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Multiple Sclerosis & Neuroimmunology Research

Researchers in Neurology, led by Staley Brod, MD, and Ahmed Obeidat, MD, investigate a variety of neuroimmunologic disorders, including multiple sclerosis, neuromyelitis optica, and autoimmune encephalitis. Their goals are to understand the etiology and pathophysiology of these disorders, improve diagnosis through advanced imaging and quantitative neurological testing, and develop and evaluate new treatments.

Brod Lab | Structural MRI in Multiple Sclerosis

The Brod lab is using brain MRI methods to measure relationships between myelinating proteins in the blood and cerebrospinal fluid (CSF) and structural changes in the brain in people with multiple sclerosis (MS). The team studies the evolution of MS-like MRI lesions longitudinally and examined potential biomarkers in the peripheral blood and CSF immune compartments (N-CAM, BDNF). To date, 13 people with MS have been enrolled who had active brain MRI scans and were not on disease modifying therapies by choice. Participants underwent baseline MRI and serum and CSF sampling, and were followed longitudinally with repeated MRI and serum measurements over 2 years. In an initial analysis of 55 scans (Brod et al., 2019), an experienced MRI analyst determined whether there was qualitatively increased or decreased MRI activity (new/resolving gadolinium (Gd) enhancement, new/enlarging/diminishing T2 lesions, new/enlarging/diminishing T1 lesions) between scans. If there was interval activity, the participants underwent repeat CSF sampling (< 7 days post MRI). The imaging, segmentation, and longitudinal analysis protocols are illustrated in Figure 1.

Longitudinal processing of MS lesions
Figure 1. Longitudinal Processing of MS Lesions. Panels a-d show an example of single-time point (baseline) and panels e-h longitudinal registration (follow up) scans. The MRI standard output includes T2 (panel a & e), Fluid Attenuated Inversion Recovery (FLAIR, panel b & f), pre-contrast T1 (panel c & g), and expert-validated automated MRI tissue segmentation (d & h), where CSF is depicted in light blue, cortical and deep gray matter in light gray, white matter in white, T2-hyperintense lesions (without a corresponding T1 hypointensity) in salmon, and T1-hypointense lesions in dark red. Qualitative changes in T2 and T1 lesions are clearly visible on longitudinally segmented images (d & h).

Analyses of changes in T1 lesion volume and CSF N-CAMAs shown in Tables 1 and 2, the analyses revealed strong relationships between T1 lesion volume and both CSF and serum N-CAM, such that increasing levels of promyelinating N-CAM were positively correlated with increasing T1 lesion volumes. In addition, decreasing serum BDNF was related to decreasing T1 volumes. These findings suggest that the brain attempts to generate reparative proteins such as N-CAM when there is brain disease in multiple sclerosis, and that manipulations of pro-myelinating proteins in the blood or CSF could provide a method to promote CNS myelination and preserve neurons in MS. We are currently searching for ways to promote this normal reparative process in experimental mice.

Currently we are seeking funds for a project that extends the data above using MRI volumetrics, MR quantitative susceptibility mapping, and targeted proteomics of MS lesions in MS patients over time, in collaboration with Tugan Muftuler, PhD, Neurosurgery; Andrew Klein, MD, Neuroradiology; and Amanda Buchberger, PhD, Biochemistry/Proteomics.

INTERTWINE Lab

ImmuNology, Tool dEvelopment, Risk Factors, Treatment Safety and Wellbeing In MS and other NEuroimmune disorders

The INTERTWINE lab, headed by Ahmed Obeidat, MD, PhD, includes a team of clinicians, scientists, fellows, residents and students working together to investigate timely issues related to multiple sclerosis (MS) and other neuroimmune disorders. The etiology of MS remains poorly understood. Our lab examines hypotheses related to the role of environmental factors, including viruses in MS development. We further extend our investigations to other neuroimmune disorders, including Neuromyelitis Optica spectrum disorders and autoimmune encephalitis. We use clinical assays while aiming to pursue more intricate assessments of viral roles in the development of neuroimmune disorders. Our team performs detailed immunophenotyping to advance our understanding of changes in the adaptive immune system in MS before and after treatment with disease modifying therapies. We aim to further characterize response to treatment and predict long-term safety concerns, if any.

