, has been with the team since October 2019. Follow him on Twitter 

Marco Meglio

Driven by a core mission to provide excellence in patient care, 

NYU Langone’s Comprehensive Epilepsy Center

 has established itself as a powerhouse in advancing the standards of epilepsy management and research. Among one of the largest epilepsy treatment programs in the world, the center is home to both budding talents and experienced clinician experts, whose expertise shines from the top down.

The center is led by Orrin Devinsky, MD, a world-renowned epilepsy researcher and activist within the community. Devinsky holds several roles within the program, including lead investigator for the Cannabidiol Trials for Epilepsy, as well as principal investigator of the SUDC Registry and Research Collaborative, a multisite collaborative that studies sudden unexplained death in children (SUDEP), created at NYU Langone and including partners Columbia University, Mayo Clinic, and notable national based forensic pathologists.

Devinsky has been a pioneer in the field and has led some of the most notable research within the epilepsy community. Since Devinsky’s earliest research efforts, dating back to 1982, he’s become a goliath of the literature, publishing more than 600 articles and book chapters, writing or editing more than 20 books, and acting as the principal investigator for multiple antiepileptic drug clinical trials. Despite his renown, the team based approach remains a key to NYU Langone’s care model, and his leadership sets an example for clinicians within the center to follow.

"We meet every week with [Orrin] Devinsky, [Jacqueline] French, [Katherine] Inoyama, etc. Everyone on the team has a different prospective and a different talent that can only make us better,” Blanca Vazquez, MD, told 

“When I say we blossom, I know that because when I sit in on these meetings, I somehow make it happen. It’s not just one person, it’s a collaboration. The uniqueness of our day-to-day operation is that we’re enchanted by this notion of ‘we can.’”

Vazquez, who is a clinical assistant professor in the Department of Neurology at NYU Grossman School of Medicine, and director of Epilepsy Clinical Trials and and the International Programs for the Epilepsy Service, has been around since the birth of the center, starting out as a fellow. She’s served as the director of Epilepsy Clinical Trials for 30 years and explained that the depth of talent at the center only helps its clinicians improve.

A team approach to treating epilepsy remains a core value of how the center operates. The team includes neurologists, neurosurgeons, and epileptologists, all who care for people with different epilepsy types and seizure disorders, including those that are most difficult to treat. For individuals whose epilepsy is not well-controlled through medication, the center has neurosurgeons on staff trained to perform several different surgical options. Patients also receive care from neuropsychiatrists, neuropsychologists, nurses, nurse practitioners, and EEG technologists who specialize in epilepsy. There is also a nutrition program for which dietitians on staff can help treat epilepsy with dietary interventions such as ketogenic and modified Atkins diets.

For Daniel Friedman, MD, having different types of experts in a centralized location is among the greatest advantages the center has to offer. Friedman, an epilepsy physician and professor in the Department of Neurology at NYU Grossman School of Medicine, told 

“We have adult and pediatric epilepsy specialists under one roof. One of the big burdens in epilepsy care is the transition of care from young children to adult epilepsy specialists. There are infrastructures in many places on how to do that transition, [so] it’s very easy here because my colleague can walk down the hall and refer a patient to them.” Friedman also currently serves as the codirector of Special Procedures for the Epilepsy Service and codirector of the Video-EEG Laboratory.

In addition to the variety and depth of available clinicians, the center contains several niche programs that offer specialized epilepsy care. The Pediatric Epilepsy Program is among them and is staffed by pediatric neurologists and other experts who care for infants and children. Additional programs focused on the most complex epilepsy disorders include the Dravet Center, Center for Epileptic Encephalopathies, and Angelman Syndrome Clinic.

Through the International Epilepsy Program, patients can also receive specialized care in accordance with their cultural background. This includes multilingual members of NYU’s staff who have established relationships with multiple epilepsy centers and neurologists around the world, which lends itself to another offering of the program: the facilitation of the continuing medical education for physicians from countries outside the US.

