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Photobiomodulation: Evaluation in a wide range of medical specialties underway
according to Juanita J. Anders, PhD.
During the annual conference of the American Society for Laser Medicine and Surgery, Dr. Anders, professor of anatomy, physiology, and genetics at the Uniformed Services University of the Health Sciences, Bethesda, Md., defined photobiomodulation (PBM) as the mechanism by which nonionizing optical radiation in the visible and near-infrared spectral range is absorbed by endogenous chromophores to elicit photophysical and photochemical events at various biological scales. Photobiomodulation therapy (PBMT) involves the use of light sources including lasers, LEDs, and broadband light, that emit visible and/or near-infrared light to cause physiological changes in cells and tissues and result in therapeutic benefits.
In dermatology, LED light therapy devices are commonly used for PBMT in wavelengths that range from blue (415 nm) and red (633 nm) to near infrared (830 nm). “Often, when PBMT is referred to by dermatologists it’s called LED therapy or LED light therapy,” Dr. Anders noted. “Some people are under the impression that this is different from PBMT. But remember: It’s not the device that’s producing the photons that is clinically relevant, but it’s the photons themselves. In both cases, the same radiances and fluence ranges are being used and the mechanisms are the same, so it’s all PBMT.”
The therapy is used to treat a wide variety of medical and aesthetic disorders including acne vulgaris, psoriasis, burns, and wound healing. It has also been used in conjunction with surgical aesthetic and resurfacing procedures and has been reported to reduce erythema, edema, bruising, and days to healing. It’s been shown that PBMT stimulates fibroblast proliferation, collagen synthesis, and extracellular matrix resulting in lifting and tightening lax skin.
According to Dr. Anders, French dermatologists Linda Fouque, MD, and Michele Pelletier, MD, performed a series of in vivo and in vitro studies in which they tested the effects of yellow and red light for skin rejuvenation when used individually or in combination. “They found that fibroblasts and keratinocytes in vitro had great improvement in their morphology both with the yellow and red light, but the best improvement was seen with combination therapy,” Dr. Anders said. “This held true in their work looking at epidermal and dermal markers in the skin, where they found the best up-regulation in protein synthesis of such markers as collagens and fibronectin were produced when a combination wavelength light was used.”
Oral mucositis and pain
PBMT is also being used to treat oral mucositis (OM), a common adverse response to chemotherapy and/or radiation therapy, which causes pain, difficulty in swallowing and eating, and oral ulceration, and often interrupts the course of treatments. Authors of a recently published review on the risks and benefits of PBMT concluded that there is consistent evidence from a small number of high-quality studies that PBMT can help prevent the development of cancer therapy–induced OM, reduce pain intensity, as well as promote healing, and enhance patient quality of life.
“They also cautioned that, due to the limited long-term follow-up of patients, there is still concern for the potential long-term risks of PBMT in cancer cell mutation and amplification,” Dr. Anders said. “They advised that PBMT should be used carefully when the irradiation beam is in the direction of the tumor zone.”
Using PBMT for modulation of pain is another area of active research. Based on work from the laboratory of Dr. Anders and others, there are two methods to modulate pain. The first is to target tissue at irradiances below 100 mW/cm2.
“In my laboratory, based on in vivo preclinical animal models of neuropathic pain, we used a 980-nm wavelength laser at 43.25 mW/cm2 transcutaneously delivered to the level of the nerve for 20 seconds,” said Dr. Anders, who is a past president of the ASLMS. “Essentially, we found that the pain was modulated by reducing sensitivity to mechanical stimulation and also by causing an anti-inflammatory shift in microglial and macrophage phenotype in the dorsal root ganglion and spinal cord of affected segments.”
The second way to modulate pain, she continued, is to target tissue at irradiances above 250 mW/cm2. She and her colleagues have conducted in vitro and in vivo studies, which indicate that treatment with an irradiance/fluence rate at 270 mW/cm2 or higher at the nerve can rapidly block pain transmission.
“In vitro, we found that if we used an 810-nm wavelength light at 300 mW/cm2, we got a disruption of microtubules in the DRG neurons in culture, specifically the small neurons, the nociceptive fibers, but we did not affect the proprioceptive fibers unless we increased the length of the treatment,” she said. “We essentially found the same thing in vivo in a rodent model of neuropathic pain.”
In a pilot study, Dr. Anders and coauthors examined the efficacy of laser irradiation of the dorsal root ganglion of the second lumbar spinal nerve for patients with chronic back pain.
They found that PBMT effectively reduced back pain equal to the effects of lidocaine.
Based on these two irradiation approaches of targeting tissue, Dr. Anders recommends that a combination therapy be used to modulate neuropathic pain going forward. “This approach would involve the initial use of a high-irradiance treatment [at least 250 mW/cm2] at the nerve to block the pain transmission,” she said. “That treatment would be followed by a series of low-irradiance treatments [10-100 mW/cm2] along the course of the involved nerve to alter chronic pathology and inflammation.”
Potential applications in neurology
Dr. Anders also discussed research efforts under way involving transcranial PBMT: the delivery of near-infrared light through the tissues of the scalp and skull to targeted brain regions to treat neurologic injuries and disorders. “There have been some exciting results in preclinical animal work and in small clinical pilot work that show that there could be possible beneficial effects in Parkinson’s disease, Alzheimer’s disease, depression, and improvement in cognition and memory after a brain injury, such as a TBI,” she said.
“Initially, though, there were a lot of questions about whether you could really deliver light to the brain through the scalp. In my laboratory, we used slices of nonfixed brain and found that the sulci within the human brain act as light-wave guides. We used an 808-nm near-infrared wavelength of light, so that the light could penetrate more deeply.” Using nonfixed cadaver heads, where the light was applied at the scalp surface, Dr. Anders and colleagues were able to measure photons down to the depth of 4 cm. “It’s generally agreed now, though, that it’s to a maximum depth of 2.5-3 cm that enough photons are delivered that would cause a beneficial therapeutic effect,” she said.
Dr. Anders disclosed that she has received equipment from LiteCure, grant funding from the Department of Defense, and that she holds advisory board roles with LiteCure and Neurothera. She has also served in leadership roles for the Optical Society and holds intellectual property rights for the Henry M. Jackson Foundation for the Advancement of Military Medicine.
according to Juanita J. Anders, PhD.
During the annual conference of the American Society for Laser Medicine and Surgery, Dr. Anders, professor of anatomy, physiology, and genetics at the Uniformed Services University of the Health Sciences, Bethesda, Md., defined photobiomodulation (PBM) as the mechanism by which nonionizing optical radiation in the visible and near-infrared spectral range is absorbed by endogenous chromophores to elicit photophysical and photochemical events at various biological scales. Photobiomodulation therapy (PBMT) involves the use of light sources including lasers, LEDs, and broadband light, that emit visible and/or near-infrared light to cause physiological changes in cells and tissues and result in therapeutic benefits.
In dermatology, LED light therapy devices are commonly used for PBMT in wavelengths that range from blue (415 nm) and red (633 nm) to near infrared (830 nm). “Often, when PBMT is referred to by dermatologists it’s called LED therapy or LED light therapy,” Dr. Anders noted. “Some people are under the impression that this is different from PBMT. But remember: It’s not the device that’s producing the photons that is clinically relevant, but it’s the photons themselves. In both cases, the same radiances and fluence ranges are being used and the mechanisms are the same, so it’s all PBMT.”
The therapy is used to treat a wide variety of medical and aesthetic disorders including acne vulgaris, psoriasis, burns, and wound healing. It has also been used in conjunction with surgical aesthetic and resurfacing procedures and has been reported to reduce erythema, edema, bruising, and days to healing. It’s been shown that PBMT stimulates fibroblast proliferation, collagen synthesis, and extracellular matrix resulting in lifting and tightening lax skin.
According to Dr. Anders, French dermatologists Linda Fouque, MD, and Michele Pelletier, MD, performed a series of in vivo and in vitro studies in which they tested the effects of yellow and red light for skin rejuvenation when used individually or in combination. “They found that fibroblasts and keratinocytes in vitro had great improvement in their morphology both with the yellow and red light, but the best improvement was seen with combination therapy,” Dr. Anders said. “This held true in their work looking at epidermal and dermal markers in the skin, where they found the best up-regulation in protein synthesis of such markers as collagens and fibronectin were produced when a combination wavelength light was used.”
Oral mucositis and pain
PBMT is also being used to treat oral mucositis (OM), a common adverse response to chemotherapy and/or radiation therapy, which causes pain, difficulty in swallowing and eating, and oral ulceration, and often interrupts the course of treatments. Authors of a recently published review on the risks and benefits of PBMT concluded that there is consistent evidence from a small number of high-quality studies that PBMT can help prevent the development of cancer therapy–induced OM, reduce pain intensity, as well as promote healing, and enhance patient quality of life.
“They also cautioned that, due to the limited long-term follow-up of patients, there is still concern for the potential long-term risks of PBMT in cancer cell mutation and amplification,” Dr. Anders said. “They advised that PBMT should be used carefully when the irradiation beam is in the direction of the tumor zone.”
Using PBMT for modulation of pain is another area of active research. Based on work from the laboratory of Dr. Anders and others, there are two methods to modulate pain. The first is to target tissue at irradiances below 100 mW/cm2.
“In my laboratory, based on in vivo preclinical animal models of neuropathic pain, we used a 980-nm wavelength laser at 43.25 mW/cm2 transcutaneously delivered to the level of the nerve for 20 seconds,” said Dr. Anders, who is a past president of the ASLMS. “Essentially, we found that the pain was modulated by reducing sensitivity to mechanical stimulation and also by causing an anti-inflammatory shift in microglial and macrophage phenotype in the dorsal root ganglion and spinal cord of affected segments.”
The second way to modulate pain, she continued, is to target tissue at irradiances above 250 mW/cm2. She and her colleagues have conducted in vitro and in vivo studies, which indicate that treatment with an irradiance/fluence rate at 270 mW/cm2 or higher at the nerve can rapidly block pain transmission.
“In vitro, we found that if we used an 810-nm wavelength light at 300 mW/cm2, we got a disruption of microtubules in the DRG neurons in culture, specifically the small neurons, the nociceptive fibers, but we did not affect the proprioceptive fibers unless we increased the length of the treatment,” she said. “We essentially found the same thing in vivo in a rodent model of neuropathic pain.”
In a pilot study, Dr. Anders and coauthors examined the efficacy of laser irradiation of the dorsal root ganglion of the second lumbar spinal nerve for patients with chronic back pain.
They found that PBMT effectively reduced back pain equal to the effects of lidocaine.
Based on these two irradiation approaches of targeting tissue, Dr. Anders recommends that a combination therapy be used to modulate neuropathic pain going forward. “This approach would involve the initial use of a high-irradiance treatment [at least 250 mW/cm2] at the nerve to block the pain transmission,” she said. “That treatment would be followed by a series of low-irradiance treatments [10-100 mW/cm2] along the course of the involved nerve to alter chronic pathology and inflammation.”
Potential applications in neurology
Dr. Anders also discussed research efforts under way involving transcranial PBMT: the delivery of near-infrared light through the tissues of the scalp and skull to targeted brain regions to treat neurologic injuries and disorders. “There have been some exciting results in preclinical animal work and in small clinical pilot work that show that there could be possible beneficial effects in Parkinson’s disease, Alzheimer’s disease, depression, and improvement in cognition and memory after a brain injury, such as a TBI,” she said.
“Initially, though, there were a lot of questions about whether you could really deliver light to the brain through the scalp. In my laboratory, we used slices of nonfixed brain and found that the sulci within the human brain act as light-wave guides. We used an 808-nm near-infrared wavelength of light, so that the light could penetrate more deeply.” Using nonfixed cadaver heads, where the light was applied at the scalp surface, Dr. Anders and colleagues were able to measure photons down to the depth of 4 cm. “It’s generally agreed now, though, that it’s to a maximum depth of 2.5-3 cm that enough photons are delivered that would cause a beneficial therapeutic effect,” she said.
Dr. Anders disclosed that she has received equipment from LiteCure, grant funding from the Department of Defense, and that she holds advisory board roles with LiteCure and Neurothera. She has also served in leadership roles for the Optical Society and holds intellectual property rights for the Henry M. Jackson Foundation for the Advancement of Military Medicine.
according to Juanita J. Anders, PhD.
During the annual conference of the American Society for Laser Medicine and Surgery, Dr. Anders, professor of anatomy, physiology, and genetics at the Uniformed Services University of the Health Sciences, Bethesda, Md., defined photobiomodulation (PBM) as the mechanism by which nonionizing optical radiation in the visible and near-infrared spectral range is absorbed by endogenous chromophores to elicit photophysical and photochemical events at various biological scales. Photobiomodulation therapy (PBMT) involves the use of light sources including lasers, LEDs, and broadband light, that emit visible and/or near-infrared light to cause physiological changes in cells and tissues and result in therapeutic benefits.
In dermatology, LED light therapy devices are commonly used for PBMT in wavelengths that range from blue (415 nm) and red (633 nm) to near infrared (830 nm). “Often, when PBMT is referred to by dermatologists it’s called LED therapy or LED light therapy,” Dr. Anders noted. “Some people are under the impression that this is different from PBMT. But remember: It’s not the device that’s producing the photons that is clinically relevant, but it’s the photons themselves. In both cases, the same radiances and fluence ranges are being used and the mechanisms are the same, so it’s all PBMT.”
The therapy is used to treat a wide variety of medical and aesthetic disorders including acne vulgaris, psoriasis, burns, and wound healing. It has also been used in conjunction with surgical aesthetic and resurfacing procedures and has been reported to reduce erythema, edema, bruising, and days to healing. It’s been shown that PBMT stimulates fibroblast proliferation, collagen synthesis, and extracellular matrix resulting in lifting and tightening lax skin.
According to Dr. Anders, French dermatologists Linda Fouque, MD, and Michele Pelletier, MD, performed a series of in vivo and in vitro studies in which they tested the effects of yellow and red light for skin rejuvenation when used individually or in combination. “They found that fibroblasts and keratinocytes in vitro had great improvement in their morphology both with the yellow and red light, but the best improvement was seen with combination therapy,” Dr. Anders said. “This held true in their work looking at epidermal and dermal markers in the skin, where they found the best up-regulation in protein synthesis of such markers as collagens and fibronectin were produced when a combination wavelength light was used.”
Oral mucositis and pain
PBMT is also being used to treat oral mucositis (OM), a common adverse response to chemotherapy and/or radiation therapy, which causes pain, difficulty in swallowing and eating, and oral ulceration, and often interrupts the course of treatments. Authors of a recently published review on the risks and benefits of PBMT concluded that there is consistent evidence from a small number of high-quality studies that PBMT can help prevent the development of cancer therapy–induced OM, reduce pain intensity, as well as promote healing, and enhance patient quality of life.