We also realize the need for a sensitive tool to assess abilities in MS and related disorders. Our team goal is to help develop a user-friendly and sensitive tool benefiting from current technological advancements in the field of biomechanical engineering. We are currently funded by the center for immunology at MCW and also have a pilot grant from the MCW Research Affairs Committee. Our team is active in writing grant proposals to fund our continuing research endeavors.

Projects

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Integration of Technology-Based Objective Measures with Self-Reported Functional Disability: Development of a Patient-Centered Measure of Outcome in Multiple Sclerosis

Summary
An integrated, multidimensional tool that aims to quantify clinical disease progression in people living with multiple sclerosis. The tool includes technology-based assessments, the use of motion sensors, neurothesiometer, computerized cognitive testing and smart-phone app. The tool further integrates patient reported outcomes into the battery of objective tests. The ultimate goal is for this tool to be utilized in clinical trials and clinical practice.

Funding
Research Affairs Committee (Medical College of Wisconsin)

Investigators
PI is Ahmed Obeidat, MD, PhD; Sub-Investigator team includes: Jeffrey Binder, MD, Julie Bobholz, PhD and Jessica Fritz, PhD; Collaborator: Aristide Merola, MD, PhD; Key Personnel: Sam Hooshmand, DO, Samantha O’Dell, BA, Lynn Wheeler, MS, CCRC

Status
Recruiting: current recruitment at 90% of target. Data analysis and main results are expected in July of 2021.

Relevant Publications

  • Obeidat AZ. The 10-Point Disability Scale in Multiple Sclerosis: Phase I Development and Planning study. In ACTRIMS Forum 2017. 2017 Feb 23. ACTRIMS.
Regulatory T cell and B cell-subset changes in patients with multiple sclerosis before and after receiving humanized anti-CD20 monoclonal antibody therapy

Summary
We aim to investigate changes in lymphocyte subtypes (T and B cells) in people newly diagnosed with MS and then examine their changes following a treatment targeted at B cell depletion.

Funding
Center for Immunology (Medical College of Wisconsin)

Investigators
PI is Ahmed Obeidat, MD, PhD; Sub-Investigator: Bonnie Dittel, PhD; Key Personnel: Calin Dumitrescu, BS, Samantha O’Dell, BA, Lynn Wheeler, MS, CCRC, Cody Gurski, BS

Status
Recruiting: current recruitment at 60% of target. Data analysis and preliminary results are expected in December of 2021.

Relevant Publications

  • Cotchett KR, Dittel BN, Obeidat AZ. Comparison of the Efficacy and Safety of Anti-CD20 B Cells Depleting Drugs in Multiple Sclerosis. Multiple Sclerosis and Related Disorders. 2021 Jan 22:102787.
Dynamics of B cell subtypes in multiple sclerosis before and after treatment

Summary
We aim to investigate whether there is an observed difference in specific subsets of B cells when they reconstitute following depletion by monoclonal antibodies. Ultimately, we aim to investigate whether B cell depletion in MS can have long lasting effects on B cell subsets.

Funding
Imagine More Award (Neuroscience Research Center)

Investigators
PI is Ahmed Obeidat, MD, PhD; Sub-Investigator: Bonnie Dittel, PhD; Key Personnel: Samantha O’Dell, BA, Lynn Wheeler, MS, CCRC, Cody Gurski, BS

Status
Recruiting: current recruitment at 40% of target. Data analysis and preliminary results are expected in July of 2022.

