MRI measurement of brain iron in patients with restless legs syndrome

Allen, Richard P.; Barker, Peter B.; Wehrl, F.; Song, Hee Kwon; Earley, Christopher J.

doi:10.1212/wnl.56.2.263

Cited by 504 publications

(285 citation statements)

References 9 publications

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“…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%

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: Questionnaires and Proceduresmentioning

confidence: 99%

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

et al. 2009

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“…Insufficient or surplus iron in the brain has been associated with various neurological diseases (6 -10). Although iron deficiency is associated with cognitive and brain structural deficits, excess brain iron is implicated in Alzheimer's, Parkinson's, and other neurodegenerative diseases (10,11). Therefore, it is not surprising that iron levels are tightly regulated in the brain (10).…”

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confidence: 99%

Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Beydoun¹,

Hamood²,

Zubieta

et al. 2017

Journal of Biological Chemistry

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Edited by Paul E. FraserIron is essential for brain function, with loss of iron homeostasis in the brain linked to neurological diseases ranging from rare syndromes to more common disorders, such as Parkinson's and Alzheimer's diseases. Iron entry into the brain is regulated by the blood-brain barrier (BBB). Molecular mechanisms regulating this transport are poorly understood. Using an in vitro model of the BBB, we identify NHE9, an endosomal cation/proton exchanger, as a novel regulator of this system. Human brain microvascular endothelial cells (hBMVECs) that constitute the BBB receive brain iron status information via paracrine signals from ensheathing astrocytes. In hBMVECs, we show that NHE9 expression is up-regulated very early in a physiological response invoked by paracrine signals from iron-starved astrocytes. Ectopic expression of NHE9 in hBMVECs without external cues induced up-regulation of the transferrin receptor (TfR) and down-regulation of ferritin, leading to an increase in iron uptake. Mechanistically, we demonstrate that NHE9 localizes to recycling endosomes in hBMVECs where it raises the endosomal pH. The ensuing alkalization of the endosomal lumen increased translocation of TfRs to the hBMVEC membrane. TfRs on the membrane were previously shown to facilitate both recycling-dependent and -independent iron uptake. We propose that NHE9 regulates TfR-dependent, recycling-independent iron uptake in hBMVECs by fine-tuning the endosomal pH in response to paracrine signals and is therefore an important regulator in iron mobilization pathway at the BBB.There is high demand for iron in the brain, one of the most metabolically active organs in the body (1, 2). Iron is a co-factor of several proteins involved in specialized brain cell functions such as synthesis of neurotransmitters and myelination (3-5). Iron is also necessary for housekeeping functions such as mitochondrial respiration and DNA synthesis, crucial for brain function (5). Insufficient or surplus iron in the brain has been associated with various neurological diseases (6 -10). Although iron deficiency is associated with cognitive and brain structural deficits, excess brain iron is implicated in Alzheimer's, Parkinson's, and other neurodegenerative diseases (10, 11). Therefore, it is not surprising that iron levels are tightly regulated in the brain (10).Iron entry into the brain is regulated by the blood-brain barrier (BBB) 3 (10). This physiological barrier is characterized by tight junctions between brain microvascular endothelial cells (BMVECs) that block passive diffusion of iron into the brain (12). BMVECs are polarized cells with one surface (apical) facing the blood and the other (basal or abluminal) facing interstitial fluid of the brain. BMVECs and ensheathing astrocytes form the regulatory axis of the BBB, modulating iron transport from blood into the brain interstitium (2, 13). It is now known that BMVECs are the focal point for regulation of cerebral iron homeostasis and not mere conduits for iron transport (14). Paracrine fac...

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“…Summarizing, it is not known whether PLM would be a consequence of the absence of superior efferences to the spinal cord, which would cause an increase in the excitability of the motoneurons, or if it is a primary phenomena coming from a generator located inside the human spinal cord. If its origin is in the superior central nervous system, it is not known if the abnormal movements would be correlated with the sleep stage 3 , relative concentration of iron in the red nucleus 16 , and lack of iron in the blood caused by anemia or central neurotransmitters disorders 17 . If its origin is intrinsic to the spinal cord, the action of the neurotransmitters in the spinal cord might be one of the causes of PLM.…”

Section: Periodic Limb Movement In Spinal Cord Injury Patientsmentioning

confidence: 99%

Spinal cord injury as a trigger to develop periodic leg movements during sleep: an evolutionary perspective

Telles

Alves

Chadi

2012

Arq. Neuro-Psiquiatr.

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Spinal cord injury as a trigger to develop periodic leg movements during sleep: an evolutionary perspectiveLesão medular como gatilho para desenvolver movimentos periódicos das pernas durante o sono: uma perspectiva evolutiva Susana Cristina Lerosa Telles, Rosana S. Cardoso Alves, Gerson ChadiThe periodic limb movement (PLM) disorder is characterized by periodic episodes of repetitive and highly stereotyped limb movements, which occur during sleep, and by clinical sleep disturbance that cannot be accounted for by another primary sleep disorder 1 . They consist of the big toe extension in combination with partial flexion of the ankle and, sometimes, hip (Fig 1). Similar movements can occur in the upper limbs. This occurrence in spinal cord injury (SCI) patients 2 (Fig 2) suggests the spinal origin of those movements, which could be due to the disruption of REM-related inhibitory spinal pathways, producing the disconnection or disinhibition of a spinal generator, which is a kind of local pacemaker 3 .Restless legs syndrome (RLS) is a sensorimotor disorder frequently related to PLM and was recently reported in SCI patients 2 . It is characterized by a complaint of a strong, nearly irresistible, urge to move the legs, which is made worse by rest (lying or sitting) and is at least partially and temporarily relieved by walking or moving the legs. The relief is usually immediate. The urge to move the legs worsens in the evening and at night 1 . Scientific reviews have addressed the probable central pattern generator (CPG) in SCI patients and its outcome to rehabilitation. We based this review on an evolutionary perspective of CPG development from invertebrates to mammals, in order to point to the probable CPG action in humans during PLM. ABSTRACTThe primary trigger to periodic limb movement (PLM) during sleep is still unknown. Its association with the restless legs syndrome (RLS) is established in humans and was reported in spinal cord injury (SCI) patients classified by the American Spinal Injury Association (ASIA) as A. Its pathogenesis has not been completely unraveled, though recent advances might enhance our knowledge about those malfunctions. PLM association with central pattern generator (CPG) is one of the possible pathologic mechanisms involved. This article reviewed the advances in PLM and RLS genetics, the evolution of CPG functioning, and the neurotransmitters involved in CPG, PLM and RLS. We have proposed that SCI might be a trigger to develop PLM.Key words: nocturnal myoclonus syndrome, restless legs syndrome, spinal cord regeneration. RESUMOO gatilho principal para o desenvolvimento de movimentos periódicos dos membros (MPM) durante o sono ainda é desconhecido. A associação entre o MPM e a síndrome das pernas inquietas (SPI) em seres humanos já foi previamente estabelecida e relatada em pacientes com lesão medular (LM), classificados pela American Spinal Injury Association (ASIA) como A. A patogênese do MPM não foi completamente desvendada, apesar de avanços recentes poderem ampliar o conhecimento sobre...

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MRI measurement of brain iron in patients with restless legs syndrome

Cited by 504 publications

References 9 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

Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Spinal cord injury as a trigger to develop periodic leg movements during sleep: an evolutionary perspective

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