Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome
Abstract
OBJECTIVE: To assess neuropathology in individuals with restless legs syndrome (RLS). METHODS: A standard neuropathologic evaluation was performed on seven brains from individuals who had been diagnosed with RLS. The substantia nigra was examined in greater detail for iron staining and with immunohistochemistry for tyrosine hydroxylase and proteins involved in iron management. Five age-matched individuals with no neurologic history served as controls. RESULTS: There were no histopathologic abnormalities unique to the RLS brains. Tyrosine hydroxylase staining in the major dopaminergic regions appeared normal in the RLS brains. Iron staining and H-ferritin staining was markedly decreased in the RLS substantia nigra. Although H-ferritin was minimally detected in the RLS brain, L-ferritin staining was strong. However, the cells staining for L-ferritin in RLS brains were morphologically distinct from those in the control brains. Transferrin receptor staining on neuromelanin-containing cells was decreased in the RLS brains compared to normal, whereas transferrin staining in these cells was increased. CONCLUSIONS: RLS may not be rooted in pathologies associated with traditional neurodegenerative processes but may be a functional disorder resulting from impaired iron acquisition by the neuromelanin cells in RLS. The underlying mechanism may be a defect in regulation of the transferrin receptors.
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Iron misregulation is implicated in the pathology of restless leg syndrome, so that concentrations of TFR, IRP1, DMT1, ferroportin, and heavy-chain ferritin are decreased in dopaminergic neurons of the substantia nigra.
“Iron misregulation is implicated in the pathology of restless leg syndrome, so that concentrations of TFR, IRP1, DMT1, ferroportin, and heavy-chain ferritin are decreased in dopaminergic neurons of the substantia nigra.198–200”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [199]
Cites
McKeith, I. G., Galasko, D., Kosaka, K., Perry, E. K., Dickson, D. W., Hansen, L. A., Salmon, D. P., Lowe, J., Mirra, S. S., Byrne, E. J., et al. (1996) · Neurology · doi:10.1212/wnl.47.5.1113 · Cited by 3,960 · see citing works
A Novel Mammalian Iron-regulated Protein Involved in Intracellular Iron Metabolism
Abboud, S., & Haile, D. J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000713200 · Cited by 1,267 · see citing works
Toward a better definition of the restless legs syndrome
Walters, A. S., Aldrich, M. S., Allen, R., Ancoli‐Israel, S., Buchholz, D., Chokroverty, S., Coccagna, G., Earley, C., Ehrenberg, B., Feest, T. G., et al. (1995) · Movement Disorders · doi:10.1002/mds.870100517 · Cited by 1,100 · see citing works
Self-citationConsensus Recommendations for the Postmortem Diagnosis of Alzheimer’s Disease
(1997) · Neurobiology of Aging · doi:10.1016/s0197-4580(97)00057-2 · Cited by 981 · see citing works
Ekbom, K. (1960) · Neurology · doi:10.1212/wnl.10.9.868 · Cited by 847 · see citing works
Restless Legs Syndrome and Sleep Bruxism: Prevalence and Association Among Canadians
Lavigne, G. J., & Montplaisir, J. Y. (1994) · SLEEP · doi:10.1093/sleep/17.8.739 · Cited by 722 · see citing works
I <scp>RON</scp> S <scp>TATUS AND</scp> N <scp>EURAL</scp> F <scp>UNCTIONING</scp>
Beard, J. L., & Connor, J. R. (2003) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.23.020102.075739 · Cited by 669 · see citing works
Self-citationCerebral amyloid angiopathy without and with cerebral hemorrhages: A comparative histological study
Vonsattel, J. P. G., Myers, R. H., Tessa Hedley‐Whyte, E., Ropper, A. H., Bird, E. D., & Richardson, E. P. (1991) · Annals of Neurology · doi:10.1002/ana.410300503 · Cited by 662 · see citing works
Prevalence and risk factors of RLS in an elderly population
