426
Views
33
CrossRef citations to date
0
Altmetric
Review

Iron and manganese-related CNS toxicity: mechanisms, diagnosis and treatment

, , , , , , & show all
Pages 243-260 | Received 15 Aug 2018, Accepted 08 Feb 2019, Published online: 21 Feb 2019

References

  • Au C, Benedetto A, Aschner M. Manganese transport in eukaryotes: the role of DMT1. Neurotoxicology. 2008 Jul;29(4):569–576. PubMed PMID: 18565586; eng.
  • Aschner M, Aschner JL. Manganese transport across the blood-brain barrier: relationship to iron homeostasis. Brain Res Bull. 1990 Jun;24(6):857–860. 036s1-9230(90)90152-P [pii]. PubMed PMID: 2372703; eng.
  • Aschner M, Gannon M. Manganese (Mn) transport across the rat blood-brain barrier: saturable and transferrin-dependent transport mechanisms. Brain Res Bull. 1994;33(3): 345–349. 0361-9230(94)90204-6 [pii]. PubMed PMID: 8293318; eng.
  • Gunter TE, Gerstner B, Gunter KK, et al. Manganese transport via the transferrin mechanism. Neurotoxicology. 2013 Jan;34:118–127. PubMed PMID: 23146871; eng.
  • Sheftel AD, Zhang AS, Brown C, et al. Direct interorganellar transfer of iron from endosome to mitochondrion. Blood. 2007 Jul 1;110(1):125–132. PubMed PMID: 17376890; eng.
  • Yin Z, Jiang H, Lee ES, et al. Ferroportin is a manganese-responsive protein that decreases manganese cytotoxicity and accumulation. J Neurochem. 2010 Mar;112(5):1190–1198. PubMed PMID: 20002294; PubMed Central PMCID: PMCPMC2819584. eng.
  • Chifman J, Laubenbacher R, Torti SV. A systems biology approach to iron metabolism. In: Corey SJ, Kimmel M, Leonard JN, editors. A systems biology approach to blood. New York (NY): Springer New York; 2014. p. 201–225.
  • Pantopoulos K, Porwal SK, Tartakoff A, et al. Mechanisms of mammalian iron homeostasis. Biochemistry. 2012;51(29):5705–5724.
  • Andrews NC. Iron metabolism: iron deficiency and iron overload. Annu Rev Genomics Hum Genet. 2000;11:75–98. PubMed PMID: 11701625.
  • Chen P, Bornhorst J, Aschner M. Manganese metabolism in humans. Front Biosci (Landmark Ed). 2018;23:1655–1679.
  • Chen P, Miah MR, Aschner M Metals and neurodegeneration. F1000Research. 2016;5. 366
  • Chen P, Chakraborty S, Mukhopadhyay S, et al. Manganese homeostasis in the nervous system. J Neurochem. 2015;134(4):601–610.
  • Zecca L, Youdim MBH, Riederer P, et al. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci. 2004;5(11):863–873.
  • Mills E, Dong X-P, Wang F, et al. Mechanisms of brain iron transport: insight into neurodegeneration and CNS disorders. Future Med Chem. 2010;2(1):51. PubMed PMID: PMC2812924
  • Rivera-Mancía S, Ríos C, Montes S. Manganese accumulation in the CNS and associated pathologies [journal article]. Biometals. 2011 October 1;24(5):811–825.
  • Ward R, Zucca FA, Duyn JH, et al. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 2014;13(10):1045–60.
  • Khan FH, Ahlberg CD, Chow CA, et al. Iron, dopamine, genetics, and hormones in the pathophysiology of restless legs syndrome [journal article]. J Neurol. 2017;1–8. DOI:10.1007/s00415-017-8431-1
  • Gonzalez-Reyes RE, Gutierrez-Alvarez AM, Moreno CB. Manganese and epilepsy: A systematic review of the literature. Brain Res Rev. 2007;53(2):332–336.
  • Carl GF, Blackwell L, Barnett F, et al. Manganese and epilepsy: brain glutamine synthetase and liver arginase activities in genetically epilepsy prone and chronically seizured rats. Epilepsia. 1993;34(3):441–446.
  • Davidson D, Ward NI. Abnormal aluminium, cobalt, manganese, strontium and zinc concentrations in untreated epilepsy. Epilepsy Res. 1988;2(5):323–330.
  • Carl G, Keen C, Gallagher B, et al. Association of low blood manganese concentrations with epilepsy. Neurology. 1986;36(12):1584.
  • Paul BT, Manz DH, Torti FM, et al. Mitochondria and iron: current questions. Expert Rev Hematol. 2017 Dec 12;10(1):65–79. PubMed PMID: PMC5538026.
  • Pantopoulos K, Porwal SK, Tartakoff A, et al. Mechanisms of mammalian iron homeostasis. Biochemistry. 2012 Jul 24;51(29):5705–5724. PubMed PMID: 22703180; PubMed Central PMCID: PMCPMC3572738.
  • Papanikolaou G, Pantopoulos K. Iron metabolism and toxicity. Toxicol Appl Pharmacol. 2005 Jan 15;202(2):199–211. PubMed PMID: 15629195.
