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Improving Interprofessional Neurology Training Using Tele-Education
Improving Interprofessional Neurology Training Using Tele-Education
Neurologic disorders are major causes of death and disability. Globally, the burden of neurologic disorders continues to increase. The prevalence of disabling neurologic disorders significantly increases with age. As people live longer, health care systems will face increasing demands for treatment, rehabilitation, and support services for neurologic disorders. The scarcity of established modifiable risks for most of the neurologic burden demonstrates how new knowledge is required to develop effective prevention and treatment strategies.1
A single-center study for chronic headache at a rural institution found that, when combined with public education, clinician education not only can increase access to care but also reduce specialist overuse, hospitalizations, polypharmacy, and emergency department visits.2 A predicted shortage of neurologists has sparked increased interest in the field and individual neurology educators are helping fuel its popularity.3-5
TELE-EDUCATION
Educating the next generation of health professionals is 1 of 4 statutory missions of the US Department of Veterans Affairs (VA).6 Tele-education (also known as telelearning and distance learning) deviates from traditional in-person classroom settings, in which the lecture has been a core pedagogic method.7 Audio, video, and online technologies provide health education and can overcome geographic barriers for rural and remote clinicians.8 Recent technological improvements have allowed for inexpensive and efficient dissemination of educational materials, including video lectures, podcasts, online modules, assessment materials, and even entire curricula.9
There has been an increase in the awareness of the parallel curriculum involving self-directed and asynchronous learning opportunities. 10 Several studies report knowledge gained via tele-education is comparable to conventional classroom learning.11-13 A systematic review of e-learning perceptions among health care students suggested benefits (eg, learning flexibility, pedagogical design, online interactions, basic computer skills, and access to technology) and drawbacks (eg, limited acquisition of clinical skills, internet connection problems, and issues with using educational platforms).1
The COVID-19 pandemic forced an abrupt cessation of traditional in-person education, forcing educational institutions and medical organizations to transition to telelearning. Solutions in the education field appeared during the pandemic, such as videoconferencing, social media, and telemedicine, that effectively addressed the sudden cessation of in-person medical education.15
Graduate medical education in neurology residency programs served as an experimental set up for tele-education during the pandemic. Residents from neurology training programs outlined the benefits of a volunteer lecturer-based online didactic program that was established to meet this need, which included exposure to subspeciality topics, access to subspecialist experts not available within the department, exposure to different pedagogic methods, interaction with members of other educational institutions and training programs, career development opportunities, and the potential for forming a community of learning.16
Not all recent educational developments are technology-based. For example, instruction focused on specific patient experiences, and learning processes that emphasize problem solving and personal responsibility over specific knowledge have been successful in neurology.17,18 Departments and institutions must be creative in finding ways to fund continuing education, especially when budgets are limited.19
ANNUAL NEUROLOGY SEMINAR
An annual Veterans Health Administration (VHA) neurology seminar began in 2019 as a 1-day in-person event. Neurologists at the Michael E. DeBakey VA Medical Center in Houston presented in 50-minute sessions. Nonspecialist clinical personnel and neurology clinicians attended the event. Attendees requested making the presentations widely available and regularly repeating the seminar.
The second neurology seminar took place during the COVID-19 pandemic. It was conducted online and advertised across the Veterans Integrated Services Network (VISN) 16. The 1-day program had 204 participants who were primarily nurses (59%) and physicians (21%); 94% agreed with the program objectives (Table 1). Participants could earn CME credits for the 7 presentations primarily by VHA experts.
Based on feedback and a needs assessment, the program expanded in 2021 and 2022. With support from the national VHA neurology office and VHA Employee Education System (EES), the Institute for Learning, Education, and Development (ILEAD), the feedback identified topics that resonate with VHA clinicians. Neurological disorders in the fields of stroke, dementia, and headache were included since veterans with these disorders regularly visit primary care, geriatrics, mental health, and other clinical offices. Updates provided in the diagnosis and treatment of common neurological disorders were well received. Almost all speakers were VHA clinicians, which allowed them to focus on topics relevant to clinical practice at the VHA.
Attendance has increased annually. In 2021, 550 clinicians registered (52% nurses) and 433 completed the postseminar survey (Table 2). In 2022, 635 participants registered and 342 completed evaluations, including attendees from other federal agencies who were invited to participate via EES TRAIN (Training Finder Real-time Affiliate Integrated Network). Forty-seven participants from other federal agencies, including the US Department of Defense, National Institute of Health, and Centers for Disease Control and Prevention, completed the feedback evaluation via TRAIN (Table 3). Participants report high levels of satisfaction each year (mean of 4.5 on a 5-point scale). Respondents preferred conventional lecture presentation and case-based discussions for the teaching format and dementia was the most requested topic for future seminars (Table 4).
The content of each seminar was designed to include . 1 topic relevant to current clinical practice. The 2020 seminar covered topics of cerebrovascular complications of COVID- 19 and living well with neurodegenerative disease in the COVID-19 era. In 2021, the seminar included COVID-19 and neurologic manifestations. In 2022, topics included trends in stroke rehabilitation. In addition, ≥ 1 session addressed neurologic issues within the VHA. In 2020, the VA Deputy National Director of Neurology presented on the VHA stroke systems of care. In 2021, there was a presentation on traumatic brain injury (TBI) in the military. In 2022, sessions covered long term neurologic consequences of TBI and use of telemedicine for neurologic disorders. Feedback on the sessions were positive (eAppendix, available at doi:10.12788/fp.0545).
At the request of the participants, individual presentations were shared via email by the course director and speakers. In collaboration with the EES, each session was recorded and the 2022 seminar was made available to registrants in TMS and EES TRAIN and via the VHA Neurology SharePoint.
DISCUSSION
The annual VHA neurology seminar is a 1-day neurology conference that provides education to general neurologists and other clinicians caring for patients with neurologic disorders. It is the first of its kind neurology education program in the VHA covering most subspecialties in neurology and aims at improving neurologic patient care and access through education. Sessions have covered stroke, epilepsy, sleep, amyotrophic lateral sclerosis, neuropathy, dementia, movement disorders and Parkinson disease, headaches, multiple sclerosis, neurorehabilitation, and telehealth.
The seminar has transitioned from an inperson meeting to a virtual format, making neurology education more convenient and accessible. The virtual format provides the means to increase educational collaborations and share lecture platforms with other federal agencies. The program offers CME credits at no cost to government employees. Recorded lectures can also be asynchronously viewed from the Neurology SharePoint without the ability to earn CME credits. These recordings may be used to educate trainees as well.
The seminar aims to educate all health care professionals caring for patients with neurologic disorders. It aims to eliminate neurophobia, the fear of neural sciences and clinical neurology, and help general practitioners, especially in rural areas, take care of patients with neurologic disorders. The seminars introduce general practitioners to VHA neurology experts; the epilepsy, headache multiple sclerosis, and Parkinson disease centers of excellence; and the national programs for telestroke and teleneurology.
Education Support in the VHA
The EES/ILEAD provides a wide variety of learning opportunities to VHA employees on a broad range of topics, making it one of the largest medical education programs in the country. Pharmacists, social workers, psychologists, therapists, nurses, physician assistants, and physicians have access to certified training opportunities to gain knowledge and skills needed to provide high-quality, veteran-centered care.
A review of geriatrics learning activities through the EES found > 15,000 lectures from 1999 to 2009 for > 300,000 attendees.20 To our knowledge, a review of neurology-related learning activities offered by the EES/ILEAD has not been completed, but the study on geriatrics shows that a similar review would be feasible, given the integrated education system, and helpful in identifying what topics are covered, formats are used, and participants are engaged in neurology education at the VHA. This is a future project planned by the neurology education workgroup.
The EES/ILEAD arranged CME credit for the VHA Neurology Seminar and assisted in organizing an online event with > 500 attendees. Technology support and tools provided by EES during the virtual seminar, such as polling and chat features, kept the audience engaged. Other specialties may similarly value a virtual, all-day seminar format that is efficient and can encourage increased participation from practitioners, nurses, and clinicians.
Future Growth
We plan to increase future participation in the annual neurology seminar with primary care, geriatrics, neurology, and other specialties by instituting an improved and earlier marketing strategy. This includes working with the VHA neurology office to inform neurology practitioners as well as other program offices in the VHA. We intend to host the seminar the same day every year to make it easy for attendees to plan accordingly. In the future we may consider hybrid in-person and virtual modalities if feasible. We plan to focus on reaching out to other government agencies through platforms like TRAIN and the American Academy of Neurology government sections. Securing funding, administrative staff, and protected time in the future may help expand the program further.
Limitations
While a virtual format offers several advantages, using it removes the feel of an in-person meeting, which could be viewed by some attendees as a limitation. The other challenges and drawbacks of transitioning to the virtual platform for a national meeting are similar to those reported in the literature: time zone differences, internet issues, and participants having difficulty using certain online platforms. Attendance could also be limited by scheduling conflicts.16 Despite a large audience attending the seminar, many clinicians do not get protected time from their institutions. Institutional and leadership support at national and local levels will likely improve participation and help participants earn CME credits. While we are still doing a preliminary needs assessment, a formal needs assessment across federal governmental organizations will be helpful.
CONCLUSIONS
The annual VHA neurology seminar promotes interprofessional education, introduces neurology subspecialty centers of excellence, improves access to renowned neurology experts, and provides neurology-related updates through a VHA lens. The program not only provides educational updates to neurology clinicians, but also increases the confidence of non-neurology clinicians called to care for veterans with neurological disorders in their respective clinics.
- GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990- 2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(5):459-480. doi:10.1016/S1474-4422(18)30499-X
- Baker V, Hack N. Improving access to care for patients with migraine in a remote Pacific population. Neurol Clin Pract. 2020;10(5):444-448. doi:10.1212/CPJ.0000000000000774
- Gutmann L, Cahill C, Jordan JT, et al. Characteristics of graduating US allopathic medical students pursuing a career in neurology. Neurology. 2019;92(17):e2051-e2063. doi:10.1212/WNL.0000000000007369
- Jordan JT, Cahill C, Ostendorf T, et al. Attracting neurology’s next generation: a qualitative study of specialty choice and perceptions. Neurology. 2020;95(8):e1080- e1090. doi:10.1212/WNL.0000000000009461
- Minen MT, Kaplan K, Akter S, et al. Understanding how to strengthen the neurology pipeline with insights from undergraduate neuroscience students. Neurology 2022;98(8):314-323. doi:10.1212/WNL.0000000000013259
- US Department of Veterans Affairs, Office of Academic Affiliations. To Educate for VA and the Nation. Updated August 1, 2024. Accessed August 15, 2024. https://www.va.gov/oaa/
- Schaefer SM, Dominguez M, Moeller JJ. The future of the lecture in neurology education. Semin Neurol. 2018;38(4):418-427. doi:10.1055/s-0038-1667042
- Curran VR. Tele-education. J Telemed Telecare. 2006;12(2):57-63. doi:10.1258/135763306776084400
- Lau KHV, Lakhan SE, Achike F. New media, technology and neurology education. Semin Neurol. 2018;38(4):457- 464. doi:10.1055/s-0038-1666985
- Quirk M, Chumley H. The adaptive medical curriculum: a model for continuous improvement. Med Teach. 2018;40(8):786-790. doi:10.1080/0142159X.2018.1484896
- Brockfeld T, Müller B, de Laffolie J. Video versus live lecture courses: a comparative evaluation of lecture types and results. Med Educ Online. 2018;23(1):1555434. doi:10.1080/10872981.2018.1555434
- Davis J, Crabb S, Rogers E, Zamora J, Khan K. Computer-based teaching is as good as face to face lecture-based teaching of evidence based medicine: a randomized controlled trial. Med Teach. 2008;30(3):302-307. doi:10.1080/01421590701784349
- Markova T, Roth LM, Monsur J. Synchronous distance learning as an effective and feasible method for delivering residency didactics. Fam Med. 2005;37(8):570-575.
