients typically tolerate relatively aggressive therapies aimed at both PD and its specific symptoms, older patients may accept less ambitious functional improvements to achieve an adequate quality of life.

“After 70 years of age, every additional year is a bonus. After 80 years, every week is a bonus. After 90 years, every minute is a bonus,” said Dr. Srinivasan, in emphasizing an appropriate clinical perspective.

NEW YORK – One reason to pursue a multimodality strategy to control the symptoms as well as the underlying pathophysiology of Parkinson’s disease (PD) is that a small but substantial proportion of patients with PD-like symptoms have a different diagnosis, according to an expert overview at the International Conference on Parkinson’s Disease and Movement Disorders.

Ted Bosworth/MDedge News

“Fifteen to 20% of patients treated for Parkinson’s disease, even in the most established centers of excellence, do not have Parkinson’s disease on necropsy,” said A.V. Srinivasan, MD, PhD, DSc, of The Tamil Nadu Dr. M.G.R. Medical University, Chennai, India.

This does not preclude benefit from antiparkinson drugs in those patients with PD-like symptoms but a different etiology. Many can benefit from increased dopamine availability, even in the absence of PD, but it emphasizes the complexity of clinical diseases associated with diminished dopamine function, according to Dr. Srinivasan. He characterized this complexity as a reason to avoid a regimented approach to PD management.

“You can just imagine how much this influences our data analysis,” said Dr. Srinivasan, referring to clinical trials designed to generate evidence-based treatment. “We should remember that we should not be too statistically oriented,” he added, citing the adage that “statistics can cause paralysis in your analysis.”

PD is associated with a vast array of neurologic and physical symptoms attributable to PD that overlap with other neurologic disorders, which is the reason that a definitive diagnosis is challenging, according to Dr. Srinivasan. Listing symptoms that should prompt consideration of an alternative diagnosis, Dr. Srinivasan said hallucinations suggest diffuse Lewy body disease, myoclonus suggests corticobasal degeneration, and amyotrophy suggests multiple system atrophy.

“These are only clues, however,” said Dr. Srinivasan, suggesting their presence should prompt consideration of alternative diagnoses, but their absence does not confirm PD.

In some cases, further work-up with one or more of the array of increasingly sophisticated imaging strategies, such as the combination of SPECT and PET, might help clinicians reach a more definitive diagnosis of the underlying pathology, a step that might guide use of dopaminergic therapies. However, effective treatment of PD symptoms does not depend on a definitive diagnosis.

Rather, Dr. Srinivasan advocated an open mind to the management of symptoms, which he indicated are best addressed empirically. As PD or other progressive movement disorders advance, the goal is to keep patients functional and comfortable.

This includes managing patients beyond prescription drugs to address such complications as dysphagia or impaired balance. He advocated practical solutions for causes of impaired quality of life such as soft foods to facilitate swallowing or walkers to keep patients ambulatory. No option that leads to symptom relief should be discounted, including alternative therapies.

“Some clinicians are strongly opposed to nontraditional therapies, such as naturopathy and homeopathy, but these have all been used in Parkinson’s,” Dr. Srinivasan said. Although he did not present data to show efficacy, he indicated that relief of symptoms and improvement of quality of life is the point of any treatment, which should be individualized by response in every patient.

And individualized therapy – in relationship to patient age – is particularly important, according to Dr. Srinivasan. While younger patients typically tolerate relatively aggressive therapies aimed at both PD and its specific symptoms, older patients may accept less ambitious functional improvements to achieve an adequate quality of life.

“After 70 years of age, every additional year is a bonus. After 80 years, every week is a bonus. After 90 years, every minute is a bonus,” said Dr. Srinivasan, in emphasizing an appropriate clinical perspective.

NEW YORK – Sending sensory feedback upstream to patients with Parkinson’s disease (PD) may offer a low-risk, nonpharmaceutical method to retain and improve motor function. These interventions may be especially helpful in the subpopulation of patients who are intolerant to exercise, with a growing body of evidence showing sustained benefit for newer sensory stimulation techniques.

Kari Oakes/MDedge News

“In a healthy person, movement is the seamless integration of sensory and motor systems,” said Ben Weinstock, DPT, speaking at the International Conference on Parkinson’s Disease and Movement Disorders, pointing out that movement stimulates the senses, and sensory stimulation improves movement.

By contrast, patients with PD experience more than just problems with motor function. Patients with PD and sensory or autonomic dysfunction may find these disturbances contributing to motor dysfunction, said Dr. Weinstock, who treats patients with PD and a variety of complex medical conditions in his private practice.