  • Piñero D, Connor J. Iron in the brain: an important contributor in normal and diseased states. The Neuroscientist. 2000; 6(6), 435–453.
  • Hare D, Ayton S, Bush A, et al. A delicate balance: iron metabolism and diseases of the brain. Front Aging Neurosci. 2013 Jul 18;5:34.
  • Oppenheimer, Beard, Lozoff, et al. Iron biology in immune function, muscle metabolism and neuronal functioning. Discussion. J Nutr. 2001 Feb;131(2S-2):568S–579S; discussion 580S.
  • Todorich B, Pasquini JM, Garcia CI, et al. Oligodendrocytes and myelination: the role of Iron. Glia. 2009 Apr 1;57(5):467–78.
  • Zecca L, Youdim MBH, Riederer P, et al. Iron, brain ageing and neurodegenerative disorders [Review Article]. Nat Rev Neurosci. 2004 Jan 11;5:863.
  • de Lima MN, Polydoro M, Laranja, DC, et al. Recognition memory impairment and brain oxidative stress induced by postnatal iron administration. Eur J Neurosci. 2005;21(9):2521–2528.
  • Dal-Pizzol F, Klamt F, Frota MLC, et al. Neonatal iron exposure induces oxidative stress in adult Wistar rat. Brain Res Dev Brain Res. 2001 Sep 23;130(1):109–14.
  • Piloni NE, Fermandez V, Videla LA, et al. Acute iron overload and oxidative stress in brain. Toxicology. 2013;314(1):174–182.
  • Ilaria P, Romina M, Francesco MM, et al. Iron handling in hippocampal neurons: activity-dependent iron entry and mitochondria-mediated neurotoxicity. Aging Cell. 2011;10(1):172–183.
  • Sripetchwandee J, Sanit J, Chattipakorn N, et al. Mitochondrial calcium uniporter blocker effectively prevents brain mitochondrial dysfunction caused by iron overload. Life Sci. 2013;92(4):298–304.
  • Crichton R. Iron metabolism: from molecular mechanisms to clinical consequences. Chicester, UK: John Wiley & Sons, Incorporated; 2016.
  • Chua A, Morgan E. Effects of iron deficiency and iron overload on manganese uptake and deposition in the brain and other organs of the rat. Biol Trace Elem Res. 1996 Oct-Nov;55(1-2):39–54.
  • Greenough MA, Camakaris J, Bush AI. Metal dyshomeostasis and oxidative stress in Alzheimer’s disease. Neurochem Int. 2013;62(5):540–555.
  • Lee DL, Strathmann FG, Walton J, et al. Iron deficiency disrupts axon maturation of the developing auditory nerve. J Neurosci. 2012;32(14):5010–5015. PubMed PMID: PMC3327472.
  • Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med. 2004 Jul;5(4):385–391. PubMed PMID: 15222997.
  • Batra J, Sood A. Iron deficiency anaemia: effect on congnitive development in children: A review. Indian J Clin Biochem. 2005;20(2):119–125. PubMed PMID: PMC3453858.
  • Allen RP, Bharmal M, Calloway M. Prevalence and disease burden of primary restless legs syndrome: results of a general population survey in the United States. Mov Disord. 2011 Jan;26(1):114–120. PubMed PMID: 21322022; eng.
  • Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003 Mar;4(2):101–119. S1389945703000108 [pii]. PubMed PMID: 14592341; eng.
  • Wagner ML, Walters AS, Fisher BC. Symptoms of attention-deficit/hyperactivity disorder in adults with restless legs syndrome. Sleep. 2004 Dec 15;27(8):1499–1504. PubMed PMID: 15683140; eng.
  • Li Y, Walters AS, Chiuve SE, et al. Prospective study of restless legs syndrome and coronary heart disease among women. Circulation. 2012 Oct 2;126(14):1689–1694. PubMed PMID: 22967852; PubMed Central PMCID: PMC3493117. eng.
  • Pennestri MH, Montplaisir J, Colombo R, et al. Nocturnal blood pressure changes in patients with restless legs syndrome. Neurology. 2007 Apr 10;68(15):1213–1218. PubMed PMID: 17420405; eng.
  • Siddiqui F, Strus J, Ming X, et al. Rise of blood pressure with periodic limb movements in sleep and wakefulness. Clin Neurophysiol. 2007 Sep;118(9):1923–1930. S1388-2457(07)00199-X [pii]. PubMed PMID: 17588809; eng
  • Walters AS, Rye DB. Review of the relationship of restless legs syndrome and periodic limb movements in sleep to hypertension, heart disease, and stroke. Sleep. 2009 May;32(5):589–597. PubMed PMID: 19480225; PubMed Central PMCID: PMC2675893. eng.
  • Allen RP, Earley CJ. The role of iron in restless legs syndrome. Mov Disord. 2007;22 Suppl 18:S440–8. PubMed PMID: 17566122.
  • Connor JR. Pathophysiology of restless legs syndrome: evidence for iron involvement. Curr Neurol Neurosci Rep. 2008 Mar;8(2):162–166. PubMed PMID: 18460286; eng.
