Cognitive Dysfunction in Multiple Sclerosis

Agenda

*Presentation times are subject to change.

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, PhD^1,3, Bruce D. Trapp, PhD<sup>1

1</sup>Department 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 Na_V1.6, 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-Cn^1,2, Jeffrey A. Wilken, PhD^1,3, Cynthia Sullivan^1,3
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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