Some of the hallmark features of PD are movement related: the cogwheel rigidity, bradykinesia, and freezing all contribute to poor balance and a fear of falling. Commonly, PD patients also experience fatigue and alterations in cognition and mood.

However, afferent small-fiber neuropathies and centrally mediated mechanisms in PD can also disturb sensory input: Vestibular function, equilibrium, proprioception, and light and deep touch may all be affected, Dr. Weinstock said.

Autonomic dysfunction can be an underappreciated feature of PD, but such manifestations as orthostatic hypotension and poor thermal regulation can have significant negative impact on quality of life for an individual with PD.

Perhaps the gravest variant of autonomic dysregulation, however, is the cardiac denervation that frequently accompanies PD, said Dr. Weinstock. “Although there is a belief that intensive exercise helps people with PD, many individuals are actually exercise intolerant because of loss of cardiac norepinephrine,” he said (J Neurochem. 2014;131[2]:219-228). “A person with PD who is exercise intolerant is at risk” of syncope, falls, and even serious cardiac events during exercise, he noted.

Cardiovascular dysautonomia in PD has been documented in serial ¹⁸F-dopamine PET scans, showing progressive reduction in uptake over the course of several years in individual patients (Neurobiol Dis. 2012 June;46[3]:572-80). Similarly, studies have shown lower cardiac radiotracer uptake in patients with PD, compared with normal controls, he said (NPJ Parkinsons Dis. 2017. doi: 10.1038/S41531-017-0017-1).

It’s not easy to determine what level of nonmotor dysfunction a given patient has at a particular point in disease progression, said Dr. Weinstock.

“There is no correlation between motor and nonmotor deterioration,” he said. “Somebody might be newly diagnosed with just a mild tremor and still have significant cardiac denervation.”

Weighing how to help an exercise-intolerant patient with PD means taking into consideration the known risks and side effect profile of PD medications, Dr. Weinstock pointed out. Increasing medications, or beginning a new drug therapy, can mean increased risk for unwanted psychiatric side effects and ototoxicity, among other potential ill effects.

Similarly, the decision to implant deep brain stimulation is not to be taken lightly, since depression can begin or worsen, and any surgical procedure carries risks.

For Dr. Weinstock, using strategies to improve sensory input are “a valid option for people with PD.” Such a strategy is safe, and even brief bouts of stimulation “can have significant, beneficial effects,” he said. “The overall goal is to avoid sedentary behavior,” with its accompanying ills, he said.

Dr. Weinstock noted that he uses different strategies to stimulate the various senses, including bright light therapy, which can help regulate circadian rhythms and promote appropriate melatonin secretion, improving sleep and upping daytime wakefulness.

Another visual strategy when working on gait is to use surface lines, a checkerboard pattern, or other targets that provide a visual goal for step length, which typically shortens with PD progression. Though more high-tech options exist, Dr. Weinstock suggested patients begin with just laying lines of masking tape along the floor to mark the target gait length. “Usually the cheap technique is a good test to see if it’s going to work,” he said.

An auditory strategy to improve the gait cycle is use of a metronome or other rhythmic auditory stimulation; music can be helpful in this regard and as a general cognitive and emotional stimulus, said Dr. Weinstock.

“Loss of smell is an early sign of Parkinson’s,” said Dr. Weinstock, and taste also can be dulled. Though offering tasty meals could help reduce risk of malnutrition in PD patients, “It remains to be seen if aromatherapy can lead to neural plasticity and reverse smell loss in PD.”

Vestibular rehabilitation techniques can help not just with balance, but also with helping to lift mood and improve functional activities, according to one study (Arq Neuropsiquiatr 2009;67[2-A]:219-23).

Other ways to provide proprioceptive feedback include the use of orthotics and textured insoles and the use of a weighted vest. Dr. Weinstock also gives consideration to skin taping, which may give patients useful feedback about their bodies’ position in space, he said.

Intriguing results have been seen with acupuncture, acupressure, and electroacupuncture for PD patients, said Dr. Weinstock. In particular, a technique called automated mechanical pressure stimulation uses a bootlike device to provide mechanical stimulation to points at the head of the great toe and on the ball of the foot at the head of the first metatarsal bone.

One functional magnetic resonance imaging (fMRI) study showed acutely increased resting state functional connectivity after such stimulation, in comparison with a sham procedure that also applied pressure, but over a broader area, he said.

After the stimulation procedure used in the study, the patients who received actual stimulation also saw improved ability to initiate voluntary movements, less tremor and rigidity, and less gait freezing (PLoS One. 2015 Oct 15. doi: 10.1371/journal.pone.0137977).