Relevant Publications

  • Cotchett KR, Dittel BN, Obeidat AZ. Comparison of the Efficacy and Safety of Anti-CD20 B Cells Depleting Drugs in Multiple Sclerosis. Multiple Sclerosis and Related Disorders. 2021 Jan 22:102787.
The Ever-Expanding Spectrum of anti-MOG associated disease

Summary
We aim to help better characterize a recently discovered clinical entity in neuroimmunology, anti-myelin oligodendrocyte glycoprotein (MOG) associated disease. We examine, clinical, radiologic, and laboratory aspects of the disease, as well as delving into future predictors of relapses.

Funding
None

Investigators
PI is Ahmed Obeidat, MD, PhD; Key Personnel: Allison Block, DO, Sam Hooshmand, DO, Michelle Maynard PharmD, Samantha O’Dell, BA, Lynn Wheeler, MS, CCRC. Collaborators: Manav Bhalla, MD, Aram Zabeti, MD, Lawrence Goldstick, MD, Samuel Marcucci, BS

Status
Active – retrospective studies.

Relevant Publications

  • Obeidat AZ, Block A, Hooshmand S. “Peppering the Pons”: CLIPPERS or Myelin Oligodendrocyte Glycoprotein Associated Disease? Accepted in final form. Multiple sclerosis and related disorders. Feb 2021.
  • Block A, Champeau D, Carlson C, Helms A, Obeidat AZ. Anti-myelin oligodendrocyte glycoprotein (MOG) associated disease masquerading as prolonged intractable nausea and vomiting. Multiple sclerosis and related disorders. 2020 Sep 1;44:102308.
  • Block AN, Obeidat AZ. (CRS01) Seasonal Variation and Other Observations in Myelin Oligodendrocyte Glycoprotein (MOG) Antibody--Associated Disease. International Journal of MS Care. 2020 May 2;22.
  • Block AN, Maynard M, Obeidat AZ. Novel Clinical Observations in Myelin Oligodendrocyte Glycoprotein (MOG) Antibody-Associated Disorders. In2019 Annual Meeting of the Consortium of Multiple Sclerosis Centers 2019 May 30. CMSC.
Safety of Disease Modifying therapies used in the treatment of MS

Summary
We aim to investigate local and large databases to elucidate specific trends of adverse events related to the use of disease modifying therapies in multiple sclerosis.

Funding
None

Investigators
PI is Ahmed Obeidat, MD, PhD; Key Personnel: Mokshal Porwal, BSs, Sam Hooshmand, DO, Michelle Maynard, PharmD, Carmen Raschka, RN, Nicola Carlisle, MD; Collaborators: Amber Salter, PhD, Sara Hooshmand, BS, Dhruvkumar Patel, BMSc

Status
Active – retrospective studies.

Relevant Publications

  • Carlisle N, Hooshmand SI, Maynard M, Hoffman L, Obeidat AZ. (DXT55) Herpes Zoster Virus (HZV) Infections Among Multiple Sclerosis Patients Treated with Various Disease-Modifying Therapies. International Journal of MS Care. 2020 May 2;22.
  • Hooshmand S, Carlisle N, Maynard M, Hoffman L, Obeidat A. Analysis of Reported Deaths While Exposed to Disease-Modifying Therapies for Multiple Sclerosis (2855).
Role of Herpes family viruses in the pathogenesis of MS

Summary
We aim to investigate environmental factors in MS, mainly the role of herpes virus family.

Funding
None

Investigators
PI is Ahmed Obeidat, MD, PhD; Key Personnel: Samuel Marcucci, BS, Collaborator: Vera Tarakanova, PhD

Status
Active – retrospective studies.

Relevant Publications

  • Marcucci SB, Obeidat AZ. EBNA1, EBNA2, and EBNA3 link Epstein-Barr virus and hypovitaminosis D in multiple sclerosis pathogenesis. Journal of neuroimmunology. 2020 Feb 15;339:577116.

Additional Information

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International Collaboration

Our team collaborates with researchers at the Jordan University of Science and Technology. Our aim is focus on global health and comparative research studies. Currently we investigate clinical biomarkers in spinal fluid in a diverse MS patient cohort including Caucasian, African American, Hispanic, Asian and Arab backgrounds.

