MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome

Earley, Christopher J.; Barker, Peter B.; Horská, Alena; Allen, Richard P.

doi:10.1016/j.sleep.2005.11.009

Cited by 227 publications

(130 citation statements)

References 12 publications

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“…Given the very small effect seen with the CSF ferritin, it is not surprising that no effect was found for the MRI. As has been shown elsewhere, the MRI determination of brain iron is substantially less sensitive then that of CSF ferritin [2,4]}. The mean changes with treatment seen in this study for MRI iron index of the substantia nigra and for the CSF ferritin were similar order but the variance for MRI data was nearly 10 times that for CSF ferritin.…”

Section: Discussionsupporting

confidence: 68%

“…MRI imaging was used to quantify iron in the brain as has been done in prior brain iron assessments of RLS patients [4,22]. All brain scans were performed on a 3.0 Tesla Philips MR scanner.…”

Section: Questionnaires and Proceduresmentioning

confidence: 99%

“…In the last 10 years there have been several studies which have examined this hypothesis in regards to brain iron. CSF analyses of ferritin, MRI quantification and B-mode imaging of iron in the brain, and finally autopsy studies have all implicate brain iron insufficiency as a primary player in the underlying pathology of RLS [2][3][4][5][6][7]. The CSF, MRI and B-mode imaging studies demonstrated brain iron changes despite measures of plasma iron status being in the normal clinical range.…”

Section: Introductionmentioning

confidence: 99%

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A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome

et al. 2009

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Objective: The aim of this study was to ascertain whether high-dose intravenous (IV) iron sucrose could improve symptoms and change brain iron concentrations in idiopathic RLS. Methods:The study was a randomized, parallel-group double-blind study of 1000 mg iron sucrose given IV versus placebo. Primary measures of the clinical status were global rating scale (GRS) and periodic leg movements of sleep (PLMS). Primary measures of brain iron status were CSF ferritin and MRI-determined iron in the substantia nigra.Results: At the time of the interim analysis there were 7 placebo and 11 iron-treated subjects. At 2-weeks post-treatment, iron treatment resulted in a small but significant increase in CSF ferritin and decrease in RLS severity (GRS) but did not change PLMS or MRI iron index. None of the secondary outcomes changed with treatment. There was no single case of clear treatment benefit in any of the patients. This interim analysis revealed an effect size that was too small to allow for adequate power to find significant differences with the planed 36-subject enrollment for either the primary objective outcome of PLMS or any of the secondary outcomes. The study was stopped at this planned breakpoint given the lack of both adequate power and any indication for clinically significant benefit.Conclusions: High-dose IV iron failed to demonstrate the robust changes reported in three prior open-label studies. Differences in iron formulation, dosing regiment, and peripheral iron status may explain some of the discrepancies between this and previous IV iron treatment studies.

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Section: Discussionsupporting

confidence: 68%

Section: Questionnaires and Proceduresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome

et al. 2009

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“…Since ferritin levels are mainly controlled by iron availability, its measurement by IHC or western blotting is usually considered as a marker of the metal distribution in the brain parenchyma, useful to confirm MRI data eventually indicating perturbation in brain iron density. For example, imaging and transcranial sonography studies indicated reduced concentration of iron in the SN of patients with early onset of the Restless Legs Syndrome, but normal iron in those with late onset (Schmidauer et al 2005;Earley et al 2006). The histological analysis of the same brain region in autopsies of the first group showed a reduction of ferritin (particularly of the H chain) in melanized neurons, that paralleled the hypointense signal of MRI (Connor et al 2003).…”

Section: Ferritin In Brain Disorders With Altered Iron Homeostasismentioning

confidence: 98%

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

2014

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Iron is an abundant transition metal that is essential for life, being associated to many enzyme and oxygen carrier proteins involved in a variety of fundamental cellular processes. At the same time the metal is potentially toxic due to its capacity to engage in the catalytic production of noxious reactive oxygen species. The control of iron availability in the cells is largely dependent on ferritins, ubiquitous proteins with storage and detoxification capacity. In mammals, cytosolic ferritins are composed of two types of subunits, the H and the L chain, assembled to form a 24-mer spherical cage. Ferritin is present also in mitochondria, in the form of a complex with 24 identical chains. Even though the proteins have been known for a long time, their study is a very active and interesting field yet. In this review we will focus our attention to mammalian cytosolic and mitochondrial ferritins, describing the most recent advancement regarding their storage and antioxidant function, the effects of their genetic mutations in human pathology, and also the possible involvement in non-iron related activities. We will also discuss recent evidence connecting ferritins and the toxicity of iron in a set of neurodegenerative disorder characterized by focal cerebral siderosis. IntroductionThe adaptation of life to an oxic environment required the development of mechanisms to deal with the transformation of the water soluble ferrous ion (Fe 2+ ) to the insoluble ferric ion (Fe 3+ ) and with the concomitant generation of dangerous reactive oxygen species (ROS). The ferritin molecules represent an important and ancient mean developed by organisms in the three domains of life to safely handle the necessary, yet potentially toxic metal. Their ability to detoxify and store the metal through safe oxidation processes protects the cells from undue iron-dependent redox chemistry, while a controlled release of the metal guarantees its availability for different and essential enzymatic reactions. Storage and detoxification of iron represent the main functions of these molecules, and much work has been done to understand the chemical and molecular details of this

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“…3 Histopathologic studies in idiopathic RLS have shown decreased iron staining in the substantia nigra and minimal transferrin-receptor staining in neuromelanin cells. 4 MR imaging studies by using T2 relaxometry metrics have shown a lower iron content of the substantia nigra in eRLS 5 and late-onset RLS. 6 With VBM, the brain volume has been assessed in patients with RLS, with conflicting findings.…”

mentioning

confidence: 99%

Investigation of Unmedicated Early Onset Restless Legs Syndrome by Voxel-Based Morphometry, T2 Relaxometry, and Functional MR Imaging during the Night-Time Hours

Margariti

Astrakas²,

Tsouli³

et al. 2011

AJNR Am J Neuroradiol

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MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome

Cited by 227 publications

References 12 publications

A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome

A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

Investigation of Unmedicated Early Onset Restless Legs Syndrome by Voxel-Based Morphometry, T2 Relaxometry, and Functional MR Imaging during the Night-Time Hours

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