Serial Brain 3D 1H MR Spectroscopy in Multiple Sclerosis

临床T2和对比增强的T1加权磁共振成像（MRI）已成为多发性硬化症（MS）的评价中选择的诊断模式，因为它们对大脑中的急性、经常是亚临床事件的敏感性以及它们测量疾病随时间的累积的能力。然而，MRI缺乏特异性，因为迄今为止，关于这些病变的数量和体积、“疾病负荷”和相关的神经功能缺损的报道相互矛盾。此外，临床MRI对隐匿性白色物质（WM）和大多数灰质（GM）病理学是完全盲的。对更可靠的替代标记物的需求经常导致质子磁共振波谱1HMRS被用于探测正常出现的WM（NAWM）及其病变的潜在代谢。由于MS发病机制始于分子细胞水平，我们建议使用最先进的、短回波时间的、三维高空间分辨率的局部和全局1H-MRS方法来检查三个假设：MS病变发生在已经代谢异常的WM区域; H2：异常代谢活动持续存在于NAWM，病变甚至没有Gd增强（“活性”的当前标记）;和H3：神经元细胞标志物N-乙酰天冬氨酸（NAA）的下降率的全局全脑定量反映了患者疾病的侵袭性，因此，可以预测它在那个人身上的未来走向。这些假设将通过随访25例复发缓解型（RR）MS患者和25例匹配对照的队列进行检验，随访时间为5年，具体目标有三个：具体目标1是对NAWM中的总体代谢物水平进行纵向随访，以建立当前MRI隐匿性疾病活动的标志物。 具体目标2是跟踪NAWM中的局部代谢，以确定在病变形成之前的病灶变化，并确定这些病变的结果-修复或变为慢性。 具体目标3是将全脑及其WM和GM部分的NAA水平与患者的临床缺陷相关联，以建立NAA作为疾病严重程度和未来病程的预测器。本研究的健康相关性是其建立、量化和验证RR MS进展的非侵入性放射代谢替代标志物的潜力，这将使我们能够：（i）测量疾病活动的当前水平，从而（ii）提高我们预测这些（年轻）患者未来病程的能力;并因此（iii）改善药物和治疗试验中的反应监测。

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.