Serial Brain 3D 1H MR Spectroscopy in Multiple Sclerosis

临床T2和对比度增强TL加权磁共振成像(MRI)已成为评估多发性硬化症(MS)的首选诊断方法，因为它们对大脑中的急性、通常是亚临床事件敏感，并且能够测量疾病随着时间的积累。然而，MRI缺乏特异性，因为到目前为止，关于这些病变的数量和体积、“疾病的负荷”以及相关的神经缺陷的报告相互矛盾。此外，临床MRI对隐匿性白质(WM)和大多数灰质(GM)的病理完全视而不见。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被用来探索正常外观白质(NAWM)及其病变的潜在代谢。由于MS的发病机制始于分子细胞水平，我们建议使用最先进的、短回声时间、三维高空间分辨率局部和全局1H-MRS方法来检验三个假设：HI：MS病变发生在已经代谢异常的WM区域；H2：NAWM中持续异常的代谢活动，病变甚至没有Gd增强(当前的活动标记)；H3：全局全脑量化神经细胞标记N-乙酰天冬氨酸(NAA)的下降率反映了患者疾病的侵袭性，因此可以预测该患者的未来进程。这些假说将通过跟踪25名复发缓解(RR)MS患者和25名匹配对照的队列进行验证，为期5年，有三个具体目标：具体目标1是对NAWM中的总体代谢物水平进行纵向跟踪，以建立当前MRI-隐匿性疾病活动的标记。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有哪些局灶性变化，并确定这些病变的结果-修复或成为慢性。具体目标3是将整个大脑及其WM和GM部分的NAA水平与患者的临床缺陷相关联，以确立NAA作为疾病严重程度和未来病程的预报器。这项研究与健康相关的是它建立、量化和验证RR MS进展的非侵入性放射代谢替代标记物的潜力，这将使我们能够：(I)评估疾病活动的当前水平，从而(Ii)提高我们预测这些(年轻)患者未来进程的能力；以及(Iii)改进对药物和治疗试验中的反应的监测。

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.