Novel MRI and 1H-MRS markers in Primary Progressive MS

描述(由申请人提供)：原发进展型(PP)占美国多发性硬化症(MS)患者总数的10%-15%，-45000人。与更常见(约80%)的复发缓解(RR)型相比，PP-MS的特点是临床恶化的严重程度与MRI指标的缺乏不同：病变较少，病变形成率较低，对比增强较少。放射标志物的不敏感性使PP-MS患者无法参加大多数新治疗的随机试验，在这些试验中，疗效是通过临床结果和MRI指标(强化和新T2病变的数量)来评估的。因此，目前没有提供任何治疗方法，即使这种表型的预后比RR-MS更差。有研究表明，临床和MR表现之间的差异可能是由于MRI-隐匿性脑病理所致。因此，我们的中心前提是，这种弥漫性微观损伤必须在疾病进展中发挥关键作用，从而导致我们提出三个假设： 假设1(HI)：持续的轴突损伤，反映为全脑./V-乙酰天冬氨酸(WBNAA)缺乏，PP-MS患者比RR-MS患者更严重，并与较差的认知表现相关。假设2(H2)：PP-MS患者的胆碱(Cho)和肌酸(Cr)水平将低于RR-MS患者，反映较少的炎症和少突胶质细胞的凋亡；最后，由于胶质增生增加，Wyo-inositol(Ml)水平将更高；假设3(H3)：PP-MS患者的灌注-MRI指标(脑血流和平均通过时间)将比RR-MS患者更严重，这是由于炎症程度较轻但持续时间较长。血流灌注指标将与脑脊液(CSF)和血液中与缺血性损伤和神经变性有关的肿瘤坏死因子-α(TNF-a)水平相关。为了验证这些假说，我们提出了三个具体目标：具体目标1：比较PP-MS、年龄和性别匹配的RR-MS和健康对照组的WBNAA、Cho、Cr和m1水平。具体目标2：比较相同三组受试者的磁共振灌注成像指标。具体目标3：将WBNAA和灌注-MRI指标相互关联，并与神经和认知损害的临床指标、脑脊液和血液中肿瘤坏死因子-1及其可溶性受体的水平相关联。本项目的健康相关性：(I)测试定量MRI和‘H-MRS潜在的疾病活动性替代标记物，以便在临床试验中有效地监测PP-MS；(Ii)探讨MS的微血管变化、脱髓鞘和神经变性之间的关系。

DESCRIPTION (provided by applicant): The primary-progressive (PP) form represents 10% -15% of the overall multiple sclerosis (MS) patient population, -45,000 in the US. Compared with the more prevalent (~80%) relapsing-remitting (RR) form of the disease, PP-MS is characterized by a discrepancy between the severity of clinical deterioration and the paucity of MRI indicators: Fewer lesions, lower lesion formation rate, and less contrast enhancement. The insensitivity of the radiological markers has precluded PP-MS patients from most randomized trials of new treatments, in which efficacy is evaluated by both clinical outcomes and MRI metrics (number of enhancing and new T2 lesions). Consequently, no treatments are currently offered, even though the prognosis for this phenotype is worse than for RR-MS. It has been suggested that the disparity between clinical and MR findings might be due to MRI-occult brain pathology. Therefore, our central premise is that such diffuse microscopic damage must play a key role in disease progression, leading us to formulate three hypotheses: Hypothesis 1 (HI): Ongoing axonal damage, reflected by whole-brain ./V-acetylaspartate (WBNAA) deficit, will be greater in PP-MS than in RR-MS and will correlate with poorer cognitive performance. Hypothesis 2 (H2): Choline (Cho) and creatine (Cr) levels will be lower in PP-MS than in RR-MS patients, reflecting less inflammation and oligodendrocyte apoptosis; finally, wyo-inositol (ml) levels will be higher due to increased gliosis; Hypothesis 3 (H3): perfusion-MRI metrics (cerebral blood flow and mean transit time) will be more impaired in PP-MS than in RR-MS patients, due to less intense but more prolonged inflammation. The perfusion metrics will be correlated with cerebrospinal fluid (CSF) and blood levels of tumor necrosis factor-a (TNF-a) which is related to ischemic injury and neurodegeneration. To test these hypotheses we propose three Specific Aims: Specific Aim 1: To compare the WBNAA, Cho, Cr and ml levels in PP-MS, age and sex matched RR-MS and healthy control subjects. Specific Aim 2: To compare the perfusion MRI metrics in the same three subject groups. Specific Aim 3: To correlate WBNAA and perfusion-MRI metrics against each other and with clinical measures of neurological and cognitive impairment, CSF and blood levels of TNF- and its soluble receptors. The health relatedness of this project: (i) To test quantitative MRI and 'H-MRS potential surrogate markers of disease activity that could facilitate effective monitoring of PP-MS in clinical trials, (ii) To investigate the relationship between microvascular changes, demyelination and neurodegeneration in MS.