News for the Multiple Sclerosis Community

Art and Hollie's Notes From The 2009 AAN Meeting In Seattle

Art and Hollie's Notes From The 2009 AAN Meeting In Seattle

American Academy of Neurology meeting 4/27/09 - 5/1/09 Seattle, WA

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. 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/aan2009seattle/

continued...

We have noted the talks we especially liked or thought were important. You can search for "Art Pick" or "Hollie Pick" to find them.


Mon 04/27:

We left Boston Monday afternoon and shortly after take off our flight was diverted to Syracuse to land for a medical emergency with one of the passengers. We didn't really get many details (rumors of a pulmonary embolism), but the defibrillator, oxygen, and saline bags were broken out. Luckily we were on our way to a medical conference and 3 doctors were on board as well as a number of nurses. As far as we know, the guy was taken off the plane alive and with a good prognosis.

After a 2.5 hour long "5 minute check", we returned to the air and managed to check in to our hotel around 4am Boston time.


Tue 04/28:

We got up early and had breakfast with Nikki Levy, Pathik Patel, and Robert Paul from Genentech. We discussed supporting/using our repository with them.

S01: Multiple Sclerosis: Epidemiology/Clinical Outcomes/Biomarkers (Art)

[S01.001] Early and Late Smoking as Independent Risk Factors for Multiple Sclerosis: A Case-Control Study
Joseph Finkelstein, Eunme Cha, Baltimore, MD, Mitchell T. Wallin, Washington, DC, Walter Royal, Christopher T. Bever, Baltimore, MD.

Using data from the National Health Interview Survey (annual survey done by the NCH and CDC) taken in 2002 when they asked about MS diagnosis and age of smoking initiation, these researchers found 87 people with MS (49 smokers) and 30,000 controls to compare the risk of MS and smoking.

Unlike other studies, they looked at people who started smoking early separate from those who started smoking later. They found that almost all of the MS risk increase found in other studies could be explained by people who started smoking early with almost no risk increase in those who started to smoke later. They did not see a similar difference when looking at diseases like cancer and COPD.

While the control arm was large enough to give statistical significance to the results, it is still a very small case population (smokers with MS).

[S01.002] Cognitive and Psychosocial Features of Childhood and Juvenile Multiple Sclerosis: A Reappraisal after 2 Years
Maria Amato, Benedetta Goretti, Florence, Italy, Angelo Ghezzi, Arconata, Italy, Silvia Lori, Besto Fiorentino, Italy, Valentina Zipoli, Firenze, Italy, Emilio Portaccio, Florence, Italy, Lucia Moiola, Milano, Italy, Monica Falautano, Milan, Italy, Maria De Caro, Mariangela Lopez, Bari, Italy, Francesco Patti, Rosario Vecchio, Catania, Italy, Carlo Pozzilli, Rome, Italy, Valentina Bianchi, Roma, Italy, Marco Roscio, Gallarate, VA, Italy, Giancarlo Comi, Milan, Italy, Maria Trojano, Bari, Italy.

In a previous study of pediatric MS, they found that 31% of 63 MS cases had cognitive impairment compared to healthy controls of a similar age. This study was a reassessment after 2 years (56 of original cases still available). They looked at things like memory, executive functioning, attention, etc.

After 2 years 70% showed cognitive impairment and 75% showed signs of deterioration. It would seem that a destructive brain disease in your developmental years is not a good thing.

[S01.003] Pediatric MS before Puberty: A Distinct CSF Inflammatory Profile
Dorothee Chabas, San Francisco, CA, Jayne Ness, Birmingham, AL, Eluen Yeh, Buffalo, NY, Nancy Kuntz, Rochester, MN, Ivan De Kouchkovsky, Jonathan Strober, San Francisco, CA, Bianca Weinstock-Guttman, Buffalo, NY, Moses Rodriguez, Rochester, MN, Emmanuelle Waubant, NMSS Network of Pediatric MS Centers of Excellence, San Francisco, CA.

This study looked at oligoclonal bands (OCB) and other immunological markers in CSF in early onset MS and found that there were distinct markers in those under 11 years vs those over. The study was small and the age of 11 fairly arbitrary, so they have a bit more work to do until these markers are clinically relevant.

[S01.004] Serum N-Acetyl-Aspartate (NAA) Levels Differ in Neuromyelitis Optica (NMO) and Multiple Sclerosis (MS)
Carla Tortorella, Maddalena Ruggieri, Rosaria Leante, Bari, Italy, Ceci Edmondo, Acquaviva delle Fonti, Italy, Elisabetta Di Monte, Bari, Italy, Maria Amato, Florence, Italy, Angelo Ghezzi, Arconata, Italy, Alessandra Lugaresi, Milan, Italy, Francesco Patti, Catania, Italy, Patrizia Sola, Milan, Italy, Giovanni Bosco Zimatore, Pietro Iaffaldano, Vita Direnzo, Paolo Livrea, Maria Trojano, Bari, Italy.

Using MRS (similar to MRI) it is possible to see that people with MS have less NAA in their brains than controls. Looking at the levels of NAA in serum and CSF in people with MS, NMO, CIS, and healthy controls (serum only) found that people with MS/CIS have higher levels of NAA and no difference between NMO and controls. Similar results were found in CSF. The serum level correlated with CSF levels, so it may be possible to use this as part of a blood test to diagnose MS/NMO.

[S01.005] Retinal Nerve Fiber Layer Thinning after Acute Optic Neuritis: Importance of 1 Month Findings
Mark J. Kupersmith, Gary Mandel, New York City, NY, Susan Anderson, Randy Kardon, Iowa City, IA.

[S01.006] Exclusive Breastfeeding and the Risk of Postpartum Relapses in Women with Multiple Sclerosis
Annette Langer-Gould, Stella M. Huang, Stanford, CA, Amethyst D. Leimpeter, Kathleen B. Albers, Stephen K. Van Den Eeden, Oakland, CA, Lorene M. Nelson, Stanford, CA.

These last two sessions were missed so we could meet with Irene Hunt and Peg McCormick of Novartis to talk to them about supporting/using the repository.

S06: Multiple Sclerosis: Immunology I (Hollie)

[S06.001] Interferon-beta Treatment Increases FoxP3 Expression and CD56bright Natural Killer Cells in Subjects with Multiple Sclerosis
Arthur A. Vandenbark, Jianya Huan, Marissa Agotsch, Dorian LaTocha, Susan Goelz, Halina Offner, Stefan Lanker, Dennis Bourdette, Portland, OR.

Interferon-beta decreases relapse rate in some people with MS, but little is known about how/why it works (its "mechanism of action"). This study looked at populations of different kinds of immune cells in 11 people with MS on IFN-b, 9 untreated people with MS, and some controls. Evaluating blood samples at different time points (3, 6, and 12 months) revealed an increase in the number of CD56-bright NK cells and CD4+CD25+FoxP3+ regulatory T cells in the treated MS subjects. The study was too small to determine whether increases in these cell populations had anything to do with any effect on relapses in the treated group.