  • Aurora RN, Kristo DA, Bista SR, et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults-an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of sleep medicine clinical practice guideline. Sleep. 2012 Aug;35(8):1039–1062. PubMed PMID: 22851801; PubMed Central PMCID: PMC3397811. eng.
  • Cho YW, Allen RP, Earley CJ. Lower molecular weight intravenous iron dextran for restless legs syndrome. Sleep Med. 2013 Jan17. [pii] S1389-9457(12)00400-5. PubMed PMID: 23333678; Eng. DOI:10.1016/j.sleep.2012.11.001
  • Ondo WG. Intravenous iron dextran for severe refractory restless legs syndrome. Sleep Med. 2010 May;11(5):494–496. PubMed PMID: 20371212; eng.
  • Belaidi AA, Bush AI. Iron neurochemistry in Alzheimer’s disease and Parkinson’s disease: targets for therapeutics. J Neurochem. 2016 Oct;139(Suppl 1):179–197. PubMed PMID: 26545340.
  • Li Y, Jiao Q, Xu H, et al. Biometal dyshomeostasis and toxic metal accumulations in the development of Alzheimer’s disease. Front Mol Neurosci. 2017;10:339. PubMed PMID: 29114205; PubMed Central PMCID: PMCPMC5660707.
  • Cheignon C, Tomas M, Bonnefont-Rousselot D, et al. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol. 2018 Apr;14:450–464. PubMed PMID: 29080524; PubMed Central PMCID: PMCPMC5680523.
  • Uranga RM, Salvador GA. Unraveling the burden of iron in neurodegeneration: intersections with amyloid beta peptide pathology. Oxid Med Cell Longev. 2018;2018:2850341. PubMed PMID: 29581821; PubMed Central PMCID: PMCPMC5831758.
  • Cristovao JS, Santos R, Gomes CM. Metals and neuronal metal binding proteins implicated in Alzheimer’s disease. Oxid Med Cell Longev. 2016;2016:9812178. PubMed PMID: 26881049; PubMed Central PMCID: PMCPMC4736980.
  • Li K, Reichmann H. Role of iron in neurodegenerative diseases. J Neural Transm (Vienna). 2016 Apr;123(4):389–399. PubMed PMID: 26794939.
  • Balejcikova L, Siposova K, Kopcansky P, et al. Fe(II) formation after interaction of the amyloid beta-peptide with iron-storage protein ferritin. J Biol Phys. 2018 May 9 PubMed PMID: 29740739; PubMed Central PMCID: PMCPMC6082800. DOI:10.1007/s10867-018-9498-3
  • Ascherio A, Schwarzschild MA. The epidemiology of Parkinson’s disease: risk factors and prevention. Lancet Neurol. 2016;15(12):1257–1272.
  • Jiang H, Wang J, Rogers J, et al. Brain iron metabolism dysfunction in Parkinson’s disease. Mol Neurobiol. 2017 May;54(4):3078–3101. PubMed PMID: 27039308.
  • Hare DJ, Double KL. Iron and dopamine: a toxic couple. Brain. 2016 Apr;139(Pt 4):1026–1035. PubMed PMID: 26962053.
  • Song N, Xie J. Iron, dopamine, and alpha-synuclein interactions in at-risk dopaminergic neurons in Parkinson’s disease. Neurosci Bull. 2018 Apr;34(2):382–384. PubMed PMID: 29380248; PubMed Central PMCID: PMCPMC5856725.
  • Zhang Z, Miah M, Culbreth M, et al. Autophagy in neurodegenerative diseases and metal neurotoxicity. Neurochem Res. 2016 Feb;41(1–2):409–422. PubMed PMID: 26869037.
  • Gorell JM, Peterson EL, Rybicki BA, et al. Multiple risk factors for Parkinson’s disease. J Neurol Sci. 2004;217(2):169–174.
  • Mischley LK, Lau RC, Bennett RD. Role of diet and nutritional supplements in Parkinson’s disease progression. Oxid Med Cell Longev. 2017;2017:6405278. PubMed PMID: 29081890; PubMed Central PMCID: PMCPMC5610862.
  • Lan AP, Chen J, Chai ZF, et al. The neurotoxicity of iron, copper and cobalt in Parkinson’s disease through ROS-mediated mechanisms. Biometals. 2016 Aug;29(4):665–678. PubMed PMID: 27349232.
  • Lingor P, Carboni E, Koch JC. Alpha-synuclein and iron: two keys unlocking Parkinson’s disease. J Neural Transm (Vienna). 2017 Aug;124(8):973–981. PubMed PMID: 28168622.
  • Moreau C, Duce JA, Rascol O, et al. Iron as a therapeutic target for Parkinson’s disease. Mov Disord. 2018 Apr;33(4):568–574. PubMed PMID: 29380903.
  • Munoz Y, Carrasco CM, Campos JD, et al. Parkinson’s disease: the mitochondria-iron link. Parkinsons Dis. 2016;2016:7049108. PubMed PMID: 27293957; PubMed Central PMCID: PMCPMC4886095.