“They also cautioned that, due to the limited long-term follow-up of patients, there is still concern for the potential long-term risks of PBMT in cancer cell mutation and amplification,” Dr. Anders said. “They advised that PBMT should be used carefully when the irradiation beam is in the direction of the tumor zone.”
Using PBMT for modulation of pain is another area of active research. Based on work from the laboratory of Dr. Anders and others, there are two methods to modulate pain. The first is to target tissue at irradiances below 100 mW/cm2.
“In my laboratory, based on in vivo preclinical animal models of neuropathic pain, we used a 980-nm wavelength laser at 43.25 mW/cm2 transcutaneously delivered to the level of the nerve for 20 seconds,” said Dr. Anders, who is a past president of the ASLMS. “Essentially, we found that the pain was modulated by reducing sensitivity to mechanical stimulation and also by causing an anti-inflammatory shift in microglial and macrophage phenotype in the dorsal root ganglion and spinal cord of affected segments.”
The second way to modulate pain, she continued, is to target tissue at irradiances above 250 mW/cm2. She and her colleagues have conducted in vitro and in vivo studies, which indicate that treatment with an irradiance/fluence rate at 270 mW/cm2 or higher at the nerve can rapidly block pain transmission.
“In vitro, we found that if we used an 810-nm wavelength light at 300 mW/cm2, we got a disruption of microtubules in the DRG neurons in culture, specifically the small neurons, the nociceptive fibers, but we did not affect the proprioceptive fibers unless we increased the length of the treatment,” she said. “We essentially found the same thing in vivo in a rodent model of neuropathic pain.”
In a pilot study, Dr. Anders and coauthors examined the efficacy of laser irradiation of the dorsal root ganglion of the second lumbar spinal nerve for patients with chronic back pain.
They found that PBMT effectively reduced back pain equal to the effects of lidocaine.
Based on these two irradiation approaches of targeting tissue, Dr. Anders recommends that a combination therapy be used to modulate neuropathic pain going forward. “This approach would involve the initial use of a high-irradiance treatment [at least 250 mW/cm2] at the nerve to block the pain transmission,” she said. “That treatment would be followed by a series of low-irradiance treatments [10-100 mW/cm2] along the course of the involved nerve to alter chronic pathology and inflammation.”
Potential applications in neurology
Dr. Anders also discussed research efforts under way involving transcranial PBMT: the delivery of near-infrared light through the tissues of the scalp and skull to targeted brain regions to treat neurologic injuries and disorders. “There have been some exciting results in preclinical animal work and in small clinical pilot work that show that there could be possible beneficial effects in Parkinson’s disease, Alzheimer’s disease, depression, and improvement in cognition and memory after a brain injury, such as a TBI,” she said.
“Initially, though, there were a lot of questions about whether you could really deliver light to the brain through the scalp. In my laboratory, we used slices of nonfixed brain and found that the sulci within the human brain act as light-wave guides. We used an 808-nm near-infrared wavelength of light, so that the light could penetrate more deeply.” Using nonfixed cadaver heads, where the light was applied at the scalp surface, Dr. Anders and colleagues were able to measure photons down to the depth of 4 cm. “It’s generally agreed now, though, that it’s to a maximum depth of 2.5-3 cm that enough photons are delivered that would cause a beneficial therapeutic effect,” she said.
Dr. Anders disclosed that she has received equipment from LiteCure, grant funding from the Department of Defense, and that she holds advisory board roles with LiteCure and Neurothera. She has also served in leadership roles for the Optical Society and holds intellectual property rights for the Henry M. Jackson Foundation for the Advancement of Military Medicine.
FROM ASLMS 2021
FDA clears next-generation DBS system for movement disorders
The SenSight Directional Lead System for DBS therapy combines two recent advancements: sensing capability that allows real-time monitoring of brain signals to optimize settings for stimulation, and a “directional lead” that enables steering of electric current for more precise targeting of stimulation through the electrode.
“Until now, sensing capability and directional leads have not been available in the same DBS system, so we have had to choose one technology or the other, based on the predicted needs of each patient,” neurosurgeon Kelly Foote, MD, who performed the first implant of the SenSight System at University of Florida (UF) Health, said in a news release.
“Now, by coupling this new directional lead with a pulse generator capable of brain sensing, we are excited to be able to offer our patients the synergistic benefits of both technologies,” added Dr. Foote, codirector of the Norman Fixel Institute for Neurological Diseases at UF Health.
Dr. Foote said DBS systems capable of adjusting therapeutic stimulation in response to continuously recorded brain signals may lead to better DBS outcomes with fewer adverse effects.
“Adding a directional lead to such a system will improve our ability to localize abnormal signals and enable us to steer current more effectively to areas in the brain where it is most beneficial,” Dr. Foote said.
“We are excited to see the clinical benefits that the new SenSight directional lead system will provide to patients and physicians in the U.S.,” added Mike Daly, vice president and general manager of brain modulation at Medtronic.
Medtronic’s SenSight directional lead DBS system received CE Mark approval in Europe in March.
A version of this article first appeared on Medscape.com.
The SenSight Directional Lead System for DBS therapy combines two recent advancements: sensing capability that allows real-time monitoring of brain signals to optimize settings for stimulation, and a “directional lead” that enables steering of electric current for more precise targeting of stimulation through the electrode.
“Until now, sensing capability and directional leads have not been available in the same DBS system, so we have had to choose one technology or the other, based on the predicted needs of each patient,” neurosurgeon Kelly Foote, MD, who performed the first implant of the SenSight System at University of Florida (UF) Health, said in a news release.
“Now, by coupling this new directional lead with a pulse generator capable of brain sensing, we are excited to be able to offer our patients the synergistic benefits of both technologies,” added Dr. Foote, codirector of the Norman Fixel Institute for Neurological Diseases at UF Health.
Dr. Foote said DBS systems capable of adjusting therapeutic stimulation in response to continuously recorded brain signals may lead to better DBS outcomes with fewer adverse effects.
“Adding a directional lead to such a system will improve our ability to localize abnormal signals and enable us to steer current more effectively to areas in the brain where it is most beneficial,” Dr. Foote said.
“We are excited to see the clinical benefits that the new SenSight directional lead system will provide to patients and physicians in the U.S.,” added Mike Daly, vice president and general manager of brain modulation at Medtronic.
Medtronic’s SenSight directional lead DBS system received CE Mark approval in Europe in March.
A version of this article first appeared on Medscape.com.
The SenSight Directional Lead System for DBS therapy combines two recent advancements: sensing capability that allows real-time monitoring of brain signals to optimize settings for stimulation, and a “directional lead” that enables steering of electric current for more precise targeting of stimulation through the electrode.
“Until now, sensing capability and directional leads have not been available in the same DBS system, so we have had to choose one technology or the other, based on the predicted needs of each patient,” neurosurgeon Kelly Foote, MD, who performed the first implant of the SenSight System at University of Florida (UF) Health, said in a news release.
“Now, by coupling this new directional lead with a pulse generator capable of brain sensing, we are excited to be able to offer our patients the synergistic benefits of both technologies,” added Dr. Foote, codirector of the Norman Fixel Institute for Neurological Diseases at UF Health.
Dr. Foote said DBS systems capable of adjusting therapeutic stimulation in response to continuously recorded brain signals may lead to better DBS outcomes with fewer adverse effects.
“Adding a directional lead to such a system will improve our ability to localize abnormal signals and enable us to steer current more effectively to areas in the brain where it is most beneficial,” Dr. Foote said.
“We are excited to see the clinical benefits that the new SenSight directional lead system will provide to patients and physicians in the U.S.,” added Mike Daly, vice president and general manager of brain modulation at Medtronic.
Medtronic’s SenSight directional lead DBS system received CE Mark approval in Europe in March.
A version of this article first appeared on Medscape.com.
Deep brain stimulation is effective over the long haul
, new research indicates.
“Subthalamic nucleus stimulation is a well recognized treatment used for improving motor conditions and quality of life in people with Parkinson’s disease. Our study, for the first time, supports its efficacy in the very long term – 15 years after surgery and 25 years since the Parkinson’s disease diagnosis,” said Elena Moro, MD, PhD, Grenoble Alpes University, Grenoble, France.
“This information is relevant for physicians, patients, and their families when they need to decide about the surgical option to deal with Parkinson’s disease,” said Dr. Moro.
The study was published online June 2 in Neurology.
‘Don’t delay’
The findings are based on 51 patients with Parkinson’s disease who underwent treatment with bilateral STN-DBS for an average of 17 years (range, 15-24 years). Their average age at diagnosis was 40 years, and the average age at device implantation was 51 years.
The results demonstrate that STN-DBS continues to be effective for motor complications for longer than 15 years, reducing time spent with dyskinesia by 75% and time spent in the off-state by 58.7%. This is similar to the amount of improvement seen 1 year after surgery.
Doses of dopaminergic medications continued to be low at long-term follow-up; dosing was reduced by 50.6% compared with baseline.
There was also continued improvement in quality of life. Scores on the Parkinson’s Disease Quality of Life Questionnaire in the very long term were 13.8% better compared with baseline.
“Few and mostly manageable device-related adverse events were observed during the follow-up,” the authors reported in their article.
“Deep brain stimulation is already recommended when a patient’s conditions are not optimized by medical treatment. Patients with Parkinson’s disease without dementia and in good general health conditions are the best candidates for this surgery,” said Dr. Moro.
“Taking into account our results and the data available in the literature, DBS surgery should not be delayed when motor conditions and quality of life decline despite medical treatment, if patients meet the inclusion criteria,” she added.
A revolutionary treatment
The authors of an accompanying editorial say these results, which indicate better motor outcomes with less medication, “reinforce why STN-DBS has revolutionized treatment for advanced Parkinson’s disease.”
Kelvin Chou, MD, of the University of Michigan, Ann Arbor, and David Charles, MD, of Vanderbilt University, Nashville, Tenn., pointed out that longer disease duration is associated with an increase in the likelihood of cognitive impairment and psychosis, both of which are risk factors for nursing home placement, and they limit the ability to use dopaminergic medications.
Although many of the patients in this cohort experienced hallucinations and psychosis over the long follow-up period, “one can imagine that the number and severity would be higher without DBS therapy,” they wrote.
Key caveats, said Dr. Chou and Dr. Charles, are that the results are based on a highly selected cohort and that the patients were managed by experts in the field of movement disorders and DBS.
Additionally, the patients’ conditions were highly responsive to levodopa; there was a 75.3% baseline improvement in Unified Parkinson’s Disease Rating Scale motor scores from the off-state to the on-state. In general, most DBS centers consider a levodopa response of approximately 30% as an acceptable cutoff for moving forward with STN-DBS, they noted.
Despite these caveats and limitations, the results of the study are important with respect to counseling potential candidates for DBS, Dr. Chou and Dr. Charles said.
“A common question that patients have is, ‘How long do the benefits of DBS last?’ We can now reassure them that, at least for STN-DBS, improvement in motor complications lasts beyond 15 years and is often accompanied by improvement in quality of life. In other words, with STN-DBS, we can uncomplicate their motor complications for the long haul,” the editorial writers concluded.
The research had no targeted funding. Moro has received honoraria from Medtronic and Abbott for consulting and lecturing and an educational grant from Boston and Newronika. A complete list of disclosures is available with the original articles.
A version of this article first appeared on Medscape.com.
, new research indicates.
“Subthalamic nucleus stimulation is a well recognized treatment used for improving motor conditions and quality of life in people with Parkinson’s disease. Our study, for the first time, supports its efficacy in the very long term – 15 years after surgery and 25 years since the Parkinson’s disease diagnosis,” said Elena Moro, MD, PhD, Grenoble Alpes University, Grenoble, France.
“This information is relevant for physicians, patients, and their families when they need to decide about the surgical option to deal with Parkinson’s disease,” said Dr. Moro.
The study was published online June 2 in Neurology.
‘Don’t delay’
The findings are based on 51 patients with Parkinson’s disease who underwent treatment with bilateral STN-DBS for an average of 17 years (range, 15-24 years). Their average age at diagnosis was 40 years, and the average age at device implantation was 51 years.
The results demonstrate that STN-DBS continues to be effective for motor complications for longer than 15 years, reducing time spent with dyskinesia by 75% and time spent in the off-state by 58.7%. This is similar to the amount of improvement seen 1 year after surgery.
Doses of dopaminergic medications continued to be low at long-term follow-up; dosing was reduced by 50.6% compared with baseline.
There was also continued improvement in quality of life. Scores on the Parkinson’s Disease Quality of Life Questionnaire in the very long term were 13.8% better compared with baseline.
“Few and mostly manageable device-related adverse events were observed during the follow-up,” the authors reported in their article.
“Deep brain stimulation is already recommended when a patient’s conditions are not optimized by medical treatment. Patients with Parkinson’s disease without dementia and in good general health conditions are the best candidates for this surgery,” said Dr. Moro.
“Taking into account our results and the data available in the literature, DBS surgery should not be delayed when motor conditions and quality of life decline despite medical treatment, if patients meet the inclusion criteria,” she added.
A revolutionary treatment
The authors of an accompanying editorial say these results, which indicate better motor outcomes with less medication, “reinforce why STN-DBS has revolutionized treatment for advanced Parkinson’s disease.”
Kelvin Chou, MD, of the University of Michigan, Ann Arbor, and David Charles, MD, of Vanderbilt University, Nashville, Tenn., pointed out that longer disease duration is associated with an increase in the likelihood of cognitive impairment and psychosis, both of which are risk factors for nursing home placement, and they limit the ability to use dopaminergic medications.
Although many of the patients in this cohort experienced hallucinations and psychosis over the long follow-up period, “one can imagine that the number and severity would be higher without DBS therapy,” they wrote.
Key caveats, said Dr. Chou and Dr. Charles, are that the results are based on a highly selected cohort and that the patients were managed by experts in the field of movement disorders and DBS.
Additionally, the patients’ conditions were highly responsive to levodopa; there was a 75.3% baseline improvement in Unified Parkinson’s Disease Rating Scale motor scores from the off-state to the on-state. In general, most DBS centers consider a levodopa response of approximately 30% as an acceptable cutoff for moving forward with STN-DBS, they noted.
Despite these caveats and limitations, the results of the study are important with respect to counseling potential candidates for DBS, Dr. Chou and Dr. Charles said.
“A common question that patients have is, ‘How long do the benefits of DBS last?’ We can now reassure them that, at least for STN-DBS, improvement in motor complications lasts beyond 15 years and is often accompanied by improvement in quality of life. In other words, with STN-DBS, we can uncomplicate their motor complications for the long haul,” the editorial writers concluded.