[S06.002] Interferon Beta (IFNB)-1b Changes B-Cell Cytokine Secretion Profile and Inhibits Th17 Cell Differentiation
Vinod S. Ramgolam, Danielle Speer, Neelima Choudhary, Silva Markovic-Plese, Chapel Hill, NC.

Another approach to the same question (why/how does IFN-b work?) looked at the evolution of CD45RA+ T cells into Th17 cells (which are thought to be pro-inflammatory and bad news for people with MS). The team found that IFN-b modulated the secretion of factors by dendritic and B cells that induce T cells to go down the Th17 path. IFN-b also is capable of affecting this transition directly.

[S06.003] Role of the Renin-Angiotensin System in Autoimmune Inflammation of the CNS: Targeting the Angiotensin II Receptor as a New Therapeutic Option in Multiple Sclerosis?
De-Hyung Lee, Bochum, Germany, Johannes Stegbauer, Dusseldorf, Germany, Silvia Seubert, Gisa Ellrichmann, Stefanie Gaupp, Bochum, Germany, Christian Rump, Dusseldorf, Germany, Ralf Gold, Ralf Linker, Bochum, Germany.

The renin-angiotensin system in the body is involved in functions such as blood pressure, artherosclerosis, and inflammation. Drugs have been developed that interfere with this system and they are in use by millions of people (aliskerin, losartan). Administering these drugs to animals with EAE resulted in milder disease. The effect did not seem to be related to lowering blood pressure, since another antihypertensive drug had no effect on EAE. Instead, it may have been due to effects on inflammation, since losartan altered the animals' populations of monocytes and dendritic cells, and also affected the expression of various chemokines. The authors propose studying these drugs in MS since they are already on the market and well-tolerated. (Maybe someone could first mine those huge insurance databases to see if people with MS who are on these drugs wind up needing steroids for relapses less often.)

[S06.004] Atacicept Inhibits Disease Activity in a Murine Model of Experimental Autoimmune Encephalomyelitis
Katherine Lewis, Pallavur Sivakumar, Shannon Okada, Kristen Bontadelli, Mark Maurer, Hongping Ren, Kimberly Waggie, Jane Gross, Seattle, WA, Paola Zaratin, Colleretto Giacosa (TO), Italy, Stacey Dillon, Seattle, WA.

The drug Atacicept is already in phase 2 MS trials but in case anyone was wondering whether that is a good idea, this study showed that the drug delayed onset and reduced severity in EAE. It also prevented the deposition of IgG and IgM antibodies and reduced inflammation in the central nervous system. Atacicept affects mature and antibody-producing B cells but spares immature B cells, so it doesn't wipe these cells out altogether. By the way, the drug's name is pronounced "a-tacky-cept" -- not "a-tassy-cept" as I originally thought.

[S06.005] Toll-Like Receptor 7/8 Dysfunction in Patients with Multiple Sclerosis on Natalizumab
Nicoline Schiess, Tory Johnson, Peter Calabresi, Avindra Nath, Baltimore, MD.

I had to miss this in order to meet with our Novartis friends, but according to the abstract, the upshot was that people with MS on natalizumab may be more susceptible to herpes reactivation due to the drug's effects on a certain immunological pathway (TLR7/8 signaling).

[S06.006] CD25, a Molecule Linked to MS Susceptibility, Has Important Effects in Initiation and Termination of T Cell Responses in Humans
Jehad Edwan, Jayne Martin, Justin Perry, Bibiana Bielekova, Bethesda, MD.

I had to miss this one too, but the abstract indicated that it had to do with attempts to understand the roles played by the CD25 molecule (part of the IL2 receptor on immune cells) in the immune system.

S11: Multiple Sclerosis: Clinical Therapeutics and Interventions (Art)

[S11.001] VLA-4 Antisense An Oligonucleotide Targeting VLA-4 mRNA (ATL1102) Significantly Reduces New Active Lesions in Patients with RR-MS
Volker Limmroth, Cologne, Germany, Frederik Barkhof, Amsterdam, The Netherlands, Nuket Desem, Melbourne, VIC, Australia.

Missed this session due to Novartis meeting, but title seems to say what's important.

[S11.002] Randomized Double-Blind Placebo-Controlled Trial of Memantine 10 mg Twice a Day for Three Months as a Treatment for Cognitive Impairment in Multiple Sclerosis
Jesus F. Lovera, New Orleans, LA, Elliot Frohman, Dallas, TX, Theodore Brown, Kirkland, WA, Daniel Bandari, Los Angeles, CA, Ruth Whitham, Katherine Wild, Dennis Bourdette, Portland, OR.

Memantine is an Alzheimer's drug. I won't bore you with the details on this as the results were that it did not appear to be effective in MS for any cognitive outcomes, and may actually make things worse based on the subjective measures from the feedback of participants and their caregivers.

[S11.003] Deep Brain Stimulation of the Caudal Zona Incerta for Tremor in Multiple Sclerosis
Jacqueline T. Bernard, Theresa E. Pretto, Richard D. Penn, Chicago, IL.

Deep brain stimulation (DBS) is when they insert a probe into your brain using stereotactic MRI and attach it to a pacemaker-like device embedded near your shoulder that you can activate with a magnet.

In this study they used it to treat tremor in MS with some pretty good results. They showed video with stimulator on and off and a woman who could not even grab a cup was able to do so with the stimulator turned on. Very small number of subjects so far, but they are hoping to do a bigger trial.

[S11.004] Effect of Natalizumab Switch in Suboptimal-Responders to First-Line Disease Modifying Therapy
Tamara Castillo-Trivino, Elizabeth Crabtree-Hartman, Bruce Cree, Douglas Goodin, Ari Green, Stephen Hauser, Ellen Mowry, San Francisco, CA, Darin Okuda, El Granada, CA, Daniel Pelletier, Scott Zamvil, Emmanuelle Waubant, San Francisco, CA.

UCSF took a bunch of patients who had breakthrough disase on a first-line therapy and offered them Tysabri. They put people in 3 groups: 1) those who agreed to switch 2) those who refused 3) those who chose to go on immunosuppressants instead.

Those who switched saw a 63% reduction in relapse rate, those who refused saw an 18% reduction (although this was not statistically significant), and those on immunosuppressants saw an 88% reduction.

It was a small study and they tried to spin it as switching to Tysabri or immunosuppressants was a good thing rather than switching to immunosuppressants was better than switching to Tysabri. It seemed fairly impressive until one audience member asked the presenter's opinion on how every study of switching (including one that the audience member had done) showed that switching was always better - the presenter was at a loss to explain.

[S11.005] Natalizumab in Patients with Relapsing Multiple Sclerosis: Updated Utilization and Safety Results Including TOUCH and TYGRIS
Carmen Bozic, Glyn Belcher, Richard Kim, Wellesley, MA, Robert Hyde, Zug, Switzerland, Frances Lynn, Mariska Kooijmans-Coutinho, Michael Panzara, Wellesley, MA.