- Naciri A, Radid M, Kharbach A, Chemsi G. E-learning in health professions education during the COVID-19 pandemic: a systematic review. J Educ Eval Health Prof. 2021;18:27. doi:10.3352/jeehp.2021.18.27
- Dedeilia A, Sotiropoulos MG, Hanrahan JG, Janga D, Dedeilias P, Sideris M. Medical and surgical education challenges and innovations in the COVID-19 era: a systematic review. In Vivo. 2020;34(3 Suppl):1603-1611. doi:10.21873/invivo.11950
- Weber DJ, Albert DVF, Aravamuthan BR, Bernson-Leung ME, Bhatti D, Milligan TA. Training in neurology: rapid implementation of cross-institutional neurology resident education in the time of COVID-19. Neurology. 2020;95(19):883-886. doi:10.1212/WNL.0000000000010753
- Frey J, Neeley B, Umer A, et al. Training in neurology: neuro day: an innovative curriculum connecting medical students with patients. Neurology. 2021;96(10):e1482- e1486. doi:10.1212/WNL.0000000000010859
- Schwartzstein RM, Dienstag JL, King RW, et al. The Harvard Medical School Pathways Curriculum: reimagining developmentally appropriate medical education for contemporary learners. Acad Med. 2020;95(11):1687-1695. doi:10.1097/ACM.0000000000003270
- Greer DM, Moeller J, Torres DR, et al. Funding the educational mission in neurology. Neurology. 2021;96(12):574- 582. doi:10.1212/WNL.0000000000011635
- Thielke S, Tumosa N, Lindenfeld R, Shay K. Geriatric focused educational offerings in the Department of Veterans Affairs from 1999 to 2009. Gerontol Geriatr Educ. 2011;32(1):38-53. doi:10.1080/02701960.2011.550214
Neurologic disorders are major causes of death and disability. Globally, the burden of neurologic disorders continues to increase. The prevalence of disabling neurologic disorders significantly increases with age. As people live longer, health care systems will face increasing demands for treatment, rehabilitation, and support services for neurologic disorders. The scarcity of established modifiable risks for most of the neurologic burden demonstrates how new knowledge is required to develop effective prevention and treatment strategies.1
A single-center study for chronic headache at a rural institution found that, when combined with public education, clinician education not only can increase access to care but also reduce specialist overuse, hospitalizations, polypharmacy, and emergency department visits.2 A predicted shortage of neurologists has sparked increased interest in the field and individual neurology educators are helping fuel its popularity.3-5
TELE-EDUCATION
Educating the next generation of health professionals is 1 of 4 statutory missions of the US Department of Veterans Affairs (VA).6 Tele-education (also known as telelearning and distance learning) deviates from traditional in-person classroom settings, in which the lecture has been a core pedagogic method.7 Audio, video, and online technologies provide health education and can overcome geographic barriers for rural and remote clinicians.8 Recent technological improvements have allowed for inexpensive and efficient dissemination of educational materials, including video lectures, podcasts, online modules, assessment materials, and even entire curricula.9
There has been an increase in the awareness of the parallel curriculum involving self-directed and asynchronous learning opportunities. 10 Several studies report knowledge gained via tele-education is comparable to conventional classroom learning.11-13 A systematic review of e-learning perceptions among health care students suggested benefits (eg, learning flexibility, pedagogical design, online interactions, basic computer skills, and access to technology) and drawbacks (eg, limited acquisition of clinical skills, internet connection problems, and issues with using educational platforms).1
The COVID-19 pandemic forced an abrupt cessation of traditional in-person education, forcing educational institutions and medical organizations to transition to telelearning. Solutions in the education field appeared during the pandemic, such as videoconferencing, social media, and telemedicine, that effectively addressed the sudden cessation of in-person medical education.15
Graduate medical education in neurology residency programs served as an experimental set up for tele-education during the pandemic. Residents from neurology training programs outlined the benefits of a volunteer lecturer-based online didactic program that was established to meet this need, which included exposure to subspeciality topics, access to subspecialist experts not available within the department, exposure to different pedagogic methods, interaction with members of other educational institutions and training programs, career development opportunities, and the potential for forming a community of learning.16
Not all recent educational developments are technology-based. For example, instruction focused on specific patient experiences, and learning processes that emphasize problem solving and personal responsibility over specific knowledge have been successful in neurology.17,18 Departments and institutions must be creative in finding ways to fund continuing education, especially when budgets are limited.19
ANNUAL NEUROLOGY SEMINAR
An annual Veterans Health Administration (VHA) neurology seminar began in 2019 as a 1-day in-person event. Neurologists at the Michael E. DeBakey VA Medical Center in Houston presented in 50-minute sessions. Nonspecialist clinical personnel and neurology clinicians attended the event. Attendees requested making the presentations widely available and regularly repeating the seminar.
The second neurology seminar took place during the COVID-19 pandemic. It was conducted online and advertised across the Veterans Integrated Services Network (VISN) 16. The 1-day program had 204 participants who were primarily nurses (59%) and physicians (21%); 94% agreed with the program objectives (Table 1). Participants could earn CME credits for the 7 presentations primarily by VHA experts.
Based on feedback and a needs assessment, the program expanded in 2021 and 2022. With support from the national VHA neurology office and VHA Employee Education System (EES), the Institute for Learning, Education, and Development (ILEAD), the feedback identified topics that resonate with VHA clinicians. Neurological disorders in the fields of stroke, dementia, and headache were included since veterans with these disorders regularly visit primary care, geriatrics, mental health, and other clinical offices. Updates provided in the diagnosis and treatment of common neurological disorders were well received. Almost all speakers were VHA clinicians, which allowed them to focus on topics relevant to clinical practice at the VHA.
Attendance has increased annually. In 2021, 550 clinicians registered (52% nurses) and 433 completed the postseminar survey (Table 2). In 2022, 635 participants registered and 342 completed evaluations, including attendees from other federal agencies who were invited to participate via EES TRAIN (Training Finder Real-time Affiliate Integrated Network). Forty-seven participants from other federal agencies, including the US Department of Defense, National Institute of Health, and Centers for Disease Control and Prevention, completed the feedback evaluation via TRAIN (Table 3). Participants report high levels of satisfaction each year (mean of 4.5 on a 5-point scale). Respondents preferred conventional lecture presentation and case-based discussions for the teaching format and dementia was the most requested topic for future seminars (Table 4).
The content of each seminar was designed to include . 1 topic relevant to current clinical practice. The 2020 seminar covered topics of cerebrovascular complications of COVID- 19 and living well with neurodegenerative disease in the COVID-19 era. In 2021, the seminar included COVID-19 and neurologic manifestations. In 2022, topics included trends in stroke rehabilitation. In addition, ≥ 1 session addressed neurologic issues within the VHA. In 2020, the VA Deputy National Director of Neurology presented on the VHA stroke systems of care. In 2021, there was a presentation on traumatic brain injury (TBI) in the military. In 2022, sessions covered long term neurologic consequences of TBI and use of telemedicine for neurologic disorders. Feedback on the sessions were positive (eAppendix, available at doi:10.12788/fp.0545).
At the request of the participants, individual presentations were shared via email by the course director and speakers. In collaboration with the EES, each session was recorded and the 2022 seminar was made available to registrants in TMS and EES TRAIN and via the VHA Neurology SharePoint.
DISCUSSION
The annual VHA neurology seminar is a 1-day neurology conference that provides education to general neurologists and other clinicians caring for patients with neurologic disorders. It is the first of its kind neurology education program in the VHA covering most subspecialties in neurology and aims at improving neurologic patient care and access through education. Sessions have covered stroke, epilepsy, sleep, amyotrophic lateral sclerosis, neuropathy, dementia, movement disorders and Parkinson disease, headaches, multiple sclerosis, neurorehabilitation, and telehealth.
The seminar has transitioned from an inperson meeting to a virtual format, making neurology education more convenient and accessible. The virtual format provides the means to increase educational collaborations and share lecture platforms with other federal agencies. The program offers CME credits at no cost to government employees. Recorded lectures can also be asynchronously viewed from the Neurology SharePoint without the ability to earn CME credits. These recordings may be used to educate trainees as well.
The seminar aims to educate all health care professionals caring for patients with neurologic disorders. It aims to eliminate neurophobia, the fear of neural sciences and clinical neurology, and help general practitioners, especially in rural areas, take care of patients with neurologic disorders. The seminars introduce general practitioners to VHA neurology experts; the epilepsy, headache multiple sclerosis, and Parkinson disease centers of excellence; and the national programs for telestroke and teleneurology.
Education Support in the VHA
The EES/ILEAD provides a wide variety of learning opportunities to VHA employees on a broad range of topics, making it one of the largest medical education programs in the country. Pharmacists, social workers, psychologists, therapists, nurses, physician assistants, and physicians have access to certified training opportunities to gain knowledge and skills needed to provide high-quality, veteran-centered care.
A review of geriatrics learning activities through the EES found > 15,000 lectures from 1999 to 2009 for > 300,000 attendees.20 To our knowledge, a review of neurology-related learning activities offered by the EES/ILEAD has not been completed, but the study on geriatrics shows that a similar review would be feasible, given the integrated education system, and helpful in identifying what topics are covered, formats are used, and participants are engaged in neurology education at the VHA. This is a future project planned by the neurology education workgroup.
The EES/ILEAD arranged CME credit for the VHA Neurology Seminar and assisted in organizing an online event with > 500 attendees. Technology support and tools provided by EES during the virtual seminar, such as polling and chat features, kept the audience engaged. Other specialties may similarly value a virtual, all-day seminar format that is efficient and can encourage increased participation from practitioners, nurses, and clinicians.
Future Growth
We plan to increase future participation in the annual neurology seminar with primary care, geriatrics, neurology, and other specialties by instituting an improved and earlier marketing strategy. This includes working with the VHA neurology office to inform neurology practitioners as well as other program offices in the VHA. We intend to host the seminar the same day every year to make it easy for attendees to plan accordingly. In the future we may consider hybrid in-person and virtual modalities if feasible. We plan to focus on reaching out to other government agencies through platforms like TRAIN and the American Academy of Neurology government sections. Securing funding, administrative staff, and protected time in the future may help expand the program further.
Limitations
While a virtual format offers several advantages, using it removes the feel of an in-person meeting, which could be viewed by some attendees as a limitation. The other challenges and drawbacks of transitioning to the virtual platform for a national meeting are similar to those reported in the literature: time zone differences, internet issues, and participants having difficulty using certain online platforms. Attendance could also be limited by scheduling conflicts.16 Despite a large audience attending the seminar, many clinicians do not get protected time from their institutions. Institutional and leadership support at national and local levels will likely improve participation and help participants earn CME credits. While we are still doing a preliminary needs assessment, a formal needs assessment across federal governmental organizations will be helpful.
CONCLUSIONS
The annual VHA neurology seminar promotes interprofessional education, introduces neurology subspecialty centers of excellence, improves access to renowned neurology experts, and provides neurology-related updates through a VHA lens. The program not only provides educational updates to neurology clinicians, but also increases the confidence of non-neurology clinicians called to care for veterans with neurological disorders in their respective clinics.
Neurologic disorders are major causes of death and disability. Globally, the burden of neurologic disorders continues to increase. The prevalence of disabling neurologic disorders significantly increases with age. As people live longer, health care systems will face increasing demands for treatment, rehabilitation, and support services for neurologic disorders. The scarcity of established modifiable risks for most of the neurologic burden demonstrates how new knowledge is required to develop effective prevention and treatment strategies.1
A single-center study for chronic headache at a rural institution found that, when combined with public education, clinician education not only can increase access to care but also reduce specialist overuse, hospitalizations, polypharmacy, and emergency department visits.2 A predicted shortage of neurologists has sparked increased interest in the field and individual neurology educators are helping fuel its popularity.3-5
TELE-EDUCATION
Educating the next generation of health professionals is 1 of 4 statutory missions of the US Department of Veterans Affairs (VA).6 Tele-education (also known as telelearning and distance learning) deviates from traditional in-person classroom settings, in which the lecture has been a core pedagogic method.7 Audio, video, and online technologies provide health education and can overcome geographic barriers for rural and remote clinicians.8 Recent technological improvements have allowed for inexpensive and efficient dissemination of educational materials, including video lectures, podcasts, online modules, assessment materials, and even entire curricula.9
There has been an increase in the awareness of the parallel curriculum involving self-directed and asynchronous learning opportunities. 10 Several studies report knowledge gained via tele-education is comparable to conventional classroom learning.11-13 A systematic review of e-learning perceptions among health care students suggested benefits (eg, learning flexibility, pedagogical design, online interactions, basic computer skills, and access to technology) and drawbacks (eg, limited acquisition of clinical skills, internet connection problems, and issues with using educational platforms).1
The COVID-19 pandemic forced an abrupt cessation of traditional in-person education, forcing educational institutions and medical organizations to transition to telelearning. Solutions in the education field appeared during the pandemic, such as videoconferencing, social media, and telemedicine, that effectively addressed the sudden cessation of in-person medical education.15
Graduate medical education in neurology residency programs served as an experimental set up for tele-education during the pandemic. Residents from neurology training programs outlined the benefits of a volunteer lecturer-based online didactic program that was established to meet this need, which included exposure to subspeciality topics, access to subspecialist experts not available within the department, exposure to different pedagogic methods, interaction with members of other educational institutions and training programs, career development opportunities, and the potential for forming a community of learning.16
Not all recent educational developments are technology-based. For example, instruction focused on specific patient experiences, and learning processes that emphasize problem solving and personal responsibility over specific knowledge have been successful in neurology.17,18 Departments and institutions must be creative in finding ways to fund continuing education, especially when budgets are limited.19
ANNUAL NEUROLOGY SEMINAR
An annual Veterans Health Administration (VHA) neurology seminar began in 2019 as a 1-day in-person event. Neurologists at the Michael E. DeBakey VA Medical Center in Houston presented in 50-minute sessions. Nonspecialist clinical personnel and neurology clinicians attended the event. Attendees requested making the presentations widely available and regularly repeating the seminar.
