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Cognitive Dysfunction in Multiple Sclerosis

Cognitive Dysfunction in Multiple Sclerosis

Tuesday, June 21, 2011 - Thursday, June 23, 2011

The New York Academy of Sciences

Presented By

Presented by the New York Academy of Sciences


Multiple Sclerosis (MS) causes cognitive deficits in approximately half of all patients including difficulty with memory, attention, executive functioning, visuospatial ability, and verbal fluency. These cognitive deficits are difficult to diagnose and often go unreported by patients, despite well-documented negative impacts on quality of life. At present, the mechanisms causing cognitive dysfunction in MS are poorly understood. This 2.5-day conference will convene physicians, neurologists, clinical neuropsychologists, cellular and molecular biologists, and patient advocates to discuss current challenges and potential solutions for improving diagnosis, treatment and management of the cognitive symptoms of MS. Plenary sessions will cover neurobiological understanding of the lesions leading to cognitive impairment in MS, improved diagnosis through combined use of neuropsychological testing and magnetic resonance imaging, and new pharmacological treatment options.


Sonya Dougal, PhD

The New York Academy of Sciences

Registration Pricing

 By: 4/29/2011After: 4/29/2011Onsite: 6/21/2011
Student Member$200$250$300
Nonmember Corporate$450$500$600
Nonmember Academia$400$450$550
Nonmember Not for Profit$400$450$550
Nonmember Student$200$250$300

Presented by

Gold Sponsors

For a full list of sponsors, please visit the Sponsors tab.


*Presentation times are subject to change.

Day 1: Tuesday, June 21, 2011

5:00 PM


5:30 PM

Welcome Remarks
Sonya Dougal, PhD, The New York Academy of Sciences

5:45 PM

Keynote Address
State of the Science in Therapeutics for Multiple Sclerosis
Aaron E. Miller, MD, Mount Sinai School of Medicine

6:30 PM

Panel Discussion

- Jeffrey Gingold, MS Patient Advocate
- Nicholas G. LaRocca, PhD, National Multiple Sclerosis Society
- Cynthia Sitcov, MS Patient Advocate

Aaron E. Miller, MD, Mount Sinai School of Medicine

7:30 PM

Networking Reception

8:30 PM

Day 1 Concludes

Day 2: Wednesday, June 22, 2011

8:15 AM

Breakfast and Registration

Session I: Cellular Neurobiology of Cognitive Impairment in Multiple Sclerosis

9:15 AM

Cellular and Molecular Pathways of Nerve Fiber Injury in Multiple Sclerosis
Peter A. Calabresi, MD, Johns Hopkins University Medical School

9:45 AM

Demyelination as a Cause of Synaptic Alteration in Hippocampi from MS Patients
Ranjan Dutta, PhD, Lerner Research Institute at the Cleveland Clinic Foundation

10:15 AM

Coffee Break

11:00 AM

Hippocampal Demyelination as a Cause of Memory Dysfunction
Bruce D. Trapp, PhD, Lerner Research Institute at the Cleveland Clinic Foundation

11:30 AM

Protein Acetylation in Demyelinating Disorders
Patrizia Casaccia, MD, PhD, Mount Sinai School of Medicine

12:00 PM

Lunch and Poster Session

SESSION II: Drug Therapeutics for Improving Cognition in Multiple Sclerosis

2:00 PM

Sodium Channels and Neuroprotection in MS
Stephen G. Waxman, MD, PhD, Yale University School of Medicine

2:30 PM

Treatment of MS Related Cognitive Problems with Adjunct Modafinil
Robert Kane, PhD, University of Maryland and Washington Neuropsychology Research Group

3:00 PM

Lessons From a Failed Trial
Lauren Krupp, PhD, SUNY Stony Brook

3:30 PM

Coffee Break

4:00 PM

Tysabri Effects on Cognition and Neurodegeneration in Multiple Sclerosis
Jacqueline T. Bernard, MD, University of Chicago

4:30 PM

Panel Discussion

5:30 PM

Day 2 Concludes

Day 3: Thursday, June 23, 2011

8:15 AM

Breakfast and Registration

SESSION III: Neuropsychological Tests to Diagnose Cognitive Impairment in MS

9:00 AM

Neuropsychological Assessment and Rehabilitation of Cognitive Dysfunction in MS
John DeLuca, PhD, Kessler Foundation

9:30 AM

Cognitive Dysfunctions in MS
Pasquale Calabrese, PhD, Ruhr-University Bochum

10:00 AM

Assessing Cognitive Dysfunction in MS: Consideration of Secondary Influences
Peter Arnett, PhD, Penn State University

10:30 AM

Coffee Break

11:00 AM

Cognitive and Imaging Genetics of MS
Heather Wishart, PhD, Dartmouth Medical School

11:30 AM

Neuroimaging Correlates of Cognitive Impairments in MS
Stephen M. Rao, PhD, Cleveland Clinic

