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

描述（由申请人提供）：原发-进展（PP）形式占总体多发性硬化（MS）患者人群的10%-15%，在美国约为45，000人。与更普遍（约80%）的复发-缓解（RR）形式的疾病相比，PP-MS的特点是临床恶化的严重程度和MRI指标的缺乏之间的差异：更少的病变，更低的病变形成率，以及更少的对比增强。放射学标记物的不敏感性使PP-MS患者无法参加大多数新治疗的随机试验，这些试验通过临床结局和MRI指标（增强和新发T2病变的数量）评价疗效。因此，目前没有提供治疗，即使这种表型的预后比RR-MS差。有人认为，临床和MR结果之间的差异可能是由于MRI隐匿性脑病理。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，这使我们提出三个假设： 假设1（HI）：持续性轴突损伤，反映在全脑。V-乙酰天冬氨酸（WBNAA）缺陷，将在PP-MS比RR-MS更大，并将与较差的认知表现。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，反映出炎症和少突胶质细胞凋亡较少;最后，由于神经胶质增生增加，肌醇（ml）水平将较高;假设3（H3）：灌注-MRI指标PP-MS患者的脑血流（脑血流量和平均通过时间）将比RR-MS患者受损更严重，这是由于炎症强度较低但时间较长。灌注度量将与脑脊髓液（CSF）和肿瘤坏死因子-α（TNF-α）的血液水平相关，肿瘤坏死因子-α与缺血性损伤和神经变性相关。为了检验这些假设，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和健康对照受试者的WBNAA、Cho、Cr和ml水平。具体目标2：比较相同三个受试者组的灌注MRI指标。具体目标3：将WBNAA和灌注-MRI指标相互关联，并与神经和认知功能障碍、CSF和TNF-α及其可溶性受体的血液水平的临床指标关联。本项目的健康相关性：（i）测试定量MRI和1H-MRS潜在的疾病活动替代标记物，这些标记物可促进临床试验中PP-MS的有效监测，（ii）研究MS中微血管变化、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.