  • Song N, Wang J, Jiang H, et al. Astroglial and microglial contributions to iron metabolism disturbance in Parkinson’s disease. Biochim Biophys Acta Mol Basis Dis. 2018 Mar;1864(3):967–973. PubMed PMID: 29317336.
  • Xu H, Wang Y, Song N, et al. New progress on the role of glia in iron metabolism and iron-induced degeneration of dopamine neurons in Parkinson’s disease. Front Mol Neurosci. 2017:10:455. PubMed PMID: 29403352; PubMed Central PMCID: PMCPMC5780449.
  • Biasiotto G, Di Lorenzo D, Archetti S, et al. Iron and Neurodegeneration: is Ferritinophagy the Link? Mol Neurobiol. 2016 Oct;53(8):5542–5574. PubMed PMID: 26468157.
  • Guiney SJ, Adlard PA, Bush AI, et al. Ferroptosis and cell death mechanisms in Parkinson’s disease. Neurochem Int. 2017 Mar;104:34–48. PubMed PMID: 28082232.
  • Chiang S, Kalinowski DS, Jansson PJ, et al. Mitochondrial dysfunction in the neuro-degenerative and cardio-degenerative disease, Friedreich’s ataxia. Neurochem Int. 2018 Jul;117:35–48. PubMed PMID: 28782591.
  • Lupoli F, Vannocci T, Longo G, et al. The role of oxidative stress in Friedreich’s ataxia. FEBS Lett. 2018 Mar;592(5):718–727. PubMed PMID: 29197070; PubMed Central PMCID: PMCPMC5887922.
  • Burk K. Friedreich Ataxia: current status and future prospects. Cerebellum Ataxias. 2017;4:4. PubMed PMID: 28405347; PubMed Central PMCID: PMCPMC5383992.
  • Ghosh R, Tabrizi SJ. Clinical features of Huntington’s disease. In: Pereira NC, de Almeida L, editors. Polyglutamine disorders. Cham: Springer International Publishing; 2018. p. 1–28.
  • Jimenez-Sanchez M, Licitra F, Underwood BR, et al. Huntington’s disease: mechanisms of pathogenesis and therapeutic strategies. Cold Spring Harb Perspect Med. 2017 Jul 1;7(7). DOI:10.1101/cshperspect.a024240
  • Agrawal S, Fox J, Thyagarajan B, et al. Brain mitochondrial iron accumulates in Huntington’s disease, mediates mitochondrial dysfunction, and can be removed pharmacologically. Free Radic Biol Med. 2018 May;20(120):317–329. PubMed PMID: 29625173; PubMed Central PMCID: PMCPMC5940499.
  • Muller M, Leavitt BR. Iron dysregulation in Huntington’s disease. J Neurochem. 2014 Aug;130(3):328–350. PubMed PMID: 24717009.
  • Horning KJ, Caito SW, Tipps KG, et al. Manganese is essential for neuronal health. Annu Rev Nutr. 2015;35(1):71–108. PubMed PMID: 25974698.
  • Rosas H, Chen Y, Doros G, et al. Alterations in brain transition metals in huntington disease: an evolving and intricate story. Arch Neurol. 2012;69(7):887–893.
  • Bowman AB, Kwakye GF, Herrero Hernández E, et al. Role of manganese in neurodegenerative diseases. J Trace Elem Med Biol. 2011;25(4):191–203.
  • Bryan MR, Bowman AB. Manganese and the insulin-IGF signaling network in Huntington’s disease and other neurodegenerative disorders. In: Aschner M, Costa LG, editors. Neurotoxicity of metals. Cham: Springer International Publishing; 2017. p. 113–142.
  • Sepers MD, Raymond LA. Mechanisms of synaptic dysfunction and excitotoxicity in Huntington’s disease. Drug Discov Today. 2014;19(7):990–996.
  • Zanardi A, Conti A, Cremonesi M, et al. Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia. EMBO Mol Med. 2018 Jan;10(1):91–106. PubMed PMID: 29183916; PubMed Central PMCID: PMCPMC5760856.
  • Kono S. Aceruloplasminemia: an update. Int Rev Neurobiol. 2013;110:125–151. PubMed PMID: 24209437.
  • Miyajima H. Aceruloplasminemia. Neuropathology. 2015 Feb;35(1):83–90. PubMed PMID: 25168455.
  • Levi S, Finazzi D. Neurodegeneration with brain iron accumulation: update on pathogenic mechanisms. Front Pharmacol. 2014;5:99. PubMed PMID: 24847269; PubMed Central PMCID: PMCPMC4019866.
  • Meyer E, Kurian MA, Hayflick SJ. Neurodegeneration with brain iron accumulation: genetic diversity and pathophysiological mechanisms. Annu Rev Genomics Hum Genet. 2015;16:257–279. PubMed PMID: 25973518.
  • Keogh MJ, Jonas P, Coulthard A, et al. Neuroferritinopathy: a new inborn error of iron metabolism. Neurogenetics. 2012 Feb;13(1):93–96. PubMed PMID: 22278127; PubMed Central PMCID: PMCPMC4038507.
