Multiple Sclerosis (MS) is the most common cause of acquired neurological dysfunction during early and mid adulthood, and affects more than one million people in North America and Western Europe. Compelling data indicate that susceptibility and resistance to MS is partly inherited. The presence of brain inflammation, loss of myelin and neuro-axonal degeneration are hallmarks of the disease. However, the link between these pathological processes remains unknown. An emerging concept bridging this knowledge gap is the alteration of glutamate metabolism causing toxicity of the central nervous system. Clinically, the vast majority of MS patients will experience progressive worsening a decade after onset of the disease. The main goal of this study is to determine the level of brain glutamate in patients with MS using a novel molecular magnetic resonance imaging technique. This non-invasive in vivo methodology provides, for the first time, an estimate of glutamate levels over large brain regions of interest. Specifically, the authors hypothesized that an excess of glutamate levels in MS patient brains is a predictor of neuronal injury, brain atrophy and accumulation of chronic clinical disability. Lastly, the effort will focus on the discovery of patterns of gene expression in the peripheral blood of MS patients through the combined use of state-of- the-art genome wide analysis and molecular biology experimental tools to predict sustained disability progression of MS patients. The authors will use unsupervised and supervised machine learning algorithms to capture relationships between gene expression levels and disease progression.

Public Health Relevance

The identification of specific molecular imaging and genetic predictive markers associated with disease progression of MS patients will accelerate advances in research and lead to better therapeutic strategies to prevent the biological process leading to brain inflammation, demyelination, axonal injury and consequent progressive neurological deficits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS062885-06
Application #
8536962
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2009-09-15
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
6
Fiscal Year
2013
Total Cost
$344,442
Indirect Cost
$137,570
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Azevedo, Christina J; Kornak, John; Chu, Philip et al. (2014) In vivo evidence of glutamate toxicity in multiple sclerosis. Ann Neurol 76:269-78
Llufriu, Sara; Kornak, John; Ratiney, Helene et al. (2014) Magnetic resonance spectroscopy markers of disease progression in multiple sclerosis. JAMA Neurol 71:840-7