 Each year, the program organizes a symposium that brings neurologists from around the world to NYU Langone. Additionally, the International Epilepsy Program is associated with the Comprehensive Epilepsy Center–Sleep Center, a dedicated facility for the study of sleep disorders in children and adults—including those triggered by epilepsy—helping to further the center’s collaborative philosophy.

NYU additionally offers a specialized center for women, the Women of Epilepsy Clinic, which is co-directed by Katherine Inoyama, MD, and Santoshi Billakota, MD. There, clinicians focus on how epilepsy impacts women throughout stages of their life, most notably pregnancy and the postpartum period.

"Even before a woman becomes pregnant, we address things about contraception, as well as their plans for future pregnancy,” Inoyama told 

. "It’s really important to plan these things early on because of how the medications and other things can impact both their fetus as well as themselves.”

Throughout pregnancy, patients are counseled on which medications are the most efficacious and safe to use. The clinic also works hand-in-hand with the patient’s OB/GYN throughout the pregnancy to ensure that all of their medical needs are met. Inoyama also noted that she meets with all of her pregnant patients a minimum of 3 times—once during each trimester—to discuss any pertinent cautionary details for her patients related to their epilepsy management.

For patients who are not pregnant but still require the addressing of disease-specific issues, the Center for Epileptic Encephalopathies, a subset of the Comprehensive Epilepsy Center, helps patients navigate the challenges caused by epileptic conditions. These include patients who have continuous spike waves in sleep, Landau-Kleffner syndrome, electrical status epilepticus of sleep, autism with regression, benign epilepsy variants, and benign occipital epilepsies.

Several of the advances in care for patients with epilepsy in recent years have been made, in part, because of the efforts from investigators at the Comprehensive Epilepsy Center. Most notably, Devinsky served as the lead investigator of the GWPCARE study group, which evaluated cannabidiol (CBD; Epidiolex; GW Pharmaceuticals) in patients with rare epilepsies such as Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).

Those efforts in GWPCARE culminated in June 2018, when the FDA made a landmark decision to approve the treatment for both DS and LGS in patients 2 years of age and older, marking the first approval of a drug for the treatment of patients with DS.

 Just 2 years later, in 2020, the FDA greenlit a new indication for CBD for the treatment of seizures associated with tuberous sclerosis complex (TSC), a rare disease that is the leading cause of genetic epilepsy.

Devinsky’s research on CBD earned him a spot in 

magazine’s 2018 list of 50 Most Influential People in Health Care.

 He and coinvestigators have not stopped with that success, though, and are currently conducting studies on several investigational antiepileptic medications such as topiramate, tiagabine, lamotrigine, vigabatrin, oxcarbazepine, and ramacemide.

"We were very proud of that work, not only because [CBD] was different, but because it also required a lot of education for patients and families to understand this different therapy. We also work hard in areas where it’s a unique process [with complex therapies], as opposed to bringing in 1 therapy for all. I think that makes us very different,” Vazquez, who also is also clinical trials codirector, said.

The research teams at the Comprehensive Epilepsy Center have had their hands on a variety of projects, including those in drug development, the genetics of epilepsy and genetic therapies, SUDEP, treatments for neuroinflammation-induced epilepsy, TSC, as well as the cross section of autism and epilepsy. Many of the research initiatives are supported by Finding a Cure for Epilepsy and Seizures, or FACES, which funds research to improve epilepsy care, advances new therapies, and fosters a supportive community for children, families, and caregivers who live with the challenges of epilepsy.

There are currently 16 research coordinators and more than 30 active research studies ongoing at the center. These include the Human Epilepsy Project (HEP), which is designed to identify biomarkers that predict epilepsy progression, treatment response, and outcomes in people with recently diagnosed focal epilepsy.

"Hopefully this will allow us to more quickly identify best therapies and tell people what to expect from the course of their epilepsy. These are bigger projects that will hopefully define and move the field forward,” Friedman said regarding HEP. Findings from that effort arguably have begun to have such an impact, as data from the HEP published by the center’s own Jacqueline French, MD, and colleagues in October 2020 showed that delayed identification of focal epilepsy can lead to morbidity-related consequences, such as motor vehicle accidents. The work pointed to the need to improve nonmotor seizure recognition, ultimately suggesting a gap in care for those whose disease onset features these seizures.