The research had no targeted funding. Moro has received honoraria from Medtronic and Abbott for consulting and lecturing and an educational grant from Boston and Newronika. A complete list of disclosures is available with the original articles.
A version of this article first appeared on Medscape.com.
, new research indicates.
“Subthalamic nucleus stimulation is a well recognized treatment used for improving motor conditions and quality of life in people with Parkinson’s disease. Our study, for the first time, supports its efficacy in the very long term – 15 years after surgery and 25 years since the Parkinson’s disease diagnosis,” said Elena Moro, MD, PhD, Grenoble Alpes University, Grenoble, France.
“This information is relevant for physicians, patients, and their families when they need to decide about the surgical option to deal with Parkinson’s disease,” said Dr. Moro.
The study was published online June 2 in Neurology.
‘Don’t delay’
The findings are based on 51 patients with Parkinson’s disease who underwent treatment with bilateral STN-DBS for an average of 17 years (range, 15-24 years). Their average age at diagnosis was 40 years, and the average age at device implantation was 51 years.
The results demonstrate that STN-DBS continues to be effective for motor complications for longer than 15 years, reducing time spent with dyskinesia by 75% and time spent in the off-state by 58.7%. This is similar to the amount of improvement seen 1 year after surgery.
Doses of dopaminergic medications continued to be low at long-term follow-up; dosing was reduced by 50.6% compared with baseline.
There was also continued improvement in quality of life. Scores on the Parkinson’s Disease Quality of Life Questionnaire in the very long term were 13.8% better compared with baseline.
“Few and mostly manageable device-related adverse events were observed during the follow-up,” the authors reported in their article.
“Deep brain stimulation is already recommended when a patient’s conditions are not optimized by medical treatment. Patients with Parkinson’s disease without dementia and in good general health conditions are the best candidates for this surgery,” said Dr. Moro.
“Taking into account our results and the data available in the literature, DBS surgery should not be delayed when motor conditions and quality of life decline despite medical treatment, if patients meet the inclusion criteria,” she added.
A revolutionary treatment
The authors of an accompanying editorial say these results, which indicate better motor outcomes with less medication, “reinforce why STN-DBS has revolutionized treatment for advanced Parkinson’s disease.”
Kelvin Chou, MD, of the University of Michigan, Ann Arbor, and David Charles, MD, of Vanderbilt University, Nashville, Tenn., pointed out that longer disease duration is associated with an increase in the likelihood of cognitive impairment and psychosis, both of which are risk factors for nursing home placement, and they limit the ability to use dopaminergic medications.
Although many of the patients in this cohort experienced hallucinations and psychosis over the long follow-up period, “one can imagine that the number and severity would be higher without DBS therapy,” they wrote.
Key caveats, said Dr. Chou and Dr. Charles, are that the results are based on a highly selected cohort and that the patients were managed by experts in the field of movement disorders and DBS.
Additionally, the patients’ conditions were highly responsive to levodopa; there was a 75.3% baseline improvement in Unified Parkinson’s Disease Rating Scale motor scores from the off-state to the on-state. In general, most DBS centers consider a levodopa response of approximately 30% as an acceptable cutoff for moving forward with STN-DBS, they noted.
Despite these caveats and limitations, the results of the study are important with respect to counseling potential candidates for DBS, Dr. Chou and Dr. Charles said.
“A common question that patients have is, ‘How long do the benefits of DBS last?’ We can now reassure them that, at least for STN-DBS, improvement in motor complications lasts beyond 15 years and is often accompanied by improvement in quality of life. In other words, with STN-DBS, we can uncomplicate their motor complications for the long haul,” the editorial writers concluded.
The research had no targeted funding. Moro has received honoraria from Medtronic and Abbott for consulting and lecturing and an educational grant from Boston and Newronika. A complete list of disclosures is available with the original articles.
A version of this article first appeared on Medscape.com.
From Neurology
Psychosis, depression tied to neurodegeneration in Parkinson’s
Depression and psychosis are significantly associated with neuronal loss and gliosis – but not with Lewy body scores – in Parkinson’s disease, data from analyses of the brains of 175 patients suggest.
Previous research has suggested a link between neuronal loss and depression in Parkinson’s disease (PD) but the impact of Lewy bodies has not been well studied, Nicole Mercado Fischer, MPH, of Johns Hopkins University, Baltimore, and colleagues wrote.
Evaluating Lewy body scores and neuronal loss/gliosis in the substantia nigra pars compacta (SN) and locus coeruleus (LC) could increase understanding of pathophysiology in PD, they said.
In a study published in the American Journal of Geriatric Psychiatry, the researchers analyzed the brains of 175 individuals with a primary diagnosis of PD.
A total of 98 participants had diagnoses of psychosis, 88 had depression, and 55 had anxiety. The average age of onset for PD was 62.4 years; 67.4% of the subjects were male, and 97.8% were White. The mean duration of illness was 16 years, and the average age at death was 78 years.
Psychosis was significantly associated with severe neuronal loss and gliosis in both the LC and SN (P = .048 and P = .042, respectively). Depression was significantly associated with severe neuronal loss in the SN (P = .042) but not in the LC. Anxiety was not associated with severe neuronal loss in either brain region. These results remained significant after a multivariate analysis, the researchers noted. However, Lewy body scores were not associated with any neuropsychiatric symptom, and severity of neuronal loss and gliosis was not correlated with Lewy body scores.
The study findings were limited by several factors, including the retrospective design and inability to collect pathology data for all patients, the researchers noted. Also, in some cases, the collection of clinical data and observation of brain tissue pathology took place years apart, and the researchers did not assess medication records.
However, the results were strengthened by the large sample size and “further support the notion that in vivo clinical symptoms of PD are either not caused by Lewy body pathology or that the relationship is confounded by the time of autopsy,” they said. and eventually by using new functional imaging techniques in vivo.”
The researchers had no financial conflicts to disclose. Two coauthors were supported in part by the National Institutes of Health.
Depression and psychosis are significantly associated with neuronal loss and gliosis – but not with Lewy body scores – in Parkinson’s disease, data from analyses of the brains of 175 patients suggest.
Previous research has suggested a link between neuronal loss and depression in Parkinson’s disease (PD) but the impact of Lewy bodies has not been well studied, Nicole Mercado Fischer, MPH, of Johns Hopkins University, Baltimore, and colleagues wrote.
Evaluating Lewy body scores and neuronal loss/gliosis in the substantia nigra pars compacta (SN) and locus coeruleus (LC) could increase understanding of pathophysiology in PD, they said.
In a study published in the American Journal of Geriatric Psychiatry, the researchers analyzed the brains of 175 individuals with a primary diagnosis of PD.
A total of 98 participants had diagnoses of psychosis, 88 had depression, and 55 had anxiety. The average age of onset for PD was 62.4 years; 67.4% of the subjects were male, and 97.8% were White. The mean duration of illness was 16 years, and the average age at death was 78 years.
Psychosis was significantly associated with severe neuronal loss and gliosis in both the LC and SN (P = .048 and P = .042, respectively). Depression was significantly associated with severe neuronal loss in the SN (P = .042) but not in the LC. Anxiety was not associated with severe neuronal loss in either brain region. These results remained significant after a multivariate analysis, the researchers noted. However, Lewy body scores were not associated with any neuropsychiatric symptom, and severity of neuronal loss and gliosis was not correlated with Lewy body scores.
The study findings were limited by several factors, including the retrospective design and inability to collect pathology data for all patients, the researchers noted. Also, in some cases, the collection of clinical data and observation of brain tissue pathology took place years apart, and the researchers did not assess medication records.
However, the results were strengthened by the large sample size and “further support the notion that in vivo clinical symptoms of PD are either not caused by Lewy body pathology or that the relationship is confounded by the time of autopsy,” they said. and eventually by using new functional imaging techniques in vivo.”
The researchers had no financial conflicts to disclose. Two coauthors were supported in part by the National Institutes of Health.
Depression and psychosis are significantly associated with neuronal loss and gliosis – but not with Lewy body scores – in Parkinson’s disease, data from analyses of the brains of 175 patients suggest.
Previous research has suggested a link between neuronal loss and depression in Parkinson’s disease (PD) but the impact of Lewy bodies has not been well studied, Nicole Mercado Fischer, MPH, of Johns Hopkins University, Baltimore, and colleagues wrote.
Evaluating Lewy body scores and neuronal loss/gliosis in the substantia nigra pars compacta (SN) and locus coeruleus (LC) could increase understanding of pathophysiology in PD, they said.
In a study published in the American Journal of Geriatric Psychiatry, the researchers analyzed the brains of 175 individuals with a primary diagnosis of PD.
A total of 98 participants had diagnoses of psychosis, 88 had depression, and 55 had anxiety. The average age of onset for PD was 62.4 years; 67.4% of the subjects were male, and 97.8% were White. The mean duration of illness was 16 years, and the average age at death was 78 years.
Psychosis was significantly associated with severe neuronal loss and gliosis in both the LC and SN (P = .048 and P = .042, respectively). Depression was significantly associated with severe neuronal loss in the SN (P = .042) but not in the LC. Anxiety was not associated with severe neuronal loss in either brain region. These results remained significant after a multivariate analysis, the researchers noted. However, Lewy body scores were not associated with any neuropsychiatric symptom, and severity of neuronal loss and gliosis was not correlated with Lewy body scores.
The study findings were limited by several factors, including the retrospective design and inability to collect pathology data for all patients, the researchers noted. Also, in some cases, the collection of clinical data and observation of brain tissue pathology took place years apart, and the researchers did not assess medication records.
However, the results were strengthened by the large sample size and “further support the notion that in vivo clinical symptoms of PD are either not caused by Lewy body pathology or that the relationship is confounded by the time of autopsy,” they said. and eventually by using new functional imaging techniques in vivo.”
The researchers had no financial conflicts to disclose. Two coauthors were supported in part by the National Institutes of Health.
FROM THE AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY
Fall prevention advice for patients with Parkinson’s
A 75-year-old man with Parkinson’s disease has had three falls over the past 4 weeks. He has been compliant with his Parkinson’s treatment. Which of the following options would most help decrease his fall risk?
A. Vitamin D supplementation
B. Vitamin B12 supplementation
C. Calcium supplementation
D. Tai chi
There has been recent evidence that vitamin D supplementation is not helpful in preventing falls in most community-dwelling older adults. Bolland and colleagues performed a meta-analysis of 81 randomized, controlled trials and found that vitamin D supplementation does not prevent fractures or falls.1 They found no difference or benefit in high-dose versus low-dose vitamin D supplementation.
The U.S. Preventive Services Task Force recommends against vitamin D supplementation for the purpose of preventing falls in community-dwelling adults over the age of 65.2 The same USPSTF report recommends exercise intervention, as having the strongest evidence for fall prevention in community-dwelling adults age 65 or older who are at risk for falls.
The benefits of tai chi
Tai chi with it’s emphasis on balance, strength training as well as stress reduction is an excellent option for older adults.
Lui and colleagues performed a meta-analyses of five randomized, controlled trials (355 patients) of tai chi in patients with Parkinson disease.3 Tai chi significantly decreased fall rates (odds ratio, 0.47; 95% confidence interval, 0.30-0.74; P = .001) and significantly improved balance and functional mobility (P < .001) in people with Parkinson disease, compared with no training.
Tai chi can also help prevent falls in a more general population of elderly patients. Lomas-Vega and colleagues performed a meta-analysis of 10 high-quality studies that met inclusion criteria evaluating tai chi for fall prevention.4 Fall risk was reduced over short-term follow-up (incident rate ratio, 0.57; 95% CI, 0.46-0.70) and a small protective effect was seen over long-term follow-up (IRR, 0.87; 95% CI, 0.77-0.98).
Pearl: Consider tai chi in your elderly patients with fall risk to increase their balance and reduce risks of falls.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. Bolland MJ et al. Lancet Diabetes Endocrinol. 2018;6(11):847.
2. U.S. Preventive Services Task Force. JAMA. 2018;319(16):1696.
3. Liu HH et al. Parkinsons Dis. 2019 Feb 21;2019:9626934
4. Lomas-Vega R et al. J Am Geriatr Soc. 2017;65(9):2037.
A 75-year-old man with Parkinson’s disease has had three falls over the past 4 weeks. He has been compliant with his Parkinson’s treatment. Which of the following options would most help decrease his fall risk?
A. Vitamin D supplementation
B. Vitamin B12 supplementation
C. Calcium supplementation
D. Tai chi
There has been recent evidence that vitamin D supplementation is not helpful in preventing falls in most community-dwelling older adults. Bolland and colleagues performed a meta-analysis of 81 randomized, controlled trials and found that vitamin D supplementation does not prevent fractures or falls.1 They found no difference or benefit in high-dose versus low-dose vitamin D supplementation.
The U.S. Preventive Services Task Force recommends against vitamin D supplementation for the purpose of preventing falls in community-dwelling adults over the age of 65.2 The same USPSTF report recommends exercise intervention, as having the strongest evidence for fall prevention in community-dwelling adults age 65 or older who are at risk for falls.
The benefits of tai chi
Tai chi with it’s emphasis on balance, strength training as well as stress reduction is an excellent option for older adults.
Lui and colleagues performed a meta-analyses of five randomized, controlled trials (355 patients) of tai chi in patients with Parkinson disease.3 Tai chi significantly decreased fall rates (odds ratio, 0.47; 95% confidence interval, 0.30-0.74; P = .001) and significantly improved balance and functional mobility (P < .001) in people with Parkinson disease, compared with no training.
Tai chi can also help prevent falls in a more general population of elderly patients. Lomas-Vega and colleagues performed a meta-analysis of 10 high-quality studies that met inclusion criteria evaluating tai chi for fall prevention.4 Fall risk was reduced over short-term follow-up (incident rate ratio, 0.57; 95% CI, 0.46-0.70) and a small protective effect was seen over long-term follow-up (IRR, 0.87; 95% CI, 0.77-0.98).
Pearl: Consider tai chi in your elderly patients with fall risk to increase their balance and reduce risks of falls.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. Bolland MJ et al. Lancet Diabetes Endocrinol. 2018;6(11):847.
2. U.S. Preventive Services Task Force. JAMA. 2018;319(16):1696.
3. Liu HH et al. Parkinsons Dis. 2019 Feb 21;2019:9626934
4. Lomas-Vega R et al. J Am Geriatr Soc. 2017;65(9):2037.
A 75-year-old man with Parkinson’s disease has had three falls over the past 4 weeks. He has been compliant with his Parkinson’s treatment. Which of the following options would most help decrease his fall risk?