Other studies of the mechanical stimulation device showed similar results, with some showing that repeated sessions helped maintain these and other benefits, such as improved walking velocity, stride length, and Timed Up and Go results – an assessment of fall risk (Int J Rehabil Res. 2015 Sep;38[3]:238-45). Treatment with the device, dubbed Gondola, is most widely available in Italy, where clinical trials are ongoing.

Stimulation to an acupuncture point located on the proximal lateral leg, near the head of the fibula, showed improvements in gait parameters and in fMRI-assessed brain connectivity as well, noted Dr. Weinstock (CNS Neurosci Ther. 2012 Sep;18[9]:781-90).

“There’s a growing amount of evidence that various types of sensory stimulation can have significant benefits for people with Parkinson’s Disease, especially for those who are exercise intolerant,” said Dr. Weinstock.

Dr. Weinstock reported no relevant disclosures.

[email protected]

NEW YORK – Sending sensory feedback upstream to patients with Parkinson’s disease (PD) may offer a low-risk, nonpharmaceutical method to retain and improve motor function. These interventions may be especially helpful in the subpopulation of patients who are intolerant to exercise, with a growing body of evidence showing sustained benefit for newer sensory stimulation techniques.

Kari Oakes/MDedge News

“In a healthy person, movement is the seamless integration of sensory and motor systems,” said Ben Weinstock, DPT, speaking at the International Conference on Parkinson’s Disease and Movement Disorders, pointing out that movement stimulates the senses, and sensory stimulation improves movement.

By contrast, patients with PD experience more than just problems with motor function. Patients with PD and sensory or autonomic dysfunction may find these disturbances contributing to motor dysfunction, said Dr. Weinstock, who treats patients with PD and a variety of complex medical conditions in his private practice.

Some of the hallmark features of PD are movement related: the cogwheel rigidity, bradykinesia, and freezing all contribute to poor balance and a fear of falling. Commonly, PD patients also experience fatigue and alterations in cognition and mood.

However, afferent small-fiber neuropathies and centrally mediated mechanisms in PD can also disturb sensory input: Vestibular function, equilibrium, proprioception, and light and deep touch may all be affected, Dr. Weinstock said.

Autonomic dysfunction can be an underappreciated feature of PD, but such manifestations as orthostatic hypotension and poor thermal regulation can have significant negative impact on quality of life for an individual with PD.

Perhaps the gravest variant of autonomic dysregulation, however, is the cardiac denervation that frequently accompanies PD, said Dr. Weinstock. “Although there is a belief that intensive exercise helps people with PD, many individuals are actually exercise intolerant because of loss of cardiac norepinephrine,” he said (J Neurochem. 2014;131[2]:219-228). “A person with PD who is exercise intolerant is at risk” of syncope, falls, and even serious cardiac events during exercise, he noted.

Cardiovascular dysautonomia in PD has been documented in serial ¹⁸F-dopamine PET scans, showing progressive reduction in uptake over the course of several years in individual patients (Neurobiol Dis. 2012 June;46[3]:572-80). Similarly, studies have shown lower cardiac radiotracer uptake in patients with PD, compared with normal controls, he said (NPJ Parkinsons Dis. 2017. doi: 10.1038/S41531-017-0017-1).

It’s not easy to determine what level of nonmotor dysfunction a given patient has at a particular point in disease progression, said Dr. Weinstock.

“There is no correlation between motor and nonmotor deterioration,” he said. “Somebody might be newly diagnosed with just a mild tremor and still have significant cardiac denervation.”

Weighing how to help an exercise-intolerant patient with PD means taking into consideration the known risks and side effect profile of PD medications, Dr. Weinstock pointed out. Increasing medications, or beginning a new drug therapy, can mean increased risk for unwanted psychiatric side effects and ototoxicity, among other potential ill effects.

Similarly, the decision to implant deep brain stimulation is not to be taken lightly, since depression can begin or worsen, and any surgical procedure carries risks.

For Dr. Weinstock, using strategies to improve sensory input are “a valid option for people with PD.” Such a strategy is safe, and even brief bouts of stimulation “can have significant, beneficial effects,” he said. “The overall goal is to avoid sedentary behavior,” with its accompanying ills, he said.

Dr. Weinstock noted that he uses different strategies to stimulate the various senses, including bright light therapy, which can help regulate circadian rhythms and promote appropriate melatonin secretion, improving sleep and upping daytime wakefulness.

