Hollie's notes from the 2010 AAN Annual Meeting in Toronto

Hollie's Notes from the 2010 AAN Meeting in Toronto

American Academy of Neurology meeting April 10-17 Toronto, Ontario

Each year Accelerated Cure Project attends the American Academy of Neurology. We try to take notes on as many presentations as we can, write them up, and make them available on MSNews for anyone to read.

You can see our notes below. If you have any questions or comments, please click on the link labeled "Hollie" above to send a message. By the way, if you're interested in seeing the abstracts for the posters and presentations from this conference, you can do so here: http://www.abstracts2view.com/aan

continued...

Mon 04/12:

The flight from Boston to Toronto was short and pleasant. I flew Porter Air which is a new Canadian airline. They actually serve real food on board and in Toronto, they land at City Airport, which is a small airport on an island in Lake Ontario right outside downtown. When you depart from Toronto, you get to wait in a lounge (available to all passengers) that offers free drinks, food, and WiFi. (Doesn't Porter realize that they're supposed to nickel-and-dime its passengers like all the other airlines?)

Tue 04/13:

One of the best reasons to attend AAN is that the amount of MS content attracts many people working in the field of MS, so I can meet with lots of colleagues face-to-face. Before the MS scientific sessions got started, I had meetings with Dr. Gary Cutter, a leading MS biostatistician from University of Alabama, Dr. Denisa Hurtukova who works in the medical affairs department at Teva, and Dr. Barbara Teter, who is the director of R&D for the New York State MS Consortium.

S01: Multiple Sclerosis: Clinical Research I

S01.001 Polysomnographic Investigation of Frequency of Sleep Disorders in Consecutive Unselected Fatigued and Non-Fatigued Multiple Sclerosis Patients
Christian Veauthier, Helena Radbruch, Gunnar Gäde, Carsten Pfüller, Jan Dörr, Judith Bellmann-Strobel, Jörn Sieb, Frauke Zipp, Paul Friedemann

I came in too late to catch this presentation, but luckily it was reviewed in the MS Highlights session later in the week.

S01.002 Color Vision and High-Resolution OCT Are Highly Sensitive for Detecting Anterior Visual Pathway Abnormalities in Multiple Sclerosis
Ari Green, Jeffrey Gelfand, Ami Cuneo, Pablo Villoslada

Visual tests are relatively easy and inexpensive to administer, and therefore might be cost-effective measures of neurodegeneration, at least when analyzing areas of the nervous system involved in vision. The presenters stated that tests of low-contrast vision and color vision could both be useful markers of neurodegeneration and are not highly correlated with each other, so they could be useful separately. Some correlation can be seen between these measures and OCT (optical coherence tomography), which is an imaging technique that assesses retinal nerve fiber loss.

S01.003 Characteristics of Walking Speed Improvement Observed in Three Well-Controlled Studies of Sustained Release Fampridine 10 mg Bid in Patients with Multiple Sclerosis
Andrew Goodman, Ted Brown, Keith Edwards, Randall Schapiro, Lawrence Marinucci, Ron Cohen, Andrew Blight

This presentation reviewed the combined results from three placebo-controlled studies of dalfampridine (Ampyra) in people with MS. Altogether, 394 subjects who had had at least one assessment after taking the drug or placebo were included in this analysis. The average disease duration of these subjects was 13 years, average EDSS was 5.7, and most subjects had progressive MS. 37% of the subjects receiving the drug were deemed to be "responders" (i.e. had mostly higher walking speeds when tested at various times after going on treatment compared with tests performed prior to treatment). Only 9% of the placebo group met the responder criteria. Also, 31% of the drug group vs. 13% of the placebo group showed walking speed improvements of at least 20%. Serious adverse events were seen in 5% of the dalfampridine subjects vs. 2% of the placebo subjects; there was one seizure in each group. In response to a question from the audience, Dr. Goodman said that no characteristic had yet been identified that could predict who might respond to the drug. He personally would consider trying it in patients with marked gait impairment.

S01.004 Use of Natalizumab in Pediatric MS Patients: A Pediatric Network Experience 
E. Ann Yeh, Lauren Krupp, Nancy Kuntz, Jayne Ness, Dorothee Chabas-Chanezon, Tanuja Chitnis, Anita Belman, Moses Rodriguez, Emmanuelle Waubant, Mark Gorman, Khurram Bashir, Network Pediatric MS Centers of Excellence, Bianca Weinstock-Guttman

A team from a network of six clinics that specialize in treating children with MS conducted a review of their records to see how Tysabri was being prescribed in this group. Out of 258 patients who had been treated with a disease-modifying drug, 24 had been treated with Tysabri. Interestingly, 33% of the Tysabri-treated patients were Hispanic, compared with 15% of all treated patients. One to four other treatments had been tried in each patient before starting Tysabri. Four of the 24 had discontinued Tysabri, but the rest are continuing with it, indicating that the drug is fairly well tolerated. However, these patients have only been treated with Tysabri for an average of 1.5 years so far, so longer term follow-up is needed.

S01.005 Measures of Early Clinical Activity as Prognostic Factors for Long-Term Clinical Outcomes in Relapsing- Remitting Multiple Sclerosis 
Anthony Traboulsee, Bernard Uitdehaag, Ludwig Kappos, Magnhild Sandberg-Wollheim, David Li, Peter Jongen, Cris Constantinescu, Elisabetta Verdun, Peter Cornelisse

Investigators analyzed data from an IFN-beta trial that had continued to follow its subjects for several years to look for factors in the early part of the study that could predict disability later on. The study included 382 subjects. 90% had stayed in the study for 4 years and 80% for 8 years. The best predictor of long-term outcome turned out to be the change in EDSS score (if any) during the first two years. Relapse rate, on the other hand, did not have a strong correlation with eventual EDSS or conversion to secondary progressive MS.