A. Vitamin D supplementation
B. Vitamin B12 supplementation
C. Calcium supplementation
D. Tai chi
There has been recent evidence that vitamin D supplementation is not helpful in preventing falls in most community-dwelling older adults. Bolland and colleagues performed a meta-analysis of 81 randomized, controlled trials and found that vitamin D supplementation does not prevent fractures or falls.1 They found no difference or benefit in high-dose versus low-dose vitamin D supplementation.
The U.S. Preventive Services Task Force recommends against vitamin D supplementation for the purpose of preventing falls in community-dwelling adults over the age of 65.2 The same USPSTF report recommends exercise intervention, as having the strongest evidence for fall prevention in community-dwelling adults age 65 or older who are at risk for falls.
The benefits of tai chi
Tai chi with it’s emphasis on balance, strength training as well as stress reduction is an excellent option for older adults.
Lui and colleagues performed a meta-analyses of five randomized, controlled trials (355 patients) of tai chi in patients with Parkinson disease.3 Tai chi significantly decreased fall rates (odds ratio, 0.47; 95% confidence interval, 0.30-0.74; P = .001) and significantly improved balance and functional mobility (P < .001) in people with Parkinson disease, compared with no training.
Tai chi can also help prevent falls in a more general population of elderly patients. Lomas-Vega and colleagues performed a meta-analysis of 10 high-quality studies that met inclusion criteria evaluating tai chi for fall prevention.4 Fall risk was reduced over short-term follow-up (incident rate ratio, 0.57; 95% CI, 0.46-0.70) and a small protective effect was seen over long-term follow-up (IRR, 0.87; 95% CI, 0.77-0.98).
Pearl: Consider tai chi in your elderly patients with fall risk to increase their balance and reduce risks of falls.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. Bolland MJ et al. Lancet Diabetes Endocrinol. 2018;6(11):847.
2. U.S. Preventive Services Task Force. JAMA. 2018;319(16):1696.
3. Liu HH et al. Parkinsons Dis. 2019 Feb 21;2019:9626934
4. Lomas-Vega R et al. J Am Geriatr Soc. 2017;65(9):2037.
Basal ganglia microcircuits offer clues to Parkinson’s symptoms
, according to a new study using a mouse model of disease.
Parkinson’s disease is characterized by a range of cognitive and motor symptoms, which appear at different disease stages. While recent research has pointed to specific neuronal subpopulations, or microcircuits, operating in the basal ganglia, researchers lacked a clear understanding of how they might correspond with specific symptom domains.
In a study published online March 15 in Nature Neuroscience, lead author Varoth Lilascharoen, PhD, of the University of California, San Diego, and colleagues reported that two different neuronal subpopulations within the external globus pallidus, an important nucleus within the basal ganglia, are associated, respectively, with movement and with reversal learning (having to adapt to a reward pattern that is the reverse of a previous pattern). This is the first time, the investigators said, that the contributions of specific microcircuits in the basal ganglia have been linked to different behaviors.
Using electrophysiology, viral tracing, and other approaches, Dr. Lilascharoen and colleagues demonstrated that two microcircuits or populations of parvalbumin-expressing neurons could be manipulated to exacerbate or alleviate the motor or cognitive deficits in the dopamine-depleted mice.
One of these microcircuits, made up of substantia nigra pars reticulata-projecting GPe-PV neurons, could be manipulated in ways that promoted or inhibited the mice’s movement. The other, which comprises parafascicular thalamus-projecting GPe-PV neurons, could be manipulated to affect reversal learning, the researchers found. Activation or inhibition of either circuit was not seen affecting function in the other.
The results shed light on the functional organization of the different basal ganglia nuclei at the circuit level, and suggest, the authors argued, that differences in how different neuronal subpopulations adapt to dopamine loss could explain some of the patterns of progression seen in Parkinson’s disease.
The findings “establish the differential contributions from two distinct GPe-PV microcircuits in specific Parkinsonian-like behaviors linked to early and late stages of the disease,” Dr. Lilascharoen and colleagues wrote in their analysis. “[F]urther elucidation of the detailed connectivity of GPe subpopulations to their downstream targets … is needed to fully define the function of each microcircuit and design better therapeutic strategies for the various behavioral impairments of Parkinson’s disease.”
Commenting on the research, Stefan Lang, MD, PhD, of the University of Calgary in Alberta said, “While Parkinson’s disease is often referred to as a movement disorder, it is well known that nonmotor symptoms, including cognitive and behavioral impairment, are common and debilitating. Impairment of basal ganglia function is known to contribute to these different symptom domains, though the specific circuits have never been elucidated. [Dr.] Lilascharoen et al. tease apart specific basal ganglia circuits associated with motor and behavioral symptoms, thereby providing evidence that distinct microcircuits might contribute to unique behaviours. As technological advances in neuromodulatory therapies continue to improve the spatial and temporal resolution of stimulation, future treatments may allow for specific targeting of behavioral impairment symptoms in Parkinson’s disease.”
Dr. Lilascharoen and Dr. Lang did not report outside funding or conflicts of interest.
, according to a new study using a mouse model of disease.
Parkinson’s disease is characterized by a range of cognitive and motor symptoms, which appear at different disease stages. While recent research has pointed to specific neuronal subpopulations, or microcircuits, operating in the basal ganglia, researchers lacked a clear understanding of how they might correspond with specific symptom domains.
In a study published online March 15 in Nature Neuroscience, lead author Varoth Lilascharoen, PhD, of the University of California, San Diego, and colleagues reported that two different neuronal subpopulations within the external globus pallidus, an important nucleus within the basal ganglia, are associated, respectively, with movement and with reversal learning (having to adapt to a reward pattern that is the reverse of a previous pattern). This is the first time, the investigators said, that the contributions of specific microcircuits in the basal ganglia have been linked to different behaviors.
Using electrophysiology, viral tracing, and other approaches, Dr. Lilascharoen and colleagues demonstrated that two microcircuits or populations of parvalbumin-expressing neurons could be manipulated to exacerbate or alleviate the motor or cognitive deficits in the dopamine-depleted mice.
One of these microcircuits, made up of substantia nigra pars reticulata-projecting GPe-PV neurons, could be manipulated in ways that promoted or inhibited the mice’s movement. The other, which comprises parafascicular thalamus-projecting GPe-PV neurons, could be manipulated to affect reversal learning, the researchers found. Activation or inhibition of either circuit was not seen affecting function in the other.
The results shed light on the functional organization of the different basal ganglia nuclei at the circuit level, and suggest, the authors argued, that differences in how different neuronal subpopulations adapt to dopamine loss could explain some of the patterns of progression seen in Parkinson’s disease.
The findings “establish the differential contributions from two distinct GPe-PV microcircuits in specific Parkinsonian-like behaviors linked to early and late stages of the disease,” Dr. Lilascharoen and colleagues wrote in their analysis. “[F]urther elucidation of the detailed connectivity of GPe subpopulations to their downstream targets … is needed to fully define the function of each microcircuit and design better therapeutic strategies for the various behavioral impairments of Parkinson’s disease.”
Commenting on the research, Stefan Lang, MD, PhD, of the University of Calgary in Alberta said, “While Parkinson’s disease is often referred to as a movement disorder, it is well known that nonmotor symptoms, including cognitive and behavioral impairment, are common and debilitating. Impairment of basal ganglia function is known to contribute to these different symptom domains, though the specific circuits have never been elucidated. [Dr.] Lilascharoen et al. tease apart specific basal ganglia circuits associated with motor and behavioral symptoms, thereby providing evidence that distinct microcircuits might contribute to unique behaviours. As technological advances in neuromodulatory therapies continue to improve the spatial and temporal resolution of stimulation, future treatments may allow for specific targeting of behavioral impairment symptoms in Parkinson’s disease.”
Dr. Lilascharoen and Dr. Lang did not report outside funding or conflicts of interest.
, according to a new study using a mouse model of disease.
Parkinson’s disease is characterized by a range of cognitive and motor symptoms, which appear at different disease stages. While recent research has pointed to specific neuronal subpopulations, or microcircuits, operating in the basal ganglia, researchers lacked a clear understanding of how they might correspond with specific symptom domains.
In a study published online March 15 in Nature Neuroscience, lead author Varoth Lilascharoen, PhD, of the University of California, San Diego, and colleagues reported that two different neuronal subpopulations within the external globus pallidus, an important nucleus within the basal ganglia, are associated, respectively, with movement and with reversal learning (having to adapt to a reward pattern that is the reverse of a previous pattern). This is the first time, the investigators said, that the contributions of specific microcircuits in the basal ganglia have been linked to different behaviors.
Using electrophysiology, viral tracing, and other approaches, Dr. Lilascharoen and colleagues demonstrated that two microcircuits or populations of parvalbumin-expressing neurons could be manipulated to exacerbate or alleviate the motor or cognitive deficits in the dopamine-depleted mice.
One of these microcircuits, made up of substantia nigra pars reticulata-projecting GPe-PV neurons, could be manipulated in ways that promoted or inhibited the mice’s movement. The other, which comprises parafascicular thalamus-projecting GPe-PV neurons, could be manipulated to affect reversal learning, the researchers found. Activation or inhibition of either circuit was not seen affecting function in the other.
The results shed light on the functional organization of the different basal ganglia nuclei at the circuit level, and suggest, the authors argued, that differences in how different neuronal subpopulations adapt to dopamine loss could explain some of the patterns of progression seen in Parkinson’s disease.
The findings “establish the differential contributions from two distinct GPe-PV microcircuits in specific Parkinsonian-like behaviors linked to early and late stages of the disease,” Dr. Lilascharoen and colleagues wrote in their analysis. “[F]urther elucidation of the detailed connectivity of GPe subpopulations to their downstream targets … is needed to fully define the function of each microcircuit and design better therapeutic strategies for the various behavioral impairments of Parkinson’s disease.”
Commenting on the research, Stefan Lang, MD, PhD, of the University of Calgary in Alberta said, “While Parkinson’s disease is often referred to as a movement disorder, it is well known that nonmotor symptoms, including cognitive and behavioral impairment, are common and debilitating. Impairment of basal ganglia function is known to contribute to these different symptom domains, though the specific circuits have never been elucidated. [Dr.] Lilascharoen et al. tease apart specific basal ganglia circuits associated with motor and behavioral symptoms, thereby providing evidence that distinct microcircuits might contribute to unique behaviours. As technological advances in neuromodulatory therapies continue to improve the spatial and temporal resolution of stimulation, future treatments may allow for specific targeting of behavioral impairment symptoms in Parkinson’s disease.”
Dr. Lilascharoen and Dr. Lang did not report outside funding or conflicts of interest.
FROM NATURE NEUROSCIENCE
Long-term benefit for DBS in treating Parkinson’s disease motor symptoms
, new research shows. In the longest follow-up study comparing the subthalamic nucleus (STN) or the globus pallidus (GPi) as treatment targets for Parkinson’s disease, investigators found DBS was effective at 10 years regardless of which of these two brain regions were treated.
“Both STN and GPi DBS maintained motor benefit out to 10 years, with improvements seen in tremor and rigidity, greater than bradykinesia,” said study author Jill L. Ostrem, MD, medical director and division chief at the University of California, San Francisco Movement Disorders and Neuromodulation Center.
“Less medication was required, and patients had fewer motor fluctuations and less dyskinesia,” she added. But nonmotor symptoms and other symptoms that are less responsive to DBS progress led to worsening disability over time.
The findings were presented at the American Academy of Neurology’s 2021 annual meeting.
Advanced patients
Many studies have examined the GPi and STN as targets for deep brain stimulation in Parkinson’s disease. Some research has compared outcomes between the two targets, but no prospective, randomized trials have evaluated outcomes beyond 3 years of treatment.
For the study, investigators examined data from Study 468, a multicenter, randomized, controlled trial conducted by the U.S. Veterans Affairs (VA) Cooperative Study Program and the National Institute of Neurological Disorders and Stroke (NINDS). In this study, a subset of patients who had been randomly assigned to deep brain stimulation of the GPi or STN were followed for up to 10 years.
Participants were examined at 2 years, 7 years, and 10 years. Eighty-five participants assigned to GPi and 70 assigned to STN completed the visit at 2 years. At 7 years, 68 GPi patients and 49 STN patients completed the visit. Forty-nine patients assigned to GPi and 28 assigned to STN completed the visit at 10 years.
The study’s primary outcome was change in the Unified Parkinson Disease Rating Scale (UPDRS) motor subscale score while off medication and on stimulation between targets. Secondary outcomes included tremor, rigidity, and bradykinesia.
The two groups of patients had comparable baseline characteristics. Mean age was approximately 59 years in both groups. The proportion of male patients was 87% in the GPi group and 83% in the STN group. White patients predominated in the GPi (98%) and STN (94%) groups.
Average disease duration was approximately 11 years, and more than 10% of patients in each group were older than 70 years, indicating a “somewhat more advanced patient cohort,” said Dr. Ostrem.
Although the study’s dropout rate was high, the researchers found no difference in baseline characteristics between patients who did and did not complete the study.
Consistent motor improvement
Motor function improved at all timepoints for patients in both study arms. Baseline UPDRS motor subscale score was 43.2 for patients assigned to GPi stimulation. This score changed to 25.8 at 2 years (P < .001), 35.4 at 7 years (P < .001), and 34.0 at 10 years (P = .10).
Baseline UPDRS motor subscale score also was 43.2 for patients assigned to STN stimulation. This score changed to 27.7 at 2 years (P < .001), 34.4 at 7 years (P < .001), and 28.3 at 10 years (P < .001). Improvements were similar between groups but tended to be greater in the STN group.
Among the study’s secondary outcomes, tremor subscales showed the greatest improvement over time, followed by rigidity subscores. Compared with GPi DBS, STN DBS was associated with greater improvement in bradykinesia subscores at 7 and 10 years (P = .03).
In addition, UPDRS I, II, and IV scores, as recorded in motor diaries, showed significant long-term improvement in both study groups. Part I (which reflects mentation and mood) and part II (which reflects activities of daily living) tended to worsen at 7 and 10 years. There were no differences between groups.
Total score on the Parkinson’s Disease Questionnaire-39 (PDQ-39), which measures function in daily living, no longer showed improvement at 7 or 10 years for either target. Rather, it showed worsening, compared with baseline.
“Cognitive impairment and gait and balance issues result in more issues with quality of life and independence,” said Dr. Ostrem.
Stimulation of both targets reduced medication use significantly. There was no difference between targets for this outcome.
The rate of device-related complications in this cohort was comparatively low, said Dr. Ostrem. In the overall study complication, the rate of DBS malfunction was 7.7%, and the rate of DBS infection was 5.8%.