The second neurology seminar took place during the COVID-19 pandemic. It was conducted online and advertised across the Veterans Integrated Services Network (VISN) 16. The 1-day program had 204 participants who were primarily nurses (59%) and physicians (21%); 94% agreed with the program objectives (Table 1). Participants could earn CME credits for the 7 presentations primarily by VHA experts.
Based on feedback and a needs assessment, the program expanded in 2021 and 2022. With support from the national VHA neurology office and VHA Employee Education System (EES), the Institute for Learning, Education, and Development (ILEAD), the feedback identified topics that resonate with VHA clinicians. Neurological disorders in the fields of stroke, dementia, and headache were included since veterans with these disorders regularly visit primary care, geriatrics, mental health, and other clinical offices. Updates provided in the diagnosis and treatment of common neurological disorders were well received. Almost all speakers were VHA clinicians, which allowed them to focus on topics relevant to clinical practice at the VHA.
Attendance has increased annually. In 2021, 550 clinicians registered (52% nurses) and 433 completed the postseminar survey (Table 2). In 2022, 635 participants registered and 342 completed evaluations, including attendees from other federal agencies who were invited to participate via EES TRAIN (Training Finder Real-time Affiliate Integrated Network). Forty-seven participants from other federal agencies, including the US Department of Defense, National Institute of Health, and Centers for Disease Control and Prevention, completed the feedback evaluation via TRAIN (Table 3). Participants report high levels of satisfaction each year (mean of 4.5 on a 5-point scale). Respondents preferred conventional lecture presentation and case-based discussions for the teaching format and dementia was the most requested topic for future seminars (Table 4).
The content of each seminar was designed to include . 1 topic relevant to current clinical practice. The 2020 seminar covered topics of cerebrovascular complications of COVID- 19 and living well with neurodegenerative disease in the COVID-19 era. In 2021, the seminar included COVID-19 and neurologic manifestations. In 2022, topics included trends in stroke rehabilitation. In addition, ≥ 1 session addressed neurologic issues within the VHA. In 2020, the VA Deputy National Director of Neurology presented on the VHA stroke systems of care. In 2021, there was a presentation on traumatic brain injury (TBI) in the military. In 2022, sessions covered long term neurologic consequences of TBI and use of telemedicine for neurologic disorders. Feedback on the sessions were positive (eAppendix, available at doi:10.12788/fp.0545).
At the request of the participants, individual presentations were shared via email by the course director and speakers. In collaboration with the EES, each session was recorded and the 2022 seminar was made available to registrants in TMS and EES TRAIN and via the VHA Neurology SharePoint.
DISCUSSION
The annual VHA neurology seminar is a 1-day neurology conference that provides education to general neurologists and other clinicians caring for patients with neurologic disorders. It is the first of its kind neurology education program in the VHA covering most subspecialties in neurology and aims at improving neurologic patient care and access through education. Sessions have covered stroke, epilepsy, sleep, amyotrophic lateral sclerosis, neuropathy, dementia, movement disorders and Parkinson disease, headaches, multiple sclerosis, neurorehabilitation, and telehealth.
The seminar has transitioned from an inperson meeting to a virtual format, making neurology education more convenient and accessible. The virtual format provides the means to increase educational collaborations and share lecture platforms with other federal agencies. The program offers CME credits at no cost to government employees. Recorded lectures can also be asynchronously viewed from the Neurology SharePoint without the ability to earn CME credits. These recordings may be used to educate trainees as well.
The seminar aims to educate all health care professionals caring for patients with neurologic disorders. It aims to eliminate neurophobia, the fear of neural sciences and clinical neurology, and help general practitioners, especially in rural areas, take care of patients with neurologic disorders. The seminars introduce general practitioners to VHA neurology experts; the epilepsy, headache multiple sclerosis, and Parkinson disease centers of excellence; and the national programs for telestroke and teleneurology.
Education Support in the VHA
The EES/ILEAD provides a wide variety of learning opportunities to VHA employees on a broad range of topics, making it one of the largest medical education programs in the country. Pharmacists, social workers, psychologists, therapists, nurses, physician assistants, and physicians have access to certified training opportunities to gain knowledge and skills needed to provide high-quality, veteran-centered care.
A review of geriatrics learning activities through the EES found > 15,000 lectures from 1999 to 2009 for > 300,000 attendees.20 To our knowledge, a review of neurology-related learning activities offered by the EES/ILEAD has not been completed, but the study on geriatrics shows that a similar review would be feasible, given the integrated education system, and helpful in identifying what topics are covered, formats are used, and participants are engaged in neurology education at the VHA. This is a future project planned by the neurology education workgroup.
The EES/ILEAD arranged CME credit for the VHA Neurology Seminar and assisted in organizing an online event with > 500 attendees. Technology support and tools provided by EES during the virtual seminar, such as polling and chat features, kept the audience engaged. Other specialties may similarly value a virtual, all-day seminar format that is efficient and can encourage increased participation from practitioners, nurses, and clinicians.
Future Growth
We plan to increase future participation in the annual neurology seminar with primary care, geriatrics, neurology, and other specialties by instituting an improved and earlier marketing strategy. This includes working with the VHA neurology office to inform neurology practitioners as well as other program offices in the VHA. We intend to host the seminar the same day every year to make it easy for attendees to plan accordingly. In the future we may consider hybrid in-person and virtual modalities if feasible. We plan to focus on reaching out to other government agencies through platforms like TRAIN and the American Academy of Neurology government sections. Securing funding, administrative staff, and protected time in the future may help expand the program further.
Limitations
While a virtual format offers several advantages, using it removes the feel of an in-person meeting, which could be viewed by some attendees as a limitation. The other challenges and drawbacks of transitioning to the virtual platform for a national meeting are similar to those reported in the literature: time zone differences, internet issues, and participants having difficulty using certain online platforms. Attendance could also be limited by scheduling conflicts.16 Despite a large audience attending the seminar, many clinicians do not get protected time from their institutions. Institutional and leadership support at national and local levels will likely improve participation and help participants earn CME credits. While we are still doing a preliminary needs assessment, a formal needs assessment across federal governmental organizations will be helpful.
CONCLUSIONS
The annual VHA neurology seminar promotes interprofessional education, introduces neurology subspecialty centers of excellence, improves access to renowned neurology experts, and provides neurology-related updates through a VHA lens. The program not only provides educational updates to neurology clinicians, but also increases the confidence of non-neurology clinicians called to care for veterans with neurological disorders in their respective clinics.
- GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990- 2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(5):459-480. doi:10.1016/S1474-4422(18)30499-X
- Baker V, Hack N. Improving access to care for patients with migraine in a remote Pacific population. Neurol Clin Pract. 2020;10(5):444-448. doi:10.1212/CPJ.0000000000000774
- Gutmann L, Cahill C, Jordan JT, et al. Characteristics of graduating US allopathic medical students pursuing a career in neurology. Neurology. 2019;92(17):e2051-e2063. doi:10.1212/WNL.0000000000007369
- Jordan JT, Cahill C, Ostendorf T, et al. Attracting neurology’s next generation: a qualitative study of specialty choice and perceptions. Neurology. 2020;95(8):e1080- e1090. doi:10.1212/WNL.0000000000009461
- Minen MT, Kaplan K, Akter S, et al. Understanding how to strengthen the neurology pipeline with insights from undergraduate neuroscience students. Neurology 2022;98(8):314-323. doi:10.1212/WNL.0000000000013259
- US Department of Veterans Affairs, Office of Academic Affiliations. To Educate for VA and the Nation. Updated August 1, 2024. Accessed August 15, 2024. https://www.va.gov/oaa/
- Schaefer SM, Dominguez M, Moeller JJ. The future of the lecture in neurology education. Semin Neurol. 2018;38(4):418-427. doi:10.1055/s-0038-1667042
- Curran VR. Tele-education. J Telemed Telecare. 2006;12(2):57-63. doi:10.1258/135763306776084400
- Lau KHV, Lakhan SE, Achike F. New media, technology and neurology education. Semin Neurol. 2018;38(4):457- 464. doi:10.1055/s-0038-1666985
- Quirk M, Chumley H. The adaptive medical curriculum: a model for continuous improvement. Med Teach. 2018;40(8):786-790. doi:10.1080/0142159X.2018.1484896
- Brockfeld T, Müller B, de Laffolie J. Video versus live lecture courses: a comparative evaluation of lecture types and results. Med Educ Online. 2018;23(1):1555434. doi:10.1080/10872981.2018.1555434
- Davis J, Crabb S, Rogers E, Zamora J, Khan K. Computer-based teaching is as good as face to face lecture-based teaching of evidence based medicine: a randomized controlled trial. Med Teach. 2008;30(3):302-307. doi:10.1080/01421590701784349
- Markova T, Roth LM, Monsur J. Synchronous distance learning as an effective and feasible method for delivering residency didactics. Fam Med. 2005;37(8):570-575.
- Naciri A, Radid M, Kharbach A, Chemsi G. E-learning in health professions education during the COVID-19 pandemic: a systematic review. J Educ Eval Health Prof. 2021;18:27. doi:10.3352/jeehp.2021.18.27
- Dedeilia A, Sotiropoulos MG, Hanrahan JG, Janga D, Dedeilias P, Sideris M. Medical and surgical education challenges and innovations in the COVID-19 era: a systematic review. In Vivo. 2020;34(3 Suppl):1603-1611. doi:10.21873/invivo.11950
- Weber DJ, Albert DVF, Aravamuthan BR, Bernson-Leung ME, Bhatti D, Milligan TA. Training in neurology: rapid implementation of cross-institutional neurology resident education in the time of COVID-19. Neurology. 2020;95(19):883-886. doi:10.1212/WNL.0000000000010753
- Frey J, Neeley B, Umer A, et al. Training in neurology: neuro day: an innovative curriculum connecting medical students with patients. Neurology. 2021;96(10):e1482- e1486. doi:10.1212/WNL.0000000000010859
- Schwartzstein RM, Dienstag JL, King RW, et al. The Harvard Medical School Pathways Curriculum: reimagining developmentally appropriate medical education for contemporary learners. Acad Med. 2020;95(11):1687-1695. doi:10.1097/ACM.0000000000003270
- Greer DM, Moeller J, Torres DR, et al. Funding the educational mission in neurology. Neurology. 2021;96(12):574- 582. doi:10.1212/WNL.0000000000011635
- Thielke S, Tumosa N, Lindenfeld R, Shay K. Geriatric focused educational offerings in the Department of Veterans Affairs from 1999 to 2009. Gerontol Geriatr Educ. 2011;32(1):38-53. doi:10.1080/02701960.2011.550214
- GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990- 2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(5):459-480. doi:10.1016/S1474-4422(18)30499-X
- Baker V, Hack N. Improving access to care for patients with migraine in a remote Pacific population. Neurol Clin Pract. 2020;10(5):444-448. doi:10.1212/CPJ.0000000000000774
- Gutmann L, Cahill C, Jordan JT, et al. Characteristics of graduating US allopathic medical students pursuing a career in neurology. Neurology. 2019;92(17):e2051-e2063. doi:10.1212/WNL.0000000000007369
- Jordan JT, Cahill C, Ostendorf T, et al. Attracting neurology’s next generation: a qualitative study of specialty choice and perceptions. Neurology. 2020;95(8):e1080- e1090. doi:10.1212/WNL.0000000000009461
- Minen MT, Kaplan K, Akter S, et al. Understanding how to strengthen the neurology pipeline with insights from undergraduate neuroscience students. Neurology 2022;98(8):314-323. doi:10.1212/WNL.0000000000013259
- US Department of Veterans Affairs, Office of Academic Affiliations. To Educate for VA and the Nation. Updated August 1, 2024. Accessed August 15, 2024. https://www.va.gov/oaa/
- Schaefer SM, Dominguez M, Moeller JJ. The future of the lecture in neurology education. Semin Neurol. 2018;38(4):418-427. doi:10.1055/s-0038-1667042
- Curran VR. Tele-education. J Telemed Telecare. 2006;12(2):57-63. doi:10.1258/135763306776084400
- Lau KHV, Lakhan SE, Achike F. New media, technology and neurology education. Semin Neurol. 2018;38(4):457- 464. doi:10.1055/s-0038-1666985
- Quirk M, Chumley H. The adaptive medical curriculum: a model for continuous improvement. Med Teach. 2018;40(8):786-790. doi:10.1080/0142159X.2018.1484896
- Brockfeld T, Müller B, de Laffolie J. Video versus live lecture courses: a comparative evaluation of lecture types and results. Med Educ Online. 2018;23(1):1555434. doi:10.1080/10872981.2018.1555434
- Davis J, Crabb S, Rogers E, Zamora J, Khan K. Computer-based teaching is as good as face to face lecture-based teaching of evidence based medicine: a randomized controlled trial. Med Teach. 2008;30(3):302-307. doi:10.1080/01421590701784349
- Markova T, Roth LM, Monsur J. Synchronous distance learning as an effective and feasible method for delivering residency didactics. Fam Med. 2005;37(8):570-575.