Our main collaborator is Prof. Khalid El-Salem

Relevant publications

  • El-Salem K, Khalil H, Al-Sharman A, Al-Mistarehi AH, Yassin A, Alhayk KA, Al Qawasmeh M, Bashayreh SY, Kofahi RM, Obeidat AZ. Serum vitamin d inversely correlates with depression scores in people with multiple sclerosis. Multiple Sclerosis and Related Disorders. 2021 Feb 1;48:102732.
  • Obeidat AZ, El-Salem K. A national telemedicine program in the Kingdom of Jordan–Editorial.Ann Med Surg (Lond). 2021 Jan 14;62:145-149.
Education Research

Dr. Obeidat has a growing interest in medical education. He is the founding director of the neuroimmunology and MS fellowship program at the Medical College of Wisconsin. Dr. Obeidat serves on national committees for medical education in the fields of neuroimmunology and MS.

Relevant publications

  • Hua LH, Obeidat AZ, Amezcua L, Cohen JA, Costello K, Dunn J, Gelfand JM, Goldman MD, Hopkins S, Jeffery D, Krieger S. Consensus Curriculum for Fellowship Training in Multiple Sclerosis and Neuroimmunology. Neurology: Clinical Practice. 2021 Jan 18.
  • Hua LH, Obeidat AZ, Longbrake EE. Outcomes and future directions for neuroimmunology/multiple sclerosis fellowship training: Survey of recent trainees. Multiple Sclerosis and Related Disorders. 2020 Sep 1;44:102296.
  • Longbrake E, Obeidat A, Dunn J, Sicotte N, Hua L. Defining the Neuroimmunology/Multiple Sclerosis Subspecialty: Surveys of Fellowship Training in the United States (699).
  • Obeidat AZ, Jassam YN, Hua LH, Cutter G, Ford CC, Halper J, Lisak RP, Sicotte NL, Longbrake EE. Education Research: Multiple sclerosis and neuroimmunology fellowship training status in the United States. Neurology. 2020 Mar 17;94(11):495-500.
Arts and Medical Humanities

Our team is interested in the intersection between arts, humanities and medicine. We aim to integrate arts into the care of people living with neuroimmune disorders. We are actively seeking grant funding for studies and projects related to integrating the arts into routine clinical care. We are currently part of a study examining the effect of recreational music making on the wellbeing of healthy older adults, and we are part of a study using art in improving health literacy in Parkinson’s disease. We are seeking further funding with community partners and other not-for-profit organizations. We completed a study on the feasibility of recreational music making in the older adults, in collaboration with non-profit organization (Cincinnati Music and Wellness) and the University of Cincinnati. The results were presented at the 2020 Annual Music and Medicine Conference and are currently in preparation for publication. We collaborate closely with Mrs. Nadia Al Khun, a visual artist who has interest in the intersection between arts and neuroscience. Dr. Obeidat serves on the editorial board of the International Journal of MS Care and his roles include helping integrate arts into the journal publications.

Featured on the cover of Neurology is the painting “The Unseen but Felt” created by artist Nadia Al Khun to capture the effects of hidden symptoms experienced by people living with MS.

MS Neuroimmunology Cover Art

Relevant publications

Press Mentions

MS and the Arts | June 20, 2019
MultipleSclerosis.net

Translating Oral Immunoactive Proteins into Therapy for Autoimmune Diseases

Oral ACTH Figure 2Experimental autoimmune encephalitis (EAE) is an inflammatory autoimmune process of the CNS that resembles multiple sclerosis (MS) and provides a useful animal model for the evaluation of mechanisms of action for potential immunomodulatory therapies. Oral ACTH can decrease clinical disease, IL-17, and Th1-like encephalitogenic IFN-g secretion, and increase Treg frequency. The mechanism by which oral ACTH decreases inflammatory proteins and increases Treg cell frequencies is unknown. IL-6 is a pivotal cytokine in the gut that determines the relative frequencies of Th17 vs Treg cells. In collaboration with Dr. Bonnie Dittel’s laboratory at the Blood Research Institute (Versiti), Dr. Brod and his team examined whether oral ACTH inhibits IL-6 in gut associated lymphoid tissue (GALT) in EAE. B6 mice were immunized with MOG peptide 35-55 and gavaged with scrambled ACTH (s-MSH) peptide or ACTH 1-39 during ongoing disease.