Another visual strategy when working on gait is to use surface lines, a checkerboard pattern, or other targets that provide a visual goal for step length, which typically shortens with PD progression. Though more high-tech options exist, Dr. Weinstock suggested patients begin with just laying lines of masking tape along the floor to mark the target gait length. “Usually the cheap technique is a good test to see if it’s going to work,” he said.

An auditory strategy to improve the gait cycle is use of a metronome or other rhythmic auditory stimulation; music can be helpful in this regard and as a general cognitive and emotional stimulus, said Dr. Weinstock.

“Loss of smell is an early sign of Parkinson’s,” said Dr. Weinstock, and taste also can be dulled. Though offering tasty meals could help reduce risk of malnutrition in PD patients, “It remains to be seen if aromatherapy can lead to neural plasticity and reverse smell loss in PD.”

Vestibular rehabilitation techniques can help not just with balance, but also with helping to lift mood and improve functional activities, according to one study (Arq Neuropsiquiatr 2009;67[2-A]:219-23).

Other ways to provide proprioceptive feedback include the use of orthotics and textured insoles and the use of a weighted vest. Dr. Weinstock also gives consideration to skin taping, which may give patients useful feedback about their bodies’ position in space, he said.

Intriguing results have been seen with acupuncture, acupressure, and electroacupuncture for PD patients, said Dr. Weinstock. In particular, a technique called automated mechanical pressure stimulation uses a bootlike device to provide mechanical stimulation to points at the head of the great toe and on the ball of the foot at the head of the first metatarsal bone.

One functional magnetic resonance imaging (fMRI) study showed acutely increased resting state functional connectivity after such stimulation, in comparison with a sham procedure that also applied pressure, but over a broader area, he said.

After the stimulation procedure used in the study, the patients who received actual stimulation also saw improved ability to initiate voluntary movements, less tremor and rigidity, and less gait freezing (PLoS One. 2015 Oct 15. doi: 10.1371/journal.pone.0137977).

Other studies of the mechanical stimulation device showed similar results, with some showing that repeated sessions helped maintain these and other benefits, such as improved walking velocity, stride length, and Timed Up and Go results – an assessment of fall risk (Int J Rehabil Res. 2015 Sep;38[3]:238-45). Treatment with the device, dubbed Gondola, is most widely available in Italy, where clinical trials are ongoing.

Stimulation to an acupuncture point located on the proximal lateral leg, near the head of the fibula, showed improvements in gait parameters and in fMRI-assessed brain connectivity as well, noted Dr. Weinstock (CNS Neurosci Ther. 2012 Sep;18[9]:781-90).

“There’s a growing amount of evidence that various types of sensory stimulation can have significant benefits for people with Parkinson’s Disease, especially for those who are exercise intolerant,” said Dr. Weinstock.

Dr. Weinstock reported no relevant disclosures.

[email protected]

NEW YORK – Sending sensory feedback upstream to patients with Parkinson’s disease (PD) may offer a low-risk, nonpharmaceutical method to retain and improve motor function. These interventions may be especially helpful in the subpopulation of patients who are intolerant to exercise, with a growing body of evidence showing sustained benefit for newer sensory stimulation techniques.

Kari Oakes/MDedge News

“In a healthy person, movement is the seamless integration of sensory and motor systems,” said Ben Weinstock, DPT, speaking at the International Conference on Parkinson’s Disease and Movement Disorders, pointing out that movement stimulates the senses, and sensory stimulation improves movement.

By contrast, patients with PD experience more than just problems with motor function. Patients with PD and sensory or autonomic dysfunction may find these disturbances contributing to motor dysfunction, said Dr. Weinstock, who treats patients with PD and a variety of complex medical conditions in his private practice.

Some of the hallmark features of PD are movement related: the cogwheel rigidity, bradykinesia, and freezing all contribute to poor balance and a fear of falling. Commonly, PD patients also experience fatigue and alterations in cognition and mood.

However, afferent small-fiber neuropathies and centrally mediated mechanisms in PD can also disturb sensory input: Vestibular function, equilibrium, proprioception, and light and deep touch may all be affected, Dr. Weinstock said.

Autonomic dysfunction can be an underappreciated feature of PD, but such manifestations as orthostatic hypotension and poor thermal regulation can have significant negative impact on quality of life for an individual with PD.

Perhaps the gravest variant of autonomic dysregulation, however, is the cardiac denervation that frequently accompanies PD, said Dr. Weinstock. “Although there is a belief that intensive exercise helps people with PD, many individuals are actually exercise intolerant because of loss of cardiac norepinephrine,” he said (J Neurochem. 2014;131[2]:219-228). “A person with PD who is exercise intolerant is at risk” of syncope, falls, and even serious cardiac events during exercise, he noted.