- Naciri A, Radid M, Kharbach A, Chemsi G. E-learning in health professions education during the COVID-19 pandemic: a systematic review. J Educ Eval Health Prof. 2021;18:27. doi:10.3352/jeehp.2021.18.27
- Dedeilia A, Sotiropoulos MG, Hanrahan JG, Janga D, Dedeilias P, Sideris M. Medical and surgical education challenges and innovations in the COVID-19 era: a systematic review. In Vivo. 2020;34(3 Suppl):1603-1611. doi:10.21873/invivo.11950
- Weber DJ, Albert DVF, Aravamuthan BR, Bernson-Leung ME, Bhatti D, Milligan TA. Training in neurology: rapid implementation of cross-institutional neurology resident education in the time of COVID-19. Neurology. 2020;95(19):883-886. doi:10.1212/WNL.0000000000010753
- Frey J, Neeley B, Umer A, et al. Training in neurology: neuro day: an innovative curriculum connecting medical students with patients. Neurology. 2021;96(10):e1482- e1486. doi:10.1212/WNL.0000000000010859
- Schwartzstein RM, Dienstag JL, King RW, et al. The Harvard Medical School Pathways Curriculum: reimagining developmentally appropriate medical education for contemporary learners. Acad Med. 2020;95(11):1687-1695. doi:10.1097/ACM.0000000000003270
- Greer DM, Moeller J, Torres DR, et al. Funding the educational mission in neurology. Neurology. 2021;96(12):574- 582. doi:10.1212/WNL.0000000000011635
- Thielke S, Tumosa N, Lindenfeld R, Shay K. Geriatric focused educational offerings in the Department of Veterans Affairs from 1999 to 2009. Gerontol Geriatr Educ. 2011;32(1):38-53. doi:10.1080/02701960.2011.550214
Improving Interprofessional Neurology Training Using Tele-Education
Improving Interprofessional Neurology Training Using Tele-Education
Immunotherapies Targeting α -Synuclein in Parkinson Disease
Parkinson disease (PD) is a progressive neurodegenerative disorder, characterized by diverse clinical symptoms. PD can present with rest tremor, bradykinesia, rigidity, falls, postural instability, and multiple nonmotor symptoms. Marras and colleagues estimated in a comprehensive meta-analysis that there were 680,000 individuals with PD in the US in 2010; this number is expected to double by 2030 based on the US Census Bureau population projections.1 An estimated 110,000 veterans may be affected by PD; hence, understanding of PD pathology, clinical progression, and effective treatment strategies is of paramount importance to the Veterans Health Administration (VHA).2
The exact pathogenesis underlying clinical features is still being studied. Pathologic diagnosis of PD relies on loss of dopamine neurons in the substantia nigra and accumulation of the abnormal protein, α-synuclein, in the form of Lewy bodies and Lewy neurites. Lewy bodies and neurites accumulate predominantly in the substantia nigra in addition to other brain stem nuclei and cerebral cortex. Lewy bodies are intraneuronal inclusions with a hyaline core and a pale peripheral halo. Central core stains positive for α-synuclein.3,4 Lewy neurites are widespread and are believed to play a larger role in the pathogenesis of PD compared with those of Lewy bodies.5
α-Synuclein
α-synuclein is a small 140 amino-acid protein with a N-terminal region that can interact with cell membranes and a highly acidic unstructured C-terminal region.6 α-synuclein is physiologically present in the presynaptic terminals of neurons and involved in synaptic plasticity and vesicle trafficking.7 There are different hypotheses about the native structure of α-synuclein. The first suggests that it exists in tetrameric form and may be broken down to monomer, which is the pathogenic form of α-synuclein. The second hypothesis suggests that it exists primarily in monomeric form, whereas other studies have shown that both forms exist and with pathologic changes, monomer accumulates in abundance and is neurotoxic.8-11 Work by Burré and colleagues shows that native α-synuclein exists in 2 forms: a soluble, cytosolic α-synuclein, which is monomeric, and a membrane-bound multimeric form.12,13
Alteration in aggregation properties of this protein is believed to play a central role in the pathogenesis of PD.14,15 Pathologic α-synuclein exists in insoluble forms that can aggregate into oligomers and fibrillar structures.16 Lysosomal dysfunction may promote accumulation of insoluble α-synuclein. Prior work has shown that several degradation pathways in lysosomes, including the ubiquitin-proteasome system and autophagy-lysosomal pathway, are down regulated, thus contributing to the accumulation of abnormal α-synuclein.17,18 Accumulation of pathologic α-synuclein leads to mitochondrial dysfunction in PD animal models, contributing further to neurotoxicity.19,20 Aggregates of phosphorylated α-synuclein have been demonstrated in dementia with Lewy body.21
In addition, α-synuclein aggregates may be released into extracellular spaces to be taken up by adjacent cells, where they can cause further misfolding and aggregation of protein.22 Previous work in animal models suggested a prion proteinlike spread of α-synuclein.23 This finding can have long-term therapeutic implications, as preventing extracellular release of abnormal form of α-synuclein will prevent the spread of pathologic protein. This can form the basis of neuroprotection in patients with PD.24
It has been proposed that α-synuclein accumulation and extracellular release initiates an immune response that leads to activation of microglia. This has been shown in PD animal models, overexpressing α-synuclein. In 2008 Park and colleagues demonstrated that microglial activation is enhanced by monomeric α-synuclein, not by the aggregated variant.25 Other studies have reported activated microglia around dopaminergic cells in substantia nigra.26 Sulzer and colleagues showed that peptides from α-synuclein can act as antigens and trigger an autoimmune reaction via T cells.27 PD may be associated with certain HLA-haplotypes.28 In other words, α-synuclein can induce neurodegeneration via different mechanisms, including alteration in synaptic vesicle transmission, mitochondrial dysfunction, neuroinflammation, and induction of humoral immunity.
Immunization
Due to these observations, there had been huge interest in developing antibody-based therapies for PD. A similar approach had been tested in Alzheimer disease (AD). Intracellular tangles of tau protein and extracellular aggregates of amyloid are the pathologic substrates in AD. Clinical trials utilizing antibodies targeting amyloid showed reduction in abnormal protein accumulation but no significant improvement in cognition.29 In addition, adverse events (AEs), such as vasogenic edema and intracerebral hemorrhage, were reported.30 Careful analysis of the data suggested that inadequate patient selection or targeting only amyloid, may have contributed to unfavorable results.31 Since then, more recent clinical trials have focused on careful patient selection, use of second generation anti-amyloid antibodies and immunotherapies targeting tau.32
Several studies have tested immunotherapies in PD animal models with the aim of targeting α-synuclein. Immunotherapies can be instituted in 2 ways: active immunization in which the immune system is stimulated to produce antibodies against α-synuclein or passive immunization in which antibodies against α-synuclein are administered directly. Once α-synuclein antibodies have crossed the blood-brain barrier, they are hypothesized to clear the existing α-synuclein. Animal studies have demonstrated the presence of these antibodies within the neurons. The mechanism of entry is unknown. Once inside the cells, the antibodies activate the lysosomal clearance, affecting intracellular accumulation of α-synuclein. Extracellularly, they can bind to receptors on scavenger cells, mainly microglia, activating them to facilitate uptake of extracellular α-synuclein. Binding of the antibodies to α-synuclein directly prevents the uptake of toxic protein by the cells, blocking the transfer and spread of PD pathology.33
Active Immunization
Active immunization against α-synuclein was demonstrated by Masliah and colleagues almost a decade ago. They administered recombinant human α-synuclein in transgenic mice expressing α-synuclein under the control of platelet-derived growth factor β. Reduction of accumulated α-synuclein in neurons with mild microglia activation was noted. It was proposed that the antibodies produced were able to bind to abnormal α-synuclein, were recognized by the lysosomal pathways, and degraded.34 Ghochikyan and colleagues developed vaccines by using α-synuclein-derived peptides. This induced formation of antibodies against α-synuclein in Lewy-bodies and neurites.35 Over time, other animal studies have been able to expand on these results.36
AFFiRiS, an Austrian biotechnology company, has developed 2 peptide vaccines PD01A and PD03A. Both peptides when administered to PD animal models caused antibody-based immune response against aggregated α-synuclein. Humoral autoimmune response was not observed in these studies; no neuroinflammation or neurotoxicity was noted. These peptides did not affect levels of physiologic α-synuclein, targeting only the aggregated form.37 These animal models showed improved motor and cognitive function. Similar results were noted in multiple system atrophy (MSA) animal models.38,39
The first human phase 1, randomized, parallel-group, single-center study recruited 32 subjects with early PD. Twelve subjects each were included in low- or high-dose treatment group, and 8 were included in the control group. Test subjects randomly received 4 vaccinations of low- or high-dose PD01A. Both doses were well tolerated, and no drug-related serious AEs were reported. The study confirmed the tolerability and safety of subcutaneous PD01A vaccine administration. These subjects were included in a 12-month, phase 1b follow-up extension study, AFF008E. In 2018, it was reported that administration of 6 doses of PD01A, 4 primary and 2 booster immunization, was safe. The vaccine showed a clear immune response against the peptide and cross-reactivity against α-synuclein targeted epitope. Booster doses stabilized the antibody titers. Significant increase in antibody titers against PD01A was seen over time, which was translated into a humoral immune response against α-synuclein. In addition, PD01A antibodies also were reported in cerebrospinal fluid.40
AFFiRiS presented results of a phase 1 randomized, placebo-controlled trial in 2017, confirming the safety of PD03A in patients with PD. The study showed a clear dose-dependent immune response against the peptide and cross-reactivity against α-synuclein targeted epitope.41 AFFiRiS recently presented results of another phase 1 clinical study assessing the safety and tolerability of vaccines PD01A and PD03A in patients with early MSA. Both vaccines were well tolerated, and PD01A induced an immune response against the peptide and α-synuclein epitope.42 These results have provided hope for further endeavors to develop active immunization strategies for PD.
