1. Multiple Sclerosis Update on Ongoing Research at the Jacobs MS Center Bianca Weinstock-Guttman, MD, Professor of Neurology SUNY University at Buffalo, UBMD Neurology

2. The Atlas of MS 2013 The Atlas of MS 2013 updates the information that was collected in 2008 on:  global epidemiology of MS  resources to diagnose  inform  treat  rehabilitate  support and provide services to people with MS around the world.

3. KEY FINDINGS The estimated number of people with MS has increased from 2.1 million in 2008 to 2.3 million in 2013. This finding reinforces the conclusions of the published epidemiological literature. MS is found in every region of the world. The 2:1 ratio of women to men with MS has not changed significantly since 2008.

4. Atlas of MS 2013

5. More research is needed In relation to quality of life and experiences of people with MS. To measure the indirect costs of MS. To understand sources and causes of inequalities in access to support, health care services and therapies. To monitor MS and related disorders through epidemiological studies and the establishment of registries.

6. Getting to What Matters to MS Patients Healthy Brain Infectious Agents Environment Tissue Injury Disease Progression

7. Types of Multiple Sclerosis

8. The Natural Course of MS: Physical Disability Confavreux C, et al. Brain. 2003;126:770-782. ●Landmarks of irreversible disability –Median time to limitation of ambulation: 8 years –Median time to requiring cane/crutch: 20 years –Median time to wheelchair confinement: 30 years 0.01.02.03.04.05.06.07.08.09.0 NormalNo disability Minimal disability Moderate disability Relatively severe disability Disability precludes full daily activities Assistance required to walk Restricted to wheelchair Restricted to bed or chair Confined to bed

9. Environmental Factors  Epstein Barr Virus  Vitamin D  Smoking  Lipids

10. Cholesterol High cholesterol is a known risk factor for heart disease and stroke  HDL – High density lipoprotein “Good” cholesterol  LDL – Low density lipoprotein “Bad” cholesterol

11. Cholesterol Cholesterol is essential 75% of cholesterol is made in the liver Remainder from the diet Cholesterol is recycled and re-used Cholesterol is the chemical building block for hormones like cortisol, estrogen, progesterone, testosterone

12. Cholesterol in the Brain The brain represents 2% of body weight Contains 25% of body cholesterol! 70% of brain cholesterol is in myelin

13. Mechanisms of Cholesterol Action in MS Effects on brain vasculature Effects on inflammation Effects on neurodegeneration Effects on vitamin D Oxysterols, which are cholesterol metabolites, have potent effects on the immune system

15. Cholesterol and Vitamin D

17. HDL Cholesterol Affects Vitamin D Higher HDL is associated with vitamin D sufficiency

19. Cholesterol & New Lesions Higher cholesterol is associated with formation of new lesions

20. Our results indicate that higher levels of anti-EBV EBNA-1 antibodies are associated with higher LDL-C and TC levels. Individuals with higher levels of anti-EBV VCA antibodies have greater progression on MRI measures in the presence of higher LDL-C.

22. Cholesterol & Optic Neuritis Higher cholesterol is associated with poorer recovery from optic neuritis

23. Lipoprotein Particles Lipids Cholesterol Proteins –  Lipoproteins  Enzymes

24. Conclusions The role of cholesterol and lipids in MS is not well understood Cholesterol may have effects on MS disease progression Careful study is needed because the cholesterol pathway is complex and inter-connected with other physiological functions.

25. Pregnancy in NYSMSC To explore whether long-term MS disability status is associated with the occurrence and/or number of live births. Analysis was based on longitudinal data of the NYSMSC registry comprised of patients from 16 MS Centers in New York State organized to prospectively collect demographic and clinical data. Women with ≥ 45 were included in this analysis. The mean number of childbirths for parous women was 2 and mean age at most recent visit was 54 (SD 7.4). Teter, B & Weinstock-Guttman, B et all; AAN, 2013 Total (N=1523) Parous (N=1195) Nulliparous (N=328)

26. Parity in NY State MS Consortium βSEHR 95% CI p- value Parity - 0.385 0.12 50.68.533-.8690.002 Cox regression model predicting progression to EDSS 6.

27. Disease-Modifying Therapies in Late Stages of Clinical Development Oral Agents Monoclonal Antibodies Dimethyl fumarate (BG-12; Tecfidera) Teriflunomide (Aubagio) Fingolimod (Gilenya) Ibudilast Alemtuzumab CD20-Targeting mAbs Ocrelizumab Ofatumumab Daclizumab Anti-Lingo1

28. Benefits Risks Meaningful impact Disease course MRI ? > efficacy than ABCR ? Window of opportunity Convenience Treatment Decisions: Considering Benefits and Risks Short-term safety Long-term safety Pregnancy issues Many unknowns ABCR = Avonex, Betaseron, Copaxone, or Rebif

29. Pediatric Network Research Priorities Epidemiology Genetics Microbioma Imaging Neuropsychology Treatment

30. Aging with MS MS beyond age 60 Knowledge and Understanding for Clinicians and patients Outcome – Disability (EDSS) and Psychosocial Well-being (LIFEware) DMT Safety and Tolerability Discontinuation 30

31. Aging with MS In addition to demographics (DOB education and marital status) Emphasis  Comorbid conditions  Insurance  Quality of Life - Patient-reported activities of daily living: Get up from sofa, climbing stairs, standing, driving, vision, fatigue  QoL – Psychosocial: Mood (depression, anxiety, stress, loneliness, guilt, life satisfaction) 31

32. Aging with MS – Potential Sample & Funding Secure funding to conduct an additional $100.00 Site Compensation for each patient ($ 50,000) Multi-Site Start-up ($2,000 to 5,000) Project Manager (PT 20,000) Structured similar to PR Study - infrastructure in place Projected funding need = $125,000 Blood and MRI – add to budget 32 AGE 201360-6465-6970-75GE 76Total Reg with/without FUP1,3671,0837065523,078 With FUP GE 20072511747334532

33. Oligodendrocyte progenitor cells for the treatment of chronic progressive multiple sclerosis PI: Burk Jubelt Co-PIs: Steve Goldman Andrew Goodman Bianca Weinstock-Guttman

34. Goldman et al., Science, 2012

35. 12 weeks 20 weeks 35 weeks NF MBP hNuclei

36. Goal: To establish a human OPC-based therapeutic for the treatment for secondary progressive multiple sclerosis Choice of target: Secondary progressive MS Hypothesis: OPCs transplanted to patients with immunologically quiescent secondary progressive multiple sclerosis will experience stabilized/improved neurological function, including cognition and mobility via functional cell-mediated effects

37. Fig. 1 Sites of neural stem cell direct implantation. N. Gupta et al., Sci Transl Med 2012;4:155ra137-155ra137 Published by AAAS

38. Acknowledgments Collaborators Murali Ramanathan, PhD Robert Zivadinov, MD, PhD Ralph Benedict, PhD Richard Browne, PhD Barbara Teter, PhD David Hojnacki, MD Channa Kolb, MD Support National MS Society Department of Defense NYSTEM NIH Biogen Idec Novartis Genzyme& Sanofi TEVA Questcor Acorda

39. Training my body = training my brain!