12:00 PM


SESSION IV: Using Brain Imaging for Understanding Cognitive Dysfunction in MS

1:00 PM

In VIvo Proton MR Spectroscopy in Multiple Sclerosis
Daniel Pelletier, MD, Yale University

1:30 PM

MRI Studies of Gray Matter Disease in MS
Massimo Filippi, MD, University of Milan

2:00 PM

Coffee Break

2:30 PM

Insights on the Birth of New MS Lesions
Daniel Reich, MD, PhD, National Institutes of Health

3:00 PM

Subregional Hippocampal Vulnerability in MS: Relationship to Cognitive Function and Mood
Nancy Sicotte, MD, Cedars-Sinai Medical Center

3:30 PM

Panel Discussion

4:30 PM

Meeting Adjourns


Peter Arnett, PhD

Penn State University

Jacqueline T. Bernard, MD

University of Chicago

Pasquale Calabrese, PhD

Ruhr-University Bochum

Peter Calabresi, MD

Johns Hopkins University Medical School

Patrizia Casaccia, MD, PhD

Mount Sinai School of Medicine

John DeLuca, PhD

Kessler Foundation

Ranjan Dutta, PhD

Learner Research Institute at the Cleveland Clinic Foundation

Massimo Filippi, MD

Univeristy San Raffaele

Jeffrey N. Gingold

MS Patient Advocate

Robert L. Kane, PhD

University of Maryland School of Medicine

Lauren Krupp, PhD

SUNY Stony Brook

Nicholas G. LaRocca, PhD

National Multiple Sclerosis Society

Aaron E. Miller, MD

Mount Sinai School of Medicine

Daniel Pelletier, MD

Yale University

Stephen M. Rao, PhD

Cleveland Clinic

Daniel Reich, MD, PhD

National Institute of Neurological Disorders and Stroke

Nancy Sicotte, MD

Cedars-Sinai Medical Center

Cynthia Sitcov

MS Patient Advocate

Bruce Trapp, PhD

Lerner Research Institute at the Cleveland Clinic Foundation

Stephen G. Waxman, MD, PhD

Yale University School of Medicine

Heather Wishart, PhD

Dartmouth Medical School

Day 2: Wednesday, June 22, 2011

Session I: Cellular Neurobiology of Cognitive Impairment in MS

Hippocampal Demyelination as a Cause of Memory Dysfunction

Bruce D. Trapp, PhD1, Anthony M Chomyk, BS1, Mary K Doud, BS1, Dale D Edberg, PhD2, Brian Bai, PhD2, Ranjan Dutta, PhD1

1Department of Neurosciences, Lerner Research Institute , Cleveland Clinic, Cleveland, OH
2Renovo Neural Inc., Cleveland, OH

Thirty to 40% of MS patients demonstrate specific memory impairment. Hippocampal demyelination is a prominent feature of many MS patients. We recently reported significant decreases in synaptic densities in demyelinated hippocampi from MS patients. Neuronal proteins involved in axonal transport, glutamate neurotransmission, axonal transport and memory-learning were also decreased. While theses changes were robust, they were obtained from MS patients with long standing disease. The development of a rodent model of hippocampal demyelination would assist in separating acute and chronic gene changes, provide a platform for testing the effects of hippocampal demyelination on memory function, and to investigate if hippocampal remyelination would reverse memory deficits. We have developed a mouse model of hippocampal demyelination using a combination of cuprizone and rapamycin. We obtained ~78% reduction in hippocampal myelin with six weeks treatment. Continuation of the treatment to 12 weeks reduced hippocampal myelin by more than 90%. When mice were returned to a normal diet, remyelination was prominent and myelin levels returned to 78% of control levels within 6 weeks. Genes related to glutamate signaling and homeostasis, synaptic plasticity and memory function were decreased in demyelinated mouse hippocampus. Protein levels of these genes returned to near control levels during remyelination indicating that loss of myelin impacts the levels of these genes. Hippocampal demyelination also had a negative impact on memory function which was reversed by 6 weeks of remyelination. Hippocampal demyelination can cause memory dysfunction and remyelination therapies should be considered as a possible therapeutic strategy for enhancement of memory function in MS patients.<

Demyelination Causes Synaptic Alterations in Hippocampi From Multiple Sclerosis Patients

Ranjan Dutta, PhD1, Ansi Chang, MD1, Mary K. Doud, BS1, Grahame J. Kidd, PhD1, Michael V. Ribuado, BS1, Elizabeth A. Young, PhD1, Robert J Fox, MD2, Susan M Staugaitis, MD, PhD1,3, Bruce D. Trapp, PhD1

1Department of Neurosciences, Lerner Research Institute
2Mellen Center for Multiple Sclerosis Treatment and Research
3Department of Anatomic Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system. While the clinical impact of gray matter pathology in MS brains is unknown, 30-40% of MS patients demonstrate memory impairment. The molecular basis of this memory dysfunction has not yet been investigated in MS patients. To investigate possible mechanisms of memory impairment in MS patients, we compared morphological and molecular changes in myelinated and demyelinated hippocampi from postmortem MS brains. Demyelinated hippocampi had minimal neuronal loss but significant decreases in synaptic density. Neuronal proteins essential for axonal transport, synaptic plasticity, glutamate neurotransmission, glutamate homeostasis and memory/learning were significantly decreased in demyelinated hippocampi, but not in demyelinated motor cortices from MS brains. Collectively, these data support hippocampal demyelination as a cause of synaptic alterations in MS patients and establish that the neuronal genes regulated by myelination reflect specific functions of neuronal subpopulations.