The finding that both targets had similar long-term sustainability of motor benefit provides reassurance that either target is a reasonable choice, said Dr. Ostrem. “I would suggest target choice be determined by a multidisciplinary team, where individual patient signs and symptoms and goals can be considered.”
Other large DBS trials with shorter follow-up durations have suggested differences between the targets. These data can guide the choice of target, said Dr. Ostrem.
“The field of DBS research has never been more exciting,” she added. Newer systems that include improved hardware and software and can record neurophysiologic data from the implanted brain leads could provide improved outcomes of DBS treatment.
“With modern DBS methods and approaches, we are learning more about Parkinson’s disease and other brain diseases, which I believe will help us to find more treatments and other interventions to slow the progression or minimize symptoms,” Dr. Ostrem concluded.
Selection bias?
Commenting on the study, Alfonso Fasano, MD, PhD, chair in neuromodulation and multidisciplinary care at University of Toronto, noted that “these are the first long-term findings resulting from a randomized trial, overall supporting the early notion that STN DBS is superior to GPi DBS in terms of bradykinesia improvement, especially in the long-run.”
The findings reflect the clinical practice of considering STN deep brain stimulation for young patients who face a longer disease duration. Younger patients might tolerate the procedure better than older patients. They also may achieve medication reduction, better motor control, and the possibility of increasing medication when side effects make increased stimulation undesirable.
“It’s interesting to note that even GPi DBS maintained an overall good outcome over time,” said Dr. Fasano. This finding contrasts with that of previous studies, but the latter were limited by selection bias, he added. “Older and frail patients were more likely to be treated with GPi DBS.”
Two factors limit the study’s findings, said Dr. Fasano. During the long study duration, many patients dropped out or were lost to follow-up. “Thus, it is conceivable that the study only enrolled the best responders in each group,” said Dr. Fasano.
In addition, the results of the trial that the current investigators analyzed are not necessarily generalizable, as those who conducted it soon recognized. The study by the VA and NINDS did not detect differences between targets, mainly because of a surprisingly low effect of STN deep brain stimulation. The researchers determined that this finding was related to the study’s inclusion criteria.
“The lack of improvement [on the PDQ-39] clearly indicates that simply treating the motor problems of Parkinson’s disease patients is not enough,” said Dr. Fasano. It also emphasizes that DBS is a symptomatic therapy with little or no effect on the disease’s natural history.
“It will be also important to see how the new data reported by Dr. Ostrem compare to the long-term outcome of the other major STN versus GPi trial from Europe,” said Dr. Fasano, referring to the NSTAPS trial.
He added that it will also be interesting to follow these cohorts for at least 5 more years in order to identify possible differences in terms of disease milestones such as dementia and survival. Previous studies have shown a reduction in survival with targets other than STN, but this finding likely reflects selection bias, he concluded.
The study was funded by the National Institute of Neurological Disorders and Stroke and the U.S. Department of Veterans Affairs. Dr. Ostrem previously has accepted consulting funds from Medtronic and Abbott. She receives grant support from Medtronic and Boston Scientific for fellowship training and clinical trial support. These companies were not involved in the study. Dr. Fasano received honoraria and research support and honoraria from Abbott, Boston Scientific, Brainlab, Ceregate, Inbrain, and Medtronic.
A version of this article first appeared on Medscape.com.
, new research shows. In the longest follow-up study comparing the subthalamic nucleus (STN) or the globus pallidus (GPi) as treatment targets for Parkinson’s disease, investigators found DBS was effective at 10 years regardless of which of these two brain regions were treated.
“Both STN and GPi DBS maintained motor benefit out to 10 years, with improvements seen in tremor and rigidity, greater than bradykinesia,” said study author Jill L. Ostrem, MD, medical director and division chief at the University of California, San Francisco Movement Disorders and Neuromodulation Center.
“Less medication was required, and patients had fewer motor fluctuations and less dyskinesia,” she added. But nonmotor symptoms and other symptoms that are less responsive to DBS progress led to worsening disability over time.
The findings were presented at the American Academy of Neurology’s 2021 annual meeting.
Advanced patients
Many studies have examined the GPi and STN as targets for deep brain stimulation in Parkinson’s disease. Some research has compared outcomes between the two targets, but no prospective, randomized trials have evaluated outcomes beyond 3 years of treatment.
For the study, investigators examined data from Study 468, a multicenter, randomized, controlled trial conducted by the U.S. Veterans Affairs (VA) Cooperative Study Program and the National Institute of Neurological Disorders and Stroke (NINDS). In this study, a subset of patients who had been randomly assigned to deep brain stimulation of the GPi or STN were followed for up to 10 years.
Participants were examined at 2 years, 7 years, and 10 years. Eighty-five participants assigned to GPi and 70 assigned to STN completed the visit at 2 years. At 7 years, 68 GPi patients and 49 STN patients completed the visit. Forty-nine patients assigned to GPi and 28 assigned to STN completed the visit at 10 years.
The study’s primary outcome was change in the Unified Parkinson Disease Rating Scale (UPDRS) motor subscale score while off medication and on stimulation between targets. Secondary outcomes included tremor, rigidity, and bradykinesia.
The two groups of patients had comparable baseline characteristics. Mean age was approximately 59 years in both groups. The proportion of male patients was 87% in the GPi group and 83% in the STN group. White patients predominated in the GPi (98%) and STN (94%) groups.
Average disease duration was approximately 11 years, and more than 10% of patients in each group were older than 70 years, indicating a “somewhat more advanced patient cohort,” said Dr. Ostrem.
Although the study’s dropout rate was high, the researchers found no difference in baseline characteristics between patients who did and did not complete the study.
Consistent motor improvement
Motor function improved at all timepoints for patients in both study arms. Baseline UPDRS motor subscale score was 43.2 for patients assigned to GPi stimulation. This score changed to 25.8 at 2 years (P < .001), 35.4 at 7 years (P < .001), and 34.0 at 10 years (P = .10).
Baseline UPDRS motor subscale score also was 43.2 for patients assigned to STN stimulation. This score changed to 27.7 at 2 years (P < .001), 34.4 at 7 years (P < .001), and 28.3 at 10 years (P < .001). Improvements were similar between groups but tended to be greater in the STN group.
Among the study’s secondary outcomes, tremor subscales showed the greatest improvement over time, followed by rigidity subscores. Compared with GPi DBS, STN DBS was associated with greater improvement in bradykinesia subscores at 7 and 10 years (P = .03).
In addition, UPDRS I, II, and IV scores, as recorded in motor diaries, showed significant long-term improvement in both study groups. Part I (which reflects mentation and mood) and part II (which reflects activities of daily living) tended to worsen at 7 and 10 years. There were no differences between groups.
Total score on the Parkinson’s Disease Questionnaire-39 (PDQ-39), which measures function in daily living, no longer showed improvement at 7 or 10 years for either target. Rather, it showed worsening, compared with baseline.
“Cognitive impairment and gait and balance issues result in more issues with quality of life and independence,” said Dr. Ostrem.
Stimulation of both targets reduced medication use significantly. There was no difference between targets for this outcome.
The rate of device-related complications in this cohort was comparatively low, said Dr. Ostrem. In the overall study complication, the rate of DBS malfunction was 7.7%, and the rate of DBS infection was 5.8%.
The finding that both targets had similar long-term sustainability of motor benefit provides reassurance that either target is a reasonable choice, said Dr. Ostrem. “I would suggest target choice be determined by a multidisciplinary team, where individual patient signs and symptoms and goals can be considered.”
Other large DBS trials with shorter follow-up durations have suggested differences between the targets. These data can guide the choice of target, said Dr. Ostrem.
“The field of DBS research has never been more exciting,” she added. Newer systems that include improved hardware and software and can record neurophysiologic data from the implanted brain leads could provide improved outcomes of DBS treatment.
“With modern DBS methods and approaches, we are learning more about Parkinson’s disease and other brain diseases, which I believe will help us to find more treatments and other interventions to slow the progression or minimize symptoms,” Dr. Ostrem concluded.
Selection bias?
Commenting on the study, Alfonso Fasano, MD, PhD, chair in neuromodulation and multidisciplinary care at University of Toronto, noted that “these are the first long-term findings resulting from a randomized trial, overall supporting the early notion that STN DBS is superior to GPi DBS in terms of bradykinesia improvement, especially in the long-run.”
The findings reflect the clinical practice of considering STN deep brain stimulation for young patients who face a longer disease duration. Younger patients might tolerate the procedure better than older patients. They also may achieve medication reduction, better motor control, and the possibility of increasing medication when side effects make increased stimulation undesirable.
“It’s interesting to note that even GPi DBS maintained an overall good outcome over time,” said Dr. Fasano. This finding contrasts with that of previous studies, but the latter were limited by selection bias, he added. “Older and frail patients were more likely to be treated with GPi DBS.”
Two factors limit the study’s findings, said Dr. Fasano. During the long study duration, many patients dropped out or were lost to follow-up. “Thus, it is conceivable that the study only enrolled the best responders in each group,” said Dr. Fasano.
In addition, the results of the trial that the current investigators analyzed are not necessarily generalizable, as those who conducted it soon recognized. The study by the VA and NINDS did not detect differences between targets, mainly because of a surprisingly low effect of STN deep brain stimulation. The researchers determined that this finding was related to the study’s inclusion criteria.
“The lack of improvement [on the PDQ-39] clearly indicates that simply treating the motor problems of Parkinson’s disease patients is not enough,” said Dr. Fasano. It also emphasizes that DBS is a symptomatic therapy with little or no effect on the disease’s natural history.
“It will be also important to see how the new data reported by Dr. Ostrem compare to the long-term outcome of the other major STN versus GPi trial from Europe,” said Dr. Fasano, referring to the NSTAPS trial.
He added that it will also be interesting to follow these cohorts for at least 5 more years in order to identify possible differences in terms of disease milestones such as dementia and survival. Previous studies have shown a reduction in survival with targets other than STN, but this finding likely reflects selection bias, he concluded.
The study was funded by the National Institute of Neurological Disorders and Stroke and the U.S. Department of Veterans Affairs. Dr. Ostrem previously has accepted consulting funds from Medtronic and Abbott. She receives grant support from Medtronic and Boston Scientific for fellowship training and clinical trial support. These companies were not involved in the study. Dr. Fasano received honoraria and research support and honoraria from Abbott, Boston Scientific, Brainlab, Ceregate, Inbrain, and Medtronic.
A version of this article first appeared on Medscape.com.
, new research shows. In the longest follow-up study comparing the subthalamic nucleus (STN) or the globus pallidus (GPi) as treatment targets for Parkinson’s disease, investigators found DBS was effective at 10 years regardless of which of these two brain regions were treated.
“Both STN and GPi DBS maintained motor benefit out to 10 years, with improvements seen in tremor and rigidity, greater than bradykinesia,” said study author Jill L. Ostrem, MD, medical director and division chief at the University of California, San Francisco Movement Disorders and Neuromodulation Center.
“Less medication was required, and patients had fewer motor fluctuations and less dyskinesia,” she added. But nonmotor symptoms and other symptoms that are less responsive to DBS progress led to worsening disability over time.
The findings were presented at the American Academy of Neurology’s 2021 annual meeting.
Advanced patients
Many studies have examined the GPi and STN as targets for deep brain stimulation in Parkinson’s disease. Some research has compared outcomes between the two targets, but no prospective, randomized trials have evaluated outcomes beyond 3 years of treatment.
For the study, investigators examined data from Study 468, a multicenter, randomized, controlled trial conducted by the U.S. Veterans Affairs (VA) Cooperative Study Program and the National Institute of Neurological Disorders and Stroke (NINDS). In this study, a subset of patients who had been randomly assigned to deep brain stimulation of the GPi or STN were followed for up to 10 years.
Participants were examined at 2 years, 7 years, and 10 years. Eighty-five participants assigned to GPi and 70 assigned to STN completed the visit at 2 years. At 7 years, 68 GPi patients and 49 STN patients completed the visit. Forty-nine patients assigned to GPi and 28 assigned to STN completed the visit at 10 years.
The study’s primary outcome was change in the Unified Parkinson Disease Rating Scale (UPDRS) motor subscale score while off medication and on stimulation between targets. Secondary outcomes included tremor, rigidity, and bradykinesia.
The two groups of patients had comparable baseline characteristics. Mean age was approximately 59 years in both groups. The proportion of male patients was 87% in the GPi group and 83% in the STN group. White patients predominated in the GPi (98%) and STN (94%) groups.
Average disease duration was approximately 11 years, and more than 10% of patients in each group were older than 70 years, indicating a “somewhat more advanced patient cohort,” said Dr. Ostrem.
Although the study’s dropout rate was high, the researchers found no difference in baseline characteristics between patients who did and did not complete the study.
Consistent motor improvement
Motor function improved at all timepoints for patients in both study arms. Baseline UPDRS motor subscale score was 43.2 for patients assigned to GPi stimulation. This score changed to 25.8 at 2 years (P < .001), 35.4 at 7 years (P < .001), and 34.0 at 10 years (P = .10).
Baseline UPDRS motor subscale score also was 43.2 for patients assigned to STN stimulation. This score changed to 27.7 at 2 years (P < .001), 34.4 at 7 years (P < .001), and 28.3 at 10 years (P < .001). Improvements were similar between groups but tended to be greater in the STN group.
Among the study’s secondary outcomes, tremor subscales showed the greatest improvement over time, followed by rigidity subscores. Compared with GPi DBS, STN DBS was associated with greater improvement in bradykinesia subscores at 7 and 10 years (P = .03).
In addition, UPDRS I, II, and IV scores, as recorded in motor diaries, showed significant long-term improvement in both study groups. Part I (which reflects mentation and mood) and part II (which reflects activities of daily living) tended to worsen at 7 and 10 years. There were no differences between groups.
Total score on the Parkinson’s Disease Questionnaire-39 (PDQ-39), which measures function in daily living, no longer showed improvement at 7 or 10 years for either target. Rather, it showed worsening, compared with baseline.
“Cognitive impairment and gait and balance issues result in more issues with quality of life and independence,” said Dr. Ostrem.
Stimulation of both targets reduced medication use significantly. There was no difference between targets for this outcome.
The rate of device-related complications in this cohort was comparatively low, said Dr. Ostrem. In the overall study complication, the rate of DBS malfunction was 7.7%, and the rate of DBS infection was 5.8%.
The finding that both targets had similar long-term sustainability of motor benefit provides reassurance that either target is a reasonable choice, said Dr. Ostrem. “I would suggest target choice be determined by a multidisciplinary team, where individual patient signs and symptoms and goals can be considered.”
