Clinical T2 and contrast-enhanced T1-weighted MRI have become the diagnostic modalities of choice to evaluate multiple sclerosis (MS) due to their sensitivity to acute, often subclinical events in the brain and their ability to measure the accumulation of lesions over time. MRI, however, lacks specificity, in that to date, there are conflicting reports concerning the number and volume of these lesions, “load of the disease,” and the neurological deficits. Furthermore, clinical MRI is blind to occult white matter (WM) and especially most gray matter (GM) pathology. The need for more reliable surrogate markers frequently leads to proton magnetic resonance spectroscopy (1H-MRS) being used to probe the underlying metabolism of normal appearing WM (NAWM) and its lesions. Since MS pathogenesis starts on molecular cellular levels, we propose to use state of the art, short echo-time, three-dimensional high-spatial resolution local and global 1H-MRS methods to examine three hypotheses: H1: That MS lesions develop in WM regions which are already metabolically abnormal; H2: Abnormal metabolic activity persists in NAWM and lesions even absent Gd-enhancement (the current marker of “activity”); and H3: That global whole-brain quantification of the decline rate of the neuronal cell marker N-acetylaspartate (NAA) reflects the aggressiveness of a patient’s disease, and therefore, could forecast its future course in that individual. These hypotheses will be tested by continuing to follow a cohort of 25 relapsing-remitting (RR) MS patients and 25 matched controls, for 5 more years, with three Specific Aims:
Specific Aim 1 is to perform longitudinal follow-up of the overall metabolites levels in the NAWM to establish markers for current MRI-occult disease activity.
Specific Aim 2 is to follow localized metabolism in NAWM to determine what focal changes preceded lesion formation and determine those lesions outcome - to repair or become chronic.
Specific Aim 3 is to correlate the NAA levels of the whole brain and its WM and GM fractions with the patients' clinical deficits to establish the NAA as a forecaster of disease severity. The health relatedness of this study is its prospect to establish, quantify and validate non-invasive metabolic surrogate markers of RR MS progression that will enable us to: (i) Gauge current level of disease activity, thereby, (ii) increase our capability to forecast its future course for these (young) patients; and consequently (iii) lead to improved monitoring of response in drug and treatment trials.

Public Health Relevance

We propose to continue a 5 year semi-annual follow-up of a cohort of 25 ‘recently diagnosed’multiple sclerosis patients (a neurological degenerative disease affecting over 400,000 Americans and representing a $5 Billion healthcare burden) and 25 matched controls with quantitative MRI and three-dimensional multi-voxel MR spectroscopy. The goals are to identify and characterize non-invasive MR markers that will correspond to these each patient’s clinical status and will detect/predict its changes and deterioration faster than the current standard of care neurological examination. Success will enable clinicians to manage the disease of individual patients better and to streamline clinical trials (less subjects for shorter periods) with better secondary markers, thereby improving patient outcome and lowering the cost of MS treatment and drug developments.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
High Priority, Short Term Project Award (R56)
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Medical Imaging Study Section (MEDI)
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Utz, Ursula
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New York University
Schools of Medicine
New York
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