  • Kumar N, Rizek P, Jog M. Neuroferritinopathy: pathophysiology, presentation, differential diagnoses and management. Tremor Other Hyperkinet Mov (N Y). 2016;6:355. PubMed PMID: 27022507; PubMed Central PMCID: PMCPMC4795517.
  • Levi S, Rovida E. Neuroferritinopathy: from ferritin structure modification to pathogenetic mechanism. Neurobiol Dis. 2015 Sep;81:134–143. PubMed PMID: 25772441; PubMed Central PMCID: PMCPMC4642653.
  • Garringer HJ, Irimia JM, Li W, et al. Effect of systemic iron overload and a chelation therapy in a mouse model of the neurodegenerative disease hereditary ferritinopathy. PLoS One. 2016;11(8):e0161341. PubMed PMID: 27574973; PubMed Central PMCID: PMCPMC5004847.
  • Hogarth P, Kurian MA, Gregory A, et al. Consensus clinical management guideline for pantothenate kinase-associated neurodegeneration (PKAN). Mol Genet Metab. 2017 Mar;120(3):278–287. PubMed PMID: 28034613.
  • Di Meo I, Carecchio M, Tiranti V. Inborn errors of coenzyme A metabolism and neurodegeneration. J Inherit Metab Dis. 2018 May 16. PubMed PMID: 29767814. DOI:10.1007/s10545-018-0193-0
  • Orellana DI, Santambrogio P, Rubio A, et al. Coenzyme A corrects pathological defects in human neurons of PANK2-associated neurodegeneration. EMBO Mol Med. 2016 Oct;8(10):1197–1211. PubMed PMID: 27516453; PubMed Central PMCID: PMCPMC5048368.
  • Drecourt A, Babdor J, Dussiot M, et al. Impaired transferrin receptor palmitoylation and recycling in neurodegeneration with brain iron accumulation. Am J Hum Genet. 2018 Feb 1;102(2):266–277. PubMed PMID: 29395073; PubMed Central PMCID: PMCPMC5985451.
  • Dusek P, Schneider SA, Aaseth J. Iron chelation in the treatment of neurodegenerative diseases. J Trace Elem Med Biol. 2016 Dec;38:81–92. PubMed PMID: 27033472.
  • Aaseth J, Alexander J, Bjorklund G, et al. Treatment strategies in Alzheimer’s disease: a review with focus on selenium supplementation. Biometals. 2016 Oct;29(5):827–839. PubMed PMID: 27530256; PubMed Central PMCID: PMCPMC5034004.
  • Adlard PA, Bush AI. Metals and Alzheimer’s disease: how far have we come in the clinic? J Alzheimers Dis. 2018;62(3):1369–1379. PubMed PMID: 29562528; PubMed Central PMCID: PMCPMC5870044.
  • Amit T, Bar-Am O, Mechlovich D, et al. The novel multitarget iron chelating and propargylamine drug M30 affects APP regulation and processing activities in Alzheimer’s disease models. Neuropharmacology. 2017 Sep;1(123):359–367. PubMed PMID: 28571715.
  • Oliveri V, Vecchio G. Prochelator strategies for site-selective activation of metal chelators. J Inorg Biochem. 2016 Sep;162:31–43. PubMed PMID: 27297691.
  • Monacelli F, Acquarone E, Giannotti C, et al. Vitamin C, aging and Alzheimer’s disease. Nutrients. 2017 Jun 27;9(7). PubMed PMID: 28654021; PubMed Central PMCID: PMCPMC5537785. DOI:10.3390/nu9070670.
  • Lang AE, Espay AJ. Disease modification in Parkinson’s disease: current approaches, challenges, and future considerations. Mov Disord. 2018 May;33(5):660–677. PubMed PMID: 29644751.
  • Maiti P, Dunbar GL. Use of curcumin, a natural polyphenol for targeting molecular pathways in treating age-related neurodegenerative diseases. Int J Mol Sci. 2018 May 31;19(6). PubMed PMID: 29857538; PubMed Central PMCID: PMCPMC6032333. DOI:10.3390/ijms19061637.
  • Xu Y, Zhang Y, Quan Z, et al. Epigallocatechin Gallate (EGCG) inhibits alpha-synuclein aggregation: a potential agent for Parkinson’s disease. Neurochem Res. 2016 Oct;41(10):2788–2796. PubMed PMID: 27364962.
  • Costa C, Tsatsakis A, Mamoulakis C, et al. Current evidence on the effect of dietary polyphenols intake on chronic diseases. Food Chem Toxicol. 2017 Dec;110:286–299. PubMed PMID: 29042289.
  • Smith LM, Parr-Brownlie LC. A neuroscience perspective of the gut theory of Parkinson’s disease. Eur J Neurosci. 2018 Feb 15. PubMed PMID: 29446158. DOI:10.1111/ejn.13869.
  • Aranca TV, Jones TM, Shaw JD, et al. Emerging therapies in Friedreich’s ataxia. Neurodegener Dis Manag. 2016 Feb;6(1):49–65.