Other large DBS trials with shorter follow-up durations have suggested differences between the targets. These data can guide the choice of target, said Dr. Ostrem.
“The field of DBS research has never been more exciting,” she added. Newer systems that include improved hardware and software and can record neurophysiologic data from the implanted brain leads could provide improved outcomes of DBS treatment.
“With modern DBS methods and approaches, we are learning more about Parkinson’s disease and other brain diseases, which I believe will help us to find more treatments and other interventions to slow the progression or minimize symptoms,” Dr. Ostrem concluded.
Selection bias?
Commenting on the study, Alfonso Fasano, MD, PhD, chair in neuromodulation and multidisciplinary care at University of Toronto, noted that “these are the first long-term findings resulting from a randomized trial, overall supporting the early notion that STN DBS is superior to GPi DBS in terms of bradykinesia improvement, especially in the long-run.”
The findings reflect the clinical practice of considering STN deep brain stimulation for young patients who face a longer disease duration. Younger patients might tolerate the procedure better than older patients. They also may achieve medication reduction, better motor control, and the possibility of increasing medication when side effects make increased stimulation undesirable.
“It’s interesting to note that even GPi DBS maintained an overall good outcome over time,” said Dr. Fasano. This finding contrasts with that of previous studies, but the latter were limited by selection bias, he added. “Older and frail patients were more likely to be treated with GPi DBS.”
Two factors limit the study’s findings, said Dr. Fasano. During the long study duration, many patients dropped out or were lost to follow-up. “Thus, it is conceivable that the study only enrolled the best responders in each group,” said Dr. Fasano.
In addition, the results of the trial that the current investigators analyzed are not necessarily generalizable, as those who conducted it soon recognized. The study by the VA and NINDS did not detect differences between targets, mainly because of a surprisingly low effect of STN deep brain stimulation. The researchers determined that this finding was related to the study’s inclusion criteria.
“The lack of improvement [on the PDQ-39] clearly indicates that simply treating the motor problems of Parkinson’s disease patients is not enough,” said Dr. Fasano. It also emphasizes that DBS is a symptomatic therapy with little or no effect on the disease’s natural history.
“It will be also important to see how the new data reported by Dr. Ostrem compare to the long-term outcome of the other major STN versus GPi trial from Europe,” said Dr. Fasano, referring to the NSTAPS trial.
He added that it will also be interesting to follow these cohorts for at least 5 more years in order to identify possible differences in terms of disease milestones such as dementia and survival. Previous studies have shown a reduction in survival with targets other than STN, but this finding likely reflects selection bias, he concluded.
The study was funded by the National Institute of Neurological Disorders and Stroke and the U.S. Department of Veterans Affairs. Dr. Ostrem previously has accepted consulting funds from Medtronic and Abbott. She receives grant support from Medtronic and Boston Scientific for fellowship training and clinical trial support. These companies were not involved in the study. Dr. Fasano received honoraria and research support and honoraria from Abbott, Boston Scientific, Brainlab, Ceregate, Inbrain, and Medtronic.
A version of this article first appeared on Medscape.com.
Nondopamine antipsychotic shows clinical signal in Parkinson’s disease psychosis
according to results of a proof-of-principle study presented at the 2021 annual meeting of the American Academy of Neurology.
In presenting study results, Stuart H. Isaacson, MD, of the Parkinson’s Disease and Movement Disorders Center in Boca Raton, Fla., noted the one potential advantage of SEP-363856 is that it does not require blood monitoring, unlike clozapine, often used as an alternative to pimavanserin, the only Food and Drug Administration–approved treatment for Parkinson’s disease psychosis.* Quetiapine has also been used off label for Parkinson’s disease psychosis, but Dr. Isaacson said this lacks the evidence supporting the other two options and has side effects including sedation and orthostatic hypotension.
“Other non–FDA-approved treatment options are limited due to their lack of efficacy, safety concerns, and exacerbation of motor symptoms,” he said.
The study involved 38 patients, 24 of whom received SEP-363856 and the rest placebo, and evaluated total scores for the novel Scale for the Assessment of Positive Symptoms for Parkinson’s Disease Psychosis (SAPS-PD) after 6 weeks of treatment. The treatment group was given one of three doses: 25 mg (n = 11), 50 mg (n = 9), and 75 mg (n = 10).
Dr. Isaacson described SEP-363856 as a novel molecule that has agonist activity at TARR1, which regulates dopamine, norepinephrine, and serotonin, as well as serotonin receptor 5-HT1A, but has no activity at the dopamine receptor D2.
“There did appear to be improvement with this medication in patients’ psychosis symptoms, using the SAPS-PD subscale to identify the frequency and severity of hallucinations and delusions, but there was also improvement in the placebo group in this small study,” Dr. Isaacson said. “That did not demonstrate significance.” The improvement was maintained through the study period.
But the gap between the treatment and placebo groups widened as the degree of response increased. The rates were identical for the 30% or above response and the 50% or above response subgroups: 27.3% and 37.5% for placebo and treatment groups, respectively. However, 25% of patients taking SEP-363856 had a 100% response in terms of SAPS-PD score versus 0% in the placebo group, Dr. Isaacson said.
The study also found Mini-Mental State Examination (MMSE) scores improved more in the treatment group, with the gap wider in those with baseline MMSE scores below 24 versus scores above 24: –5.2 (standard deviation, 2.81) versus –2.1 (SD, 3.00; P = .460).
“The scope of daytime and nighttime sleep both showed improvement, with the score for daytime sleep being significant,” Dr. Isaacson said of the treatment group. “Importantly, UPDRS [Unified Parkinson’s Disease Rating Scale] Part III motor scores showed no difference from placebo. Indeed, there was a trend toward improvement, but this again was not significant.” That’s noteworthy, he said, because other antipsychotics, with the exception of clozapine – which requires blood monitoring – are contraindicated in PDP because of their effect on motor function.
During question-and-answer, Dr. Isaacson noted that the complete response rate of 25% with SEP-363856 compared favorably with the 14% complete response rate reported with pimavanserin in the pivotal trial.
“Hopefully greater-powered studies will be performed to further identify and determine the safety and efficacy and tolerably of SEP-363856 in Parkinson’s psychosis, aiming to minimize the placebo effect and to try to hopefully identify its efficacy in relationship to other treatments,” Dr. Isaacson said.
“Right now with only one approved treatment, one that has efficacy but requires blood monitoring, and another treatment that may be fraught sometimes with sleepiness and other side effects, we need other alternatives for our patients as many of them resort to lowering and lowering their dopaminergic therapies with the consequence [of] worsening motor activity,” Dr. Isaacson said.
“This study further supports the concept that Parkinson’s disease psychosis involves much more than simply dopamine,” said Daniel E. Kremens, MD, codirector of the Parkinson’s disease and movement disorders division at Thomas Jefferson University, Philadelphia. “Targeting nondopaminergic targets allows us to treat the psychosis without worsening motor symptoms. By targeting TAAR-1 along with 5HT1A, SEP-363856 is a novel compound that appears to be well tolerated and may treat PDP without worsening motor symptoms,”
Sunovion Pharmaceuticals provided funding for the study. Dr. Isaacson has no financial relationships to disclose. Three study coauthors are employees of Sunovion. Dr. Kremens reported serving as a consultant to Sunovion.
*Correction, 5/17/21: An earlier version of this article misstated the blood monitoring requirements for pimavanserin.
according to results of a proof-of-principle study presented at the 2021 annual meeting of the American Academy of Neurology.
In presenting study results, Stuart H. Isaacson, MD, of the Parkinson’s Disease and Movement Disorders Center in Boca Raton, Fla., noted the one potential advantage of SEP-363856 is that it does not require blood monitoring, unlike clozapine, often used as an alternative to pimavanserin, the only Food and Drug Administration–approved treatment for Parkinson’s disease psychosis.* Quetiapine has also been used off label for Parkinson’s disease psychosis, but Dr. Isaacson said this lacks the evidence supporting the other two options and has side effects including sedation and orthostatic hypotension.
“Other non–FDA-approved treatment options are limited due to their lack of efficacy, safety concerns, and exacerbation of motor symptoms,” he said.
The study involved 38 patients, 24 of whom received SEP-363856 and the rest placebo, and evaluated total scores for the novel Scale for the Assessment of Positive Symptoms for Parkinson’s Disease Psychosis (SAPS-PD) after 6 weeks of treatment. The treatment group was given one of three doses: 25 mg (n = 11), 50 mg (n = 9), and 75 mg (n = 10).
Dr. Isaacson described SEP-363856 as a novel molecule that has agonist activity at TARR1, which regulates dopamine, norepinephrine, and serotonin, as well as serotonin receptor 5-HT1A, but has no activity at the dopamine receptor D2.
“There did appear to be improvement with this medication in patients’ psychosis symptoms, using the SAPS-PD subscale to identify the frequency and severity of hallucinations and delusions, but there was also improvement in the placebo group in this small study,” Dr. Isaacson said. “That did not demonstrate significance.” The improvement was maintained through the study period.
But the gap between the treatment and placebo groups widened as the degree of response increased. The rates were identical for the 30% or above response and the 50% or above response subgroups: 27.3% and 37.5% for placebo and treatment groups, respectively. However, 25% of patients taking SEP-363856 had a 100% response in terms of SAPS-PD score versus 0% in the placebo group, Dr. Isaacson said.
The study also found Mini-Mental State Examination (MMSE) scores improved more in the treatment group, with the gap wider in those with baseline MMSE scores below 24 versus scores above 24: –5.2 (standard deviation, 2.81) versus –2.1 (SD, 3.00; P = .460).
“The scope of daytime and nighttime sleep both showed improvement, with the score for daytime sleep being significant,” Dr. Isaacson said of the treatment group. “Importantly, UPDRS [Unified Parkinson’s Disease Rating Scale] Part III motor scores showed no difference from placebo. Indeed, there was a trend toward improvement, but this again was not significant.” That’s noteworthy, he said, because other antipsychotics, with the exception of clozapine – which requires blood monitoring – are contraindicated in PDP because of their effect on motor function.
During question-and-answer, Dr. Isaacson noted that the complete response rate of 25% with SEP-363856 compared favorably with the 14% complete response rate reported with pimavanserin in the pivotal trial.
“Hopefully greater-powered studies will be performed to further identify and determine the safety and efficacy and tolerably of SEP-363856 in Parkinson’s psychosis, aiming to minimize the placebo effect and to try to hopefully identify its efficacy in relationship to other treatments,” Dr. Isaacson said.
“Right now with only one approved treatment, one that has efficacy but requires blood monitoring, and another treatment that may be fraught sometimes with sleepiness and other side effects, we need other alternatives for our patients as many of them resort to lowering and lowering their dopaminergic therapies with the consequence [of] worsening motor activity,” Dr. Isaacson said.
“This study further supports the concept that Parkinson’s disease psychosis involves much more than simply dopamine,” said Daniel E. Kremens, MD, codirector of the Parkinson’s disease and movement disorders division at Thomas Jefferson University, Philadelphia. “Targeting nondopaminergic targets allows us to treat the psychosis without worsening motor symptoms. By targeting TAAR-1 along with 5HT1A, SEP-363856 is a novel compound that appears to be well tolerated and may treat PDP without worsening motor symptoms,”
Sunovion Pharmaceuticals provided funding for the study. Dr. Isaacson has no financial relationships to disclose. Three study coauthors are employees of Sunovion. Dr. Kremens reported serving as a consultant to Sunovion.
*Correction, 5/17/21: An earlier version of this article misstated the blood monitoring requirements for pimavanserin.
according to results of a proof-of-principle study presented at the 2021 annual meeting of the American Academy of Neurology.
In presenting study results, Stuart H. Isaacson, MD, of the Parkinson’s Disease and Movement Disorders Center in Boca Raton, Fla., noted the one potential advantage of SEP-363856 is that it does not require blood monitoring, unlike clozapine, often used as an alternative to pimavanserin, the only Food and Drug Administration–approved treatment for Parkinson’s disease psychosis.* Quetiapine has also been used off label for Parkinson’s disease psychosis, but Dr. Isaacson said this lacks the evidence supporting the other two options and has side effects including sedation and orthostatic hypotension.
“Other non–FDA-approved treatment options are limited due to their lack of efficacy, safety concerns, and exacerbation of motor symptoms,” he said.
The study involved 38 patients, 24 of whom received SEP-363856 and the rest placebo, and evaluated total scores for the novel Scale for the Assessment of Positive Symptoms for Parkinson’s Disease Psychosis (SAPS-PD) after 6 weeks of treatment. The treatment group was given one of three doses: 25 mg (n = 11), 50 mg (n = 9), and 75 mg (n = 10).
Dr. Isaacson described SEP-363856 as a novel molecule that has agonist activity at TARR1, which regulates dopamine, norepinephrine, and serotonin, as well as serotonin receptor 5-HT1A, but has no activity at the dopamine receptor D2.
“There did appear to be improvement with this medication in patients’ psychosis symptoms, using the SAPS-PD subscale to identify the frequency and severity of hallucinations and delusions, but there was also improvement in the placebo group in this small study,” Dr. Isaacson said. “That did not demonstrate significance.” The improvement was maintained through the study period.
But the gap between the treatment and placebo groups widened as the degree of response increased. The rates were identical for the 30% or above response and the 50% or above response subgroups: 27.3% and 37.5% for placebo and treatment groups, respectively. However, 25% of patients taking SEP-363856 had a 100% response in terms of SAPS-PD score versus 0% in the placebo group, Dr. Isaacson said.
The study also found Mini-Mental State Examination (MMSE) scores improved more in the treatment group, with the gap wider in those with baseline MMSE scores below 24 versus scores above 24: –5.2 (standard deviation, 2.81) versus –2.1 (SD, 3.00; P = .460).
“The scope of daytime and nighttime sleep both showed improvement, with the score for daytime sleep being significant,” Dr. Isaacson said of the treatment group. “Importantly, UPDRS [Unified Parkinson’s Disease Rating Scale] Part III motor scores showed no difference from placebo. Indeed, there was a trend toward improvement, but this again was not significant.” That’s noteworthy, he said, because other antipsychotics, with the exception of clozapine – which requires blood monitoring – are contraindicated in PDP because of their effect on motor function.
During question-and-answer, Dr. Isaacson noted that the complete response rate of 25% with SEP-363856 compared favorably with the 14% complete response rate reported with pimavanserin in the pivotal trial.
“Hopefully greater-powered studies will be performed to further identify and determine the safety and efficacy and tolerably of SEP-363856 in Parkinson’s psychosis, aiming to minimize the placebo effect and to try to hopefully identify its efficacy in relationship to other treatments,” Dr. Isaacson said.