*** Art Pick

This was a presentation of data from Biogen (by Biogen) on the latest Tysabri safety data.

Current Tysabri usage:

  • 52K people on Tysabri (27.7K in the US)
  • 25K on Tysabri >= 12 months
  • 14.4K >= 18 mos
  • 6.8K >= 24 mos
There have been 6 reported PML cases post-marketing (since drug trials concluded). 5 in the EU, 1 in the US. These people had been on Tysabri between 12 and 31 months. The rate of PML was 1 in 1000 in the trial, post-marketing it is 1.2 in 10,000.

Of the 6 cases, there has been only one fatality. They have treated the PML with plasma exchange and immunoabsorption to remove the Tysabri from the blood stream and with mefloquine to attack the JC Virus responsible for the PML.

The TYGRIS observational study monitoring adverse events has 5111 patients enrolled and there has been a 4% rate of Serious Adverse Events with a profile no different than that seen in the original trials.

One member of the audience (not me) asked how they could hear about new cases other than from the WSJ and pharma reps (usually from Biogen's competitors). The presenter was unaware that they have a weekly posting on their web site and suggesting contacting the Medical Affairs office. Biogen really needs to get on top of this and stop being so lame about making this info available.

S17: Multiple Sclerosis: Genetics/Pathology (Hollie)

[S17.001] Two Different Arg19 Mutations in the N-terminus of Aquaporin-4 Suggest a Molecular Mechanism for Susceptibility to Neuromyelitis Optica
Marcelo Matiello, Janet Schaefer-Klein, David Hebrink, Rochester, MN, Daniel Kingsbury, Portland, OR, Vanda Lennon, Brian Weinshenker, Rochester, MN.

This was a study that we supported by providing NMO DNA samples from our repository so I was very excited to see it on the agenda. I came in late due to our previous meeting, but arrived in time to see "Accelerated Cure Project" listed along with the other sample providers. Yippee! This research team analyzed the gene encoding the protein (AQP4) that appears to be targeted by antibodies in NMO. They did find some mutations in people with NMO but not controls which might have played a role in making them susceptible to this disease.

[S17.002] Long Term Isolated Optic Neuritis and Benign Multiple Sclerosis Carry Alleles Protecting from Malignant Progression
Gabriele C. De Luca, Rochester, MN, Sreeram V. Ramagopalan, Katie Morrison, Lahiru Handunnetthi, Michael Chao, Sarah M. Orton, Matthew R. Lincoln, David A. Dyment, Oxford, United Kingdom, Dessa Sadovnick, Vancouver, BC, Canada, George Ebers, Oxford, United Kingdom, Jette Frederiksen, Glostrup, Copenhagen, Denmark.

*** Hollie Pick

This team was curious whether genetic factors influence whether someone susceptible to demyelination has a one-time event, or goes on to develop a "benign" version of MS, or perhaps goes on to develop a severe ("malignant") form of MS. They analyzed genetic variants in subjects with an isolated optic neuritis (ION) episode (who had been followed for many years to make sure no other symptoms occurred), subjects with benign or malignant MS as determined by EDSS scores over time, and controls. The presence of HLA DRB1*1501 was similar in the MS and ION subjects, and higher than in controls as expected. However, people with malignant MS were more likely to have two copies of *1501 than those with benign MS or ION. They also looked at some non-HLA genes that turned out to have similar frequencies in the ION and MS subjects (IL7R, IL2RA, CLEC16A, CD58, and EVI5). However, one variant of KIF1B differed significantly between malignant MS and ION.

It may be that ION is an incomplete version ("forme fruste") of MS, never reaching the stage of a second episode, and that ION and MS have a similar genetic background with other genes influencing how far and how fast the disease develops. The team is now going to continue their analysis, classifying subjects in terms of their MRIs in addition to EDSS.

[S17.003] HLA-DRB1*0401 and HLA-DRB1*0408 Are Strongly Associated with the Development of Antibodies Against Interferon-beta Therapy in Multiple Sclerosis
Sabine Cepok, Munchen, Germany, Steve Hoffmann, Leipzig, Germany, Verena Grummel, Klaus Lehmann-Horn, Munchen, Germany, Joerg Hackermueller, Peter F. Stadler, Leipzig, Germany, Hans-Peter Hartung, Dusseldorf, Germany, Achim Berthele, Munchen, Germany, Florian Deisenhammer, Innsbruck, Tirol, Austria, Ralf Wasmuth, Leipzig, Germany, Bernhard Hemmer, Munchen, Germany.

Some people with MS who go on IFN-beta develop antibodies to the drug and why this happens is not known (how/whether these antibodies have any effect on efficacy is another question). This group analyzed HLA genes in MS subjects with and without these antibodies. They found that some genes (DRB1*0401, *0408, and *1601) were associated with having antibodies, and some (DRB1*0404, *1101, and *1104) were associated with not having them. These variants may influence antibody production by affecting how protein fragments are processed and presented to B cells.

[S17.004] Axonal Loss in Primary Progressive MS is Less Dependent on Demyelination than in Secondary Progressive MS
Emma C. Tallantyre, Nottingham, United Kingdom, Lars Boe, Bergen, Norway, Lowe James, Nikos Evangelou, Nottingham, United Kingdom.

The questions examined here were whether axonal loss correlates with disability, and are there different patterns of axonal loss in PPMS and SPMS. Cervical spinal cord autopsy sections from 17 PPMS subjects, 30 SPMS subjects, and 7 controls were stained for myelin and neurofilament (a protein in axons). The extent of demyelination was higher in both white matter and gray matter in SPMS subjects compared with PPMS. Most lesions in both groups were classifed as "chronic inactive." SPMS and PPMS subjects had similar amounts of axonal loss overall, which correlated with EDSS scores immediately before death. However, in lesions, axonal loss was higher in PPMS than in SPMS. So while there were fewer plaques in the PPMS samples, those plaques had higher levels of axonal loss. The research team will be doing a similar analysis lower down the spine in the lumbar region to see if the same pattern exists there.

[S17.005] Increased Inflammation in Diffusely Injured White Matter and in Remyelinated Plaques Correlates with Active Demyelination in Progressive Multiple Sclerosis
Stephan Bramow, Copenhagen, Denmark, Josa M. Frischer, Vienna, Austria, Per S. Sorensen, Copenhagen, Denmark, Hans Lassmann, Vienna, Austria, Henning Laursen, Copenhagen, Denmark.

This study also compared SPMS and PPMS samples, taken from the brain (except the cortex) and the spinal cord. The team calculated the size of areas featuring different types of pathology/activity (such as diffuse white matter injury and remyelination). The SPMS brain samples had great total plaque area, and more areas with active demyelination than the PPMS samples. The PPMS samples contained more areas with remyelination. Diffuse perivascular inflammation correlated with the percentage of area that had active demyelination. Inflammatory demyelination was negatively correlated with remyelination. Based on these findings, the team hypothesizes that persistent inflammation may interfere with remyelination attempts.