Passive Immunization
Passive immunization against α-synuclein was first reported by Masliah and colleagues in 2011. A monoclonal antibody against the C-terminus of α-synuclein, 9E4, was injected into a transgenic mouse model of PD. There was reduction in α-synuclein aggregates in the brain along with improvement in motor and cognitive impairment.43 The C-terminus of α-synuclein plays a key role in the pathogenesis of PD. Changes in the C-terminus of α-synuclein induces formation of α-synuclein oligomers and subsequent neuronal spread. Antibody binds to the C-terminus and prevents structural changes that can lead to oligomerization of α-synuclein. Since the first study by Masliah, few other immunization studies utilized different antibodies against the C-terminus of α-synuclein. It was shown in a mouse model that binding of such antibodies promoted clearance of the α-synuclein by microglia.44
Based on these animal studies, Prothena Biosciences (South San Francisco, CA) designed a phase 1, double-blind, randomized, placebo-controlled clinical trial of prasinezumab (investigational monoclonal antibody against C-terminus of α-synuclein), in subjects without PD. The results showed that it was well tolerated, and there was dose-dependent reduction in the levels of free
BIIB054 is another monoclonal antibody that targets the N-terminal of α-synuclein. In animal models, antibodies targeting the N-terminus reduced α-synuclein triggered cell death and reduced the number of activated microglia.48 BIIB054, from Biogen (Cambridge, MA), was studied in 40 healthy subjects and was well tolerated with a favorable safety profile and could cross the blood-brain barrier. Like the prasinezumab study, this also was an ascending-dose study to assess safety and tolerability. In 2018, a randomized, double-blind, placebo-controlled, single-ascending dose study in patients with PD reported that BIIB054 was well tolerated, and the presence of BIIB054-synuclein complexes in the plasma were confirmed.49 A phase 2, multicenter, randomized, double-blind, placebo-controlled study (SPARK) with an active-treatment dose-blinded period, designed to evaluate the safety, pharmacokinetics, and the pharmacodynamics of BIIB054 is currently recruiting patients with PD.
Finally, BioArctic (Stockholm, Sweden) developed antibodies that are selective for oligomeric forms of α-synuclein, which it licensed to AbbVie (North Chicago, Il).50 These antibodies do not target the N- or C-terminus of α-synuclein. Since α-synuclein oligomers play an important role in the pathogenesis of PD, targeting them with antibodies at an early stage may prove to be an effective strategy for removal of pathogenic α-synuclein. Clinical trials are forthcoming.
Conclusions
Immunotherapy against α-synuclein has provided a new therapeutic avenue in the field of neuroprotection. Results from the first human clinical trial are promising, but despite these results, more work is needed to clarify the role of α-synuclein in the pathogenesis of PD in humans. Most of the work concerning α-synuclein aggregation and propagation has been reported in animal models. Whether similar process exists in humans is a debatable question. Similarly, more knowledge is needed about how and where in the human brain antibodies act to give neuroprotective effects. Timing of administration of immunotherapies in real time will be a crucial question.
PD is clinically evident once 80% of dopaminergic neurons in substantia nigra are lost due to neurodegeneration. Should immunotherapy be administered to symptomatic patients with PD, or if it will be beneficial only for presymptomatic, high-risk patients needs to be determined. Like AD trials, not only careful selection of patients, but determination of optimal timing for treatment will be essential. As the understanding of PD pathogenesis and therapeutics evolves, it will become clear whether immunization targeting α-synuclein will modify disease progression.
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18. Ryan BJ, Hoek S, Fon EA, Wade-Martins R. Mitochondrial dysfunction and mitophagy in Parkinson’s: from familial to sporadic disease. Trends Biochem Sci. 2015;40(4):200-210. doi:10.1016/j.tibs.2015.02.003
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31. Wisniewski T, Goñi F. Immunotherapy for Alzheimer’s disease. Biochem Pharmacol. 2014;88(4):499-507. doi:10.1016/j.bcp.2013.12.020
32. Herline K, Drummond E, Wisniewski T. Recent advancements toward therapeutic vaccines against Alzheimer’s disease. Expert Rev Vaccines. 2018;17(8):707-721. doi:10.1080/14760584.2018.1500905
33. Bergstrom AL, Kallunki P, Fog K. Development of passive immunotherapies for synucleopathies. Mov Disord. 2015;31(2):203-213. doi:10.1002/mds.26481
34. Masliah E, Rockenstein E, Adame A, et al. Effects of α-synuclein immunization in a mouse model of Parkinson’s disease. Neuron. 2005;46(6):857-868. doi:10.1016/j.neuron.2005.05.010
35. Ghochikyan A, Petrushina I, Davtyan H, et al. Immunogenicity of epitope vaccines targeting different B cell antigenic determinants of human α-synuclein: feasibility study. Neurosci Lett. 2014;560:86-91. doi:10.1016/j.neulet.2013.12.028
36. Sanchez-Guajardo V, Annibali A, Jensen PH, Romero-Ramos M. α-synuclein vaccination prevents the accumulation of Parkinson’s disease-like pathologic inclusions in striatum in association with regulatory T cell recruitment in a rat model. J Neuropathol Exp Neurol. 2013;72(7):624-645. doi:10.1097/NEN.0b013e31829768d2
37. Mandler M, Valera E, Rockenstein E, et al. Next generation active immunization approach for synucleinopathies: Implications for Parkinson’s disease clinical trials. Acta Neuropathol. 2014;127(6):861-879. doi:10.1007/s00401-014-1256-4
38. Mandler M, Valera E, Rockenstein E, et al. Active immunization against α-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multisystem atrophy. Mol Neurodegen. 2015;10:721. doi:10.1186/s13024-015-0008-9
39. Schneeberger A, Tierney L, Mandler M. Active immunization therapies. Mov Disord. 2015;31(2):214-224. doi:10.1002/mds.26377
40. Zella SMA, Metzdorf J, Ciftci E, et al. Emerging immunotherapies for Parkinson disease. Neurol Ther. 2019;8(1):29-44. doi:10.1007/s40120-018-0122-z
41. AFFiRiS AG. AFFiRiS announces top line results of first-in-human clinical study using AFFITOPE PD03A, confirming immunogenicity and safety profile in Parkinson’s disease patients. https://affiris.com/wp-content/uploads/2018/10/praff011prefinal0607wo-embargo-1.pdf. Published June 7, 2017. Accessed July 29, 2020.
42. AFFiRiS AG. AFFiRiS announces results of a phase I clinical study using AFFITOPEs PD01A and PD03A, confirming safety and tolerability for both compounds as well as immunogenicity for PD01A in early MSA patients. http://sympath-project.eu/wp-content/uploads/PR_AFF009_V1.pdf Published March 1, 2018. Accessed July 29, 2020.
43. Masliah E, Rockenstein E, Mante M, et al. Passive immunization reduces behavioral and neuropathological deficits in an alphasynuclein transgenic model of Lewy body disease. PLoS One. 2011;6(4):e19338. doi:10.1371/journal.pone.0019338
44. Bae EJ, Lee HJ, Rockenstein E, et al. Antibody aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission. J Neurosci. 2012;32(39):1345-13469. doi:10.1523/JNEUROSCI.1292-12.2012
45. Schenk DB, Koller M, Ness DK, et al. First‐in‐human assessment of PRX002, an anti–α‐synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211-218. doi:10.1002/mds.26878.
46. Jankovic J, Goodman I, Safirstein B, et al. Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-α -synuclein monoclonal antibody, in patients with Parkinson disease: a randomized clinical trial. JAMA Neurol. 2018;75(10):1206-1214. doi:10.1001/jamaneurol.2018.1487
47. Jankovic J. Pathogenesis-targeted therapeutic strategies in Parkinson’s disease. Mov Disord. 2019;34(1):41-44. doi:10.1002/mds.27534
48. Shahaduzzaman M, Nash K, Hudson C, et al. Anti-human α-synuclein N-terminal peptide antibody protects against dopaminergic cell death and ameliorates behavioral deficits in an AAV-α-synuclein rat model of Parkinson’s disease. PLoS One. 2015;10(2):E0116841. doi:10.1371/journal.pone.0116841
49. Brys M, Hung S, Fanning L, et al. Randomized, double-blind, placebo-controlled, single ascending dose study of anti-α-synuclein antibody BIIB054 in patients with Parkinson disease. Neurology. 2018;90(suppl 15):S26.001. doi:10.1002/mds.27738
50. Brundin P, Dave KD, Kordower JH. Therapeutic approaches to target α-synuclein pathology. Exp Neurol. 2017;298(pt B):225-235. doi:10.1016/j.expneurol.2017.10.003
Parkinson disease (PD) is a progressive neurodegenerative disorder, characterized by diverse clinical symptoms. PD can present with rest tremor, bradykinesia, rigidity, falls, postural instability, and multiple nonmotor symptoms. Marras and colleagues estimated in a comprehensive meta-analysis that there were 680,000 individuals with PD in the US in 2010; this number is expected to double by 2030 based on the US Census Bureau population projections.1 An estimated 110,000 veterans may be affected by PD; hence, understanding of PD pathology, clinical progression, and effective treatment strategies is of paramount importance to the Veterans Health Administration (VHA).2
The exact pathogenesis underlying clinical features is still being studied. Pathologic diagnosis of PD relies on loss of dopamine neurons in the substantia nigra and accumulation of the abnormal protein, α-synuclein, in the form of Lewy bodies and Lewy neurites. Lewy bodies and neurites accumulate predominantly in the substantia nigra in addition to other brain stem nuclei and cerebral cortex. Lewy bodies are intraneuronal inclusions with a hyaline core and a pale peripheral halo. Central core stains positive for α-synuclein.3,4 Lewy neurites are widespread and are believed to play a larger role in the pathogenesis of PD compared with those of Lewy bodies.5
α-Synuclein
α-synuclein is a small 140 amino-acid protein with a N-terminal region that can interact with cell membranes and a highly acidic unstructured C-terminal region.6 α-synuclein is physiologically present in the presynaptic terminals of neurons and involved in synaptic plasticity and vesicle trafficking.7 There are different hypotheses about the native structure of α-synuclein. The first suggests that it exists in tetrameric form and may be broken down to monomer, which is the pathogenic form of α-synuclein. The second hypothesis suggests that it exists primarily in monomeric form, whereas other studies have shown that both forms exist and with pathologic changes, monomer accumulates in abundance and is neurotoxic.8-11 Work by Burré and colleagues shows that native α-synuclein exists in 2 forms: a soluble, cytosolic α-synuclein, which is monomeric, and a membrane-bound multimeric form.12,13
Alteration in aggregation properties of this protein is believed to play a central role in the pathogenesis of PD.14,15 Pathologic α-synuclein exists in insoluble forms that can aggregate into oligomers and fibrillar structures.16 Lysosomal dysfunction may promote accumulation of insoluble α-synuclein. Prior work has shown that several degradation pathways in lysosomes, including the ubiquitin-proteasome system and autophagy-lysosomal pathway, are down regulated, thus contributing to the accumulation of abnormal α-synuclein.17,18 Accumulation of pathologic α-synuclein leads to mitochondrial dysfunction in PD animal models, contributing further to neurotoxicity.19,20 Aggregates of phosphorylated α-synuclein have been demonstrated in dementia with Lewy body.21
In addition, α-synuclein aggregates may be released into extracellular spaces to be taken up by adjacent cells, where they can cause further misfolding and aggregation of protein.22 Previous work in animal models suggested a prion proteinlike spread of α-synuclein.23 This finding can have long-term therapeutic implications, as preventing extracellular release of abnormal form of α-synuclein will prevent the spread of pathologic protein. This can form the basis of neuroprotection in patients with PD.24
It has been proposed that α-synuclein accumulation and extracellular release initiates an immune response that leads to activation of microglia. This has been shown in PD animal models, overexpressing α-synuclein. In 2008 Park and colleagues demonstrated that microglial activation is enhanced by monomeric α-synuclein, not by the aggregated variant.25 Other studies have reported activated microglia around dopaminergic cells in substantia nigra.26 Sulzer and colleagues showed that peptides from α-synuclein can act as antigens and trigger an autoimmune reaction via T cells.27 PD may be associated with certain HLA-haplotypes.28 In other words, α-synuclein can induce neurodegeneration via different mechanisms, including alteration in synaptic vesicle transmission, mitochondrial dysfunction, neuroinflammation, and induction of humoral immunity.