Cardiovascular dysautonomia in PD has been documented in serial ¹⁸F-dopamine PET scans, showing progressive reduction in uptake over the course of several years in individual patients (Neurobiol Dis. 2012 June;46[3]:572-80). Similarly, studies have shown lower cardiac radiotracer uptake in patients with PD, compared with normal controls, he said (NPJ Parkinsons Dis. 2017. doi: 10.1038/S41531-017-0017-1).

It’s not easy to determine what level of nonmotor dysfunction a given patient has at a particular point in disease progression, said Dr. Weinstock.

“There is no correlation between motor and nonmotor deterioration,” he said. “Somebody might be newly diagnosed with just a mild tremor and still have significant cardiac denervation.”

Weighing how to help an exercise-intolerant patient with PD means taking into consideration the known risks and side effect profile of PD medications, Dr. Weinstock pointed out. Increasing medications, or beginning a new drug therapy, can mean increased risk for unwanted psychiatric side effects and ototoxicity, among other potential ill effects.

Similarly, the decision to implant deep brain stimulation is not to be taken lightly, since depression can begin or worsen, and any surgical procedure carries risks.

For Dr. Weinstock, using strategies to improve sensory input are “a valid option for people with PD.” Such a strategy is safe, and even brief bouts of stimulation “can have significant, beneficial effects,” he said. “The overall goal is to avoid sedentary behavior,” with its accompanying ills, he said.

Dr. Weinstock noted that he uses different strategies to stimulate the various senses, including bright light therapy, which can help regulate circadian rhythms and promote appropriate melatonin secretion, improving sleep and upping daytime wakefulness.

Another visual strategy when working on gait is to use surface lines, a checkerboard pattern, or other targets that provide a visual goal for step length, which typically shortens with PD progression. Though more high-tech options exist, Dr. Weinstock suggested patients begin with just laying lines of masking tape along the floor to mark the target gait length. “Usually the cheap technique is a good test to see if it’s going to work,” he said.

An auditory strategy to improve the gait cycle is use of a metronome or other rhythmic auditory stimulation; music can be helpful in this regard and as a general cognitive and emotional stimulus, said Dr. Weinstock.

“Loss of smell is an early sign of Parkinson’s,” said Dr. Weinstock, and taste also can be dulled. Though offering tasty meals could help reduce risk of malnutrition in PD patients, “It remains to be seen if aromatherapy can lead to neural plasticity and reverse smell loss in PD.”

Vestibular rehabilitation techniques can help not just with balance, but also with helping to lift mood and improve functional activities, according to one study (Arq Neuropsiquiatr 2009;67[2-A]:219-23).

Other ways to provide proprioceptive feedback include the use of orthotics and textured insoles and the use of a weighted vest. Dr. Weinstock also gives consideration to skin taping, which may give patients useful feedback about their bodies’ position in space, he said.

Intriguing results have been seen with acupuncture, acupressure, and electroacupuncture for PD patients, said Dr. Weinstock. In particular, a technique called automated mechanical pressure stimulation uses a bootlike device to provide mechanical stimulation to points at the head of the great toe and on the ball of the foot at the head of the first metatarsal bone.

One functional magnetic resonance imaging (fMRI) study showed acutely increased resting state functional connectivity after such stimulation, in comparison with a sham procedure that also applied pressure, but over a broader area, he said.

After the stimulation procedure used in the study, the patients who received actual stimulation also saw improved ability to initiate voluntary movements, less tremor and rigidity, and less gait freezing (PLoS One. 2015 Oct 15. doi: 10.1371/journal.pone.0137977).

Other studies of the mechanical stimulation device showed similar results, with some showing that repeated sessions helped maintain these and other benefits, such as improved walking velocity, stride length, and Timed Up and Go results – an assessment of fall risk (Int J Rehabil Res. 2015 Sep;38[3]:238-45). Treatment with the device, dubbed Gondola, is most widely available in Italy, where clinical trials are ongoing.

Stimulation to an acupuncture point located on the proximal lateral leg, near the head of the fibula, showed improvements in gait parameters and in fMRI-assessed brain connectivity as well, noted Dr. Weinstock (CNS Neurosci Ther. 2012 Sep;18[9]:781-90).

“There’s a growing amount of evidence that various types of sensory stimulation can have significant benefits for people with Parkinson’s Disease, especially for those who are exercise intolerant,” said Dr. Weinstock.

Dr. Weinstock reported no relevant disclosures.

[email protected]