Evening Activities
For dinner we went out with Peter Riskind and Carolina Ionete (UMass) and Jen (Brigham & Women's). We had a great time despite the efforts of our snooty waiter to make us feel inferior.


Wed 04/29:

We stopped by the plenary session to catch our friend Alberto Ascherio's talk on Vitamin D and MS - it was a good review of where our understanding is these days. All of which we've covered previously at MSNews.

Hollie had lunch with the vivacious Paula Lazzeri, treasurer of the Transverse Myelitis Association.

S21: Multiple Sclerosis: Clinical Trials (Art & Hollie)

Presentation of the John Dystel Prize for Multiple Sclerosis Research

The prize was awarded to David Miller from the UK for his work on imaging in MS. He gave a talk about imaging in MRI, where we are (useful for diagnosis and treatment effect) and where we're going (high field strength).

[S21.003] Efficacy and Safety of Rituximab in Patients with Primary Progressive Multiple Sclerosis (PPMS): Results of a Randomized Double-Blind Placebo-Controlled Multicenter Trial
Kathleen Hawker, West Chester, OH, Paul O'Connor, Toronto, ON, Canada, Mark Freedman, Ottawa, ON, Canada, Peter Calabresi, Baltimore, MD, Jack Antel, Westmount, QC, Canada, Jack Simon, Wilsonville, OR, Stephen Hauser, Emmanuelle Waubant, San Francisco, CA, Timothy Vollmer, Aurora, CO, Hillel Panitch, Burlington, VT, Zhang Jiameng, Peter Chin, Craig H. Smith, South San Francisco, CA.

*** Hollie Pick

Rituximab is a monoclonal antibody (mAb) that depletes CD20+ B-cells. Its efficacy has been shown in RRMS, so this study looked at what it does in PPMS (for which there are no treatments).

This trial had 439 subjects with 292 on drug and 147 on placebo. 85% of the participants completed the trial which went on for 96 weeks and involved 4 infusions. They tracked lesion load, brain volume, and time to confirmed progression.

Serious Adverse Events (SAEs) that appeared drug related were largely infusion reactions and infections.

Overall, there was a slight, but not statistically significant, time to progression benefit, a reduction in T2 lesions, and no difference in brain volume change. So basically the drug did not seem to help when the entire group was examined.

However, in people less than 50 years old who had enhancing lesions, those who were on rituximab had a much lower risk of progression than those on placebo (24% vs. 51%). Interestingly, analyzing based on disease duration instead of age did not show the same difference between drug and placebo. So there may be hope for treating PPMS, at least in younger people with enhancing lesions.

[S21.004] Oral Fingolimod (FTY720) Versus Interferon Beta-1a in RelapsingRemitting Multiple Sclerosis: Results from a Phase III Study (TRANSFORMS)
Jeffrey Cohen, Cleveland, OH, Jean Pelletier, Marseille, France, Ludwig Kappos, Basel, Switzerland, Xavier Montalban, Barcelona, Spain, Hans-Peter Hartung, Dusseldorf, Germany, Giancarlo Comi, Milan, Italy, Bhupendra O. Khatri, Milwaukee, WI, Frederik Barkhof, Amsterdam, The Netherlands, Tracy Stites, James Jin, East Hanover, NJ, Stacy Wu, Basel, Switzerland, Shreeram Aradhye, East Hanover, NJ, TRANSFORMS Study Group.

*** Art Pick

This trial compared fingolimod (FTY720) from Novartis to Avonex from Biogen Idec. This study involved 1292 subjects at 172 centers in 18 countries and looked at annualized relapse rate (ARR) over 12 months in people who took .5mg/day FTY vs 1.25mg/day FTY vs 1/wk Avonex.

The .5mg group saw a 52% reduction in ARR vs Avonex and the 1.25mg group saw a 38% reduction vs Avonex. 80% of FTY subjects were relapse free at the end of a year vs 60% on Avonex. They also saw fewer new or enlarged lesions in the FTY group vs Avonex. A nonsignificant trend toward lower progression was also seen in the FTY group.

SAE levels were notably higher in the 1.25mg FTY group, including 2 herpesvirus infection related deaths, and more people in the high-dose group dropped out. The cancer rate in the FTY groups was also notably higher, although the absolute numbers were still low. This is probably what people will be watching as more people get FTY.

One audience member noted that the trial had been open to people who had been on an MS treatment in the past, and that some of these had been on Avonex. He asked what percentage of subjects in this trial had developed neutralizing antibodies to Avonex. The presenter didn't know, nor did he know how many subjects had had disease activity while on Avonex. It seems like an important topic to know something about, because if your control arm includes people who previously didn't do well on the control drug, that's going to bias the results of the trial in favor of the study drug and isn't a fair test.

[S21.005] The CombiRx Cohort at Baseline with Clinical and MRI Differences by Diagnostic Criteria
Fred Lublin, New York, NY, Stacey S. Cofield, Gary R. Cutter, Birmingham, AL, Robin Conwit, Lutherville, MD, Ponnada Narayana, Flavia Nelson, Jerry Wolinsky, Houston, TX.

This presentation provided only status and no conclusions on the CombiRx trial comparing Glatiramir Acetate (GA) + Interferon (IFN) vs GA alone vs IFN alone. They are currently fully enrolled with 1008 subjects and are scheduled to be complete in 2012.

[S21.006] A Single Center, Randomized, Double-Blinded, Placebo-Controlled Crossover Pilot Study of the Effects of American Ginseng on Multiple Sclerosis Fatigue
Edward Kim, Portland, OR, Jesus Lovera, Metairie, LA, Laura Schaben, Bend, OR, Dennis Bourdette, Ruth Whitham, Portland, OR.

This study looked at the affect of Ginseng (100-400mg/day) for 6 weeks on MS fatigue. They saw no positive effect, but they tried really hard to squeeze something positive out of the data proving that if you torture data hard enough it will confess to anything. They also used their time to provide a little advertisement for (an admittedly interesting) data collection device they invented.

S31: Multiple Sclerosis: Imaging I (Hollie)

[S31.001] 7-Tesla MRI Improves the Detection of Cortical Lesions in Multiple Sclerosis
Emma C. Tallantyre, Paul S. Morgan, Jennifer E. Dixon, Ali Al-Radaideh, Matthew J. Brookes, Nikos Evangelou, Peter G. Morris, Nottingham, United Kingdom.

This study compared three imaging modes (3T Flair, 3T DIR, and 7T MP-RAGE) and found the 7T method was best at establishing the location of lesions with relation to the cortex, but only by a bit. A combination of DIR and 7T may be the best approach.

[S31.002] In Vivo Evidence of Glutamate Toxicity in MS: A Longitudinal Spectroscopy Study
Daniel Pelletier, John Kornak, Bill Chu, San Francisco, CA, Darin T. Okuda, El Granada, CA, Sarah J. Nelson, Radhika Srinivasan, San Francisco, CA.