Immunization
Due to these observations, there had been huge interest in developing antibody-based therapies for PD. A similar approach had been tested in Alzheimer disease (AD). Intracellular tangles of tau protein and extracellular aggregates of amyloid are the pathologic substrates in AD. Clinical trials utilizing antibodies targeting amyloid showed reduction in abnormal protein accumulation but no significant improvement in cognition.29 In addition, adverse events (AEs), such as vasogenic edema and intracerebral hemorrhage, were reported.30 Careful analysis of the data suggested that inadequate patient selection or targeting only amyloid, may have contributed to unfavorable results.31 Since then, more recent clinical trials have focused on careful patient selection, use of second generation anti-amyloid antibodies and immunotherapies targeting tau.32
Several studies have tested immunotherapies in PD animal models with the aim of targeting α-synuclein. Immunotherapies can be instituted in 2 ways: active immunization in which the immune system is stimulated to produce antibodies against α-synuclein or passive immunization in which antibodies against α-synuclein are administered directly. Once α-synuclein antibodies have crossed the blood-brain barrier, they are hypothesized to clear the existing α-synuclein. Animal studies have demonstrated the presence of these antibodies within the neurons. The mechanism of entry is unknown. Once inside the cells, the antibodies activate the lysosomal clearance, affecting intracellular accumulation of α-synuclein. Extracellularly, they can bind to receptors on scavenger cells, mainly microglia, activating them to facilitate uptake of extracellular α-synuclein. Binding of the antibodies to α-synuclein directly prevents the uptake of toxic protein by the cells, blocking the transfer and spread of PD pathology.33
Active Immunization
Active immunization against α-synuclein was demonstrated by Masliah and colleagues almost a decade ago. They administered recombinant human α-synuclein in transgenic mice expressing α-synuclein under the control of platelet-derived growth factor β. Reduction of accumulated α-synuclein in neurons with mild microglia activation was noted. It was proposed that the antibodies produced were able to bind to abnormal α-synuclein, were recognized by the lysosomal pathways, and degraded.34 Ghochikyan and colleagues developed vaccines by using α-synuclein-derived peptides. This induced formation of antibodies against α-synuclein in Lewy-bodies and neurites.35 Over time, other animal studies have been able to expand on these results.36
AFFiRiS, an Austrian biotechnology company, has developed 2 peptide vaccines PD01A and PD03A. Both peptides when administered to PD animal models caused antibody-based immune response against aggregated α-synuclein. Humoral autoimmune response was not observed in these studies; no neuroinflammation or neurotoxicity was noted. These peptides did not affect levels of physiologic α-synuclein, targeting only the aggregated form.37 These animal models showed improved motor and cognitive function. Similar results were noted in multiple system atrophy (MSA) animal models.38,39
The first human phase 1, randomized, parallel-group, single-center study recruited 32 subjects with early PD. Twelve subjects each were included in low- or high-dose treatment group, and 8 were included in the control group. Test subjects randomly received 4 vaccinations of low- or high-dose PD01A. Both doses were well tolerated, and no drug-related serious AEs were reported. The study confirmed the tolerability and safety of subcutaneous PD01A vaccine administration. These subjects were included in a 12-month, phase 1b follow-up extension study, AFF008E. In 2018, it was reported that administration of 6 doses of PD01A, 4 primary and 2 booster immunization, was safe. The vaccine showed a clear immune response against the peptide and cross-reactivity against α-synuclein targeted epitope. Booster doses stabilized the antibody titers. Significant increase in antibody titers against PD01A was seen over time, which was translated into a humoral immune response against α-synuclein. In addition, PD01A antibodies also were reported in cerebrospinal fluid.40
AFFiRiS presented results of a phase 1 randomized, placebo-controlled trial in 2017, confirming the safety of PD03A in patients with PD. The study showed a clear dose-dependent immune response against the peptide and cross-reactivity against α-synuclein targeted epitope.41 AFFiRiS recently presented results of another phase 1 clinical study assessing the safety and tolerability of vaccines PD01A and PD03A in patients with early MSA. Both vaccines were well tolerated, and PD01A induced an immune response against the peptide and α-synuclein epitope.42 These results have provided hope for further endeavors to develop active immunization strategies for PD.
Passive Immunization
Passive immunization against α-synuclein was first reported by Masliah and colleagues in 2011. A monoclonal antibody against the C-terminus of α-synuclein, 9E4, was injected into a transgenic mouse model of PD. There was reduction in α-synuclein aggregates in the brain along with improvement in motor and cognitive impairment.43 The C-terminus of α-synuclein plays a key role in the pathogenesis of PD. Changes in the C-terminus of α-synuclein induces formation of α-synuclein oligomers and subsequent neuronal spread. Antibody binds to the C-terminus and prevents structural changes that can lead to oligomerization of α-synuclein. Since the first study by Masliah, few other immunization studies utilized different antibodies against the C-terminus of α-synuclein. It was shown in a mouse model that binding of such antibodies promoted clearance of the α-synuclein by microglia.44
Based on these animal studies, Prothena Biosciences (South San Francisco, CA) designed a phase 1, double-blind, randomized, placebo-controlled clinical trial of prasinezumab (investigational monoclonal antibody against C-terminus of α-synuclein), in subjects without PD. The results showed that it was well tolerated, and there was dose-dependent reduction in the levels of free
BIIB054 is another monoclonal antibody that targets the N-terminal of α-synuclein. In animal models, antibodies targeting the N-terminus reduced α-synuclein triggered cell death and reduced the number of activated microglia.48 BIIB054, from Biogen (Cambridge, MA), was studied in 40 healthy subjects and was well tolerated with a favorable safety profile and could cross the blood-brain barrier. Like the prasinezumab study, this also was an ascending-dose study to assess safety and tolerability. In 2018, a randomized, double-blind, placebo-controlled, single-ascending dose study in patients with PD reported that BIIB054 was well tolerated, and the presence of BIIB054-synuclein complexes in the plasma were confirmed.49 A phase 2, multicenter, randomized, double-blind, placebo-controlled study (SPARK) with an active-treatment dose-blinded period, designed to evaluate the safety, pharmacokinetics, and the pharmacodynamics of BIIB054 is currently recruiting patients with PD.
Finally, BioArctic (Stockholm, Sweden) developed antibodies that are selective for oligomeric forms of α-synuclein, which it licensed to AbbVie (North Chicago, Il).50 These antibodies do not target the N- or C-terminus of α-synuclein. Since α-synuclein oligomers play an important role in the pathogenesis of PD, targeting them with antibodies at an early stage may prove to be an effective strategy for removal of pathogenic α-synuclein. Clinical trials are forthcoming.
Conclusions
Immunotherapy against α-synuclein has provided a new therapeutic avenue in the field of neuroprotection. Results from the first human clinical trial are promising, but despite these results, more work is needed to clarify the role of α-synuclein in the pathogenesis of PD in humans. Most of the work concerning α-synuclein aggregation and propagation has been reported in animal models. Whether similar process exists in humans is a debatable question. Similarly, more knowledge is needed about how and where in the human brain antibodies act to give neuroprotective effects. Timing of administration of immunotherapies in real time will be a crucial question.
PD is clinically evident once 80% of dopaminergic neurons in substantia nigra are lost due to neurodegeneration. Should immunotherapy be administered to symptomatic patients with PD, or if it will be beneficial only for presymptomatic, high-risk patients needs to be determined. Like AD trials, not only careful selection of patients, but determination of optimal timing for treatment will be essential. As the understanding of PD pathogenesis and therapeutics evolves, it will become clear whether immunization targeting α-synuclein will modify disease progression.
Parkinson disease (PD) is a progressive neurodegenerative disorder, characterized by diverse clinical symptoms. PD can present with rest tremor, bradykinesia, rigidity, falls, postural instability, and multiple nonmotor symptoms. Marras and colleagues estimated in a comprehensive meta-analysis that there were 680,000 individuals with PD in the US in 2010; this number is expected to double by 2030 based on the US Census Bureau population projections.1 An estimated 110,000 veterans may be affected by PD; hence, understanding of PD pathology, clinical progression, and effective treatment strategies is of paramount importance to the Veterans Health Administration (VHA).2
The exact pathogenesis underlying clinical features is still being studied. Pathologic diagnosis of PD relies on loss of dopamine neurons in the substantia nigra and accumulation of the abnormal protein, α-synuclein, in the form of Lewy bodies and Lewy neurites. Lewy bodies and neurites accumulate predominantly in the substantia nigra in addition to other brain stem nuclei and cerebral cortex. Lewy bodies are intraneuronal inclusions with a hyaline core and a pale peripheral halo. Central core stains positive for α-synuclein.3,4 Lewy neurites are widespread and are believed to play a larger role in the pathogenesis of PD compared with those of Lewy bodies.5
α-Synuclein
α-synuclein is a small 140 amino-acid protein with a N-terminal region that can interact with cell membranes and a highly acidic unstructured C-terminal region.6 α-synuclein is physiologically present in the presynaptic terminals of neurons and involved in synaptic plasticity and vesicle trafficking.7 There are different hypotheses about the native structure of α-synuclein. The first suggests that it exists in tetrameric form and may be broken down to monomer, which is the pathogenic form of α-synuclein. The second hypothesis suggests that it exists primarily in monomeric form, whereas other studies have shown that both forms exist and with pathologic changes, monomer accumulates in abundance and is neurotoxic.8-11 Work by Burré and colleagues shows that native α-synuclein exists in 2 forms: a soluble, cytosolic α-synuclein, which is monomeric, and a membrane-bound multimeric form.12,13
Alteration in aggregation properties of this protein is believed to play a central role in the pathogenesis of PD.14,15 Pathologic α-synuclein exists in insoluble forms that can aggregate into oligomers and fibrillar structures.16 Lysosomal dysfunction may promote accumulation of insoluble α-synuclein. Prior work has shown that several degradation pathways in lysosomes, including the ubiquitin-proteasome system and autophagy-lysosomal pathway, are down regulated, thus contributing to the accumulation of abnormal α-synuclein.17,18 Accumulation of pathologic α-synuclein leads to mitochondrial dysfunction in PD animal models, contributing further to neurotoxicity.19,20 Aggregates of phosphorylated α-synuclein have been demonstrated in dementia with Lewy body.21
In addition, α-synuclein aggregates may be released into extracellular spaces to be taken up by adjacent cells, where they can cause further misfolding and aggregation of protein.22 Previous work in animal models suggested a prion proteinlike spread of α-synuclein.23 This finding can have long-term therapeutic implications, as preventing extracellular release of abnormal form of α-synuclein will prevent the spread of pathologic protein. This can form the basis of neuroprotection in patients with PD.24
It has been proposed that α-synuclein accumulation and extracellular release initiates an immune response that leads to activation of microglia. This has been shown in PD animal models, overexpressing α-synuclein. In 2008 Park and colleagues demonstrated that microglial activation is enhanced by monomeric α-synuclein, not by the aggregated variant.25 Other studies have reported activated microglia around dopaminergic cells in substantia nigra.26 Sulzer and colleagues showed that peptides from α-synuclein can act as antigens and trigger an autoimmune reaction via T cells.27 PD may be associated with certain HLA-haplotypes.28 In other words, α-synuclein can induce neurodegeneration via different mechanisms, including alteration in synaptic vesicle transmission, mitochondrial dysfunction, neuroinflammation, and induction of humoral immunity.
