Cognitive Dysfunction in Multiple Sclerosis: New Approaches to Diagnosis and Treatment

Poster Session Wednesday, June 22, 2011 12:00 – 2:00 pm

POSTER PRESENTERS

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Alexander Gow

2.

Elizabeth S. Gromisch

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Jia Liu

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David A. Lowe

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Thomas Prod’homme

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James F. Sumowski

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1) MYELIN DYSFUNCTION, NEURAL PROCESSING ABNORMALITIES, AND BEHAVIORAL PHENOTYPES Kathleen Maheras, BS, Michael McCormick, MD, and Alexander Gow, PhD Wayne State University, Detroit, MI The pathophysiological processes that underlie cognitive dysfunction and lead to behavioral disorders have been a rich source of debate for many years. Most studies are focused on abnormal development of neurons or on aberrant neurochemistry in different classes of these cells, and a wealth of genetic evidence points to genes involved in neurotransmitter biology. In addition, a number of neuroimaging, morphologic and genetic studies suggest abnormalities in glial cell biology. Indeed, cognitive decline is apparent in several degenerative white matter diseases, and loss-offunction phenotypes associated with the inactivation of myelin genes cause behavioral deficits. These myelin mutants perform similarly to mice lacking neuron-specific genes in tests such as prepulse inhibition or memory and learning tasks. In the current study, we have initiated an analysis of auditory processing in the CNS of a myelin mutant that lacks expression of the Claudin 11 gene in oligodendrocytes. Unlike many mutant phenotypes where the molecular function of the ablated gene products are unknown or understood at a superficial level, the function of Claudin 11 in generating tight junctions within myelin sheaths is known in great detail. Furthermore, mathematical modeling describes the mechanism of action of these tight junctions, which is to increase the myelin resistance of small diameter fibers and maximize conduction velocity. Slower conduction, as shown here in the auditory pathway, is relevant to the pathophysiology of a number of neurological diseases including multiple sclerosis.

2) USING A HIGHLY ABBREVIATED CVLT-II TO DETECT VERBAL MEMORY DEFICITS: AN ROC ANALYSIS IN THE MS POPULATION Elizabeth S. Gromisch, BS1, Vance Zemon, PhD1, MaryAnn Piccone, MD2, Frederick W. Foley, PhD1,2 Ferkauf Graduate School of Psychology, Yeshiva University, Bronx, NY 2 Holy Name Medical Center Multiple Sclerosis Center, Teaneck, NJ

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Multiple sclerosis is an autoimmune disorder of the central nervous system in which more than half of patients experience cognitive dysfunction. One issue in screening and monitoring for cognitive dysfunction in MS is the time required to administer assessments. In this study, we focused on the California Verbal Learning Test, second edition (CVLT-II), a test of verbal memory encoding and retrieval. We hypothesized that one to two trials of the CVLT-II can detect verbal memory problems in MS accurately. Using CVLT-II data from chart reviews, we performed ROC analyses of trial one raw data (N=127), trial two raw data (N=123), and trial one and trial two raw data combined (N=123) against standardized total scores, choosing two standard deviations from the mean as a cutoff for impairment. The results show that administration of only the first two trials of the CVLT-II can detect verbal memory deficits with excellent sensitivity and specificity.

3) CRITICAL ROLE OF HISTONE METHYLATION IN OLIGODENDROCYTE PROGENITOR DIFFERENTIATION Jia Liu1, Muzhou Wu1, Tanja Kuhlmann2 and Patrizia Casaccia1 1 Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 2 Institute of Neuropathology, University Hospital Münster, Münster, Germany Failure to remyelinate after demyelinating lesions contributes to the clinical progression detected in Multiple Sclerosis (MS). Oligodendrocytes are the myelin-forming cells in the central nervous system. We have previously demonstrated that the differentiation of oligodendrocyte progenitor cells (OPC) requires histone deacetylation to decrease the levels of oligodendrocyte differentiation inhibitors. However, histone deacetylation is a transient modification that is followed by histone methylation and DNA methylation. Here, we focus our study on the role of histone methylation in OPC differentiation. We show that OPC differentiating into myelinating oligodendrocytes are characterized by increasing levels of me2K9H3 and me3K9H3. Similar changes were detected in the developing rodent corpus callosum. This was consistent with increased expression of the histone methyltransferases (HMT) responsible for this modification (i.e. G9a), in the oligodendrocyte lineage. Inhibition of H3K9 methylation during a specific temporal window led to decreased expression of myelin genes and decreased the number of mature oligodendrocytes in primary cultures. Interestingly, we also detected increased levels of me2K9H3 and me3K9H3 in the normal-appearing white matter of MS patients. Together, these data suggest a critical role of H3K9 methylation in OPC differentiation and myelination (Supported by Fellowship FG1874-A-1 from National Multiple Sclerosis Society to JL, RO1-NS42925 and NMSS RG4134-A9 to PCB).