Rothdach, A., Trenkwalder, C., Haberstock, J., Keil, U., & Berger, K. (2000) · Neurology · doi:10.1212/wnl.54.5.1064 · Cited by 653 · see citing works
Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome
Earley, C. J., Connor, J. R., Beard, J. L., Malecki, E. A., Epstein, D. K., & Allen, R. P. (2000) · Neurology · doi:10.1212/wnl.54.8.1698 · Cited by 618 · see citing works
Self-citationMRI measurement of brain iron in patients with restless legs syndrome
Allen, R. P., Barker, P. B., Wehrl, F., Song, H. K., & Earley, C. J. (2001) · Neurology · doi:10.1212/wnl.56.2.263 · Cited by 570 · see citing works
Self-citationIron Status and Restless Legs Syndrome in the Elderly
O’Keeffe, S. T., GAVIN, K., & Lavan, J. N. (1994) · Age and Ageing · doi:10.1093/ageing/23.3.200 · Cited by 492 · see citing works
Iron and The Restless Legs Syndrome
Sun, E. R., Chen, C. A., Ho, G., Earley, C. J., & Allen, R. P. (1998) · SLEEP · doi:10.1093/sleep/21.4.381 · Cited by 469 · see citing works
Self-citationStriatal dopaminergic function in restless legs syndrome
Turjanski, N., Lees, A., & Brooks, D. (1999) · Neurology · doi:10.1212/wnl.52.5.932 · Cited by 445 · see citing works
Frequency of hippocampal formation atrophy in normal aging and Alzheimer's disease
De Leon, M. J., George, A. E., Golomb, J., Tarshish, C., Convit, A., Kluger, A., De Santi, S., Mc Rae, T., Ferris, S. H., Reisberg, B., et al. (1997) · Neurobiology of Aging · doi:10.1016/s0197-4580(96)00213-8 · Cited by 429 · see citing works
The Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder
Hening, W., Richard Allen, P., Earley, C. J., Kushida, C. A., Picchietti, D. L., & Silber, M. H. (1999) · SLEEP · doi:10.1093/sleep/22.7.970 · Cited by 321 · see citing works
Self-citationBurdo, J. R., Menzies, S. L., Simpson, I. A., Garrick, L. M., Garrick, M. D., Dolan, K. G., Haile, D. J., Beard, J. L., & Connor, J. R. (2001) · Journal of Neuroscience Research · doi:10.1002/jnr.1256 · Cited by 297 · see citing works
Self-citationMichaud, M., Soucy, J., Chabli, A., Lavigne, G. J., & Montplaisir, J. Y. (2002) · Journal of Neurology · doi:10.1007/pl00007859 · Cited by 278 · see citing works
Faucheux, B. A., Nillesse, N., Damier, P., Spik, G., Prigent, A., Pierce, A., Leveugle, B., Kubis, N., Hauw, J., & Agid, Y. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.21.9603 · Cited by 218 · see citing works
Restless Legs Syndrome among Working-Aged Women
Ulfberg, J., Nyström, B., Carter, N., & Edling, C. (2001) · European Neurology · doi:10.1159/000050750 · Cited by 182 · see citing works
Isoforms of ferritin have a specific cellular distribution in the brain
Connor, J. R., Boeshore, K. L., Benkovic, S. A., & Menzies, S. L. (1994) · Journal of Neuroscience Research · doi:10.1002/jnr.490370405 · Cited by 179 · see citing works
Self-citationValidation of the Johns Hopkins restless legs severity scale
Allen, R. P., & Earley, C. J. (2001) · Sleep Medicine · doi:10.1016/s1389-9457(00)00080-0 · Cited by 174 · see citing works
Self-citationVariations in Dietary Iron Alter Brain Iron Metabolism in Developing Rats
Piñero, D. J., Li, N., Connor, J. R., & Beard, J. L. (2000) · Journal of Nutrition · doi:10.1093/jn/130.2.254 · Cited by 163 · see citing works
Self-citationStaedt, J., Stoppe, G., Kögler, A., et al. (1995) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/bf02191538 · Cited by 135 · see citing works
Cellular distribution of iron in the brain of the Belgrade rat
Burdo, J. R., Martin, J., Menzies, S. L., Dolan, K. G., Romano, M. A., Fletcher, R. J., Garrick, M. D., Garrick, L. M., & Connor, J. R. (1999) · Neuroscience · doi:10.1016/s0306-4522(99)00207-9 · Cited by 130 · see citing works
Self-citationAltered cellular distribution of iron in the central nervous system of myelin deficient rats
Connor, J. R., & Menzies, S. L. (1990) · Neuroscience · doi:10.1016/0306-4522(90)90320-4 · Cited by 124 · see citing works