Immunization
Due to these observations, there had been huge interest in developing antibody-based therapies for PD. A similar approach had been tested in Alzheimer disease (AD). Intracellular tangles of tau protein and extracellular aggregates of amyloid are the pathologic substrates in AD. Clinical trials utilizing antibodies targeting amyloid showed reduction in abnormal protein accumulation but no significant improvement in cognition.29 In addition, adverse events (AEs), such as vasogenic edema and intracerebral hemorrhage, were reported.30 Careful analysis of the data suggested that inadequate patient selection or targeting only amyloid, may have contributed to unfavorable results.31 Since then, more recent clinical trials have focused on careful patient selection, use of second generation anti-amyloid antibodies and immunotherapies targeting tau.32
Several studies have tested immunotherapies in PD animal models with the aim of targeting α-synuclein. Immunotherapies can be instituted in 2 ways: active immunization in which the immune system is stimulated to produce antibodies against α-synuclein or passive immunization in which antibodies against α-synuclein are administered directly. Once α-synuclein antibodies have crossed the blood-brain barrier, they are hypothesized to clear the existing α-synuclein. Animal studies have demonstrated the presence of these antibodies within the neurons. The mechanism of entry is unknown. Once inside the cells, the antibodies activate the lysosomal clearance, affecting intracellular accumulation of α-synuclein. Extracellularly, they can bind to receptors on scavenger cells, mainly microglia, activating them to facilitate uptake of extracellular α-synuclein. Binding of the antibodies to α-synuclein directly prevents the uptake of toxic protein by the cells, blocking the transfer and spread of PD pathology.33
Active Immunization
Active immunization against α-synuclein was demonstrated by Masliah and colleagues almost a decade ago. They administered recombinant human α-synuclein in transgenic mice expressing α-synuclein under the control of platelet-derived growth factor β. Reduction of accumulated α-synuclein in neurons with mild microglia activation was noted. It was proposed that the antibodies produced were able to bind to abnormal α-synuclein, were recognized by the lysosomal pathways, and degraded.34 Ghochikyan and colleagues developed vaccines by using α-synuclein-derived peptides. This induced formation of antibodies against α-synuclein in Lewy-bodies and neurites.35 Over time, other animal studies have been able to expand on these results.36
AFFiRiS, an Austrian biotechnology company, has developed 2 peptide vaccines PD01A and PD03A. Both peptides when administered to PD animal models caused antibody-based immune response against aggregated α-synuclein. Humoral autoimmune response was not observed in these studies; no neuroinflammation or neurotoxicity was noted. These peptides did not affect levels of physiologic α-synuclein, targeting only the aggregated form.37 These animal models showed improved motor and cognitive function. Similar results were noted in multiple system atrophy (MSA) animal models.38,39
The first human phase 1, randomized, parallel-group, single-center study recruited 32 subjects with early PD. Twelve subjects each were included in low- or high-dose treatment group, and 8 were included in the control group. Test subjects randomly received 4 vaccinations of low- or high-dose PD01A. Both doses were well tolerated, and no drug-related serious AEs were reported. The study confirmed the tolerability and safety of subcutaneous PD01A vaccine administration. These subjects were included in a 12-month, phase 1b follow-up extension study, AFF008E. In 2018, it was reported that administration of 6 doses of PD01A, 4 primary and 2 booster immunization, was safe. The vaccine showed a clear immune response against the peptide and cross-reactivity against α-synuclein targeted epitope. Booster doses stabilized the antibody titers. Significant increase in antibody titers against PD01A was seen over time, which was translated into a humoral immune response against α-synuclein. In addition, PD01A antibodies also were reported in cerebrospinal fluid.40
AFFiRiS presented results of a phase 1 randomized, placebo-controlled trial in 2017, confirming the safety of PD03A in patients with PD. The study showed a clear dose-dependent immune response against the peptide and cross-reactivity against α-synuclein targeted epitope.41 AFFiRiS recently presented results of another phase 1 clinical study assessing the safety and tolerability of vaccines PD01A and PD03A in patients with early MSA. Both vaccines were well tolerated, and PD01A induced an immune response against the peptide and α-synuclein epitope.42 These results have provided hope for further endeavors to develop active immunization strategies for PD.
Passive Immunization
Passive immunization against α-synuclein was first reported by Masliah and colleagues in 2011. A monoclonal antibody against the C-terminus of α-synuclein, 9E4, was injected into a transgenic mouse model of PD. There was reduction in α-synuclein aggregates in the brain along with improvement in motor and cognitive impairment.43 The C-terminus of α-synuclein plays a key role in the pathogenesis of PD. Changes in the C-terminus of α-synuclein induces formation of α-synuclein oligomers and subsequent neuronal spread. Antibody binds to the C-terminus and prevents structural changes that can lead to oligomerization of α-synuclein. Since the first study by Masliah, few other immunization studies utilized different antibodies against the C-terminus of α-synuclein. It was shown in a mouse model that binding of such antibodies promoted clearance of the α-synuclein by microglia.44
Based on these animal studies, Prothena Biosciences (South San Francisco, CA) designed a phase 1, double-blind, randomized, placebo-controlled clinical trial of prasinezumab (investigational monoclonal antibody against C-terminus of α-synuclein), in subjects without PD. The results showed that it was well tolerated, and there was dose-dependent reduction in the levels of free
BIIB054 is another monoclonal antibody that targets the N-terminal of α-synuclein. In animal models, antibodies targeting the N-terminus reduced α-synuclein triggered cell death and reduced the number of activated microglia.48 BIIB054, from Biogen (Cambridge, MA), was studied in 40 healthy subjects and was well tolerated with a favorable safety profile and could cross the blood-brain barrier. Like the prasinezumab study, this also was an ascending-dose study to assess safety and tolerability. In 2018, a randomized, double-blind, placebo-controlled, single-ascending dose study in patients with PD reported that BIIB054 was well tolerated, and the presence of BIIB054-synuclein complexes in the plasma were confirmed.49 A phase 2, multicenter, randomized, double-blind, placebo-controlled study (SPARK) with an active-treatment dose-blinded period, designed to evaluate the safety, pharmacokinetics, and the pharmacodynamics of BIIB054 is currently recruiting patients with PD.
Finally, BioArctic (Stockholm, Sweden) developed antibodies that are selective for oligomeric forms of α-synuclein, which it licensed to AbbVie (North Chicago, Il).50 These antibodies do not target the N- or C-terminus of α-synuclein. Since α-synuclein oligomers play an important role in the pathogenesis of PD, targeting them with antibodies at an early stage may prove to be an effective strategy for removal of pathogenic α-synuclein. Clinical trials are forthcoming.
Conclusions
Immunotherapy against α-synuclein has provided a new therapeutic avenue in the field of neuroprotection. Results from the first human clinical trial are promising, but despite these results, more work is needed to clarify the role of α-synuclein in the pathogenesis of PD in humans. Most of the work concerning α-synuclein aggregation and propagation has been reported in animal models. Whether similar process exists in humans is a debatable question. Similarly, more knowledge is needed about how and where in the human brain antibodies act to give neuroprotective effects. Timing of administration of immunotherapies in real time will be a crucial question.
PD is clinically evident once 80% of dopaminergic neurons in substantia nigra are lost due to neurodegeneration. Should immunotherapy be administered to symptomatic patients with PD, or if it will be beneficial only for presymptomatic, high-risk patients needs to be determined. Like AD trials, not only careful selection of patients, but determination of optimal timing for treatment will be essential. As the understanding of PD pathogenesis and therapeutics evolves, it will become clear whether immunization targeting α-synuclein will modify disease progression.
1. Marras C, Beck JC, Bower JH, et al; Parkinson’s Foundation P4 Group. Prevalence of Parkinson’s disease across North America. NPJ Parkinsons Dis. 2018;4(1):21. doi:10.1038/s41531-018-0058-0
2. Mantri S, Duda JE, Morley JF. Early and accurate identification of Parkinson disease among US veterans. Fed Pract. 2019;36(suppl 4):S18-S23. doi:10.12788/fp.37-0034
3. Braak H, Del Tredici K. Neuropathological staging of brain pathology in sporadic Parkinson’s disease: separating the wheat from the chaff. J Parkinsons Dis. 2017;7(suppl 1):S71-S85. doi:10.3233/JPD-179001
4. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. α-synuclein in Lewy bodies. Nature. 1997;388(6645):839-840. doi:10.1038/42166
5. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197-211. doi:10.1016/s0197-4580(02)00065-9
6. Bendor JT, Logan TP, Edwards RH. The function of α-synuclein. Neuron. 2013;79(6):1044-1066. doi:10.1016/j.neuron.2013.09.004
7. Burré J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Südhof TC. α-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science. 2010;329(5999):1663-1667. doi:10.1126/science.1195227
8. Binolfi A, Fernández CO, Sica MP, Delfino JM, Santos J. Recognition between a short unstructured peptide and a partially folded fragment leads to the thioredoxin fold sharing native-like dynamics. Proteins. 2012;80(5):1448-1464. doi:10.1002/prot.24043
9. Fauvet B, Mbefo MK, Fares MB, et al. α-synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer. J Biol Chem. 2012;287(19):15345-15364. doi:10.1074/jbc.M111.318949.
10. Wang W, Perovic I, Chittuluru J, et al. A soluble α-synuclein construct forms a dynamic tetramer. Proc Natl Acad Sci USA. 2011;108(43):17797-17802. doi:10.1073/pnas.1113260108
11. Bellucci A, Zaltieri M, Navarria L, Grigoletto J, Missale C, Spano P. From α-synuclein to synaptic dysfunctions: new insights into the pathophysiology of Parkinson’s disease. Brain Res. 2012;1476:183-202. doi:10.1016/j.brainres.2012.04.014
12. Burré J, Vivona S, Diao J, Sharma M, Brunger AT, Südhof TC. Properties of native α-synuclein. Nature. 2013;498(7453):E4-E7.
13. Burré J, Sharma M, Südhof TC. α-synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation. Proc Natl Acad Sci USA. 2014;111(40):E4274-E4283. doi:10.1073/pnas.1416598111
14. Wong YC, Krainc D. α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med. 2017;23(2):1-13. doi:10.1038/nm.4269
15. Burré J, Sharma M, Südhof TC. Definition of a molecular pathway mediating α-synuclein neurotoxicity. J Neurosci. 2015;35(13):5221-5232. doi:10.1523/JNEUROSCI.4650-14.2015
16. Lee HJ, Khoshaghideh F, Patel S, Lee SJ. Clearance of α-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci. 2004;24(8):1888-1896. doi:10.1523/JNEUROSCI.3809-03.2004
17. Rideout HJ, Dietrich P, Wang Q, Dauer WT, Stefanis L . α-synuclein is required for the fibrillar nature of ubiquitinated inclusions induced by proteasomal inhibition in primary neurons. J Biol Chem. 2004;279(45):46915-46920. doi:10.1074/jbc.M405146200
18. Ryan BJ, Hoek S, Fon EA, Wade-Martins R. Mitochondrial dysfunction and mitophagy in Parkinson’s: from familial to sporadic disease. Trends Biochem Sci. 2015;40(4):200-210. doi:10.1016/j.tibs.2015.02.003
19. Winklhofer KF, Haass C. Mitochondrial dysfunction in Parkinson’s disease. Biochem Biophys Acta. 2010;1802(1):29-44. doi:10.1016/j.bbadis.2009.08.013
20. Lee HJ, Bae EJ, Lee SJ. Extracellular α-synuclein: a novel and crucial factor in Lewy body diseases. Nat Rev Neurol. 2014;10(2):92-98. doi:10.1038/nrneurol.2013.275
21. Colom-Cadena M, Pegueroles J, Herrmann AG, et al. Synaptic phosphorylated α-synuclein in dementia with Lewy bodies. Brain. 2017;140(12):3204-3214. doi:10.1093/brain/awx275
22. Volpicelli-Daley LA, Luk KC, Patel TP, et al. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. 2011;72(1):57-71. doi:10.1016/j.neuron.2011.08.033
23. Masuda-Suzukake M, Nonaka T, Hosokawa M, et al. Prion-like spreading of pathological α-synuclein in brain. Brain. 2013;136(pt 4):1128-1138. doi:10.1093/brain/awt037
24. Hasegawa M, Nonaka T, Masuda-Suzukake M. Prion-like mechanisms and potential therapeutic targets in neurodegenerative disorders. Pharmacol Ther. 2017;172:22-33. doi:10.1016/j.pharmthera.2016.11.010
25. Park JY, Paik SR, Jou I, Park SM. Microglial phagocytosis is enhanced by monomeric α-synuclein, not aggregated alpha-synuclein: implications for Parkinson’s disease. Glia. 2008;56(11):1215-1223. doi:10.1002/glia.20691
26. Blandini F. Neural and immune mechanisms in the pathogenesis of Parkinson’s disease. J Neuroimmune Pharmacol. 2013;8(1):189-201. doi:10.1007/s11481-013-9435-y
27. Sulzer D, Alcalay RN, Garretti F, et al. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature. 2017;546(7660):656-661. doi:10.1038/nature22815
28. Hamza TH, Zabetian CP, Tenesa A, et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genetics. 2010;42(9):781-785. doi:10.1038/ng.642
29. Holmes C, Boche D, Wilkinson D, et al. Long term effects of Aβ42 immunisation in Alzheimer’s disease: follow up of a randomized, placebo-controlled phase I trial. Lancet. 2008;372(9634):216-223. doi:10.1016/S0140-6736(08)61075-2
30. Sperling R, Salloway S, Brooks DJ, et al. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012;11:241-249. doi:10.1016/S1474-4422(12)70015-7
31. Wisniewski T, Goñi F. Immunotherapy for Alzheimer’s disease. Biochem Pharmacol. 2014;88(4):499-507. doi:10.1016/j.bcp.2013.12.020
32. Herline K, Drummond E, Wisniewski T. Recent advancements toward therapeutic vaccines against Alzheimer’s disease. Expert Rev Vaccines. 2018;17(8):707-721. doi:10.1080/14760584.2018.1500905
33. Bergstrom AL, Kallunki P, Fog K. Development of passive immunotherapies for synucleopathies. Mov Disord. 2015;31(2):203-213. doi:10.1002/mds.26481
34. Masliah E, Rockenstein E, Adame A, et al. Effects of α-synuclein immunization in a mouse model of Parkinson’s disease. Neuron. 2005;46(6):857-868. doi:10.1016/j.neuron.2005.05.010
35. Ghochikyan A, Petrushina I, Davtyan H, et al. Immunogenicity of epitope vaccines targeting different B cell antigenic determinants of human α-synuclein: feasibility study. Neurosci Lett. 2014;560:86-91. doi:10.1016/j.neulet.2013.12.028
36. Sanchez-Guajardo V, Annibali A, Jensen PH, Romero-Ramos M. α-synuclein vaccination prevents the accumulation of Parkinson’s disease-like pathologic inclusions in striatum in association with regulatory T cell recruitment in a rat model. J Neuropathol Exp Neurol. 2013;72(7):624-645. doi:10.1097/NEN.0b013e31829768d2
37. Mandler M, Valera E, Rockenstein E, et al. Next generation active immunization approach for synucleinopathies: Implications for Parkinson’s disease clinical trials. Acta Neuropathol. 2014;127(6):861-879. doi:10.1007/s00401-014-1256-4
38. Mandler M, Valera E, Rockenstein E, et al. Active immunization against α-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multisystem atrophy. Mol Neurodegen. 2015;10:721. doi:10.1186/s13024-015-0008-9
39. Schneeberger A, Tierney L, Mandler M. Active immunization therapies. Mov Disord. 2015;31(2):214-224. doi:10.1002/mds.26377
40. Zella SMA, Metzdorf J, Ciftci E, et al. Emerging immunotherapies for Parkinson disease. Neurol Ther. 2019;8(1):29-44. doi:10.1007/s40120-018-0122-z
41. AFFiRiS AG. AFFiRiS announces top line results of first-in-human clinical study using AFFITOPE PD03A, confirming immunogenicity and safety profile in Parkinson’s disease patients. https://affiris.com/wp-content/uploads/2018/10/praff011prefinal0607wo-embargo-1.pdf. Published June 7, 2017. Accessed July 29, 2020.