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4) COGNITION BATTERY FOR THE PRECLINICAL EVALUATION OF TREATMENTS FOR COGNITIVE DEFICITS IN MS David A. Lowe, PhD, Jessica Malberg, PhD, Neil Paterson, MD, PhD PsychoGenics, Inc. Tarrytown, NY Forty to 60% of Multiple Sclerosis (MS) patients show cognitive deficits – particularly in processing speed, long term memory and executive function. Given the lack of effect of current MS treatments on cognition, a need for preclinical assessment of novel MS compounds on cognition is clear. Here, we describe a preclinical battery for examining the effects of novel therapeutics on various domains of cognition, in both normal as well as experimental rodent MS models. This battery uses constructs that define specific separable domains of cognition, an approach found useful in studying cognitive deficits in schizophrenia. In this battery, processing speed is considered the construct of working memory, and is tested in the preclinical delayed-matching to position assay. Deficits in long-term memory are assessed with the novel object recognition and Morris Water Maze tests. In MS, deficits are also seen in executive function, such as the ability to adapt to changing situations. Executive function tests in our rodent battery involve reversal learning (cued or spatial) paradigms. Additional tests exist in our battery for other domains of cognition: perception, attention, social/emotional processing and motivation. For each of these cognitive domains, similar tests exist in non-human primates, offering translational strategies to the clinic. Taken together, these tests comprise a functional battery which can be used to establish the magnitude of deficits in experimental rodent MS models, the reversal of these deficits by novel therapeutics, and importantly, can help identify specific cognitive tests for assessing patients and their responses to a particular novel treatment.

5) IN VIVO TREATMENT WITH TEMSIROLIMUS AMELIORATES EAE AND IS ASSOCIATED WITH BOTH ANTI-INFLAMMATORY AND NEUROPROTECTIVE PROPERTIES Thomas Prod’homme, PhD1, Juan Carlos Patarroyo, BS1, Mayra Senices1, Shawn O’Neil, DVM, PhD2, Zachary Stewart, AS2, Mary Collins, PhD1, Cheryl Nickerson-Nutter, PhD1, Deborah Young, PhD1 1 Pfizer Biotherapeutics, Cambridge, MA 2 Pfizer Drug Safety R&D, Andover, MA The serine/threonine protein kinase mammalian target of rapamycin (mTOR) plays an important role in the modulation of both innate and adaptive immune responses. mTOR regulates diverse functions of professional antigen-presenting cells, has important roles in the activation of effector T cells and also regulates the function and proliferation of regulatory T cells (Treg). Oral dosing of temsirolimus (TMS), an ester analog of rapamycin with improved pharmaceutical properties, significantly reduced clinical signs of EAE, including incidence, onset and disease severity. This modulation, which was observed by direct immunization and adoptive transfer, was associated with a reduction of both inflammatory foci and demyelinated lesions in the CNS. Therapeutic administration of TMS at first onset of clinical signs reduced the severity of disease and prevented subsequent relapses. TMS influenced PLP(139-151)-specific T cell proliferation at nanomolar concentrations, and significantly reduced the secretion of pro-inflammatory cytokines, including IL-17, IFN- and TNF. Proliferation of most immune cell types, including B cells, macrophages and dendritic cells, was reduced in vivo, but numbers of CD4+CD25+FoxP3+ Treg remained unaffected. TMS treatment also demonstrated neuroprotective properties by promoting axon regeneration and remyelination, and by reducing apoptosis and activation of microglia. Although further investigation is required, the combination of both anti-inflammatory and neuroprotective effects support TMS as a potential new oral therapy for MS treatment.

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6) L-APHETAMINE IMPROVES MEMORY IN MS PATIENTS WITH MEMORY IMPAIRMENT James F. Sumowski, PhD1, 2, Nancy Chiaravalloti, PhD1, 2, David Erlanger, PhD3 , Tanya Kaushik, PsyD3, Ralph H.B. Benedict, PhD4, John DeLuca, PhD 1, 2, 5 1

Kessler Foundation Research Center, West Orange, NJ Department of Physical Medicine and Rehabilitation, UMDNJ –New Jersey Medical School, Newark, NJ 3 Memen Pharmaceuticals, LLC, New York, NY 4 Jacobs Neurological Institute, State University of New York at Buffalo, Buffalo, NY 5 Department of Neurology and Neurosciences, UMDNJ –New Jersey Medical School, Newark, NJ 2

Memory impairment is prevalent among persons with Multiple Sclerosis (MS), but no drugs are approved to treat these memory problems. We examined the effect of l-amphetamine versus placebo on auditory/verbal memory and visual/spatial memory in MS patients with and without baseline memory impairment. This abstract represents a reanalysis of a previously published clinical trial in which MS patients were randomly assigned to treatment (30mg l-amphetamine, N = 99) or placebo (N = 37) in a four-week, double-blind, parallel-group, dose titration trial. Auditory/verbal memory (CVLT-II: Long Delay Free Recall) and visual/spatial memory (BVMT-R: Delayed Recall) were assessed at baseline and follow-up across subgroups of patients with intact baseline memory (mean = 50th percentile) or impaired baseline memory (mean = 2nd percentile). Primary analyses: 2 (l-amphetamine, placebo) x 2 (baseline, followup), x 2 (baseline memory intact, baseline memory impaired) ANOVAs performed separately for auditory/verbal and visual/spatial memory. For both auditory/verbal and visual/spatial memory, we observed significant 2x2x2 interactions, whereby l-amphetamine improved memory more than placebo and this effect was specific to patients with baseline memory impairment. Among memory-impaired patients, memory improved about 48.5% for those on l-amphetamine, but only 1.0% on placebo. Taken together, treatment with l-amphetamine produced large memory gains among memoryimpaired MS patients. This finding has important clinical implications, especially as recent clinical trials of other drugs (e.g., donepezil) have failed to improve memory among MS patients.

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