Restless Legs Syndrome (RLS) is a common sensory-motor disorder whose symptoms predominans Legs Syndrome (RLS) is a common sensory-motor disorder whose symptoms predominant at night and often lead to significant sleep loss and changes in one's quality of life. Like Parkinson's disease, restless legs syndrome is exquisitely sensitive to dopamine agents and aggravated or precipitated by dopamine antagonists. Previous studies and our pilot data are consistent with an involvement of brain iron and dopamine in the pathogenesis of RLS. Based on that data we have proposed that RLS symptoms result from altered dopaminergic mechanisms, which are precipitated by a relative or absolute reduction of iron in the brain. Prior PET and SPECT studies found small decreases in D2R binding potentials and one study have reported abnormal prolactin release. These studies were all done during the day when subjects are asymptomatic and therefore the clinical relevance of the findings is in question. Prior studies have also suggested the presence of brain-iron-insufficiency state in restless legs syndrome. Although the obvious iron-dopamine relation is tyrosine hydroxylase's dependency on iron as a co-factor, animal studies suggest a more dynamic effect of CNS iron reduction on dopaminergic function. Of relevance to this Project is that iron-deficiency animals show similar CNS DA abnormalities to those observed in the limited PET studies of restless legs syndrome . This project is designed to assess abnormalities expected in the tuberoinfundibular (prolactin pulsatility), Nigrostriatal (Pet imaging of midbrain and striatum) and mesolimbic (PET imaging of nucleus accumbens) DA systems. Our general model leads to the following hypotheses to be tested in this project: (1) PET and pulsatile prolactin indices of the dopaminergic activity will be altered in RLS patients compared with controls; degree of abnormalities noted in these indices will correlate (2) with CSF and/or MRI indices of brain iron status and/or (3) with clinical symptom severity. A 4-PET procedure will assess D2R binding potential and Bmax; DAT; and DA release (amphetamine challenge) in the N. Accumbens, Striatum, and Substantia Nigra of RLS and control subjects. Prolactin will be measured at 10-minute intervals to determine release and pulsatility values. Using CSF and MRI measurements of iron will assess the CNS iron status. RLS severity will be based on subjective (rating scale and diary) and objective (PSG) measurements.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-3 (02))
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Mitler, Merrill
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Johns Hopkins University
Schools of Medicine
United States
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