42. AFFiRiS AG. AFFiRiS announces results of a phase I clinical study using AFFITOPEs PD01A and PD03A, confirming safety and tolerability for both compounds as well as immunogenicity for PD01A in early MSA patients. http://sympath-project.eu/wp-content/uploads/PR_AFF009_V1.pdf Published March 1, 2018. Accessed July 29, 2020.
43. Masliah E, Rockenstein E, Mante M, et al. Passive immunization reduces behavioral and neuropathological deficits in an alphasynuclein transgenic model of Lewy body disease. PLoS One. 2011;6(4):e19338. doi:10.1371/journal.pone.0019338
44. Bae EJ, Lee HJ, Rockenstein E, et al. Antibody aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission. J Neurosci. 2012;32(39):1345-13469. doi:10.1523/JNEUROSCI.1292-12.2012
45. Schenk DB, Koller M, Ness DK, et al. First‐in‐human assessment of PRX002, an anti–α‐synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211-218. doi:10.1002/mds.26878.
46. Jankovic J, Goodman I, Safirstein B, et al. Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-α -synuclein monoclonal antibody, in patients with Parkinson disease: a randomized clinical trial. JAMA Neurol. 2018;75(10):1206-1214. doi:10.1001/jamaneurol.2018.1487
47. Jankovic J. Pathogenesis-targeted therapeutic strategies in Parkinson’s disease. Mov Disord. 2019;34(1):41-44. doi:10.1002/mds.27534
48. Shahaduzzaman M, Nash K, Hudson C, et al. Anti-human α-synuclein N-terminal peptide antibody protects against dopaminergic cell death and ameliorates behavioral deficits in an AAV-α-synuclein rat model of Parkinson’s disease. PLoS One. 2015;10(2):E0116841. doi:10.1371/journal.pone.0116841
49. Brys M, Hung S, Fanning L, et al. Randomized, double-blind, placebo-controlled, single ascending dose study of anti-α-synuclein antibody BIIB054 in patients with Parkinson disease. Neurology. 2018;90(suppl 15):S26.001. doi:10.1002/mds.27738
50. Brundin P, Dave KD, Kordower JH. Therapeutic approaches to target α-synuclein pathology. Exp Neurol. 2017;298(pt B):225-235. doi:10.1016/j.expneurol.2017.10.003
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19. Winklhofer KF, Haass C. Mitochondrial dysfunction in Parkinson’s disease. Biochem Biophys Acta. 2010;1802(1):29-44. doi:10.1016/j.bbadis.2009.08.013
20. Lee HJ, Bae EJ, Lee SJ. Extracellular α-synuclein: a novel and crucial factor in Lewy body diseases. Nat Rev Neurol. 2014;10(2):92-98. doi:10.1038/nrneurol.2013.275
21. Colom-Cadena M, Pegueroles J, Herrmann AG, et al. Synaptic phosphorylated α-synuclein in dementia with Lewy bodies. Brain. 2017;140(12):3204-3214. doi:10.1093/brain/awx275
22. Volpicelli-Daley LA, Luk KC, Patel TP, et al. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. 2011;72(1):57-71. doi:10.1016/j.neuron.2011.08.033
23. Masuda-Suzukake M, Nonaka T, Hosokawa M, et al. Prion-like spreading of pathological α-synuclein in brain. Brain. 2013;136(pt 4):1128-1138. doi:10.1093/brain/awt037
24. Hasegawa M, Nonaka T, Masuda-Suzukake M. Prion-like mechanisms and potential therapeutic targets in neurodegenerative disorders. Pharmacol Ther. 2017;172:22-33. doi:10.1016/j.pharmthera.2016.11.010
25. Park JY, Paik SR, Jou I, Park SM. Microglial phagocytosis is enhanced by monomeric α-synuclein, not aggregated alpha-synuclein: implications for Parkinson’s disease. Glia. 2008;56(11):1215-1223. doi:10.1002/glia.20691
26. Blandini F. Neural and immune mechanisms in the pathogenesis of Parkinson’s disease. J Neuroimmune Pharmacol. 2013;8(1):189-201. doi:10.1007/s11481-013-9435-y
27. Sulzer D, Alcalay RN, Garretti F, et al. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature. 2017;546(7660):656-661. doi:10.1038/nature22815
28. Hamza TH, Zabetian CP, Tenesa A, et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genetics. 2010;42(9):781-785. doi:10.1038/ng.642
29. Holmes C, Boche D, Wilkinson D, et al. Long term effects of Aβ42 immunisation in Alzheimer’s disease: follow up of a randomized, placebo-controlled phase I trial. Lancet. 2008;372(9634):216-223. doi:10.1016/S0140-6736(08)61075-2
30. Sperling R, Salloway S, Brooks DJ, et al. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012;11:241-249. doi:10.1016/S1474-4422(12)70015-7
31. Wisniewski T, Goñi F. Immunotherapy for Alzheimer’s disease. Biochem Pharmacol. 2014;88(4):499-507. doi:10.1016/j.bcp.2013.12.020
32. Herline K, Drummond E, Wisniewski T. Recent advancements toward therapeutic vaccines against Alzheimer’s disease. Expert Rev Vaccines. 2018;17(8):707-721. doi:10.1080/14760584.2018.1500905
33. Bergstrom AL, Kallunki P, Fog K. Development of passive immunotherapies for synucleopathies. Mov Disord. 2015;31(2):203-213. doi:10.1002/mds.26481
34. Masliah E, Rockenstein E, Adame A, et al. Effects of α-synuclein immunization in a mouse model of Parkinson’s disease. Neuron. 2005;46(6):857-868. doi:10.1016/j.neuron.2005.05.010
35. Ghochikyan A, Petrushina I, Davtyan H, et al. Immunogenicity of epitope vaccines targeting different B cell antigenic determinants of human α-synuclein: feasibility study. Neurosci Lett. 2014;560:86-91. doi:10.1016/j.neulet.2013.12.028
36. Sanchez-Guajardo V, Annibali A, Jensen PH, Romero-Ramos M. α-synuclein vaccination prevents the accumulation of Parkinson’s disease-like pathologic inclusions in striatum in association with regulatory T cell recruitment in a rat model. J Neuropathol Exp Neurol. 2013;72(7):624-645. doi:10.1097/NEN.0b013e31829768d2
37. Mandler M, Valera E, Rockenstein E, et al. Next generation active immunization approach for synucleinopathies: Implications for Parkinson’s disease clinical trials. Acta Neuropathol. 2014;127(6):861-879. doi:10.1007/s00401-014-1256-4
38. Mandler M, Valera E, Rockenstein E, et al. Active immunization against α-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multisystem atrophy. Mol Neurodegen. 2015;10:721. doi:10.1186/s13024-015-0008-9
39. Schneeberger A, Tierney L, Mandler M. Active immunization therapies. Mov Disord. 2015;31(2):214-224. doi:10.1002/mds.26377
40. Zella SMA, Metzdorf J, Ciftci E, et al. Emerging immunotherapies for Parkinson disease. Neurol Ther. 2019;8(1):29-44. doi:10.1007/s40120-018-0122-z
41. AFFiRiS AG. AFFiRiS announces top line results of first-in-human clinical study using AFFITOPE PD03A, confirming immunogenicity and safety profile in Parkinson’s disease patients. https://affiris.com/wp-content/uploads/2018/10/praff011prefinal0607wo-embargo-1.pdf. Published June 7, 2017. Accessed July 29, 2020.
42. AFFiRiS AG. AFFiRiS announces results of a phase I clinical study using AFFITOPEs PD01A and PD03A, confirming safety and tolerability for both compounds as well as immunogenicity for PD01A in early MSA patients. http://sympath-project.eu/wp-content/uploads/PR_AFF009_V1.pdf Published March 1, 2018. Accessed July 29, 2020.
43. Masliah E, Rockenstein E, Mante M, et al. Passive immunization reduces behavioral and neuropathological deficits in an alphasynuclein transgenic model of Lewy body disease. PLoS One. 2011;6(4):e19338. doi:10.1371/journal.pone.0019338
44. Bae EJ, Lee HJ, Rockenstein E, et al. Antibody aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission. J Neurosci. 2012;32(39):1345-13469. doi:10.1523/JNEUROSCI.1292-12.2012
45. Schenk DB, Koller M, Ness DK, et al. First‐in‐human assessment of PRX002, an anti–α‐synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211-218. doi:10.1002/mds.26878.
46. Jankovic J, Goodman I, Safirstein B, et al. Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-α -synuclein monoclonal antibody, in patients with Parkinson disease: a randomized clinical trial. JAMA Neurol. 2018;75(10):1206-1214. doi:10.1001/jamaneurol.2018.1487
47. Jankovic J. Pathogenesis-targeted therapeutic strategies in Parkinson’s disease. Mov Disord. 2019;34(1):41-44. doi:10.1002/mds.27534
48. Shahaduzzaman M, Nash K, Hudson C, et al. Anti-human α-synuclein N-terminal peptide antibody protects against dopaminergic cell death and ameliorates behavioral deficits in an AAV-α-synuclein rat model of Parkinson’s disease. PLoS One. 2015;10(2):E0116841. doi:10.1371/journal.pone.0116841
49. Brys M, Hung S, Fanning L, et al. Randomized, double-blind, placebo-controlled, single ascending dose study of anti-α-synuclein antibody BIIB054 in patients with Parkinson disease. Neurology. 2018;90(suppl 15):S26.001. doi:10.1002/mds.27738
50. Brundin P, Dave KD, Kordower JH. Therapeutic approaches to target α-synuclein pathology. Exp Neurol. 2017;298(pt B):225-235. doi:10.1016/j.expneurol.2017.10.003