Friedman and Devinsky have been involved in several research efforts that assess the risk factors, mechanisms, epidemiology, neuropathology, and genetics of SUDEP. The center also launched the North American SUDEP Registry in 2011, which connects key leaders and researchers from around the world with clinicians from NYU Langone. The largest international study of SUDEP has also been initiated and includes data collected from the US, Canada, Europe, and Australia.

The commitment to research has run deep through education as well. The NYU Grossman School of Medicine was ranked the second-best medical school in the nation for research, according to U.S. News’ 2022 “Best Graduate Schools.”

 In addition, there are currently 220 laboratories devoted to biomedical research and 53 countries represented within those labs at the school.

Studies of women with epilepsy, with the aforementioned particular focus on the care of these women during their childbearing years, has long been a commitment for the center. It remains just 1 of 3 centers that conducted the Women with Epilepsy: Pregnancy Outcomes and Delivery (WEPOD) study, which demonstrated for the first time that women with epilepsy do not have specific problems with fertility and that the rate of miscarriage is no higher in women with epilepsy than in women without epilepsy.

"My hope is that in the future we’ll be able to gather additional data about the exposure of anti-seizure medications and how they can impact a fetus. That’s down the road and still in the works,” Inoyama noted.

Utilizing Technology and Growing Precision Medicine

There has also been an effort within the center to improve the quality of life for patients with epilepsy through advances in technology. Noninvasive and easy-to-use sensors that detect seizure-related movements, muscle activity, and changes in autonomic function have been heavily researched at NYU Langone. The center has been involved in studies examining the accuracy of these sensors, including the MP5 mattress movement monitor, the Brain Sentinel SPEAC surface EMG sensor, and the Empactica Embrace watch.

"It’s no joke that we need to embrace technology. We have had amazing developments in neuroimaging, fMRI, PET MRI, electroencephalography (EEG), and tractography,” Vazquez told 

We don’t just look at standard EEGs, [either]. We have stereo EEGs, intracranial EEGs, high-intensity EEGs. Understanding the primary pathology and treating on an individual basis, or using precision medicine, has allowed us to develop so many different teams."

Some patients whose epilepsy is more difficult to control may be eligible to undergo epilepsy surgery as an option for treatment. These procedures are extremely sensitive and must only be performed by highly trained experts, making the past 6 years at NYU Langone particularly notable, as its surgeons have performed more than 300 brain surgeries for adults with epilepsy in that time. Approximately 90% of the best candidates for surgery have had complete seizure control after surgery at the center, and another roughly 65% of those who have had epilepsy surgery at the center have become free of seizures completely.

Types of surgeries the center conducts include temporal lobe section, corpus callosotomy, lesionectomy, hemispherectomy and hemispherotomy, multiple subpial transection, and resection of frontal, paretal, or occipital areas of the brain. Vagus nerve stimulation (VNS), which involves implanting a stimulating device the size of a silver dollar under the skin of the upper chest, has been performed by NYU experts about 1700 times. Following implantation, the physician programs the device to deliver small electrical signals to the vagus nerve and into the brain at periodic intervals.

"With these devices, we meet with patients regularly to do programming and tweak the settings, as well as improve detection sets or stimulation parameters. It takes time, but the effect has been very promising,” Inoyama noted. "I’ve seen a lot of success stories with these devices. We are also involved in the RNS post approval studies by tracking patients and their seizure frequencies to see how the procedure is impacting them.”

RNS, or responsive neurostimulation, has been another revolutionary option for individuals older than 18 years who have poorly controlled focal epilepsy and are not candidates for other procedures. Unlike VNS, the RNS device automatically detects a seizure when it happens. The person with the device uses a remote monitor to send data from the device to a cloud database, after which is then reviewed by the treating doctor.

