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

描述（由申请人提供）：原发性进行性（PP）形式占整个多发性硬化症（MS）患者群体的10% -15%，在美国为-45,000。与更普遍的（~80%）复发缓解型（RR）疾病相比，PP-MS的特点是临床恶化的严重程度与MRI指标的缺乏之间存在差异：病变较少，病变形成率较低，对比增强较少。放射学标志物的不敏感性使PP-MS患者无法参与大多数新疗法的随机试验，这些试验的疗效是通过临床结果和MRI指标（增强和新T2病变的数量）来评估的。因此，尽管这种表型的预后比RR-MS差，但目前尚无治疗方法。临床和磁共振结果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在疾病进展中必须发挥关键作用，这导致我们提出三个假设：

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.