MR spectroscopy is a form of imaging that can detect levels of certain molecules in tissues, for example glutamate in brain tissue as a marker of MS activity. This technique was used in 332 MS subjects followed over time, as well as 45 controls. A significant increase was seen in the glutamate concentration in white matter in MS subjects vs. controls, while levels in the gray matter were similar in the MS vs. control groups. However, in MS subjects, higher glutamate levels measured at study entry predicted loss of NAA (an axonal molecule) in gray matter over two years. Loss of NAA in gray matter predicted loss of brain volume over three years. These effects were not seen in white matter, however.

[S31.003] A Novel MRI Sequence, the Fast Gray Matter Acquisition T1 Inversion Recovery (FGATIR), Is Superior to Fluid Attenuated Inversion Recovery (FLAIR) for the Resolution of White Matter Lesions (WMLs)
Ihtsham Haq, Atchar Sudhyadhom, Nelson Hwynn, Frank J. Bova, Kelly Foote, Michael Okun, Gainesville, FL.

A research group that doesn't normally work on MS came up with a new MRI technique that appears to be better than the standard method at detecting white matter lesions. In a test of three people with MS, the new method was better able to distinguish separate lesions near each other that the standard method would blur together -- resulting in a higher lesion count. It also provides sharper contrast.

[S31.004] Brain Atrophy Predicts Disability Progression in Multiple Sclerosis
Elizabeth Fisher, Jar-Chi Lee, Richard A. Rudick, Cleveland, OH.

In this study, 63 MS subjects were followed prospectively for an average of 6.6 years, evaluated with MRIs once or twice a year and also evaluated for progression using the MSFC and EDSS scales. The researchers analyzed the early MRI results to see if any were good predictors of later progression. They found that none of the MRI measurements predicted progression using the EDSS. However, several were predictive of progression using the MSFC scale. The best predictors were baseline white matter fraction and year-to-year gray matter atrophy.

[S31.005] Flattening of Cerebral Cortex in Multiple Sclerosis: Potential Marker of Early White Matter Injury
Martin Kavec, Danielle Balriaux, Mathieu Vokaer, Brussels, Belgium.

This was an interesting presentation that examined a different aspect of brain anatomy than the usual lesion and atrophy measurements. The cortex (the gray matter on the outside of the brain) has a wavy, folded structure which is hypothesized to be affected by tension from the axons in the white matter. If this hypothesis is correct, then dissection of axons could cause a flattening of the cortex and a change in cortical shape. The degree of folding can be calculated using MRI images, producing a measurement called Local Gyrification Index (LGI), and research in healthy controls shows that aging affects LGI, as well as cortical thinning.

Researchers calculated cortical thickness and LGI in 36 people with RRMS to see whether MS disease processes affect these characteristics as well. They found both thinning and thickening in the MS subjects and conjectured that the thickening may be due to inflammation. LGI change and thinning were found in different areas in the controls vs. the MS subjects. In the MS subjects, LGI was decreased in some areas but increased in others, so the conclusions to be drawn are unclear, but this seems like something worth following up on. As we get better at imaging cortical lesions, for example, it would be interesting to see whether lesion location is correlated with thinning/thickening and LGI change.

S39: Multiple Sclerosis: Immunology II (Art)

Immunology sessions are, in Art's opinion, usually incredibly opaque, overly technical, boringly presented, and painful to sit through. These next presentations did not disappoint.

[S39.001] Prion Protein Is a Key Regulator of T Cell Activation, Differentiation, and Survival
Wei Hu, Dallas, TX, Stefan Nessler, Bernhard Hemmer, Munich, Germany, Todd Eagar, Dallas, TX, Lawrence Kane, Pittsburgh, PA, Rutger Leliveld, Andreas Muller-Schiffmann, Dusseldorf, Germany, Anne Gocke, Dallas, TX, Amy Lovett-Racke, Columbus, OH, Li-Hong Ben, Rehana Hussain, Dallas, TX, Andreas Breil, Dusseldorf, Germany, Jeffrey Elliott, Paul Carson, Petra Cravens, Mahendra Singh, Dallas, TX, Benjamin Petsch, Lothar Stitz, Greifswald-Insel Riems, Germany, Michael Racke, Columbus, OH, Carsten Korth, Dusseldorf, Germany, Olaf Stuve, Dallas, TX.

The Prion Protein is highly expressed in neurons and its function is not known. These researchers found that it seems to be involved in regulating the severity of EAE. EAE is worse without the protein and better when there is more of it. They appeared to do a good job of demonstrating this conclusively, but I missed the part where they indicate any relevance to humans or MS.

[S39.002] Characterization of Signal Transduction Pathways Involved in Glatiramer Acetate (GA, Copolymer-1, Copaxone)-Induced Type II Monocyte Differentiation
Nicolas Molnarfi, Thomas Prodhomme, Scott Zamvil, San Francisco, CA, Martin Weber, Munich, Germany.

This totally went over my head but was aimed at trying to understand what Copaxone might be doing in our bodies by looking at it in a dish.

[S39.003] The Central Nervous System as an Effector Site of Secretory Immunity in Multiple Sclerosis
Dorothee Chabas, San Francisco, CA, Danielle Seilhean, Flore Rozenberg, Paris, France, Tarek Sharshar, Garches, France, Seiji Nishino, Palo Alto, CA, Bertrand Fontaine, Olivier Lyon-Caen, Paris, France, Emmanuel Mignot, Palo Alto, CA, Canh Quan, Paris, France.

The presenter described this work as showing how the brain may behave immunologically as a mucosal organ like the gut or mammary glands. They looked at secretory immunity (the body's line of defense) via SIgA (which is different from plain IgA). Looking in CSF and serum samples they found SIgA in 58% of their MS samples compared to 12% of their non-MS samples. Its levels were higher in RRMS and during relapses. It did not show up in serum.

[S39.004] Gender Differences in Immunomodulatory Effects of 1,25 Dihydroxyvitamin D3 in Multiple Sclerosis
Jorge Correale, Mara C. Ysrraelit, Mara I. Gaitn, Buenos Aires, Argentina.

This was a litany of differences found in cytokines, t-cells, mRNA, etc. in cells from males and females when exposed to Vitamin D. It would seem to indicate an increased protective effect of Vitamin D in females but not males. This agrees with Vit D protective effect in EAE but does not agree with the latitude and sunshine studies that see no such gender bias. Perhaps EAE is not a good model of MS. Nah! We can use EAE, so we should keep using it. OK, I'm done being sarcastic.

[S39.005] Anti-Aquaporin-4 Antibody Production from Peripheral B Cells in Neuromyelitis Optica
Chihiro Suzuki, Ichiro Nakashima, Toshiyuki Takahashi, Sendai, Japan, Amit Bar-Or, Montreal, QC, Canada, Yasuto Itoyama, Kazuo Fujihara, Sendai, Japan.

Looking at a very small number of subjects (11 NMO, 5 MS, 8 healthy), these researchers saw some evidence that the AQP4-Ab that seems to be unique to NMO is produced by B-Cells.

Late Breaking Science (Hollie)

[LBS.001] Results from the CLARITY Study: a Phase III, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Oral Cladribine in Relapsing-Remitting Multiple Sclerosis (RRMS)
Gavin Giovannoni, MBBCH, PhD,London, United Kingdom

*** Hollie Pick

Dr. Giovannoni presented results from the CLARITY study of cladribine (an oral anti-cancer drug from EMD Serono being tested in MS). This was a 96-week, placebo-controlled study with 1,326 subjects. The treatment arms included (1) placebo, (2) four courses of cladribine (total 3.5 mg/kg), and (3) 6 courses of cladribine (total 5.25 mg/kg). A course of cladribine consisted of 1-2 tablets per day for 4-5 consecutive days for 2-4 consecutive months each year. Around 90% of subjects in each group completed the study, and dropouts due to adverse events were low.

Here are the results: A ~55% reduction in annualized relapse rate was seen in the cladribine groups vs. placebo (relapse rates were 0.14 or 0.15 vs. 0.33 in placebo). 80% of the cladribine recipients were relapse-free compared with 60% of the placebo subjects. There was a 31-33% relative reduction in sustained progression and a 75-85% relative reduction in MRI lesions. There were two deaths in each arm and five malignancies in the cladribine arms vs. none in the placebo arm. These malignancies occurred in different organ systems. Very low levels of immune cells (lymphopenia and leukopenia) were seen in some cladribine recipients, although this was expected since the drug targets immune cells.

So, this looks like another interesting oral drug with an easy dosing schedule and potential benefits in MS, but potentially severe side effects to go with it. People with MS will have a lot to consider in a few years assuming several of these new drugs are approved to treat the disease.

Evening Activities

After the sessions, we went to dinner with Rip Kinkel (Beth Israel), Tim Coetzee (NMSS Fast Forward), and Ben Greenberg (UTSW). The food was not as good, but then again the service was not as snooty either.


Thu 04/30:

Morning Activities
Hollie and Art met with Steve Bushnell, Rosella Medori, and Diego Cadavid of Biogen to talk about the use of our repository.

At lunch we met with Tim Vollmer (RMMSC/U Colorado). He moved from Barrow Neurological Institute (where we have a repository site) to Colorado (where we are about to launch a repository site) so it was good to catch up.

S41: Multiple Sclerosis: Clinical Outcomes (Art)

[S41.001] A Clinical-MRI Composite Score Predictive of Longer Term Outcome in RRMS
Gary R. Cutter, Birmingham, AL, Maria Pia Sormani, Genova, Italy, Jack Simon, Wilsonville, OR, Richard Rudick, Solon, OH.

This study investigated withere the Sormani Score had any ability to predict EDSS outcome. They found it had some measure of predictability in the data set they analyzed.

Score computed by this equation:
.64 * sqrt(# relapses in previous 2 years) + .26 * sqrt(# Gd lesions)

[S41.002] Falls in Multiple Sclerosis: Prevalance and Risk Factors
Patricia Noritake Matsuda, Alyssa Bamer, Anne Shumway-Cook, Shana L. Johnson, George H. Kraft, Dagmar Amtmann, Seattle, WA.

This study did a longitudinal survey of 474 people with MS on their falling behavior. They found that 60% of people reported falling, with many of those falls requiring some sort of medical attention. These falls occurred mainly during transfers and walking and were caused by trips/slips or tiredness.

[S41.003] Quantitative Sensorimotor Measures in a Heterogeneous Multiple Sclerosis Cohort
Scott D. Newsome, Kathleen M. Zackowski, Peter A. Calabresi, Baltimore, MD.

This study used devices to measure vibration sensation, and ankle and hip strength in 100 subjects. Vibration sensation was reduced in people with MS as was ankle/hip strength. People with SPMS were weakest and had the least vibration sensation compared to RRMS and PPMS.

They found a correlation with EDSS and the 25 foot timed walk and the researchers believe these devices might be a more sensitive measure for clinical trials.

[S41.004] Clinically Meaningful Change in Cognitive Function as Confirmed by Work Disability
Sarah A. Morrow, Allison Drake, Bianca Weinstock-Guttman, Fredrick Munschauer, Ralph Benedict, Buffalo, NY.

This study looked at the results of a battery of neuropsychological tests on people who had employment status changes due to disability. They found some tests correlated with the change, but gave not clear mention of the clinical utility of the results.

[S41.005] Cognitive Impairment Predicts the Clinical Conversion to Multiple Sclerosis in Patients with Clinically Isolated Syndromes
Valentina Zipoli, Benedetta Goretti, Emilio Portaccio, Maria Pia Amato, Florence, Italy.

Measuring cognitive impairment in people with a first demyelinating event in which 46% converted to clinically definite MS (CDMS). They found that 64% of those who failed 2 tests converted and 89% of those who failed 3 tests converted. So it would appear, in this small (56 subject) study, that CIS to MS conversion can be predicted by cognitive impairment at baseline.

[S41.006] Urometric Profile in a MS Population: Relation between Subjective and Objective Measures of Bladder Dysfunction
Shalom Haggiag, Giovanni Bolla, Claudio Gasperini, Simonetta Galgani, Rome, Italy.

This study measured urologic problems using devices and compared the results to the subjective reports of bladder problems by the patients themselves. There was no correlation indicating it is probably a good idea to get your bladder function tested rather than just go by what you think is happening. You're possibly wrong.

[S41.007] Incidental Multiple Sclerosis like Lesions in Asymptomatic Patients; Analysis of 864 Consecutive MRI at a Tertiary Care Hospital in Karachi, Pakistan
Farhan Rizvi, Mohammad Wasay, Muhammad Azeemuddin, Adnan Yousuf, Karachi, Pakistan, Sten Fredrikson, Stockholm, Sweden.

Pakistan has a very low reported rate of MS. Looking at MRIs of 864 people in pakistan, they found 6 with MRIs suggestive of MS. The prevalence of MS in Pakistan may be higher than thought.

[S41.008] Follow-Up of 70 Patients with Subclinical Multiple Sclerosis: What Can We Learn from MRI and CSF on Clinical Conversion Profile?
Christine Lebrun Frenay, Nice, France, Caroline Bensa, Paris, France, Sandrine Wiertlevski, Nantes, France, Marc Debouverie, Nancy, France, David Brassat, Toulouse, France, Jean Pelletier, Marseille, France, Ayman Tourbah, Paris Cedex 13, France, Bruno Brochet, Bordeaux, France, Pierre Labauge, Nimes Cedex 4, France, Jerome De Seze, Strasbourg, France, Frederic Berthier, Nice, France, Pierre Clavelou, Clermont-Ferrand, France.

Following 70 people with radiological isolated syndrome (RIS, MRI that looks like demyelination), they found that 33% converted to CIS (having a clinical manifestation of demyelination). They found that a higher number of T2 lesions correlated with a higher risk of conversion. Again, not much discussion on the clinical relevance of this finding.

S47: Multiple Sclerosis: Immunology III (Hollie)

[S47.001] Targeting CNS-Autoimmunity and Repair Using the Secretory Leukocyte Protease Inhibitor (SLPI)
Andre M. Mueller, Jacqueline Dinzey, Xiomara Pedr, New York, NY, Andreas Steinbrecher, Regensburg, Germany, Saud A. Sadiq, New York, NY.

SLPI is a protein that is produced within inflammatory lesions by macrophages, astrocytes, and neuronal cells, and is also expressed by human mesenchymal stem cells. Antibodies to SLPI were shown to aggravate EAE symptoms so SLPI may have an immunomodulatory effect. SLPI was also shown to stimulate proliferation of neuronal stem cells and differentiation of oligodendrocytes. So SLPI may be a potential MS therapy although this data is very preliminary.

[S47.002] Inhibition of GAPDH Activity and Induction of Neuronal Apoptosis and Axonal Degeneration by Antibodies Present in the Cerebrospinal Fluid and Brain Tissue of Patients with Multiple Sclerosis
Yufen Qin, Johanna Kolln, Yiping Zhang, Stanley van den Noort, Gaby Thai, Michael Demetriou, Neal Hermanowicz, Irvine, CA.

GAPDH and TPI are two proteins important in cellular metabolism and other functions. Analysis of CSF samples from MS subjects found that about 2/3 had antibodies to GAPDH and about 1/2 had antibodies to TPI (higher percentages than in people with an initial demyelinating symptom or other neurological diseases). In those subjects who have anti-GAPDH antibodies, these antibodies make up a significant percentage of all of their CSF antibodies. Furthermore, the greater the concentration of anti-GAPDH, the more GAPDH activity is inhibited. GAPDH is expressed by axons, so anti-GAPDH may be involved in axonal damage in MS.

[S47.003] The Immunomodulator Fingolimod (FTY720) Increases Myelin Production Following Demyelination of Organotypic Cerebellar Slices
Veronique E. Miron, Peter J. Darlington, Montreal, QC, Canada, Samuel K. Ludwin, Kingston, ON, Canada, Andrew A. Jarjour, Timothy E. Kennedy, Jack P. Antel, Montreal, QC, Canada.

*** Hollie Pick

MS drug candidate FTY720 is known to sequester immune cells in lymph nodes, but it also appears to affect cells in the central nervous system. This study sought to learn more about its CNS effects. Researchers used cultures of brain tissue from newborn mice and added FTY720 -- no effect was seen under this control condition. They then induced demyelination with lysolechithin in these cultures. Untreated cultures showed signs of partial remyelination, but cultures treated with FTY720 showed lots more remyelination. The researchers also saw formation of nodes of Ranvier, indicating restoration of function. The drug also induced oligos and oligo precursor cells to extend processes ("arms"). The number of microglia and astrocytes in treated cultures was also much greater than was present initially after demyelination. Next steps for this group include using an in vivo model of demyelination and determining whether FTY720 affects remyelination through an direct effect on oligos, or indirectly via microglia.

[S47.004] Fish Diet Prevents Demyelination, Clinical Symptoms and MRI Activity in the Cuprizone Model
ivind Torkildsen, Linn Anne Brunborg, Frits Thorsen, Anne Marita Milde, Sverre Jarl Mrk, Bergen, Norway, Martin Stangel, Hannover, Germany, Kjell-Morten Myhr, Lars B, Bergen, Norway.

Cuprizone is a substance that scientists can feed mice to induce demyelination. Diets high in fish may be protective against MS, so a research team decided to feed cuprizone to mice along with salmon, or cod liver oil, or soybean oil. The mice that were fed salmon had less weight loss and greater activity than the other two sets of mice. They also had a smaller volume of hyperintense lesions, less pronounced demyelination, and fewer microglia (although they had the same number of astrocytes as the other mice).

The presenter thought it was interesting that fatty fish protected against EAE but cod liver oil didn't. Maybe substances in fish other than fatty acids or vitamin D play a role in MS, since both of those are also found in abundance in cod liver oil. The presenter also wondered if they would get the same or different results if they tried this experiment in EAE.

[S47.005] Capacity of Human Fetal Oligodendrocyte Progenitors To Differentiate and Ensheath Axons in Response to Growth Factors
QiaoLing Cui, Gabiella Fragoso, Veronique Miron, Guillermina Almazan, Jack P. Antel, Montreal, QC, Canada.

This study examined the effect of different growth factors on oligo precursor cells (OPCs), and was conducted using a culture of human fetal neural progenitor cells. Dr. Antel reported that growth factors IGF-1 and BDNF helped OPCs differentiate into oligos, and also helped these oligos attach to axons and ensheath them with myelin.

[S47.006] Whole Genome Analysis of the Effect of Interferon-beta Treatment on Different Peripheral Blood Cell Populations in Multiple Sclerosis Patients
Xiao-song Zhao, Yuhong Yang, Michael Racke, Columbus, OH, Laurie Davis, Dallas, TX.

This was another "why does IFNb help in MS?" study. Blood samples from six people with MS drawn before and after they went on IFN-beta were analyzed for gene expression patterns. IFN-beta reduced the expression of genes associated with the "bad" Th17 cells, so perhaps it works by inducing T-cell shifts. I wonder why the conference planners didn't put this talk back-to-back with S06.002 (above) since their conclusions were so similar.

[S47.007] Role of 15-oxysterols in Neuroinflammation
Mauricio F. Farez, Francisco J. Quintana, Antonio H. Iglesias, Boston, MA, Claudia Lucchinetti, Rochester, MN, Guillermo Izquierdo, Miguel Lucas, Sevilla, Spain, Howard Weiner, Boston, MA.

*** Hollie Pick

Dr. Weiner's team has been working with a microarray of antigens to see what the antibodies in MS subjects' serum bind to. This may help reveal what the immune system is targeting in MS. For example, they previously determined that reactivity to heat shock protein is increased in RRMS but decreased in SPMS. Now they are looking for serum antibody signatures that may distinguish different subtypes of MS. Using Claudia Lucchinetti's classification system, they determined that subtype 2 is associated with reactivity to myelin antigens, and subtype 1 is associated with reactivity to cholesterols. Analyzing the cholesterols further, they found a higher level of certain 15-oxysterols (oxidized derivatives of cholesterols) in SPMS subjects compared with RRMS or healthy controls. One of these, 15-HC, activates a protein called PARP-1 in microglia and astrocytes. PARP-1 expression is increased in certain cells in SPMS and a progressive version of EAE; inhibiting PARP-1 after onset ameliorates progressive EAE. It turns out that 15-HC activates PARP-1 through a pathway involving toll-like receptor 2 (TLR2). Dr. Weiner suggested that blocking the TLR2 pathway would possibly help in MS. In addition, 15-HC may be a useful marker of progression in MS. The team has seen it upregulated in PPMS as well but needs to explore this further. It would certainly be good to have a better way of telling when someone has PPMS or has gone from RRMS to SPMS.

