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Using a mouse model of MS, termed as experimental autoimmune encephalomyelitis (EAE), we performed chemical exchange saturation transfer (CEST) MRI at a very early stage before symptom onset (6\u00a0days post\u2010induction) for assessment of changes in tissues that appear \u201cnormal\u201d with conventional MRI. The collected CEST Z\u2010spectra signals (S<jats:sub>sat<\/jats:sub>\/S<jats:sub>0<\/jats:sub>) were analyzed using a histogram\u2010guided method to determine the contributions from various offset frequencies. Histogram analysis showed that EAE mice exhibit a more heterogeneous distribution with lower peak heights in the hindbrain compared with na\u00efve mice at saturation offsets of 1 and 2\u00a0ppm. At these two offsets, both the mean S<jats:sub>sat<\/jats:sub>\/S<jats:sub>0<\/jats:sub> and the mean MTR<jats:sub>asym<\/jats:sub> values in the cerebellum and brain stem are significantly different between EAE and na\u00efve mice (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Immunofluorescent staining validated the presence of neuroinflammation, with IBA1\u2010positive cells detected throughout the hindbrain including the cerebellum and brain stem. Follow\u2010up MRI at the symptom onset (score\u00a0=\u00a01.5\u20132.5, 13\u00a0days post\u2010induction) confirmed gadolinium\u2010enhanced periventricular lesions. CEST Z\u2010spectra signals also changed by this time. The proposed three\u2010level histogram\u2010oriented analysis is simple to execute and robust for detecting subtle changes in Z\u2010spectra signals, which does not require a priori knowledge of damage locations or contributing offset components. CEST MRI signals at 1 and 2\u00a0ppm were sensitive to the subtle pathological changes at an early stage in EAE mice, and have potential as novel imaging biomarkers complementary to functional and physiological MRI measures.<\/jats:p>","DOI":"10.1002\/nbm.4139","type":"journal-article","created":{"date-parts":[[2019,7,25]],"date-time":"2019-07-25T03:46:12Z","timestamp":1564026372000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["CEST MRI with distribution\u2010based analysis for assessment of early stage disease activity in a mouse model of multiple sclerosis: An initial study"],"prefix":"10.1002","volume":"32","author":[{"given":"Tao","family":"Liu","sequence":"first","affiliation":[{"name":"Russell H. 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