“Right now with only one approved treatment, one that has efficacy but requires blood monitoring, and another treatment that may be fraught sometimes with sleepiness and other side effects, we need other alternatives for our patients as many of them resort to lowering and lowering their dopaminergic therapies with the consequence [of] worsening motor activity,” Dr. Isaacson said.
“This study further supports the concept that Parkinson’s disease psychosis involves much more than simply dopamine,” said Daniel E. Kremens, MD, codirector of the Parkinson’s disease and movement disorders division at Thomas Jefferson University, Philadelphia. “Targeting nondopaminergic targets allows us to treat the psychosis without worsening motor symptoms. By targeting TAAR-1 along with 5HT1A, SEP-363856 is a novel compound that appears to be well tolerated and may treat PDP without worsening motor symptoms,”
Sunovion Pharmaceuticals provided funding for the study. Dr. Isaacson has no financial relationships to disclose. Three study coauthors are employees of Sunovion. Dr. Kremens reported serving as a consultant to Sunovion.
*Correction, 5/17/21: An earlier version of this article misstated the blood monitoring requirements for pimavanserin.
FROM AAN 2021
Study shows potential of remote Parkinson’s disease genotyping
according to a pilot study sponsored by the Parkinson’s Foundation.
“Overall we found high levels of participant satisfaction with Parkinson’s testing and genetic counseling and no significant difference in outcomes concerning satisfaction, knowledge, and impact of genetic testing between disclosure of results and genetic counseling in-person by either a neurologist or a genetic counselor or via telephone by a remove genetic counselor at a centralized center,” said Jennifer L. Verbrugge, MS, a genetic counselor at Indiana University, Indianapolis, in reporting results of the PD GENEration pilot study, presented at the 2021 annual meeting of the American Academy of Neurology.
COVID complication
The study launched in the summer of 2019 with the goal of enrolling 600 participants. However, because of the COVID-19 pandemic, enrollment was truncated. The pilot study eventually enrolled 289 patients, 205 of whom returned their postgenetic counseling surveys, Ms. Verbrugge said. The pilot study goal was to evaluate the feasibility and impact of in-person versus remote genetic testing and counseling for people with Parkinson’s disease.
“The study hopes to reach its ultimate goal, which is to deliver Parkinson’s disease–related genetic testing and counseling to upward of 15,000 people with Parkinson’s,” Ms. Verbrugge said. The program is also planning to expand to include Spanish speakers.
In the pilot study, genetic results were positive in 17% of patients, with 15% (n = 42) having positive heterozygous variants and 8% having variants of uncertain significance. “We did not see significant differences in these outcomes when we compared the mode and genetic counselors involved,” Ms. Verbrugge said.
The study did find that in-person testing and counseling “was associated with increased participant feelings that they were partners in care,” Ms. Verbrugge added. “This is something we are going to continue to evaluate as time goes on.”
However, as the COVID-19 pandemic pushed clinicians to develop virtual platforms, it resulted in a function through which participants can complete all genetic study activities remotely, she said. The study organizers anticipate that as pandemic restrictions ease, they will be able to reach their original goal of 600 participants along with those recruited in an expansion phase.
“As restrictions related to the pandemic ease, we anticipate that more Parkinson’s disease gene-targeted clinical trials will emerge, with aims to recruit people who carry certain gene variants,” Ms. Verbrugge said in an interview. “Many people with Parkinson’s disease may therefore benefit from genetic testing and learning if they carry a Parkinson’s disease related gene variant from participation in the PD GENEration study.”
Increasing patient access
To scale up to the 15,000-population goal for the program, PD GENEration has launched a new protocol designed to increase patient access at new study sites, Ms. Verbrugge said. “This protocol includes an abbreviate version of the clinical data collected, while it maintains the critical component of genetic counseling in the testing process.”
Going forward, the PD GENEration study will focus on improving access to genetic testing and counseling in underrepresented and rural populations, Ms. Verbrugge said. “These efforts will also generate valuable genomic data, allowing researchers to learn more about the causes of Parkinson’s disease in diverse and underrepresented populations. The study will be expanding research efforts concerning the genomic data to gain insights about the seven key genes studied as well as new genes linked to Parkinson’s disease.”
The work of the PD GENEration study is timely, said David K. Simon, MD, PhD, of Harvard Medical School and director of the Parkinson’s Disease & Movement Disorders Center at Beth Israel Deaconess Medical Center, both in Boston. “This is very important to identify such patients now, as clinical trials targeting people with specific genetic mutations or variants are coming soon, and in some cases already are underway. The feasibility and speed of enrollment for those trials will be greatly facilitate if we know in advance who are the people with Parkinson’s disease who have mutations that would make them eligible for the particular trials.”
The fact that the study provides free genetic testing to people with Parkinson’s disease isn’t to be overlooked. “This was an important study to address the question of whether or not remote genetic counseling was feasible and effective, and the results are meaningful given the randomized prospective design,” Dr. Simon said.
Ms. Verbrugge has no relevant relationships to disclose. Dr. Simon reports receiving research funding from the Parkinson’s Foundation.
according to a pilot study sponsored by the Parkinson’s Foundation.
“Overall we found high levels of participant satisfaction with Parkinson’s testing and genetic counseling and no significant difference in outcomes concerning satisfaction, knowledge, and impact of genetic testing between disclosure of results and genetic counseling in-person by either a neurologist or a genetic counselor or via telephone by a remove genetic counselor at a centralized center,” said Jennifer L. Verbrugge, MS, a genetic counselor at Indiana University, Indianapolis, in reporting results of the PD GENEration pilot study, presented at the 2021 annual meeting of the American Academy of Neurology.
COVID complication
The study launched in the summer of 2019 with the goal of enrolling 600 participants. However, because of the COVID-19 pandemic, enrollment was truncated. The pilot study eventually enrolled 289 patients, 205 of whom returned their postgenetic counseling surveys, Ms. Verbrugge said. The pilot study goal was to evaluate the feasibility and impact of in-person versus remote genetic testing and counseling for people with Parkinson’s disease.
“The study hopes to reach its ultimate goal, which is to deliver Parkinson’s disease–related genetic testing and counseling to upward of 15,000 people with Parkinson’s,” Ms. Verbrugge said. The program is also planning to expand to include Spanish speakers.
In the pilot study, genetic results were positive in 17% of patients, with 15% (n = 42) having positive heterozygous variants and 8% having variants of uncertain significance. “We did not see significant differences in these outcomes when we compared the mode and genetic counselors involved,” Ms. Verbrugge said.
The study did find that in-person testing and counseling “was associated with increased participant feelings that they were partners in care,” Ms. Verbrugge added. “This is something we are going to continue to evaluate as time goes on.”
However, as the COVID-19 pandemic pushed clinicians to develop virtual platforms, it resulted in a function through which participants can complete all genetic study activities remotely, she said. The study organizers anticipate that as pandemic restrictions ease, they will be able to reach their original goal of 600 participants along with those recruited in an expansion phase.
“As restrictions related to the pandemic ease, we anticipate that more Parkinson’s disease gene-targeted clinical trials will emerge, with aims to recruit people who carry certain gene variants,” Ms. Verbrugge said in an interview. “Many people with Parkinson’s disease may therefore benefit from genetic testing and learning if they carry a Parkinson’s disease related gene variant from participation in the PD GENEration study.”
Increasing patient access
To scale up to the 15,000-population goal for the program, PD GENEration has launched a new protocol designed to increase patient access at new study sites, Ms. Verbrugge said. “This protocol includes an abbreviate version of the clinical data collected, while it maintains the critical component of genetic counseling in the testing process.”
Going forward, the PD GENEration study will focus on improving access to genetic testing and counseling in underrepresented and rural populations, Ms. Verbrugge said. “These efforts will also generate valuable genomic data, allowing researchers to learn more about the causes of Parkinson’s disease in diverse and underrepresented populations. The study will be expanding research efforts concerning the genomic data to gain insights about the seven key genes studied as well as new genes linked to Parkinson’s disease.”
The work of the PD GENEration study is timely, said David K. Simon, MD, PhD, of Harvard Medical School and director of the Parkinson’s Disease & Movement Disorders Center at Beth Israel Deaconess Medical Center, both in Boston. “This is very important to identify such patients now, as clinical trials targeting people with specific genetic mutations or variants are coming soon, and in some cases already are underway. The feasibility and speed of enrollment for those trials will be greatly facilitate if we know in advance who are the people with Parkinson’s disease who have mutations that would make them eligible for the particular trials.”
The fact that the study provides free genetic testing to people with Parkinson’s disease isn’t to be overlooked. “This was an important study to address the question of whether or not remote genetic counseling was feasible and effective, and the results are meaningful given the randomized prospective design,” Dr. Simon said.
Ms. Verbrugge has no relevant relationships to disclose. Dr. Simon reports receiving research funding from the Parkinson’s Foundation.
according to a pilot study sponsored by the Parkinson’s Foundation.
“Overall we found high levels of participant satisfaction with Parkinson’s testing and genetic counseling and no significant difference in outcomes concerning satisfaction, knowledge, and impact of genetic testing between disclosure of results and genetic counseling in-person by either a neurologist or a genetic counselor or via telephone by a remove genetic counselor at a centralized center,” said Jennifer L. Verbrugge, MS, a genetic counselor at Indiana University, Indianapolis, in reporting results of the PD GENEration pilot study, presented at the 2021 annual meeting of the American Academy of Neurology.
COVID complication
The study launched in the summer of 2019 with the goal of enrolling 600 participants. However, because of the COVID-19 pandemic, enrollment was truncated. The pilot study eventually enrolled 289 patients, 205 of whom returned their postgenetic counseling surveys, Ms. Verbrugge said. The pilot study goal was to evaluate the feasibility and impact of in-person versus remote genetic testing and counseling for people with Parkinson’s disease.
“The study hopes to reach its ultimate goal, which is to deliver Parkinson’s disease–related genetic testing and counseling to upward of 15,000 people with Parkinson’s,” Ms. Verbrugge said. The program is also planning to expand to include Spanish speakers.
In the pilot study, genetic results were positive in 17% of patients, with 15% (n = 42) having positive heterozygous variants and 8% having variants of uncertain significance. “We did not see significant differences in these outcomes when we compared the mode and genetic counselors involved,” Ms. Verbrugge said.
The study did find that in-person testing and counseling “was associated with increased participant feelings that they were partners in care,” Ms. Verbrugge added. “This is something we are going to continue to evaluate as time goes on.”
However, as the COVID-19 pandemic pushed clinicians to develop virtual platforms, it resulted in a function through which participants can complete all genetic study activities remotely, she said. The study organizers anticipate that as pandemic restrictions ease, they will be able to reach their original goal of 600 participants along with those recruited in an expansion phase.
“As restrictions related to the pandemic ease, we anticipate that more Parkinson’s disease gene-targeted clinical trials will emerge, with aims to recruit people who carry certain gene variants,” Ms. Verbrugge said in an interview. “Many people with Parkinson’s disease may therefore benefit from genetic testing and learning if they carry a Parkinson’s disease related gene variant from participation in the PD GENEration study.”
Increasing patient access
To scale up to the 15,000-population goal for the program, PD GENEration has launched a new protocol designed to increase patient access at new study sites, Ms. Verbrugge said. “This protocol includes an abbreviate version of the clinical data collected, while it maintains the critical component of genetic counseling in the testing process.”
Going forward, the PD GENEration study will focus on improving access to genetic testing and counseling in underrepresented and rural populations, Ms. Verbrugge said. “These efforts will also generate valuable genomic data, allowing researchers to learn more about the causes of Parkinson’s disease in diverse and underrepresented populations. The study will be expanding research efforts concerning the genomic data to gain insights about the seven key genes studied as well as new genes linked to Parkinson’s disease.”
The work of the PD GENEration study is timely, said David K. Simon, MD, PhD, of Harvard Medical School and director of the Parkinson’s Disease & Movement Disorders Center at Beth Israel Deaconess Medical Center, both in Boston. “This is very important to identify such patients now, as clinical trials targeting people with specific genetic mutations or variants are coming soon, and in some cases already are underway. The feasibility and speed of enrollment for those trials will be greatly facilitate if we know in advance who are the people with Parkinson’s disease who have mutations that would make them eligible for the particular trials.”
The fact that the study provides free genetic testing to people with Parkinson’s disease isn’t to be overlooked. “This was an important study to address the question of whether or not remote genetic counseling was feasible and effective, and the results are meaningful given the randomized prospective design,” Dr. Simon said.
Ms. Verbrugge has no relevant relationships to disclose. Dr. Simon reports receiving research funding from the Parkinson’s Foundation.
FROM AAN 2021
Can exercise prevent cognitive decline in patients with early Parkinson’s disease?
, new research suggests. Investigators found that patients with Parkinson’s disease who were APOE epsilon4 carriers had greater cognitive decline compared with non-APOE epsilon4 carriers, but the findings also revealed higher physical activity appeared to slow cognitive decline in this higher risk group.
“The main finding of the current study is that higher physical activity was related to slower APOE epsilon4-associated cognitive decline in patients with early Parkinson’s disease, which was shown to be robust in sensitivity analyses,” wrote the researchers, led by Ryul Kim, MD, Inha University Hospital, Incheon, Korea.
The study was published online March 31 in Neurology.
Unclear mechanism
The APOE epsilon4 allele is known to be a “major risk factor” for Alzheimer’s disease, but “accumulating evidence shows that this allele also has a potential role in cognitive impairment in Parkinson’s disease,” the authors noted.
Previous research shows physical activity has beneficial effects in patients with Parkinson’s disease, but the mechanisms underlying these effects are “not well understood.” Additional data suggest physical activity modifies the APOE epsilon4 effect on the development and progression of Alzheimer’s disease.
“These observations led us to hypothesize that physical activity also plays a role in modulating the association between APOE [epsilon4] and cognition in Parkinson’s disease,” but no studies have yet reported on this interaction in patients with Parkinson’s disease, the authors noted.
To investigate, they drew on data from the Parkinson’s Progression Markers Initiative (PPMI) – a cohort study conducted to identify Parkinson’s disease progression markers.
The current analysis included 173 patients recently diagnosed with Parkinson’s disease but not yet treated for the condition. The cohort’s mean age was 63.3 ± 10.0 years, age of Parkinson’s disease onset was 59.4 ± 10.0 years, and 68% were male. Of these participants, 46 were APOE epsilon4 carriers.
Dopamine transporter (DAT) activity was assessed using imaging at enrollment and again at years 2 and 4. Cognitive function was assessed at years 2, 3, and 4 using the Montreal Cognitive Assessment (MoCA) test.
Protective effect
Although APOE epsilon4 carriers tended to be younger than noncarriers, the age of Parkinson’s disease onset did not differ between the 2 groups, and there were also no significant differences between the groups in demographic and clinical variables.
