IV IRON METABOLISM IN RLS\PAR }

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。不宁腿综合症(RLS)是一种多巴胺反应的感觉-运动障碍，其症状在夜间占主导地位，导致严重的睡眠不足和生活质量的改变。中枢神经系统(CNS)铁代谢改变可能在RLS中起关键作用。血清铁蛋白降低与RLS症状增加相关。RLS患者脑脊液铁蛋白降低，脑脊液转铁蛋白升高，提示脑铁储存减少。开放标记、非控制的铁疗法在治疗一些RLS患者中已经很有效。我们的初步数据支持RLS是由改变的多巴胺能机制引起的，这种机制是由大脑中铁的相对或绝对减少引起的。我们也有数据表明，从血清到脑组织的正常铁转移可能减少，可能与血脑屏障的异常转移有关。这表明静脉注射铁可以纠正RLS的脑铁缺乏。因此，我们的假设是：(1)静脉补铁能改善中枢神经系统(CNS)的铁状态。(2)静脉补铁可改善RLS患者的症状。(3)静脉铁治疗改善中枢神经系统铁状况将同时改善RLS的测量；(4)静脉铁治疗的反应因出现RLS症状的年龄而异。在一项随机的双盲试验中，铁1000毫克或安慰剂将作为单次静脉注射给RLS患者。预计单一静脉注射治疗将在2-12个月内缓解RLS症状。我们将通过脑脊液中铁蛋白、其他铁相关蛋白的测量以及脑铁储存的核磁共振测量来评估输注后中枢神经系统铁状态的变化。输液后，RLS的变化将使用临床状态的标准主观和客观测量来评估。在治疗前、治疗后2周、12个月或症状复发时，将获得脑脊液中的铁值、血清铁值、MRI脑部测量以及睡眠和制动试验的临床评估。临床评分、腿部活动仪记录和血清铁蛋白将在治疗后每月获得。脑脊液铁蛋白的变化将与我们之前的研究进行比较。症状将与脑脊液铁蛋白和磁共振铁值相关。我们的研究表明，早发和晚发的RLS对铁的反应可能存在差异。因此，根据症状出现的年龄进行治疗反应将单独进行评估。一项预期的发现表明，静脉注射铁可以减少大脑铁缺乏，并显着减少RLS症状，这有力地支持了我们的由大脑铁缺乏引起的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. 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.