On top of these procedures, the Comprehensive Epilepsy Center also offers 16 inpatient video-EEG-monitored beds in a specialized Epilepsy Monitoring Unit. Each bed has the capacity for 64 channels of EEG data with online computer analysis for 24-hour seizure and spike detection.

Vazquez explained that the overall collaborative nature of the center and the far-reaching efforts of the physicians and clinicians who operate within it has given her a great sense of pride since coming to the center. “Coming to the community and understanding the doctors and how they work in different areas has been very fulfilling for my mission as a physician to have this quality of comprehensive epilepsy care accessible to patients in the Brooklyn community,” she said.

"Something that is sometimes hard to define is the quality of providers that you work with. Not just in research, but in the care that they deliver and the devotion that they have towards their patents,” Inoyama added. "That’s something special that we have at NYU that can’t necessarily be measured in metrics or papers. That type of care might not necessarily be available everywhere."

1. Orrin Devinsky. My research. NYU Langone Health website. Accessed August 4, 2021. 

https://nyulangone.org/doctors/1679581623/orrin-devinsky

2. Comprehensive Epilepsy Center. NYU Langone Health website. Accessed August 4, 2021. 

https://nyulangone.org/locations/comprehensive-epilepsy-center

3. International Epilepsy Program. NYU Langone Health. Accessed August 4, 2021. 

https://nyulangone.org/locations/comprehensive-epilepsy-center/international-epilepsy-program

4. Center for Epileptic Encephalopathies. NYU Langone Health website. Accessed August 4, 2021. 

https://nyulangone.org/locations/comprehensive-epilepsy-center/center-for-epileptic-encephalopathies

5. Devinsky O, Patel AN, Cross H, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. 

2018;378:1888-1897. doi: 10.1056/NEJMoa1714631

6. FDA Approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. News release. FDA. June 25, 2018. Accessed August 4, 2021. 

https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms

7. FDA approves Epidiolex (cannabidiol) oral solution to treat seizures associated with tuberous sclerosis complex. News release. GW Pharmaceuticals. August 3, 2020. Accessed August 4, 2021. 

https://www.globenewswire.com/news-release/2020/08/03/2071601/0/en/FDA-Approves-EPIDIOLEX-cannabidiol-Oral-Solution-to-Treat-Seizures-Associated-with-Tuberous-Sclerosis-Complex.html

8. NYU Langone Visionaries included in TIME Magazine’s 50 Most Influential People in Health Care 2018. News release. NYU Langone. October 18, 2018. Accessed August 4, 2021. 

https://nyulangone.org/news/nyu-langone-visionaries-included-time-magazines-50-most-influential-people-health-care-2018

9. Comprehensive Epilepsy Center Research. NYU Langone Health website. Accessed August 4, 2021. 

https://med.nyu.edu/departments-institutes/neurology/divisions-centers/epilepsy/research

10. Pellinen J, Tafuro E, Yang A, et al. Focal nonmotor versus motor seizures: The impact on diagnostic delay in focal epilepsy. 

. 2020;61(12):2643-2652. doi: 10.1111/epi.16707.

11. 2022 Best Medical Schools: Research. US News. Updated 2021. Accessed August 4, 2021. 

https://www.usnews.com/best-graduate-schools/top-medical-schools/research-rankings

12. Surgery for Epilepsy & Seizure Disorders in Adults. NYU Langone website. Accessed August 4, 2021. 

https://nyulangone.org/conditions/epilepsy-seizure-disorders-in-adults/treatments/surgery-for-epilepsy-seizure-disorders-in-adults

13. Vagus nerve stimulation for epilepsy & seizure disorders in adults. NYU Langone website. Accessed August 4, 2021. 

https://nyulangone.org/conditions/epilepsy-seizure-disorders-in-adults/treatments/vagus-nerve-stimulation-for-epilepsy-seizure-disorders-in-adults

14. Responsive neurostimulation for epilepsy & seizure disorders in adults. NYU Langone website. Accessed August 4, 2021. 

https://nyulangone.org/conditions/epilepsy-seizure-disorders-in-adults/treatments/responsive-neurostimulation-for-epilepsy-seizure-disorders-in-adults

Articles

Led by a team of the top talents, NYU Langone’s Comprehensive Epilepsy Center’s contributions to drug development and improving the quality of life for patients stands alone. 

NYU Langone’s Comprehensive Epilepsy Center Elevates Care Standards, Drug Development

Despite observing a high SARS-CoV-2 seroconversion rate among patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), those treated with an anti-CD20 therapy had a seroconversion rate 2 times as low as untreated patients or patients receiving a non-anti-CD20 disease modifying therapy (DMT). According to the study authors, these findings, while heterogenous in nature, warrant monitoring the long-term risk of reinfection and specific vaccination strategies for patients within these populations.

Senior author Valerie Pourcher, MD, PhD, associate professor, Hôpital de la Pitié Salpêtrière, and colleagues collected blood samples of 119 patients (115 MS, 4 NMOSD; mean age, 43 years) diagnosed with COVID-19 between February 19, 2020, and February 26, 2021. Index of anti-S lgA, anti-N lgG; titer of anti-S IgG; and levels of IgG, IgA, and IgM were compared between groups of patients with several DMTs using 1-way analysis of variance (ANOVA) and subsequent t-test for 1-by-1 group comparisons if needed.

Overall, seroconversion rate was 80.6% (n = 96) within 5 months (standard deviation [SD], 3.4) after infection. Specific subanalysis showed that those on anti-CD20 therapies had lower anti-S IgG positivity (

= .05), and a lower anti-N IgG positivity (

<.001) in comparison to other DMT groups. Notably, there were no observed differences on such outcomes between the other DMT subgroups.

"Postvaccination serological follow-up studies will be necessary to investigate the potential effect of anti-CD20 and other DMTs on humoral response to SARS-CoV-2 vaccine and eventually to adapt the vaccine strategy,” Pourcher et al wrote. "Importantly, the association between the time from last anti-CD20 infusion and the seroconversion may lead to recommend anti-COVID-19 vaccination timing as far as possible from anti-CD20 infusion, for example, starting from 4 months after infusion.”

Temporal Evolution of MRI Lesions Identified in Different CNS Demyelinating Disorders

Among the 3 levels of DMTs (anti-CD20, n = 21; other DMTs, n = 77; no DMT, n = 21), only 47.6% (n = 10) of those on anti-CD20 had at least 1 SARS-CoV-2 Ig positivity, in comparison to 85.7% (n = 66) for patients on other DMTs and 95.2% (n = 20) for patients not on DMTs (

After finding no correlation between time from COVID-19 and anti-S IgG titer (

= .82), investigators performed linear regressions to test whether this finding holds at the level of each DMT group. Not only did patients on anti-CD20 show a higher rate of anti-S IgG decrease over time, but a trend was found for an interaction between time and DMT group (

= .06) for these patients compared with the 2 other groups after adding the variable “time by DMT group.”

Among independent variables including DMT group, time from COVID-19, total IgG level, age, sex, obesity, and COVID-19 severity, only those on anti-CD20 therapies were associated with a decreased odd of positive serology (odds ratio, 0.07 [95% CI, 0.01-0.69]; 

Using the same variables, found that being on an anti-CD20 was associated with a decreased anti-S IgG titer (estimate, –1.06 [95% CI, –1.79 to –0.34]; 

= .004), while hospitalization for COVID-19 was also associated with a decreased anti-S IgG titer (estimate, –0.97 [95% CI, –1.86 to –0.08]; 

= .03). Additionally, total IgG level was also positively associated with anti-S IgG titer (estimate, 0.16 [95% CI, 0-0.32]; 

= .05). Although not significant, investigators did observe a positive association between obesity and anti-S IgG titer (estimate, 0.89 [95% CI, –0.09 to 1.81]; 

There has been previous research published regarding anti-CD20 use among patients with MS throughout the COVID-19 pandemic. A study from Sormani et al showed that anti-CD20 agents such as ocrelizumab (Ocrevus; Genentech) or rituximab (Rituxan; Genentech/Biogen) may lead to an 

. Methylprednisolone treatment within the last month was also associated with a worse outcome.

 who have received mRNA-COVID-19 vaccines while being treated with DMTs were also identified by another group of researchers earlier this year. They found that only cladribine (Mavenclad; EMD Serono) was the only DMT to not impair humoral response.