There were larger declines in MoCA scores in the APOE epsilon4 carriers versus the noncarriers (0.21 ± 1.40 and 0.08 ± 1.15 respectively).
The APOE epsilon4 allele was associated with a “steeper” rate of cognitive decline, compared with the non-APOE epsilon4 allele (estimate −1.33 [95% confidence interval, −2.12 to −0.47, P = .002).
There was a significant interaction of physical activity, APOE epsilon4, and time: Higher physical activity was associated with slower APOE epsilon4-related cognitive decline (estimate 0.007 [0.003 to 0.011, P = .001).
However, the researchers found no significant main effects of the APOE epsilon4 allele or physical activity on the change in the MoCA score.
“Considering that dopaminergic treatment may affect cognitive function, particularly in the early stage of Parkinson’s disease, we additionally included the levodopa daily equivalent dose (LEDD) and its interaction with time as covariates in the model,” the investigators noted.
They found that the interactive association between physical activity and the APOE epsilon4 allele on cognitive decline remained significant, even when participants who had normal cognitive performance at year 2 were included in the study population or when LEDD variables were included as covariates in the model.
Both high- and low-intensity exercise were significantly associated with slower APOE epsilon4-related cognitive decline.
There was no significant interaction between physical activity and APOE epsilon4 with changes in striatal DAT activities.
“Increased physical activity attenuated APOE epsilon4-related vulnerability to early cognitive decline in patients with Parkinson’s disease,” the authors noted, adding that the effect “did not appear to be mediated by striatal dopamine activity.”
They hypothesized that physical activity may “offer a greater protective effect” on cerebral amyloid accumulation in APOE epsilon4 carriers. It is also possible that physical activity will counteract the negative impact of the APOE epsilon4 allele through improved brain mechanism and decreased neuroinflammation.
‘The next blockbuster drug’
Commenting on the study in an interview, Bastiaan R. Bloem, MD, PhD, director of the center of expertise for Parkinson & movement disorders, Radboud University Medical Center, Nijmegen, Netherlands, said exercise might be seen as “the next blockbuster drug.”
Dr. Bloem, who was not involved in the study, noted there is “quite robust evidence now that exercise acts as symptomatic therapy, like a drug, alleviating sleep [disturbances], depression, constipation, and motor symptoms.”
The study “sheds new light on the idea of exercise as not only alleviating symptoms but actually as a potential disease modifier,” said Dr. Bloem, whose research has focused on the beneficial effects of a rigorous exercise program, combined with tablet-based gamificaton and a reward system in stabilizing motor symptoms in patients with Parkinson’s disease over time.
“The reward system created additional motivation for the patients with Parkinson’s disease who often experience depression and apathy that interfere with motivation,” he said.
The current study has important take-home messages for practicing clinicians. “Physicians should encourage exercise in patients, and patients should also take the lead themselves,” Dr. Bloem said. “It doesn’t matter what type of exercise you do, but it should have an aerobic component, should be safe so the patient doesn’t fall down, should have enough intensity to cause the patient to pant, and should be individualized and enjoyable so the patients stick to it,” he emphasized.
Dr. Bloem noted that yoga and mindfulness are also helpful. “If we’ve learned anything from the COVID-19 crisis, it’s that chronic stress is deleterious to all of us and particularly bad for people with PD, because you need dopamine to be able to handle stress, and the lack of dopamine in people with PD makes them deteriorate faster.”
The study was supported by a research grant of National Research Foundation by the Ministry of Science and ICT (MSIT) in Korea. The authors and Dr. Bloem have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests. Investigators found that patients with Parkinson’s disease who were APOE epsilon4 carriers had greater cognitive decline compared with non-APOE epsilon4 carriers, but the findings also revealed higher physical activity appeared to slow cognitive decline in this higher risk group.
“The main finding of the current study is that higher physical activity was related to slower APOE epsilon4-associated cognitive decline in patients with early Parkinson’s disease, which was shown to be robust in sensitivity analyses,” wrote the researchers, led by Ryul Kim, MD, Inha University Hospital, Incheon, Korea.
The study was published online March 31 in Neurology.
Unclear mechanism
The APOE epsilon4 allele is known to be a “major risk factor” for Alzheimer’s disease, but “accumulating evidence shows that this allele also has a potential role in cognitive impairment in Parkinson’s disease,” the authors noted.
Previous research shows physical activity has beneficial effects in patients with Parkinson’s disease, but the mechanisms underlying these effects are “not well understood.” Additional data suggest physical activity modifies the APOE epsilon4 effect on the development and progression of Alzheimer’s disease.
“These observations led us to hypothesize that physical activity also plays a role in modulating the association between APOE [epsilon4] and cognition in Parkinson’s disease,” but no studies have yet reported on this interaction in patients with Parkinson’s disease, the authors noted.
To investigate, they drew on data from the Parkinson’s Progression Markers Initiative (PPMI) – a cohort study conducted to identify Parkinson’s disease progression markers.
The current analysis included 173 patients recently diagnosed with Parkinson’s disease but not yet treated for the condition. The cohort’s mean age was 63.3 ± 10.0 years, age of Parkinson’s disease onset was 59.4 ± 10.0 years, and 68% were male. Of these participants, 46 were APOE epsilon4 carriers.
Dopamine transporter (DAT) activity was assessed using imaging at enrollment and again at years 2 and 4. Cognitive function was assessed at years 2, 3, and 4 using the Montreal Cognitive Assessment (MoCA) test.
Protective effect
Although APOE epsilon4 carriers tended to be younger than noncarriers, the age of Parkinson’s disease onset did not differ between the 2 groups, and there were also no significant differences between the groups in demographic and clinical variables.
There were larger declines in MoCA scores in the APOE epsilon4 carriers versus the noncarriers (0.21 ± 1.40 and 0.08 ± 1.15 respectively).
The APOE epsilon4 allele was associated with a “steeper” rate of cognitive decline, compared with the non-APOE epsilon4 allele (estimate −1.33 [95% confidence interval, −2.12 to −0.47, P = .002).
There was a significant interaction of physical activity, APOE epsilon4, and time: Higher physical activity was associated with slower APOE epsilon4-related cognitive decline (estimate 0.007 [0.003 to 0.011, P = .001).
However, the researchers found no significant main effects of the APOE epsilon4 allele or physical activity on the change in the MoCA score.
“Considering that dopaminergic treatment may affect cognitive function, particularly in the early stage of Parkinson’s disease, we additionally included the levodopa daily equivalent dose (LEDD) and its interaction with time as covariates in the model,” the investigators noted.
They found that the interactive association between physical activity and the APOE epsilon4 allele on cognitive decline remained significant, even when participants who had normal cognitive performance at year 2 were included in the study population or when LEDD variables were included as covariates in the model.
Both high- and low-intensity exercise were significantly associated with slower APOE epsilon4-related cognitive decline.
There was no significant interaction between physical activity and APOE epsilon4 with changes in striatal DAT activities.
“Increased physical activity attenuated APOE epsilon4-related vulnerability to early cognitive decline in patients with Parkinson’s disease,” the authors noted, adding that the effect “did not appear to be mediated by striatal dopamine activity.”
They hypothesized that physical activity may “offer a greater protective effect” on cerebral amyloid accumulation in APOE epsilon4 carriers. It is also possible that physical activity will counteract the negative impact of the APOE epsilon4 allele through improved brain mechanism and decreased neuroinflammation.
‘The next blockbuster drug’
Commenting on the study in an interview, Bastiaan R. Bloem, MD, PhD, director of the center of expertise for Parkinson & movement disorders, Radboud University Medical Center, Nijmegen, Netherlands, said exercise might be seen as “the next blockbuster drug.”
Dr. Bloem, who was not involved in the study, noted there is “quite robust evidence now that exercise acts as symptomatic therapy, like a drug, alleviating sleep [disturbances], depression, constipation, and motor symptoms.”
The study “sheds new light on the idea of exercise as not only alleviating symptoms but actually as a potential disease modifier,” said Dr. Bloem, whose research has focused on the beneficial effects of a rigorous exercise program, combined with tablet-based gamificaton and a reward system in stabilizing motor symptoms in patients with Parkinson’s disease over time.
“The reward system created additional motivation for the patients with Parkinson’s disease who often experience depression and apathy that interfere with motivation,” he said.
The current study has important take-home messages for practicing clinicians. “Physicians should encourage exercise in patients, and patients should also take the lead themselves,” Dr. Bloem said. “It doesn’t matter what type of exercise you do, but it should have an aerobic component, should be safe so the patient doesn’t fall down, should have enough intensity to cause the patient to pant, and should be individualized and enjoyable so the patients stick to it,” he emphasized.
Dr. Bloem noted that yoga and mindfulness are also helpful. “If we’ve learned anything from the COVID-19 crisis, it’s that chronic stress is deleterious to all of us and particularly bad for people with PD, because you need dopamine to be able to handle stress, and the lack of dopamine in people with PD makes them deteriorate faster.”
The study was supported by a research grant of National Research Foundation by the Ministry of Science and ICT (MSIT) in Korea. The authors and Dr. Bloem have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests. Investigators found that patients with Parkinson’s disease who were APOE epsilon4 carriers had greater cognitive decline compared with non-APOE epsilon4 carriers, but the findings also revealed higher physical activity appeared to slow cognitive decline in this higher risk group.
“The main finding of the current study is that higher physical activity was related to slower APOE epsilon4-associated cognitive decline in patients with early Parkinson’s disease, which was shown to be robust in sensitivity analyses,” wrote the researchers, led by Ryul Kim, MD, Inha University Hospital, Incheon, Korea.
The study was published online March 31 in Neurology.
Unclear mechanism
The APOE epsilon4 allele is known to be a “major risk factor” for Alzheimer’s disease, but “accumulating evidence shows that this allele also has a potential role in cognitive impairment in Parkinson’s disease,” the authors noted.
Previous research shows physical activity has beneficial effects in patients with Parkinson’s disease, but the mechanisms underlying these effects are “not well understood.” Additional data suggest physical activity modifies the APOE epsilon4 effect on the development and progression of Alzheimer’s disease.
“These observations led us to hypothesize that physical activity also plays a role in modulating the association between APOE [epsilon4] and cognition in Parkinson’s disease,” but no studies have yet reported on this interaction in patients with Parkinson’s disease, the authors noted.
To investigate, they drew on data from the Parkinson’s Progression Markers Initiative (PPMI) – a cohort study conducted to identify Parkinson’s disease progression markers.
The current analysis included 173 patients recently diagnosed with Parkinson’s disease but not yet treated for the condition. The cohort’s mean age was 63.3 ± 10.0 years, age of Parkinson’s disease onset was 59.4 ± 10.0 years, and 68% were male. Of these participants, 46 were APOE epsilon4 carriers.
Dopamine transporter (DAT) activity was assessed using imaging at enrollment and again at years 2 and 4. Cognitive function was assessed at years 2, 3, and 4 using the Montreal Cognitive Assessment (MoCA) test.
Protective effect
Although APOE epsilon4 carriers tended to be younger than noncarriers, the age of Parkinson’s disease onset did not differ between the 2 groups, and there were also no significant differences between the groups in demographic and clinical variables.
There were larger declines in MoCA scores in the APOE epsilon4 carriers versus the noncarriers (0.21 ± 1.40 and 0.08 ± 1.15 respectively).
The APOE epsilon4 allele was associated with a “steeper” rate of cognitive decline, compared with the non-APOE epsilon4 allele (estimate −1.33 [95% confidence interval, −2.12 to −0.47, P = .002).
There was a significant interaction of physical activity, APOE epsilon4, and time: Higher physical activity was associated with slower APOE epsilon4-related cognitive decline (estimate 0.007 [0.003 to 0.011, P = .001).
However, the researchers found no significant main effects of the APOE epsilon4 allele or physical activity on the change in the MoCA score.
“Considering that dopaminergic treatment may affect cognitive function, particularly in the early stage of Parkinson’s disease, we additionally included the levodopa daily equivalent dose (LEDD) and its interaction with time as covariates in the model,” the investigators noted.
They found that the interactive association between physical activity and the APOE epsilon4 allele on cognitive decline remained significant, even when participants who had normal cognitive performance at year 2 were included in the study population or when LEDD variables were included as covariates in the model.
Both high- and low-intensity exercise were significantly associated with slower APOE epsilon4-related cognitive decline.
There was no significant interaction between physical activity and APOE epsilon4 with changes in striatal DAT activities.
“Increased physical activity attenuated APOE epsilon4-related vulnerability to early cognitive decline in patients with Parkinson’s disease,” the authors noted, adding that the effect “did not appear to be mediated by striatal dopamine activity.”
They hypothesized that physical activity may “offer a greater protective effect” on cerebral amyloid accumulation in APOE epsilon4 carriers. It is also possible that physical activity will counteract the negative impact of the APOE epsilon4 allele through improved brain mechanism and decreased neuroinflammation.
‘The next blockbuster drug’
Commenting on the study in an interview, Bastiaan R. Bloem, MD, PhD, director of the center of expertise for Parkinson & movement disorders, Radboud University Medical Center, Nijmegen, Netherlands, said exercise might be seen as “the next blockbuster drug.”
Dr. Bloem, who was not involved in the study, noted there is “quite robust evidence now that exercise acts as symptomatic therapy, like a drug, alleviating sleep [disturbances], depression, constipation, and motor symptoms.”
The study “sheds new light on the idea of exercise as not only alleviating symptoms but actually as a potential disease modifier,” said Dr. Bloem, whose research has focused on the beneficial effects of a rigorous exercise program, combined with tablet-based gamificaton and a reward system in stabilizing motor symptoms in patients with Parkinson’s disease over time.
“The reward system created additional motivation for the patients with Parkinson’s disease who often experience depression and apathy that interfere with motivation,” he said.
The current study has important take-home messages for practicing clinicians. “Physicians should encourage exercise in patients, and patients should also take the lead themselves,” Dr. Bloem said. “It doesn’t matter what type of exercise you do, but it should have an aerobic component, should be safe so the patient doesn’t fall down, should have enough intensity to cause the patient to pant, and should be individualized and enjoyable so the patients stick to it,” he emphasized.
Dr. Bloem noted that yoga and mindfulness are also helpful. “If we’ve learned anything from the COVID-19 crisis, it’s that chronic stress is deleterious to all of us and particularly bad for people with PD, because you need dopamine to be able to handle stress, and the lack of dopamine in people with PD makes them deteriorate faster.”
The study was supported by a research grant of National Research Foundation by the Ministry of Science and ICT (MSIT) in Korea. The authors and Dr. Bloem have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY