IV IRON METABOLISM IN RLS\PAR }

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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.