IV IRON METABOLISM IN RLS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 不宁腿综合征（RLS）是一种多巴胺反应性感觉运动障碍，其症状在夜间占主导地位，导致显著的睡眠丧失和生活质量的变化。中枢神经系统（CNS）铁代谢的改变可能在RLS中起关键作用。血清铁蛋白的降低与RLS症状的增加相关。RLS患者脑脊液（CSF）铁蛋白减少，CSF转铁蛋白增加，表明脑铁储备减少。开放标签、非对照铁剂治疗对某些RLS患者有效。 我们的初步数据支持RLS的结果从改变多巴胺能机制，这是沉淀的铁在大脑中的相对或绝对减少。我们也有数据表明铁从血清到脑组织的正常转移可能减少，这可能与通过血脑屏障的异常运输有关。这表明静脉注射（IV）铁可以纠正RLS中的脑铁缺乏。因此，我们的假设是：（1）静脉铁剂治疗将改善中枢神经系统（CNS）的铁状态。(2)静脉铁剂治疗将改善RLS患者的症状。(3)IV铁剂治疗改善CNS铁状态将平行改善RLS指标，（4）对IV铁剂治疗的反应根据RLS症状发作时的年龄而不同。 在一项随机、双盲试验中，RLS患者将接受1000 mg铁或安慰剂单次IV给药。预计单次IV治疗将缓解RLS症状2-12个月。我们将使用CSF铁蛋白、其他铁相关蛋白的测量值和脑铁储存的MRI测量值来评估输注后CNS铁状态的变化。输注后，将使用临床状态的标准主观和客观指标评估RLS变化。将在治疗前、治疗后2周和12个月或症状恢复时获得CSF中的铁值、血清铁值、MRI脑部测量值以及睡眠和固定试验的临床评价。治疗后每月获得临床评分、腿部活动仪记录和血清铁蛋白。将CSF铁蛋白变化与我们先前研究的变化进行比较。症状将与CSF铁蛋白和MRI铁值相关。我们的研究表明，早期和晚期发作的RLS对铁的反应可能存在差异。因此，将单独评价基于症状发作年龄的治疗反应。 IV铁减少脑铁不足并显著减少RLS症状的预期发现强烈支持我们由脑铁不足引起的RLS模型。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Restless Legs Syndrome (RLS) is a dopamine-responsive, sensory-motor disorder whose symptoms predominate at night leading to significant sleep loss and changes in one's quality of life. Altered Central Nervous System (CNS) iron metabolism may play a pivotal role in RLS. Decreasing serum ferritin has shown to correlate with increasing RLS symptoms. RLS patients have decreased Cerebral Spinal Fluid (CSF) ferritin and increased CSF transferrin, suggesting decreases in brain iron stores. Open-labeled, non-controlled iron therapy has been effective in treating some patients with RLS. Our preliminary data supports that RLS results from altered dopaminergic mechanisms, which are precipitated by a relative or absolute reduction of iron in the brain. We also have data indicating there may be a decrease in the normal transfer of iron from serum to brain tissue possibly related to abnormal transport across the blood brain barrier. This indicates that intravenous (IV) iron may correct the brain iron deficits in RLS. Therefore, our hypotheses are: (1) IV iron therapy will improve the Central Nervous System (CNS) iron status. (2) IV iron therapy will improve symptoms in RLS patients. (3) Improved CNS iron status with IV iron treatment will parallel improvements in measures of RLS and, (4) the response to IV iron therapy differs based upon age at onset of RLS symptoms. \par Iron 1000-mg or placebo will be given as a single IV dose to RLS patients in a randomized, double blind trial. It is anticipated that single IV treatment will provide relief of RLS symptoms for 2-12 months. We will evaluate post-infusion changes in CNS iron status using CSF measurements of ferritin, other iron-related proteins and MRI measurements of brain iron stores. Post-infusion, RLS changes will be assessed using standard subjective and objective measures of clinical status. Iron values in CSF, serum iron values, MRI brain measures and clinical evaluations with sleep and immobilization tests will be obtained prior to treatment, 2-weeks after treatment and at 12-months or when symptoms return. Clinical ratings, Leg Activity Meter recordings and serum ferritin will be obtained monthly after treatment. CSF ferritin changes will be compared to those from our prior studies. Symptoms will be correlated with CSF ferritin and MRI iron values. Our studies demonstrated possible differences in response to iron for early and late onset RLS. So treatment response based on the age of symptom onset will be evaluated separately. An expected finding that IV iron reduces the brain iron insufficiency and dramatically reduces the RLS symptoms strongly supports our model of RLS caused by brain iron insufficiency.