Grant Support: NMSS RG-4280, NIH NS38667 and NIH NS35058.

Protein Acetylation in Deymelinating Disorders

Patrizia Casaccia MD, PhD, JinYoung Kim PhD, Jeffery Haines, PhD
1Department of Neuroscience and Friedman Brain Institute at Mount Sinai School of Medicine, New York, NY

One of the greatest challenges in clinical neurology is the management of disability consequent to axonal damage in the young adult population. There is no treatment for the slow and progressive deterioration observed in demyelinating disorders, such as multiple sclerosis (MS). These causes of disability in young adults affect a large population at the peak of their productivity and create an enormous emotional and financial burden for our society and underscore the importance of unveiling the underlying mechanisms. Neuropathological studies have described two types of axonal damage in post-mortem brains of patients with MS demyelinated axons with localized swellings and axonal interruptions with terminal stumps. Our laboratory has recently identified the cytosolic localization of a deacetylase enzyme that is localized in the nucleus in physiological conditions. This localization leads to impaired mitochondrial transport in cultured neurons and preceded the detection of localized swellings and axonal transections. The enzyme is also found in dystrophic axons in the brain of Multiple Sclerosis patients, where its localization coincides with hyperacetylation of nuclear substrates. Thus we propose protein acetylation/deacetylation as an important target for regulating neuronal and glial function in demyelinating disorders.

SESSION II: Drug Therapeutics for Improving Cognition in MS

Sodium Channels as Targets for Neuroprotection in MS

Stephen G. Waxman, MD, PhD, Yale University School of Medicine

Voltage-gated sodium channels play many roles in the CNS, and have emerged as significant participants in the pathophysiology of MS.  It is now well-established that the presence of increased numbers of sodium channels, in denuded parts of the axon membrane that had been channel-poor prior to demyelination, can restore the ability of some demyelinated axons to conduct impulses.  Sodium channels also, however, participate in the injury cascade that leads to axonal degeneration in MS.  This has significant implications for neuroprotection.  This lecture will review the following advances in this area:

  • Persistent sodium current, via sodium channels, can trigger calcium-importing reverse Na/Ca exchange that leads to axonal degeneration under conditions where the ability of axons to maintain ionic homeostasis is exceeded.
  • Sodium channel NaV1.6, which is present at normal nodes and also expressed along some chronically demyelinated axons, produces a persistent current, and is co-localized with the sodium-calcium exchanger in degenerating axons, both in EAE and MS.
  • Sodium channel blockade, with tetrodotoxin and with clinically used sodium channel blockers (phenytoin, carbamazapine, flecanaide) have a protective effect on CNS axons in EAE.
  • As a result of these observations, several trials of sodium channel blockers in MS have been initiated.
  • Confounding factors, in exploration of sodium channel blockade as a neuroprotective strategy, include the expression of sodium channels in inflammatory cells (microglia, macrophages, t-cells) and astrocytes, rebound effects after sodium channel blocker withdrawal in EAE, and the challenges of assessing neuroprotective effects in view of the effects of sodium channel blockers.


Treatment of MS Related Cognitive Problems with Adjunct

Robert L. Kane, PhD ABPP-Cn1,2, Jeffrey A. Wilken, PhD1,3, Cynthia Sullivan1,3
1Washington Neuropsychology Research Group
2University of Maryland School of Medicine
3Georgetown University

Treatment of MS Related Cognitive Problems with Adjunct Modafinil: Imaging data suggests that cognitive problems in MS are more associated with destructive than enhancing lesions. Hence, there is an interest in pharmacological interventions that might improve cognition secondary to treating other symptoms of MS. In this talk we present results from a study designed to determine whether adjunct treatment of fatigue with modafinil results in improved cognitive functioning. The hypothesis was that in addition to combating fatigue, modafinil treatment might also results in enhanced attention and in an improvement in other cognitive domains reliant on attention. Participants in the study were patients with relapsing-remitting MS who also demonstrated problems with attention on formal examination. All patients were being treated with intramuscular interferon beta-1a. A randomly selected subgroup was also given modafinil as an adjunct therapy. An analysis done at 4 months following initiation of modafinil treatment demonstrated improvements in levels of fatigue and cognition for the group receiving this adjunct treatment.

*Additional abstracts coming soon.

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