S01.006 Clinical and NeuroImaging Predictors of Responsiveness to Immunomodulating Therapies in a Large Single-Center Cohort of Patients with Relapsing-Remitting Multiple Sclerosis (RRMS) 
Giancarlo Comi, Marzia Romeo, Filippo Martinelli Boneschi, Vittorio Martinelli, Giuseppe Liberatore, Mariaemma Rodegher

In this study, a research team followed 1062 people with MS who were starting an MS therapy, giving them annual MRIs and quarterly neurological exams. The team then analyzed factors that might affect response to therapy, defined as full, partial, or no response based on combinations of relapse and MRI activity measures. After one year on treatment, 53% had a full response, with no relapses and no MRI activity. After two years, the percentage was 36%. Interestingly, full response was more common in people with a higher age at MS onset and higher age when beginning MS treatment. Lower disease activity at baseline (lower EDSS, lower relapse rate, and fewer MRI active lesions) was also associated with response, which seems logical. Patients on Copaxone had a lower average baseline relapse rate and MRI activity, and a higher likelihood of full response, than patients receiving interferon beta. However, Dr. Comi said that each of these factors were only modestly predictive, and noted a few limitations of the study including use of arbitrary outcome measures and fairly short follow-up time.

S01.007 Mitoxantrone Treatment in Neuromyelitis Optica (NMO) 
Masaru Matsui, Kiyoe Ohta, Keiko Tanaka, Masayuki Tahara, Mitsuhiro Ohta, Masami Tanaka

This talk described a small trial (9 subjects) of mitoxantrone to treat NMO. The treatment appeared to reduce relapse rate, from an average of 6 in the two years prior to the study to an average of 3 in the two years post-treatment. Titers of anti-aquaporin4 antibody (an NMO biomarker) were also reduced, from a range of 176-716 down to 0-135. So mitoxantrone may be an option for treating NMO as well as MS. Dr. Ohta also mentioned that his clinic is experimenting with daclizumab to treat NMO.

S01.008 Interim Analysis of Open-Label Extension Studies of Sustained Release Fampridine in Patients with Multiple Sclerosis 
Andrew Goodman, Ted Brown, Keith Edwards, Randall Schapiro, Lawrence Marinucci, Ron Cohen, Andrew Blight, MS-F203, MS-F204, MS-F203EXT, and MS-F204EXT Study

Dr. Goodman presented interim results from an extension of a clinical trial for fampridine. Some of the subjects have now been followed for over two years. Results indicate that in people who appear to respond to the drug, its efficacy is maintained over time, although walking speed still continues to decline over time. Four subjects have experienced seizures while on the drug, and one subject had a seizure 22 days after discontinuing the drug. No new safety issues have been seen.

S11 Multiple Sclerosis: Clinical Trials I

S11.001 Optimal Design and Analysis of Phase I/II Clinical Trials in Multiple Sclerosis with Gadolinium Enhancing Lesions as the Endpoint 
Brian Healy, David Ikle, Gary Cutter

Even though MRI lesion activity isn't officially recognized by the FDA as an alternative to relapse rate or progression for demonstrating treatment efficacy, MRIs are still included in studies because they can provide information into whether a drug is having an effect on MS disease activity or not. To help investigators decide how to design trials using gadolinium-enhancing (Gd+) lesions as an outcome measure, a team of statisticians developed a computer simulation into which parameters such as predicted treatment effect could be programmed. The simulation can provide parameters such as number of subjects and frequency of scans in order to maximize the power of the study and minimize the cost. The team demonstrated one scenario which gave an optimal scanning frequency of every other month.

S11.002 Twice Weekly Versus Daily Glatiramer Acetate: Results of a Randomized, Rater-Blinded Prospective Clinical Trial Clinical and MRI Study in Relapsing- Remitting MS 
Christina Caon, Jai Perumal, Alexandros Tselis, Wendy Ching, Fen Bao, Zahid Latif, Imad Zak, Omar Khan

This talk described a pilot study to investigate the effects of taking Copaxone on a reduced schedule (twice a week) compared with the regular daily dosing. 48 subjects who had already been on Copaxone for at least a year were randomized between the two dosing arms. At the end of two years, no significant differences between the two groups were seen in relapse rates or other clinical or MRI measures. The twice-weekly group had fewer incidences of lipoatrophy and none of the systemic post-injection reactions sometimes experienced after Copaxone injections. Since this was only a small study, Dr. Khan could not yet recommend that people switch away from the standard dosing schedule. However, he said that if someone is considering going off the drug because of factors related to daily injections, he/she might consider trying reducing the frequency instead.

S11.003 A Randomized, Controlled Trial of Neuroprotection with Lamotrigine in Secondary Progressive Multiple Sclerosis 
Raju Kapoor, Julian Furby, Thomas Hayton, Kenneth Smith, Daniel Altmann, Robert Brenner, Jeremy Chataway, Richard Hughes, David Miller

Lamotrigine is a sodium channel blocker that is prescribed for epilepsy and bipolar disorder. A team of investigators performed a placebo-controlled study to see if it could be neuroprotective in people with MS. Their study included 120 people with secondary progressive MS and the main outcome was central cerebral volume as measured by MRI. After two years, there were no significant differences between the two groups; however, the lamotrigine group had slightly greater brain volume loss than the placebo group. This volume loss partially reversed after stopping the treatment. A similar effect of brain volume loss has been seen with some immunomodulatory drugs -- this is called pseudoatrophy and may be due to lesions shrinking due to reduced edema (water). However, in this study there was no effect on lesions so the cause of this increased atrophy is unclear. The lamotrigine drug group did score better on the 25 foot timed walk than the placebo group, so perhaps this drug is worth further study if the atrophy issue could be understood.

S11.004 Oral Fingolimod (FTY720) vs Placebo in Relapsing-Remitting Multiple Sclerosis: 24-Month Clinical Efficacy Results from a Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase III Study (FREEDOMS) 
Ludwig Kappos, Paul O’Connor, Chris Polman, Reinhard Hohlfeld, Ernst-WilhelmRadue, Peter Calabresi, Krzysztof Selmaj, Catherine Agoropoulou, Malgorzata Leyk, Lixin Zhang-Auberson, on Behalf of the FREEDOMS Study Group

This talk described some of the clinical results of the FREEDOMS study of oral fingolimod (now called Gilenia) which were published in the New England Journal of Medicine earlier this year (see our write-up). Compared with subjects receiving placebo, subjects who received the drug had less disability progression, or even some improvement on EDSS scores, fewer relapses, and higher scores on functional tests. An audience member asked whether something like PML could eventually emerge with this drug. Dr. Kappos responded by saying this hasn't been seen yet but it's a possibility with longer-term treatment.

S11.005 Oral Fingolimod (FTY720) Reduces Inflammatory Activity vs Placebo in Relapsing-Remitting Multiple Sclerosis: 24-Month MRI Results from a Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase III Study (FREEDOMS) 
Ernst-Wilhelm Radue, Paul O’Connor, Chris Polman, Reinhard Hohlfeld, Peter Calabresi, Krzysztof Selmaj, Catherine Agoropoulou, Lixin Zhang-Auberson, Malgorzata Leyk, Ludwig Kappos, on Behalf of the FREEDOMS Study Group

Continuing the discussion of FTY720, this talk covered the imaging results from the same clinical trial. The drug showed significant improvements over placebo in several areas (number of Gd+ lesions, number of new/enlarging T2 lesions, change in lesion volume, and change in brain volume). For example, the cumulative number of new/enlarging T2 lesions at 24 months was 9.8 in the placebo group vs. 2.5 in the drug group. Differences between the two groups were seen as early as the first scan at six months. Unlike in other drug trials, no pseudoatrophy was observed in the treatment group; rather, the drug group had a slower rate of atrophy than the placebo group. This rate was even close to the range of normal brain atrophy in people without MS. Dr. Radue speculated that FTY720 acts more slowly than other immunomodulatory drugs, so perhaps there is not the dramatic loss of inflammation and edema that is seen with other drugs that gives the appearance of lower brain volume.

Following this talk, one of the moderators of this session, Dr. Annette Langer-Gould, asked the previous two presenters to address the potential safety concerns associated with FTY720, such as a cardiac problem called AV block (atrioventricular block) and a condition involving swelling of the retina called macular edema. Dr. Kappos said that the data so far does not indicate a need for cardiac monitoring. As for macular edema, screening before administration of the drug and again at 3 months should be sufficient to detect whether this is a concern. Because the drug traps certain immune cells in lymph nodes, it may increase the risk of infection. However, Dr. Kappos said that lymphocyte counts probably wouldn't be helpful as an indicator of immune function. Dr. Langer-Gould noted reports of pneumonia from the studies, but Dr. Kappos felt that these were likely to be chance events. He also thought that skin cancer isn't a major concern, but that screening for this would nevertheless make sense.

After the conference was over for the day, I joined a group from UMass Medical Center (one of our repository sites) for dinner in Toronto's financial district.

Wed 04/14:

Wednesday morning started with meetings with one of our advisory board members, Dr. Judy Abdalla from Quintiles, and with Dr. Alberto Ascherio from the Harvard School of Public Health. For lunch I went through the exhibit hall, meeting new contacts and picking up information on products that might be useful for our MS repository.

The afternoon presented a dilemma. Normally in each presentation session there are two sessions on MS, so I have to choose which one not to attend. However, the AAN meeting organizers scheduled an extra MS session on imaging for Wednesday afternoon, so this time I had to choose which two sessions not to attend! And of course all three were among the most interesting of the meeting. I opted to attend the first few talks in the Imaging session and then switch over to the end of the Clinical Trials session -- then stay for the beginning of the Biomarkers session before going back for the end of the Imaging session.

IN7-1: Platform Session: Integrated Neuroscience: Multiple Sclerosis Imaging

IN7-1.001 Correlation of Retinal Nerve Fiber Layer Thickness in Optical Coherence Tomography with Visual Cortex MR Spectroscopy and Brain Atrophy in Multiple Sclerosis
Caspar F. Pfueller, Alexander U. Brandt, Jens T. Wuerfel, Florian Schubert, Bernadeta Walaszek, Helmar Waiczies, Markus Bock, Frauke Zipp, Friedemann Paul, Bernd Ittermann

The thickness of the retinal nerve can be reduced by disease processes in MS and can be quickly measured by an imaging technique called OCT (optical coherence tomography). This team wanted to see how atrophy of the retinal nerve correlated with other imaging measurements of neurodegeneration in MS. They found that retinal nerve fiber layer thickness (RNFLT) correlated with brain volume, with a neural marker (NAA) in the visual cortex, and with the presence of optic neuritis. However, RNFLT was not correlated with NAA in normal appearing white matter.

IN7-1.002 The Role of CD 4 T-Cells and Epitope Specific CD8 T-Cells in the Formation of T1 Hypointense Lesions in a Murine Model of MS
Istvan Pirko, Rochester, MN, Jeremiah McDole, Yi Chen, Anne K. Lohrey, Scott R. Dunn, Aaron J. Johnson

Theiler's Murine Encephalitis Virus (TMEV) is a model of MS in which mice develop lesions in the brain (not just the spine) that can include T1 hypointense lesions ("black holes"). Researchers working with this model hypothesized that CD8+ T cells were responsible for the formation of these persistent lesions. They transferred CD8+ cells into mice who had not developed these specific lesions, and found that the mice had indeed developed black holes. They also found that CD4+ T cells were protective against these lesions. Following up further on these results, the researchers are analyzing brain tissue samples from these mice and are seeing CD8+ cell debris in the lesions. They speculate that targeting certain CD8+ cells might help prevent the formation of black holes.

IN7-1.003 Quantitative Venous Vasculature Assessment on Susceptibility-Weighted Imaging Reflects Presence of Severe Chronic Venous Insufficiency in the Brain Parenchyma of Multiple Sclerosis Patients. A Case-Control Study
Guy U. Poloni, Paolo Zamboni, Mark Haacke, Stefano Bastianello, Michael G. Dwyer, Niels Bergsland, Claudiu Schirda, David Wack, Christopher Magnano, Bianca Weinstock-Guttman, Fabrizio Salvi, David Hojnacki, Robert Zivadinov

Susceptibility-weighted imaging is an imaging technique that is sensitive to the presence of iron-associated molecules (ferritin, hemosiderin and deoxyhemoglobin), and therefore it can be used to visualize blood vessels such as veins in the brain. This study used SWI to image 62 MS subjects and 33 age and sex-matched controls to analyze vein size and structure. The MS subjects had a lower absolute venous volume than the controls. Other differences were seen -- MS subjects had a higher average distance between veins and a lower relative amount of intracranial volume taken up by veins. However, no differences were seen between RRMS and SPMS subjects. In the future, this group would like to perform the same measurements in specific regions of the brain and correlate these measurements with clinical and MRI measures as well as with the presence of CCSVI. An audience member remarked that if the veins of people with MS drain more slowly due to blockages, shouldn't that result in greater vein volumes upstream, like you would find when a river is dammed? Dr. Poloni responded that these findings might be due to neurodegeneration resulting in lower blood flow and therefore a reduced vascular system.

Chronic Cerebrospinal Venous Insufficiency and Multiple Sclerosis: A Paradigm Shift in the Physiology of Cerebral Venous Return
Paolo Zamboni

I returned to the imaging session to hear the last speaker, Dr. Zamboni, describe firsthand his findings of venous blockage in people with MS. He showed some images of CCSVI, described his hypothesis, and briefly reviewed the findings from his clinical study. Robert Zivadinov also presented some further results from the follow-up imaging study being performed at the University of Buffalo. These results also show an association with MS, although they are not nearly as striking as Dr. Zamboni's results. Here are the Buffalo results:
Percentage of group that had two or more CCSVI criteria:

• Healthy controls: 22-25%
• Clinically isolated syndrome: 38-42%
• Other neurological disease: 42-45%
• MS: 56-62%

Percentage of group that had one or more CCSVI criteria:

• Healthy controls: 55%
• Clinically isolated syndrome: 76%
• Other neurological disease: 65%
• MS: 81%

The Buffalo results showed no correlation with age. However, the prevalence of CCSVI is much higher in people with SPMS (90%). In healthy controls, there was only a slightly higher prevalence in people who had a relative with MS.

As expected, there were a lot of questions for Dr. Zamboni from the audience, such as:
Q: Have you ever studied patients whose MS onset occurred at an early age, to help determine if MS is due to congenital venous defects?
A: Not yet, but this needs to be done.
Q: What are the chances of restenosis (recurrence of blockage) after treating a blocked vein?
A: 47% of the internal jugular veins he has treated with balloon angioplasty have restenosed, but they can be retreated. He does not recommend stenting at all.
Q: Do you find that CCSVI stenoses persist over time?
A: Yes, he saw the same things when he brought people back for a second round of imaging.
Q: How could CCSVI be related to the immune system, which we know is involved in MS due to genetic studies and effects of immunological treatments?
A: His hypothesis relates to the dynamics of blood flow and how this affects the endothelial cells lining the surface of blood vessels. Oscillatory and/or reverse flow may stimulate these cells, causing the upregulation of inflammatory genes and production of cytokines. He would like to investigate this hypothesis in the lab.
Q: The fact that iron is found in MS lesions doesn't necessarily mean it arrives there through leakage of blood cells through veins -- iron could be deposited by other cells or other mechanisms.
A: Yes, this is true, although this part of the CCSVI hypothesis is consistent with other evidence.

Neurologists are getting lots of questions from their patients about this topic and accordingly, there was a big crowd on hand for this talk. A live webcast sponsored by the National MS Society was also held earlier in the day -- you can view a recording or read the transcript on the NMSS web site.

S21 Multiple Sclerosis: Clinical Trials II

S21.005 Atorvastatin Reduces the Risk of New Brain MRI Lesions in Patients with Clinically Isolated Syndrome (CIS) Compared to Placebo 
Emmanuelle Waubant, Daniel Pelletier, Michele Mass, Jeffrey Cohen, Mariko Kita, Anne Cross, Amit Bar-Or, Timothy Vollmer, Michael Racke, Olaf Stuve, Steven Schwid, Andrew Goodman, Norman Kachuck, Jana Preiningerova, Bianca Weinstock-Guttman , Peter Calabresi, Aaron Miller, Masoud Mokhtarani, David Iklé, Stacey Murphy, Linna Ding, Ellen Rosenberg, ITN020AI Study Management Team, Collin Spencer, Scott Zamvil

Dr. Waubant presented some additional information from a study in which statins were administered to people with a single MS symptom. The goal of the study was to see if atorvastatin (Lipitor) would prevent additional symptoms and thus reduce the chances of being diagnosed with MS. That goal was not met; however, the drug may have still had some beneficial effect since 55% of the statin group compared with 27% of the placebo group were free of new T2 lesions during the one-year trial. A greater percentage of the statin group also remained free of Gd+ lesions.

S21.006 Pilot Phase I/II Clinical Trial with Autologous Mesenchymal Stem Cells in Patients with Multiple Sclerosis and Amyotrophic Lateral Sclerosis
Dimitrios Karussis, Clementine Karageorgiou, Basan Gowda-Kurkalli, Adi Vaknin-Dembinsky, John Gomori, Ibrahim Kassis, Panayiota Petrou, Jeff Bulte, Shimon Slavin

Mesenchymal stem cells (MSCs) are obtained from bone marrow and typically produce blood, fat, and bone cells. However, they can also be induced to become neural cells. They are easy to culture and expand so they are potentially good candidates for experimental stem cell therapies in MS and other neurological diseases. Dr. Karussis described a trial where MSCs were extracted from 15 people with MS and 19 people with ALS, cultured, and then injected back into the subjects' blood and/or spinal fluid. The MS subjects had an average EDSS of 6.6 and had not responded to available immunomodulatory therapies. After six months, there was a trend toward a lower EDSS in the MS subjects (from 6.6 down to 5.9). Analysis of blood samples taken 24 hours after injection showed evidence of a shift toward immune regulation in the immune cells. No unexpected MRI activity was seen within the six month post-injection period. Cells from some of the subjects had been labeled to be visible on MRI, and the investigators were able to detect these cells in the occipital horns (areas of the brain adjacent to the lateral ventricles) as well as in the spinal cord. No major safety concerns had arisen but further monitoring of these subjects for long-term safety outcomes is needed.

S21.007 Omega-3 Fatty Acids as an Adjunct Therapy for Depression in Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Pilot Trial 
Lynne Shinto, Gail Marracci, Lauren Stuber, Dennis Bourdette

A study of 39 people with MS with mild to moderate depression compared three-month courses of fish oil (a source of omega-3 fatty acids) and soybean oil (used as a placebo) to see if omega-3 could improve depression in MS. 80% of the subjects remained in the study through the 3-month visit and were screened for evidence of continued depression. No significant effect on depression was seen for the fish oil treatment -- about half of the people in both groups reported a remission of their depression. The fish oil also did not affect cytokine levels in the blood, nor did it affect clinical scores, with one exception. The fish oil group did have a greater average improvement on the PASAT test, but this group had a higher percentage of college-educated people than the placebo group, which may have biased this result. Fish oil did lead to high levels of certain fatty acids (EPA and DHA) in red blood cell membranes. No significant safety issues were reported.

S21.008 Analysis of Clinical and Radiological Disease Activity-Free Status in Patients with Relapsing Remitting Multiple Sclerosis (RRMS) Treated with Cladribine Tablets, in the Double-Blind, 96-Week CLARITY Study 
Gavin Giovannoni, Giancarlo Comi, Stuart Cook, Kottil Rammohan, Peter Rieckmann, Per Soelberg Sørensen, Patrick Vermersch, Peter Chang, Anthony Hamlett, Rehan Verjee, Bruno Musch, Steven Greenberg

This talk presented data from the CLARITY study of oral cladribine. This study has been described before at meetings and the trial results were also documented in the New England Journal of Medicine article mentioned above, but this talk focused on the number of subjects who were "disease activity-free" (a new way of measuring efficacy). Being clinically disease activity-free was defined as having no relapses and no sustained EDSS progression. Being radiologically disease activity-free was defined as having no Gd+ lesions and no new or enlarging T2 lesions. Many combinations of these outcomes were presented, with the cladribine group consistently having a higher percentage of subjects free of disease activity than the placebo group. When all clinical and radiological outcomes were included, 43% of the cladribine recipients were disease activity-free compared with 16% of the placebo subjects. Dr. Giovannoni suggested that "disease activity-free" may become the preferred outcome in future clinical trials since that is the ideal outcome. An audience member also suggested including an outcome related to atrophy for progressive forms of the disease that are not characterized by relapses.

S31 Multiple Sclerosis: Biomarkers

S31.001 Evaluation of New Immunological Targets in Neuromyelitis Optica 
Jean-Baptiste Chanson, Ilaria Paolini, Nicolas Collongues, Maria-Claudia Alcaro, Frédéric Blanc, Francesca Barbetti, Marie Fleury, Elisa Peroni, Paolo Rovero, Gabrielle Rudolf, Francesco Lolli, Elisabeth Trifilieff, Anna-Maria Papini, Jérôme de Seze

The fact that antibodies against aquaporin-4 (AQP4) have been found in the serum of people with NMO not only helps with diagnosing this disease but also gives scientists a great lead for exploring the causes of NMO and developing new treatments. However, not all people with NMO have this antibody, so some research teams are looking for additional immune targets that can be similarly leveraged. Dr. Chanson's group screened serum from NMO subjects and controls against a library of peptides from myelin and other proteins. They found antibodies to peptides from MBP, glucosylated CSF114, and unlipoylated PDH in 28-36% of the NMO samples. No patterns were seen in terms of people being antibody positive for more than one peptide, nor did presence of these antibodies correlate with severity of disease. 70% of the samples that were negative for antibodies to AQP4 were positive for at least one of these new peptides. Further work will explore whether antibodies to these peptides can be found in people with MS and other diseases, as well as how these peptides might be involved in NMO.

S31.002 Effects of Natalizumab Treatment on the Presence of JC Virus DNA in Blood or Urine in Multiple Sclerosis Patients 
Richard Rudick, Paul O’Connor, Chris Polman, Andrew Goodman, Soma Ray, Stephanie Jurgensen, Susan Goelz, Fiona Forrestal, Leonid Gorelik, Alfred Sandrock

The next two papers dealt with the issue of identifying people at risk of developing PML before or during natalizumab treatment, so that new cases of PML can be prevented. Dr. Rudick described a study that analyzed plasma samples from the STRATA clinical study for the presence of DNA from the JC virus (the cause of PML). Two assays were used -- a commercial assay (ViraCor) and a more sensitive assay developed by the NIH. Samples from 6 of 1397 subjects tested positive for the virus; 3 of these subjects had been on natalizumab and the other 3 had not. One of the natalizumab subjects developed a persistent viremia (presence of virus in the blood), and none of them developed PML. Samples were also tested from subjects who had developed PML after receiving natalizumab in a clinical trial. Not one of the 73 samples that had been collected during the trial tested positive for JC virus; however, it could be detected in samples taken after the subjects developed PML. Urine samples from the STRATA study were also tested for JCV DNA. JC virus was found in about 25% of the urine samples analyzed, but the presence of the virus in urine did not increase with longer treatment duration. Dr. Rudick concluded that monitoring JCV DNA in blood or urine using commercial assays is not helpful in assessing risk of PML.

S31.003 Evaluation of the Incidence of Anti-JCV Antibodies in a Cohort of Natalizumab-Treated MS Patients 
Leonid Gorelik, Sarah Bixler, Michaela Lerner, Ewa Wilson, Anne Cheung, Ling Ling Chen, Melissa Berman, Mary Crossman, Ken Simon, Brian Schlain, Susan Goelz, Meena Subramanyam

This study asked a similar question as the previous one, but looked for the presence of antibodies to JCV in blood samples. Out of 831 subjects in the STRATA trial, 54% were positive for antibodies to JCV, a percentage that is similar to that seen in healthy controls. Analysis of samples taken on an annual basis showed that the prevalence of anti-JCV antibodies increases by about 2% per year. Antibody prevalence was higher in people who were positive for JCV DNA in their urine; however, some subjects who were negative for JCV in urine still had had antibody reactivity. Serum samples were available for 13 people who developed PML; each of these subjects were positive for JCV antibodies several months prior to developing PML. An audience member asked whether the titers (levels) of JCV antibodies in these 13 people were seen to rise prior to PML onset -- the presenter said that this test has not been done yet.

S31.004 Anti-GAGA4 IgM Antibodies (gMS[®Dx Test) Differentiate Newly Diagnosed Relapsing -Remitting Multiple Sclerosis Patients From Other Inflammatory Demyelinating Disease Patients Within One Year from Diagnosis 
Jennifer Yarden, Hollie Schmidt, Jette Frederiksen, Hayrettin Tumani, Johannes Brettschneider, Sana Abdul, Sven Jarius, Brigitte Wildemann, Diego Franciotta, Larissa Spector, Ella Fire, Nir Dotan

I was especially interested in this talk, because samples from our repository were used in this research. A company called Glycominds is developing a diagnostic test for MS based on the presence of antibodies to the glycan molecule GAGA4. They analyzed serum samples taken from 72 people within a year of their MS diagnosis, as well as samples from 124 subjects with other inflammatory demyelinating diseases. The test they developed has a specificity of 89% (low rate of false positives) and a sensitivity of 28% (high rate of false negatives). Antibodies to other related proteins (GAGA3, P63) are also being evaluated in conjunction with anti-GAGA4 to see how their inclusion may improve the accuracy of the test.

On Wednesday evening I joined a group from Glycominds for dinner. We were all staying at the same hotel, so we got to play the "whose room is the smallest" game. :-)

Thursday 04/15:

Thursday morning started with meetings with our scientific advisor Dr. Ben Greenberg, and with Jacinta Behne, Dr. Michael Yeaman and Dr. Katja van Herle from the Guthy Jackson Charitable Foundation. This foundation was established recently to accelerate research into treatments and cures for NMO, and through their support we are enrolling people with NMO into our repository so that scientists studying this disease have a readily accessible source of samples to analyze.

MS Highlights

The next session was a review of several of the MS-related presentations and posters, picked by two MS neurologists, Mark Freedman and Lauren Krupp. Having this overview was very nice, especially since there's no way to personally see everything at this meeting. Here are some of the findings that Drs. Freedman and Krupp chose to highlight in their reviews -- I'm only including ones that I haven't covered elsewhere in these notes:

• Fingolimod traps immune cells in the lymph nodes, but leaves certain memory cells in the periphery. Johnson et al. created an experimental chamber in the lab to study response of these cells to signals, and found that they were less responsive to certain signaling molecules (CXCL12 and CCL2) which may help keep them out of the central nervous system.
• A trial of oral teriflunomide plus glatiramer acetate (Copaxone) vs. Copaxone plus placebo showed that the teriflunomide combination reduced Gd+ lesions on MRI, similar to a different trial of IFN-beta plus teriflunomide. No new safety issues were seen.
• A lab study found that factors produced by mesenchymal stem cells inhibit the proliferation of Th1 cells while increasing the frequency of Th17 T cells. These factors also inhibit IFN-gamma and IL-10 secretion while increasing IL-17a. The fact that these stem cells, which show evidence of being helpful in MS, may promote the growth and activity of inflammatory Th17 cells is something that needs to be investigated further.
• An imaging study using MRI and OCT (which measures the thickness of the retinal nerve fiber) on 104 MS subjects and 15 controls showed that the retinal nerve fiber layer thickness was correlated with the volumes of certain white and gray matter structures, including ones not related to vision. This suggests that OCT may be useful for monitoring the success of repair mechanisms.
• Using PET scanning with a marker that labels macrophages, a research team found that activated microglia were present in the cortical gray matter of both SPMS and RRMS subjects. However, microglia activation was more pronounced in SPMS compared with RRMS subjects, and was higher in SPMS subjects with greater disability. This suggests that as MS evolves, microglia take over from lymphocytes as drivers of disease activity, and that cortical activity of microglia may play an important role of progression of disability.
• Dr. Claudia Luchinetti and her collaborators have continued their extensive study of brain tissue samples, analyzing nearly 2500 plaques from 143 MS autopsies. They classify plaques into four categories: active, smoldering, inactive and shadow (showing evidence of myelin regeneration). Active plaques tend to predominate in acute or relapsing MS, with the four immunological patterns this group previously identified seen among patients (all active plaques in a patient fit a single pattern). Smoldering plaques tend to predominate in chronic progressive MS and are similar across all the subjects in terms of their immune profile.
• An investigation of sleep disorders in people with MS found that 49/66 suffered from various disorders (restless leg syndrome, breathing problems, insomnia). These disorders were highly prevalent in people with MS who were suffering from fatigue (25/26) but were also common in those without fatigue (24/40). These results suggest that the presence of sleep disorders should be checked (and treated if possible) in anyone with MS who is battling fatigue.
• Another fatigue-related study by Calabrese et al. using MRI found lower volumes in certain brain structures (the striatal-thalamic-front cortex system) in MS subjects with fatigue. This suggests that there is a cognitive component of fatigue associated with the posterior parietal cortex, perhaps involving the posterior attention system. Similarly, Riccitelli et al. found loss of gray matter in frontal lobe regions participating in the sensorimotor network in subjects with fatigue.
• A drug called donepezil (trade name Aricept) is marketed to improve memory function in people with Alzheimer's disease. A multicenter trial (randomized and placebo-controlled) was conducted to see if this drug could similarly help with memory impairment in people with MS. Unfortunately, the study produced negative results -- no significant improvements were seen in memory, attention, fluency, or visual or spatial processing. Dr. Krupp said that the drug might still be helpful in patients with clear-cut signs of dementia, however.
• Plasma exchange therapy is sometimes used when severe attacks don't respond to steroid treatment. A study to determine how long plasma exchange can be delayed found that it can still be effective at least six months after the onset of the relapse.
• A study by Okuda, et al, found that in people with radiologically isolated syndromes (evidence of lesions on MRI without clinical symptoms), the presence of spinal cord lesions was highly predictive for later developing an MS symptom, independent of the presence of brain lesions. Another study reported the outcome of people with a clinically isolated syndrome (CIS) after following them for a number of years. Of 105 people with a CIS followed for 6 years, 51% had developed another MS symptom during that time and were diagnosed with MS, 15% had been diagnosed with MS based on MRI evidence of new lesions, and 33% were still at CIS status. Of those followed for 20 years, 61% had been diagnosed with MS based on new symptoms, 11% had been diagnosed with MS based on MRI, and 27% still had only a CIS.
• Blood samples from pediatric patients with a single MS-like symptom were analyzed to find predictors of recurrent disease. Lower levels of E-selectin, P-selectin, and osteopontin were detected in those patients who went on to develop additional symptoms.
• Another pediatric study found that low serum vitamin D levels were strong predictors of relapse in kids with MS or CIS. Each 10 ng/ml increment in vitamin D level was associated with a 34% lower rate of relapse. It's not yet clear whether vitamin D itself helps prevent relapse or whether vitamin D is related to relapse risk through another factor. Clinical trials are needed to resolve this question.
• Dr. Krupp also remarked on the CCSVI results prevented at the meeting. She noted that the Buffalo results show a less strong association with MS than the original results from Italy. Nobody yet knows what the association means, and treating CCSVI is still premature. The study of decreased venous volume in people with MS is somewhat contradictive to the CCSVI hypothesis, since if veins are occluded, one might expect to find congestion and therefore higher venous volume.

After this session, I met with Dr. Steve Bushnell who works on biomarker research at Biogen.

S41 Multiple Sclerosis: Clinical Immunology

S41.004 Novel Neuroprotective Outcomes of Vitamin D in Models of Multiple Sclerosis 
Scott Sloka, Claudia Silva, Janet Wang, Yan Fan, Luanne Metz, Peter Stys, Wee Yong

Vitamin D, which may help reduce risk of MS, is known to play a role in the immune system, but a team of researchers wanted to know how the nutrient might also affect the nervous system. When they created a cell culture with human neurons and T cells, they saw that the T cells damaged the axons, but the damage was reduced when the T cells had been pre-treated with vitamin D. Vitamin D pre-treatment also had the effect of reducing the degree of interaction between T cells and neurons, as well as reducing the expression of adhesion molecules by T cells. Culturing neurons with vitamin D helped protect them against neurotoxicity from hydrogen peroxide exposure. These neurons also had a greater degree of branching and higher production of growth factors. The team also administered vitamin D to mice with EAE at the peak of their disease. Vitamin D reduced the severity of the disease; in addition, tissue analysis showed that axonal counts were higher in treated mice than in non-treated mice.

S41.005 Effect of Laquinimod on Monocyte Subsets
Tal Birnberg, Steffen Jung

Laquinimod is an immunomodulatory drug that appears to prevent immune cells from entering the central nervous system. This study examined laquinimod's effects on the immune cell repertoire in mice. The drug reduced the number of CD4+ dendritic cells in healthy mice and in mice with EAE; normally, mice with EAE have greater numbers of CD4+ dendritic cells. A shift was also seen in the types of monocytes in circulation: after laquinimod treatment, there was a shift to cells expressing a molecule called Ly6C. The presenter concluded that laquinimod either blocks Ly6C+ cells from entering the central nervous system, thereby keeping them in the bloodstream, or that it shifts the immune system towards producing more Ly6C+ cells.

S51: Multiple Sclerosis Clinical Research II

S51.001 Multiple Sclerosis: Quality of Life and Perceived Deficit-Relationship to Cognition in a Community-Based Study 
Mark Gudesblatt, Myassar Zarif, Barbara Bumstead, Max Gutman, Lori Fafard, Laura Graffitti, Carol Seidel, Lourdes Cruz, Serina Fahie, Joan Bohuslaw, Chris Burke, Jocelyn Caputo, Susan Riley, Ely Simon, Glen Doniger

A community neurological practice tested 352 MS patients using a computerized cognitive testing program called NeuroTrax Mindstreams to look for links between quality of life and cognition in people with MS. Dr. Gudesblatt pointed out that these are important aspects of health that are not well captured by standard MS measures such as EDSS, MRIs, and relapse rates. The team found many types of connections between cognitive impairment and reduced quality of life. The strongest relationship was with information processing. The team also assessed the accuracy of the subjects' perceptions of their own cognitive functioning and found that the match between perceived and actual deficits was not very good. However, the clinicians' perceptions of their patients' deficits were more accurate, especially in the area of speed of response. An audience member also pointed out that spouses/significant others also give better estimates than people with MS.

S51.002 Multiple Sclerosis: Fatigue and Depression: Effects on Cognition in a Community-Based Study 
Mark Gudesblatt, Myassar Zarif, Barbara Bumstead, Max Gutman, Lori Fafard, Laura Graffitti, Carol Seidel, Lourdes Cruz, Serina Fahie, Joan Bohuslaw, Chris Burke, Jocelyn Caputo, Susan Riley, Ely Simon, Glen Doniger

The same team as in the previous study also examined the link between fatigue and cognition. They found that executive function, attention, and motor skills were all inversely associated with fatigue. Depression was also inversely associated with executive function, although only when comparing severe vs. moderate depression.

S51.003 CSF Identification of Novel Initiating Targets and Putative Prognostic Markers of Multiple Sclerosis in Pediatric-Onset CNS Demyelination 
Ajit Singh Dhaunchak, Brenda Banwell, Douglas Arnold, Dessa Sadovnick, Christopher Becker, Howard Schulman, David Colman, Amit Bar-Or

A research team used a technique called mass spectrometry to analyze the proteins present in the cerebrospinal fluid (CSF) of 19 children with an initial MS-like symptom. They followed the children for an average of 2.7 years, during which 8 had new relapses and were diagnosed with MS. Out of 16,190 peptides found in the CSF samples, 561 or 3% significantly differed between the children who developed MS and those who did not. These proteins included some that play a role in the connection between axons and glial cells. However, proteins found in compact myelin were not represented. The researchers speculate that the nodes of Ranvier may be an important early target site for immune activity in pediatric acute demyelination.

S51.004 The Self IgG Repertoire Directed Against CNS Antigens Discriminates NMO From MS and Healthy Subjects
Hélíne Zéphir, Didier Lefranc, Nicolas Collongues, Frédéric Blanc, Patricia Dussart, Sylvain Dubucquoi, Marie Fleury, F. Viallet, Alain Créange, Jean-François Pélissier, Lionel Prin, Jérôme de Síze, Patrick Vermersch

Serum from 50 people with NMO, 36 people with MS, and 17 healthy controls were tested using a substrate of CNS proteins to find antigens that are targeted by antibodies in NMO and MS. 27 bands representing antigens from the brain, spinal cord, and optic nerve were found to discriminate between the two diseases with 99% accuracy. The team's next step is to identify the antigenic targets in these bands using mass spectroscopy. An audience member recommended validating this test with a different set of samples to make sure that this set of antigens wasn't specific just to this set of serum samples.

That was it for the conference! I had a little time left before my flight, so I went up the elevator in the CN Tower (the third tallest freestanding building in the world) and very bravely stood on the glass floor through which you can see all the way down to Rogers Centre stadium where the Toronto Blue Jays play.