  • Kieburtz K, Reilmann R, Olanow CW. Huntington’s disease: current and future therapeutic prospects. Mov Disord. 2018 Jul;33(7):1033–1041. PubMed PMID: 29737569.
  • Dickey AS, La Spada AR. Therapy development in Huntington disease: from current strategies to emerging opportunities. Am J Med Genet A. 2018 Apr;176(4):842–861. PubMed PMID: 29218782; PubMed Central PMCID: PMCPMC5975251.
  • Poli L, Alberici A, Buzzi P, et al. Is aceruloplasminemia treatable? Combining iron chelation and fresh-frozen plasma treatment. Neurol Sci. 2017 Feb;38(2):357–360. PubMed PMID: 27817091.
  • Fernsebner K, Zorn J, Kanawati B, et al. Manganese leads to an increase in markers of oxidative stress as well as to a shift in the ratio of Fe(ii)/(iii) in rat brain tissue [10.1039/C4MT00022F]. Metallomics. 2014;6(4):921–931.
  • Stamelou M, Tuschl K, Chong WK, et al. Dystonia with brain manganese accumulation resulting from SLC30A10 mutations: A new treatable disorder. Mov Disord. 2012;27(10):1317–1322.
  • Tuschl K, Clayton PT, Gospe SM Jr., et al. Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man. Am J Hum Genet. 2012 Mar 9;90(3):457–466. PubMed PMID: 22341972; PubMed Central PMCID: PMC3309187.
  • Quadri M, Federico A, Zhao T, et al. Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease. Am J Hum Genet. 2012;90(3):467–477.
  • Gunter TE, Gerstner B, Lester T, et al. An analysis of the effects of Mn2+ on oxidative phosphorylation in liver, brain, and heart mitochondria using state 3 oxidation rate assays. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):65–75. PubMed PMID: 20800605; PubMed Central PMCID: PMC3004221.
  • Roth JA, Feng L, Walowitz J, et al. Manganese‐induced rat pheochromocytoma (PC12) cell death is independent of caspase activation. J Neurosci Res. 2000;61(2):162–171.
  • Malecki EA. Manganese toxicity is associated with mitochondrial dysfunction and DNA fragmentation in rat primary striatal neurons. Brain Res Bull. 2001 May 15;55(2):225–228.
  • Zhang J, Cao R, Cai T, et al. The role of autophagy dysregulation in manganese-induced dopaminergic neurodegeneration. Neurotox Res. 2013 Nov 1. 244:478–490. English.
  • Schrantz N, Blanchard DA, Mitenne F, et al. Manganese induces apoptosis of human B cells: caspase-dependent cell death blocked by bcl-2. Cell Death Differ. 1999;6(5):445–453.
  • Hirata Y, Adachi K, Kiuchi K. Activation of JNK pathway and induction of apoptosis by manganese in PC12 cells. J Neurochem. 1998;71(4):1607–1615.
  • Angeli S, Barhydt T, Jacobs R, et al. Manganese disturbs metal and protein homeostasis in Caenorhabditis elegans [10.1039/C4MT00168K]. Metallomics. 2014;6(10):1816–1823.
  • Reaney S, Smith D. Manganese oxidation state mediates toxicity in PC12 cells. Toxicol Appl Pharmacol. 2005;205(3):271–281.
  • Dupont C, Tanaka Y. Blood manganese levels in children with convulsive disorder. Biochem Med. 1985;33(2):246–255.
  • Kürekçi AE, Alpay F, Tanindi Ş, et al. Plasma trace element, plasma glutathione peroxidase, and superoxide dismutase levels in epileptic children receiving antiepileptic drug therapy. Epilepsia. 1995;36(6):600–604.
  • Papavasiliou P, Miller ST. Generalized seizures alter the cerebral and peripheral metabolism of essential metals in mice. Exp Neurol. 1983;82(1):223–236.
  • Carl GF, Critchfield J, Thompson J, et al. Genetically epilepsy‐prone rats are characterized by altered tissue trace element concentrations. Epilepsia. 1990;31(3):247–252.
  • Couper J. Sur les effets du peroxide de manganèse. J Chim Méd Pharm Toxicol. 1837;3:223–225.
  • Bowler RM, Gocheva V, Harris M, et al. Prospective study on neurotoxic effects in manganese-exposed bridge construction welders. Neurotoxicology. 2011 Oct;32(5):596–605. PubMed PMID: 21762725.
  • O’Neal SL, Zheng W. Manganese toxicity upon overexposure: a decade in review [journal article]. Curr Environ Health Rep. 2015;2(3):315–328.
  • Bouabid S, Tinakoua A, Lakhdar‐Ghazal N, et al. Manganese neurotoxicity: behavioral disorders associated with dysfunctions in the basal ganglia and neurochemical transmission. J Neurochem. 2016;136(4):677–691.
  • Kwakye GF, Paoliello MM, Mukhopadhyay S, et al. Manganese-induced parkinsonism and Parkinson’s Disease: shared and distinguishable features. Int J Environ Res Public Health. 2015 Jul 6;12(7):7519–7540. PubMed PMID: 26154659; PubMed Central PMCID: PMCPMC4515672.