[S47.008] The Effect of Laquinimod on Lymphocyte VLA-4 Properties under Shear Flow Conditions
Liat Hayardeny, Netanya, Israel, Sara Feigelson, Valentin Grabovsky, Rehovot, Israel, Joel Kaye, Rotem Keshet, Guy Cinamon, Netanya, Israel, Ronen Alon, Rehovot, Israel.

Laquinimod has the effect of increasing anti-inflammatory cytokines and decreasing pro-inflammatory cytokines. It ameliorates EAE and results in less inflammation in the brain. A team of investigators wanted to see if the drug's effects had to do with reducing entry of immune cells through the blood-brain barrier. They used an experimental system where they could watch blood flow in a chamber and see if cells would attach to the vessel wall. They used blood taken from mice who were immunized with MOG (or not) and who were treated with laquinimod (or not). They found that laquinimod partially and indirectly affected activation of VLA-4 (a molecule on T cells that facilitates attachment to vessel walls) -- and that this effect was more selective than general blocking of VLA-4 which is what Tysabri provides. The effect on VLA-4 was specific only for mature effector T cells, not naive T cells.

S51: Multiple Sclerosis: Imaging II (Art & Hollie)

[S51.001] Axial and Radial Diffusivity as MR Biomarkers of Axonal and Myelin Injury in Ex-Vivo Multiple Sclerosis Cervical Spinal Cords
Eric C. Klawiter, Kathryn Trinkaus, Hsiao-Fang Liang, Shu-Wei Sun, Matthew Budde, Robert T. Naismith, Robert Schmidt, Sheng-Kwei Song, Anne H. Cross, Tammie Benzinger, St. Louis, MO.

An imaging technique called Diffusion Tensor Imaging (DTI) was compared to MS histological (tissue inspection) findings. DTI measures how easily water molecules can move through tissue in different directions. For instance, it's easier for water molecules to move along the direction of an axon bundle and more difficult for them to move perpendicular to it. A specific measurement, radial diffusivity, was higher in areas of demyelination, and another one, relative anisotropy, was correlated with axonal count. Axial diffusivity did not correlated with axonal loss which contrasts with the results from animal models. However, the presenter noted that the animals had acute disease and the MS subjects had chronic MS which may account for the difference (I'm not sure why). 90% of the regions studied, even those containing normal appearing tissue, had abnormal DTI values.

[S51.002] Quantitative Assessment of Brain Iron by R2* Relaxometry in Patients with Clinically Isolated Syndrome or Relapsing Remitting Multiple Sclerosis
Michael Khalil, Christian Enzinger, Christian Langkammer, Maria Tscherner, Mirja Wallner-Blazek, Margit Jehna, Stefan Ropele, Siegrid Fuchs, Franz Fazekas, Graz, Austria.

Iron is needed for neuronal metabolism, but high levels of iron in the brain are harmful. Using a particular MRI technique in 37 RRMS and 32 CIS subjects, this research team found that high levels of iron were found in some brain areas (e.g., the basal ganglia) and that levels in the putamen correlated with disease duration and gray matter atrophy. The team controlled their results for the effects of age, since iron accumulation increases over time. Long-term follow-up may help show whether iron accumulation is just a side effect of MS, or is itself a contributor to brain tissue damage.

[S51.003] Children with Acute Demyelinating Syndromes Exhibit Age-Dependent Slowing of Brain Growth Compared to Healthy Children
Rezwan Ghassemi, Sridar Narayanan, Vladimir Fonov, Zografos Caramanos, Paul Giacomini, Simon J. Francis, Montreal, QC, Canada, Donald Louis Collins, Monteal, QC, Canada, Amit Bar-Or, Montreal, QC, Canada, Dessa Sadovnick, Vancouver, BC, Canada, Brenda Banwell, Toronto, ON, Canada, Douglas Arnold, Montreal, QC, Canada.

This study compared the brain volume change over one year in a cohort of children with demyelination with healthy controls. They pointed out the issue of doing serial MRIs on children because their brains are changing sizes and registering previous MRIs with newer ones poses some technical challenges. They found that the rate of brain growth in the kids with demyelination was slower compared with controls before the age of 10. An audience member asked whether MS therapies would help with brain growth, and the response was that they didn't know, but also that not all of the kids with demyelinating syndromes had MS so they wouldn't all be on MS drugs anyway.

[S51.004] T2 and T1 Lesion Volume as Predictors of Neuropsychological Impairment in Children and Adolescents with MS
Christine Till, Toronto, ON, Canada, Rezwan Ghassemi, Montreal, QC, Canada, Emily Ursell, Toronto, ON, Canada, Douglas Arnold, Sridar Narayanan, Montreal, QC, Canada, John G. Sled, Brenda Banwell, Toronto, ON, Canada.

This study looked at cognitive function in pediatric MS and whether there are any MRI correlates. 28 subjects were given standardized intelligence tests. Although global intelligence was normal across the whole group, the team found that children with an earlier age of disease onset had lower IQs. 36% of their subjects were considered cognitively impaired and were typically children with earlier age of onset and longer disease duration. T2 lesion volume correlated with cognitive impairment, in particular with processing speed and attention. T1 lesion volume was not correlated with cognitive impairment, but it was associated with depression as was T2 lesion volume. The team is currently examining brain volume to see if it has any relationship with cognitive scores.

In the Q&A for this talk, we learned that braces throw off the MRI results, and so at Sick Kids Hospital in Toronto, when an MRI is needed in a child with braces, they have an orthodontist take the braces off and put them back on again afterward! Poor kids!

[S51.005] Cognitive Compensation Failure in RRMS Patients
Melissa C. Bonnet, Michele Allard, Bixente Dilharreguy, Mathilde Deloire, Vincent Dousset, Klaus Petry, Bruno Brochet, Bordeaux, France.

This study used fMRI to see how different parts of the brain are activated to compensate for faulty neural connections in MS. People with MS and controls were asked to do simple or complex tasks while the fMRI measured brain activity. People with MS showed re-routing of brain activity in the cerebrum which allowed them to have similar performance to the controls on the simple tasks. However, on the complicated tasks, their performance was worse. Better performance in the MS subjects was associated with activation of part of the cerebral cortex, which compensated for loss of connection to the cerebellum. However, apparently this capacity to compensate has a limit, which was exceeded in the more complicated task test.

Evening Activities

Art and Hollie went to the home of some of our old MIT buddies who cooked us a wonderful dinner.


Fri 05/01:

We got up bright and early and had an uneventful trip back to Boston with no medical emergencies this time.

Thanks, this was a nice overview of the conference in plain English for us non-scientific types!

As always, your notes are great. Thanks for all the work you do while attending these conferences. Having been a "professional conference" attendee for many years when I was still working, I remember how fried my brain was after just one day! I'm amazed at your stamina in being able to sit through so many of these presentations, all of which appeared to be highly complicated and detailed, and then translate what you heard!

Thank you for taking notes to share with those of us who have been diagnosed with MS.

I found the report on smoking to be very interesting.

I am so curious to find out whether or not a mother who smoked during pregnancy created a risk (for a future dx of MS) for the children she bore?

Kathy