1. Louapre C, Ibrahim M, Maillart E, et al. Anti-CD20 therapies decrease humoral immune response to SARS-CoV-2 in patients with multiple sclerosis or neuromyelitis optica spectrum disorders. 

. Published online August 2, 2021. doi: 10.1136/jnnp-2021-326904

2. Sormani MP, Rossi ND, Schiavetti I, et al. Disease‐modifying therapies and coronavirus disease 2019 severity in multiple sclerosis. 

3. Achiron A, Mandel M, Dreyer-Alster S, et al. Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies. 

. Published online April 22, 2021. doi: 10.1177/17562864211012835

Among independent variables including DMT group, time from COVID-19 infection, total IgG level, age, sex, obesity, and COVID-19 severity, only the anti-CD20 group was associated with decreased odds of positive serology. 

Anti-CD20 Therapy for MS and NMOSD Linked to Lower COVID-19 Antibody Response

The need for treatments for patients with Alzheimer disease (AD) remains a high priority, and a new, uniquely designed drug is making its way through the clinical pipeline. Cortexyme’s atuzaginstat, a novel bacterial virulence factor inhibitor previously known as COR388, has been shown to be well-tolerated in a phase 1 setting, with additional trends of efficacy on clinical scales and significant improvement on a computerized speech assessment and 2 relevant biomarkers. The phase 2/3 GAIN trial (NCT03823404), designed to be potentially pivotal for the therapy, completed enrollment in November 2020 and is expected to have topline efficacy data on the drug published in December 2021.

The novel mechanism of action of atuzaginstat is based on the discovery of gingipains, toxic protease virulence factors from the bacterial pathogen, porphyromonas gingivalis (Pg), which are found in more than 90% of brains with AD. At the 

2021 Alzheimer’s Association International Conference

, July 26-30, Mike Detke, MD, PhD, chief medical officer, Cortexyme, presented an update and baseline data from GAIN on behalf of the company. He noted that the enrolled subjects have characteristics consistent with AD and Pg infection, indicating an appropriate population to test the efficacy and safety of atuzaginstat.

On a new iteration of NeuroVoices, Detke discussed the GAIN trial in its entirety, including why its dental substudy sets it apart from traditional AD clinical trials. He also provided in-depth detail on unique mechanism of atuzaginstat, what has been previously observed with Pg in AD, and the associations between periodontal disease and AD.

: Can you provide an overview on the phase 2/3 GAIN study?

The phase 3 GAIN trial is designed to be a gold standard test of this drug for disease modification in patients with mild to moderate Alzheimer disease, corresponding to Mini Mental State Exam scores between 24 and 12, inclusive at the outset of the study. We’ll be treating patients for a year, using widely accepted co-primary outcomes of the ADAS-Cog, which measures cognition, and the ADCS-ADL, which measures activities of daily living or ability to function. We’re looking at a lot of biomarkers and traditional secondary outcomes as well, including traditional biomarkers such as amyloid, tau, etc.

The GAIN trial has 2 features that are quite unique. First, we’re looking at a number of different biomarkers related to infection with porphyromonas gingivalis, our purported causal agent. We’ll look at biomarkers of porphyromonas gingivalis, biomarkers of inflammation, and so forth. The other aspect that is unique is that about 40% of the patients went to clinical trial sites that had a nearby affiliated dental site. They’re getting dental exams done too which is important for several reasons. We think, and it’s been reported in the literature too, that this is the key bacterium or causal agent in periodontal disease or advanced gum disease. We want to see if the drug is effective there as well. It’s statistically powered to have a 90% chance to see 50% reduction in decline, the decline typically seen in Alzheimer disease.