Ingested (oral) ACTH inhibited ongoing clinical disease, as shown in Figure 2. In the lamina propria (LP) immune compartment, there were significantly fewer CD11b+ and CD4+ IL-6 producing lymphocytes from ACTH fed mice compared to s-MSH fed mice. There was also a decrease in the frequency of IL-17 and IFN-g producing spleen cells and an increase in CD4+FoxP3+ Treg cell frequency in ACTH fed mice compared to s-MSH fed control spleens.

The results demonstrate that ingested ACTH inhibits EAE clinical disease by inhibiting IL-6 in the GALT. The administration of endogenous immune-active proteins via the gut offers an alternative to systemic application with ease of administration in chronic clinical use (Rollwagen and Baqar, 1996) and patient convenience, and would be a great step forward because gut delivery is easy, well tolerated, and inexpensive with a favorable therapeutic index. We have already administered ACTH to humans but lacked information on the mechanism of ACTH in the gut. These experiments in mice help us understand the mechanism of action and provide a rationale for pursuing further clinical trials are planned in MS subjects.

Oral ACTH Figure 3
Figure 3

In addition, our studies have shown that IL-6, a critical cytokine in gut immune cells, is inhibited by oral ACTH. The flow diagrams in Figure 3 above show that oral ACTH decreases the frequency of IL-6 producing CD11b+ dendritic cells in the lamina propria from 22% to 12%.

Oral ACTH Figure 4
Figure 4

Next we showed that IL-17, a critical cytokine in EAE generation is also inhibited by oral ACTH in the lamina propria. The flow diagrams in Figure 4 above show that oral ACTH decreases the frequency of IL-6 producing CD11b+ dendritic cells in the lamina propria from 6.75% to 1.43%.

Oral ACTH Figure 5
Figure 5

Next we showed that regulatory T cells (Tregs) that diminish disease in MS, are increased by oral ACTH in the spleen. The flow diagrams in Figure 5 above show that oral ACTH increases the frequency of Tregs cells in the lamina propria from 2.9% to 6.0%.

Oral ACTH Figure 6
Figure 6

Finally, as shown above in Figure 6 above, oral ACTH decreases the frequency of IFN-g producing T cells in the CNS (central nervous system) of the mice fed ACTH in contrast to the mice fed control peptide.

These experiments showing that IL-6, other inflammatory factors, and clinical disease can be controlled by ingesting an immune-active protein will lead to human clinical trials using oral ACTH in MS.

Meet Our Team

Faculty

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Staley A. Brod, MD

Professor

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Ahmed Zayed Obeidat, MD, PhD

Associate Professor

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Bonnie N. Dittel, PhD

Senior Investigator, Versiti Blood Research Institute; Professor, Microbiology & Immunology

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Jessica Francis, MD

Associate Professor

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Sam I. Hooshmand, DO

Assistant Professor

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Andrew P. Klein, MD

Chief, Associate Professor

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Aristide Merola, MD, PhD

Neurologist and Movement Disorder Specialist, Ohio State University

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L. Tugan Muftuler, PhD

Associate Professor

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Vera Tarakanova, PhD

Associate Professor

Staff and Students

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Calin Dumitrescu

Medical Student

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Leah Hoffman

Pharmacy Student, Concordia University

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Samuel Marcucci

Medical Student, University of Cincinnati

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Michelle Maynard, PharmD

Clinical Pharmacist, Froedtert Hospital