This Project focuses on determining: first, the abnormalities in the CNS dopaminergic system in RLS (Phase 1) and second, the effect of iron treatment on the established DA abnormalities (Phase 2). Phase 1 is designed to explore for abnormalities in the tuberoinfundibular (prolactin pulsatility), nigrostriatal (PET imaging of midbrain and striatum), and mesolimbic (PET imaging of ventral striatum/n, accumbens) DAergic systems during the day. The DA-2 receptor (D2R) binding potential and Bmax, DA transporter (DAT) and DA synaptic release will be measured with state-of-the- art PET imaging techniques from 8:30 - 12:00AM. Prolactin will be measured during the morning, before and after metoclopramide to assess DAergic sensitivity to D2R blockage. Any changes that are found in the DA system will be correlated with MRI measures of regional brain iron concentrations and measures of clinical severity. Idiopathic RLS patients and aged-matched controls will be studied in this Phase. In Phase 2, the effect of a single 1000-mg IV dose of iron on the DA abnormalities that are found on PET or prolactin assessment in Phase 1 (or in the current RO1 PET study), will be assessed. The IV iron infusion techniques to be used in this phase are similar to those used in Project #2. The primary analysis in this Phase will involve the effects of IV iron on the dopaminergic system.
Aim 1 : To determine dopaminergic differences between RLS and controls by PET scanning techniques and measures of prolactin.
Aim 2 : To evaluate the normal circadian changes in the dopaminergic systems and assess differences in these circadian changes between RLS and normal controls.
Aim 3 : To determine if there are any significant correlations between the abnormalities in the CNS dopamine system and CNS iron status in RLS.
Aim 4 : To determine if there is any significant correlation between measurements of dopaminergic activity and RLS symptoms.
Aim 5 : To determine the causal relation between brain iron and dopaminergic function in RLS.
| Connor, James R; Patton, Stephanie M; Oexle, Konrad et al. (2017) Iron and restless legs syndrome: treatment, genetics and pathophysiology. Sleep Med 31:61-70 |
| Allen, Richard P; Donelson, Nathan C; Jones, Byron C et al. (2017) Animal models of RLS phenotypes. Sleep Med 31:23-28 |
| Skeba, Patrick; Hiranniramol, Kasidet; Earley, Christopher J et al. (2016) Inter-movement interval as a primary stable measure of periodic limb movements of sleep. Sleep Med 17:138-43 |
| Allen, Richard P (2015) Restless Leg Syndrome/Willis-Ekbom Disease Pathophysiology. Sleep Med Clin 10:207-14, xi |
| Unger, Erica L; Bianco, Laura E; Jones, Byron C et al. (2014) Low brain iron effects and reversibility on striatal dopamine dynamics. Exp Neurol 261:462-8 |
| Unger, E L; Jones, B C; Bianco, L E et al. (2014) Diurnal variations in brain iron concentrations in BXD RI mice. Neuroscience 263:54-9 |
| Unger, E L; Earley, C J; Thomsen, L L et al. (2013) Effects of IV iron isomaltoside-1000 treatment on regional brain iron status in an iron-deficient animal. Neuroscience 246:179-85 |
| Allen, Richard P; Barker, Peter B; Horská, Alena et al. (2013) Thalamic glutamate/glutamine in restless legs syndrome: increased and related to disturbed sleep. Neurology 80:2028-34 |
| Jellen, L C; Lu, L; Wang, X et al. (2013) Iron deficiency alters expression of dopamine-related genes in the ventral midbrain in mice. Neuroscience 252:13-23 |
| Earley, Christopher J; Kuwabara, Hiroto; Wong, Dean F et al. (2013) Increased synaptic dopamine in the putamen in restless legs syndrome. Sleep 36:51-7 |
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