Why is atuzaginstat’s mechanism so effective to treat this population?

It has a unique and interesting mechanism. The theory is that this bacterium, porphyromonas gingivalis, colonizes the mouth and gets into the brain. The bacterium is unusual in 2 ways. One is that it gets inside of the cells. It’s an intracellular bacterium, which is very unusual. The other is that its asacralytic, meaning it doesn’t live off sugars for its food, or fuel, it lives off proteins. Those 2 features together make it damaging because it gets inside of cells to feed on proteins. It releases proteases, or molecules that chop up other proteins. Those proteases go around inside the body, chopping up tau and 

, and basically the cell infrastructure. In a medical way, it’s essentially digesting the cell from within. It’s a little like having termites in your brain cells or in your gum tissue.

It has also developed some immune evasion strategies that make it hard to get rid of. Because its intracellular, some antibiotics don’t get to it. In the mouth, it often lives in these plaques, which antibiotics don’t penetrate. It can become dormant and antibiotic resistant. We’ve known over the years that you can’t treat periodontal disease or Alzheimer disease with a week’s worth of antibiotic. We know we can’t kill the bacterium. What we did is develop a drug that targets those proteases, which are causing all the damage inside the cell.

Our drug binds covalently, thereby irreversibly inactivating those proteases. That has 2 effects. First, since these gingipain proteases are causing all the damage in the pathology, once you get rid of them you take that all away. You also starve off the food supply of protein fragments to the bacterium. You see the level of bacterium going down significantly. It’s hard to get rid of the bacterium completely because it goes dormant and its endemic in the population. Our hypothesis is that this will probably need a long-term treatment.

As for its efficacy, I’m excited because there’s so much converging evidence that supports this theory and support that it will be efficacious. Multiple papers published by third party sources have showed that the biggest 2 risk factors for Alzheimer disease are lower level of education and periodontal disease. That’s 1 piece of evidence. We’ve showed in a mouse model that if you take rub porphyromonas gingivalis on regular non-genetically modified mice, they all get the pathology of Alzheimer disease plaques, tangles, inflammatory markers like TNF alpha. That mouse model has been replicated by 5 independent labs. Replication and verification by fellow sciences is an important part of the process.

Working with a third-party group, the University of Aukland, we looked at a brain bank of patients with Alzheimer and age-matched controls and saw that gingipains occurred in almost 95% of cases. Our phase 1 data is encouraging. Our baseline data from the phase 2/3 GAIN trial support the hypothesis. GAIN is an Alzheimer disease trial. We’re looking at periodontal disease, but the primary goal is in mild to moderate Alzheimer disease. We recruited patients with Alzheimer disease, but had no entry criteria required for periodontal disease or even encouraging people with periodontal disease. Among the population that got dental exams at baseline, a little over 90% of them had moderate to severe periodontal disease. The background rate in the population at this age is more like 40% to 50%. The fact that we have 90% of a cohort of 200 is certainly highly statistically significant and supports the idea that there’s a single cause behind both Alzheimer disease and periodontal disease. All this converging evidence is what makes me enthusiastic about seeing the results of the GAIN trial next quarter.

Detke M. An update and baseline data from the phase 2/3 GAIN trial of COR388 (atuzaginstat) a novel bacterial virulence factor inhibitor for the treatment of Alzheimer's disease. Presented at AAIC2021; July 26-30. Abstract 259. 

The chief medical officer of Cortexyme discussed the company’s investigational agent atuzaginstat, its mechanism of action, and the findings of the phase 2/3 GAIN trial.

NeuroVoices: Mike Detke, MD, PhD, on Atuzaginstat’s Potential in Alzheimer Disease, Periodontal Disease

Researchers from the Michael J. Fox Foundation and IBM recently published data on a newly developed statistical progression model that identifies 8 Parkinson disease (PD) states and categorizes patients based on differences in motor and nonmotor symptoms and disease progression.

