Clinical T2 and contrast-enhanced Tl-weighted magnetic resonance imaging (MRI) have become the diagnostic modalities of choice in the evaluation of multiple sclerosis (MS) due to their sensitivity to acute, often subclinical events in the brain and their ability to measure the accumulation of the disease over time. MRI, however, lacks specificity, in that to date, there are conflicting reports concerning the number and volume of these lesions, """"""""the load of the disease,"""""""" and the associated neurological deficits. Furthermore, clinical MRI is completely blind to occult white matter (WM) and most gray matter (GM) pathology. The need for more reliable surrogate markers frequently leads to proton magnetic resonance spectroscopy 1HMRS being used to probe the underlying metabolism of normal appearing WM (NAWM) and the lesions in it. Since MS pathogenesis starts on molecular cellular levels, we propose to use state of the art, short echotime, three-dimensional high-spatial resolution local and global 1H-MRS methods to examine three hypotheses: HI: 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 following a cohort of 25 relapsingremitting (RR) MS patients and 25 matched controls, for 5 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 and future course. The health relatedness of this study is its potential to establish, quantify and validate non-invasive radiological 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050520-02
Application #
7116838
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Utz, Ursula
Project Start
2005-09-01
Project End
2010-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$571,921
Indirect Cost
Name
New York University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Kirov, Ivan I; Liu, Shu; Tal, Assaf et al. (2017) Proton MR spectroscopy of lesion evolution in multiple sclerosis: Steady-state metabolism and its relationship to conventional imaging. Hum Brain Mapp 38:4047-4063
Mazgaj, Robert; Tal, Assaf; Goetz, Raymond et al. (2016) Hypo-metabolism of the rostral anterior cingulate cortex associated with working memory impairment in 18 cases of schizophrenia. Brain Imaging Behav 10:115-23
Glodzik, Lidia; Sollberger, Marc; Gass, Achim et al. (2015) Global N-acetylaspartate in normal subjects, mild cognitive impairment and Alzheimer's disease patients. J Alzheimers Dis 43:939-47
Grossman, Elan J; Kirov, Ivan I; Gonen, Oded et al. (2015) N-acetyl-aspartate levels correlate with intra-axonal compartment parameters from diffusion MRI. Neuroimage 118:334-43
Wu, W E; Babb, J S; Tal, A et al. (2015) Early glial activation precedes neurodegeneration in the cerebral cortex after SIV infection: a 3D, multivoxel proton magnetic resonance spectroscopy study. HIV Med 16:381-7
Tal, Assaf; Gonen, Oded (2015) Spectroscopic localization by simultaneous acquisition of the double-spin and stimulated echoes. Magn Reson Med 73:31-43
Soher, Brian J; Wu, William E; Tal, Assaf et al. (2014) Automated whole-brain N-acetylaspartate proton MRS quantification. NMR Biomed 27:1275-84
Serulle, Yafell; Rusinek, Henry; Kirov, Ivan I et al. (2014) Differentiating shunt-responsive normal pressure hydrocephalus from Alzheimer disease and normal aging: pilot study using automated MRI brain tissue segmentation. J Neurol 261:1994-2002
Kierans, Andrea S; Kirov, Ivan I; Gonen, Oded et al. (2014) Myoinositol and glutamate complex neurometabolite abnormality after mild traumatic brain injury. Neurology 82:521-8
Cohen, Ouri; Tal, Assaf; Gonen, Oded (2014) Three-dimensional Hadamard-encoded proton spectroscopic imaging in the human brain using time-cascaded pulses at 3 Tesla. Magn Reson Med 72:923-33

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