Self-citationDiminished iron acquisition by cells and tissues of Belgrade laboratory rats
Farcich, E. A., & Morgan, E. H. (1992) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1992.262.2.r220 · Cited by 50 · see citing works
BLOM, S., & Ekbom, K. (1961) · Acta Medica Scandinavica · doi:10.1111/j.0954-6820.1961.tb00286.x · Cited by 38 · see citing works
Microscopic R2* mapping of reduced brain iron in the Belgrade rat
Zywicke, H. A., van Gelderen, P., Connor, J. R., Burdo, J. R., Garrick, M. D., Dolan, K. G., Frank, J. A., & Bulte, J. W. M. (2002) · Annals of Neurology · doi:10.1002/ana.10216 · Cited by 28 · see citing works
Self-citation
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The role of iron in brain ageing and neurodegenerative disorders
Ward, R. J., Zucca, F. A., Duyn, J. H., Crichton, R. R., & Zecca, L. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70117-6 · Cited by 1,819 · see citing works
Imaging iron stores in the brain using magnetic resonance imaging
Haacke, E. M., Cheng, N. Y. C., House, M. J., Liu, Q., Neelavalli, J., Ogg, R. J., Khan, A., Ayaz, M., Kirsch, W., & Obenaus, A. (2005) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2004.10.001 · Cited by 995 · see citing works
Zecca, L., Stroppolo, A., Gatti, A., Tampellini, D., Toscani, M., Gallorini, M., Giaveri, G., Arosio, P., Santambrogio, P., Fariello, R. G., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403495101 · Cited by 495 · see citing works
Restless legs syndrome: Revisiting the dopamine hypothesis from the spinal cord perspective
Clemens, S., Rye, D., & Hochman, S. (2006) · Neurology · doi:10.1212/01.wnl.0000223316.53428.c9 · Cited by 465 · see citing works
Evidence‐Based Recommendations for the Assessment and Management of Sleep Disorders in Older Persons
Bloom, H. G., Ahmed, I., Alessi, C. A., Ancoli‐Israel, S., Buysse, D. J., Kryger, M. H., Phillips, B. A., Thorpy, M. J., Vitiello, M. V., & Zee, P. C. (2009) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2009.02220.x · Cited by 464 · see citing works
Neurophysiology of sleep and wakefulness: basic science and clinical implications
Schwartz, J., & Roth, T. (2008) · Current Neuropharmacology · doi:10.2174/157015908787386050 · Cited by 289 · see citing works
The role of iron in restless legs syndrome
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- Authors
- Connor, J. R., Boyer, P. J., Menzies, S. L., Dellinger, B., Allen, R. P., Ondo, W. G., & Earley, C. J.
- Affiliations
- Pennsylvania State University (US)
- Venue
- Neurology
- Published
- 2003-08-12
- Volume
- 61
- Issue
- 3
- Pages
- 304-309
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- OpenAlex
- W1981352341
- Cited by
- 548
- References
- 29
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 7 · 2023: 16 · 2022: 14 · 2021: 20 · 2020: 22 · 2019: 15 · 2018: 19 · 2017: 15 · 2016: 21 · 2015: 22 · 2014: 32 · 2013: 37 · 2012: 19
- FWCI
- 20.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Restless Legs Syndrome Foundation
- National Institute on Aging (R01 AG 16362, R01AG016362)
- National Institute of Neurological Disorders and Stroke (R01 NS 38704, R01NS038704)
- Topics
- Health Sciences › Medicine › Epidemiology › Restless Legs Syndrome Research
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- restless legs syndrome, substantia nigra, ferritin, transferrin receptor, tyrosine hydroxylase, dopaminergic neurons, iron deficiency, neuropathology
- MeSH terms
- Iron Deficiencies, Ferroportin, Solute Carrier Family 11, Member 2, Aged, Aged, 80 and over, Female, Ferritins, Humans, Immunohistochemistry, Iron, Male, Melanins, Middle Aged, Neurons, Receptors, Transferrin, Restless Legs Syndrome, Substantia Nigra, Transferrin, Tyrosine 3-Monooxygenase, Cation Transport Proteins, Iron-Binding Proteins
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