Lead author Kristen A. Severson, PhD, Center for Computational Health, IBM, and colleagues collected data on 423 patients with early PD and 196 health controls (HCs) for up to 7 years from the Parkinson’s Progression Markers Initiative (PPMI). A contrastive latent variable model was applied followed by a novel personalized input-output hidden Markov model to define disease states.

"With validation of the model in real-world settings with diverse cohorts capturing a range of clinically relevant short-term and long-term outcomes, and further refinement to leverage a minimal set of emerging clinical or biomarker assessments that best identify granular states of Parkinson's disease progression, our model has the potential to translate to a prognostication tool in the clinic, and a predictive tool that might be used for clinical trial sample enrichment,” Severson et al wrote.

Additionally, Severson and colleagues noted that the model accounts for the effects of Parkinson's disease medications—something prior models have considered in a limited fashion or not at all. "We modelled medication effects as deviations from disease states, which vary across states and participants. An ideal model might allow these factors to vary together, with individualized response varying over time. However, most studies do not have enough data to accurately estimate time-varying, individualized response. Therefore, we compromise by allowing each patient to have a non-time-varying personalized response to medication and a time-varying response which is a function of disease state," they wrote.

Novel PET Imaging Tracer Shows Promise for Parkinson Disease Diagnosis

Seven clinically relevant key outcomes that did not contribute to the discovery model were defined to test the clinical relevance of the identified states: mild cognitive impairment (MCI), dementia, dyskinesia, motor fluctuation, functional impairment from motor fluctuations, Hoehn and Yahr score greater than 3, and death. The investigators validated their results using an independent sample of 610 patients with PD from the National Institute of Neurological Disorders and Stroke Parkinson’s Disease Biomarker Program (PDBP).

States were indexed starting from state 1, which was mildest, to state 8, which was considered terminal. There were multiple agreements between the model-designed state and the clinical observations for individuals assigned to that state. For instance, states 5 and 8 were associated with greater postural instability or gait difficulty, and most pairwise comparisons of states in these measures were assessed by Movement Disorders Society–Unified Parkinson Disease Rating Scale (MDS-UPDRS) 

In the PPMI cohort, state 8 accounted for 94 (56%) of 169 MCI cases, 18 (95%) of 19 dementia cases, 5 (71%) of 7 dyskinesia cases, 22 (55%) of 40 motor fluctuation cases, 58 (68%) of 85 functionally impactful motor fluctuation cases, 28 (90%) of 31 cases with Hoehn and Yahr scores greater than 3, and 10 (56%) of 18 instances of death. In the PDBP cohort, state 8 accounted for 9 (82%) of 11 dyskinesia cases, 13 (54%) of 24 motor fluctuation cases, 162 (74%) of 219 functionally impactful motor fluctuation cases, and 65 (97%) of 67 cases with Hoehn and Yahr scores greater than 3.

At the outset of the PPMI cohort, state 1 was the most observed state, accounting for 96 of 233 participants (29%) in the PPMI-training set and 21 of 83 participants (25%) in the PPMI-testing set. In total, 4 of 333 (1%) PPMI-training participants and 3 of 83 (4%) PPMI-testing participants were in state 8 at the study onset. By year 5, 41% and 58% of patients in each group, respectively, reached state 8. Although, Kaplan-Meier analysis showed that the ranking of the starting state did not match the ranking of reaching state 8 within 5 years.

Throughout the entire study period, the most observed state transitions were from 7 to 8, 6 to 7, and 4 to 6. Notably, no state transitions were observed from 1 to 8, 2 to 3, or 4 to 7. Overall, participants in state 5 had the shortest time to state 8 (PPMI-training set: median time, 2.75 years [95% CI, 1.75-4.25]; PPMI-testing set: median time, 2.25 [95% CI, 0.5-3.25]), and were significantly more likely to reach state 8 with participants starting in states 1, 3, and 4.

Severson KA, Chahine LM, Smolensky LA, et al. Discovery of Parkinson’s disease states and disease progression modelling: a longitudinal data study using machine learning. 

The model discovered nonsequential, overlapping disease progression trajectories, supporting the use of nondeterministic disease progression models. 

Marco Meglio

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