  • Guilarte TR, Gonzales KK. Manganese-induced parkinsonism is not idiopathic Parkinson’s Disease: environmental and genetic evidence. Toxicol Sci. 2015 Aug;146(2):204–212. PubMed PMID: 26220508; PubMed Central PMCID: PMCPMC4607750.
  • Guilarte TR. Manganese and Parkinson’s disease: a critical review and new findings. Environ Health Perspect. 2010 Aug;118(8):1071–1080. PubMed PMID: 20403794; PubMed Central PMCID: PMC2920085. eng.
  • Bouabid S, Tinakoua A, Lakhdar-Ghazal N, et al. Manganese Neurotoxicity: behavioral disorders associated with dysfunctions in the basal ganglia and neurochemical transmission. J Neurochem. 2015 Nov 26. PubMed PMID: 26608821. DOI:10.1111/jnc.13442
  • Cersosimo MG, Koller WC. The diagnosis of manganese-induced parkinsonism. Neurotoxicology. 2006 May;27(3):340–346. PubMed PMID: 16325915.
  • Chen P, Chakraborty S, Mukhopadhyay S, et al. Manganese homeostasis in the nervous system. J Neurochem. 2015 Aug;134(4):601–610. PubMed PMID: 25982296; PubMed Central PMCID: PMCPMC4516557.
  • Bowman AB, Kwakye GF, Herrero Hernandez E, et al. Role of manganese in neurodegenerative diseases. J Trace Elem Med Biol. 2011 Dec;25(4):191–203. PubMed PMID: 21963226; PubMed Central PMCID: PMC3230726.
  • Aschner M, Erikson KM, Herrero Hernandez E, et al. Manganese and its role in Parkinson’s disease: from transport to neuropathology. Neuromolecular Med. 2009;11(4):252–266. PubMed PMID: 19657747; PubMed Central PMCID: PMCPMC4613768.
  • Tuschl K, Mills PB, Clayton PT. Manganese and the brain. Int Rev Neurobiol. 2013;110:277–312. PubMed PMID: 24209443.
  • Fukushima T, Tan X, Luo Y, et al. Relationship between blood levels of heavy metals and Parkinson’s disease in China. Neuroepidemiology. 2010;34(1):18–24. PubMed PMID: 19893325.
  • Hozumi I, Hasegawa T, Honda A, et al. Patterns of levels of biological metals in CSF differ among neurodegenerative diseases. J Neurol Sci. 2011 Apr 15;303(1–2):95–99. PubMed PMID: 21292280.
  • Racette BA, Criswell SR, Lundin JI, et al. Increased risk of parkinsonism associated with welding exposure. Neurotoxicology. 2012 Oct;33(5):1356–1361. PubMed PMID: 22975422.
  • Racette BA, Tabbal SD, Jennings D, et al. Prevalence of parkinsonism and relationship to exposure in a large sample of Alabama welders. Neurology. 2005 Jan 25;64(2):230–235. PubMed PMID: 15668418; eng.
  • Gorell JM, Johnson CC, Rybicki BA, et al. Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson’s disease. Neurotoxicology. 1999 Apr–Jun;20(2–3):239–247. PubMed PMID: 10385887; eng.
  • Mortimer JA, Borenstein AR, Nelson LM. Associations of welding and manganese exposure with Parkinson disease: review and meta-analysis. Neurology. 2012 Sep 11;79:1174–1180. PubMed PMID: 22965675; PubMed Central PMCID: PMCPMC3525308.
  • Willis AW, Evanoff BA, Lian M, et al. Metal emissions and urban incident Parkinson disease: a community health study of Medicare beneficiaries by using geographic information systems. Am J Epidemiol. 2010 Dec 15;172(12):1357–1363. PubMed PMID: 20959505; PubMed Central PMCID: PMCPMC2998201.
  • Finkelstein MM, Jerrett M. A study of the relationships between Parkinson’s disease and markers of traffic-derived and environmental manganese air pollution in two Canadian cities. Environ Res. 2007 Jul;104(3):420–432. PubMed PMID: 17445792.
  • Palacios N, Fitzgerald K, Roberts AL, et al. A prospective analysis of airborne metal exposures and risk of Parkinson disease in the nurses’ health study cohort. Environ Health Perspect. 2014 Sep;122(9):933–938. PubMed PMID: 24905870; PubMed Central PMCID: PMCPMC4154211.
  • Roth JA. Correlation between the biochemical pathways altered by mutated parkinson-related genes and chronic exposure to manganese. Neurotoxicology. 2014 Sep;44:314–325. PubMed PMID: 25149416.
  • Chen P, Parmalee N, Aschner M. Genetic factors and manganese-induced neurotoxicity. Front Genet. 2014;5:265. PubMed PMID: 25136353; PubMed Central PMCID: PMCPMC4120679.
  • Wu CR, Tsai CW, Chang SW, et al. Carnosic acid protects against 6-hydroxydopamine-induced neurotoxicity in in vivo and in vitro model of Parkinson’s disease: involvement of antioxidative enzymes induction. Chem Biol Interact. 2015 Jan;5(225):40–46. PubMed PMID: 25446857.
  • Higashi Y, Asanuma M, Miyazaki I, et al. Parkin attenuates manganese-induced dopaminergic cell death. J Neurochem. 2004 Jun;89(6):1490–1497. PubMed PMID: 15189352.
  • Tan J, Zhang T, Jiang L, et al. Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein. J Biol Chem. 2011 Aug 26;286(34):29654–29662. PubMed PMID: 21724849; PubMed Central PMCID: PMC3191006.
  • Rentschler G, Covolo L, Haddad AA, et al. ATP13A2 (PARK9) polymorphisms influence the neurotoxic effects of manganese. Neurotoxicology. 2012 Aug;33(4):697–702. PubMed PMID: 22285144; PubMed Central PMCID: PMCPMC3997180.
  • Cai T, Yao T, Zheng G, et al. Manganese induces the overexpression of alpha-synuclein in PC12 cells via ERK activation. Brain Res. 2010 Nov 4;1359:201–207. PubMed PMID: 20735995.
  • Xu B, Liu W, Deng Y, et al. Inhibition of calpain prevents manganese-induced cell injury and alpha-synuclein oligomerization in organotypic brain slice cultures. PLoS One. 2015;10(3):e0119205. PubMed PMID: 25756858; PubMed Central PMCID: PMCPMC4355489.
  • Verina T, Schneider JS, Guilarte TR. Manganese exposure induces alpha-synuclein aggregation in the frontal cortex of non-human primates. Toxicol Lett. 2013 Mar 13;217(3):177–183. PubMed PMID: 23262390; PubMed Central PMCID: PMC3638947.
  • Li Y, Sun L, Cai T, et al. alpha-Synuclein overexpression during manganese-induced apoptosis in SH-SY5Y neuroblastoma cells. Brain Res Bull. 2010 Mar 16;81(4––5):428–433. PubMed PMID: 19932157.
  • Faraone SV, Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies. Psychol Med. 2006 Feb;36(2):159–165. PubMed PMID: 16420712.
  • Polanczyk G, de Lima MS, Horta BL, et al. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry. 2007 Jun;164(6):942–948. PubMed PMID: 17541055.
  • Polanczyk G, Rohde LA. Epidemiology of attention-deficit/hyperactivity disorder across the lifespan. Curr Opin Psychiatry. 2007 Jul;20(4):386–392. PubMed PMID: 17551354.
  • Banerjee TD, Middleton F, Faraone SV. Environmental risk factors for attention-deficit hyperactivity disorder. Acta Paediatr. 2007 Sep;96(9):1269–1274. PubMed PMID: 17718779.
  • Braun JM, Kahn RS, Froehlich T, et al. Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Environ Health Perspect. 2006 Dec;114(12):1904–1909. PubMed PMID: 17185283; PubMed Central PMCID: PMCPMC1764142.
  • Kollins SH, Adcock RA. ADHD, altered dopamine neurotransmission, and disrupted reinforcement processes: implications for smoking and nicotine dependence. Prog Neuropsychopharmacol Biol Psychiatry. 2014 Jul 3;52:70–78.
  • Sharma A, Couture J. A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Ann Pharmacother. 2014 Feb;48(2):209–225. PubMed PMID: 24259638.
  • Farias AC, Cunha A, Benko CR, et al. Manganese in children with attention-deficit/hyperactivity disorder: relationship with methylphenidate exposure [Clinical Trial Research Support, Non-U.S. Gov’t]. J Child Adolesc Psychopharmacol. 2010 Apr;20(2):113–118. PubMed PMID: 20415606.
  • Yousef S, Adem A, Zoubeidi T, et al. Attention deficit hyperactivity disorder and environmental toxic metal exposure in the United Arab Emirates. J Trop Pediatr. 2011 Dec;57(6):457–460. PubMed PMID: 21300623.
  • Liu W, Huo X, Liu D, et al. S100beta in heavy metal-related child attention-deficit hyperactivity disorder in an informal e-waste recycling area. Neurotoxicology. 2014 Dec;45:185–191. PubMed PMID: 25451971.
  • Bouchard M, Laforest F, Vandelac L, et al. Hair manganese and hyperactive behaviors: pilot study of school-age children exposed through tap water. Environ Health Perspect. 2007 Jan;115(1):122–127. PubMed PMID: 17366831; PubMed Central PMCID: PMCPMC1797845.
  • Oulhote Y, Mergler D, Barbeau B, et al. Neurobehavioral function in school-age children exposed to manganese in drinking water. Environ Health Perspect. 2014 Dec;122(12):1343–1350. PubMed PMID: 25260096; PubMed Central PMCID: PMCPMC4256698.
  • Khan K, Factor-Litvak P, Wasserman GA, et al. Manganese exposure from drinking water and children’s classroom behavior in Bangladesh. Environ Health Perspect. 2011 Oct;119(10):1501–1506. PubMed PMID: 21493178; PubMed Central PMCID: PMCPMC3230445.
  • Ericson JE, Crinella FM, Clarke-Stewart KA, et al. Prenatal manganese levels linked to childhood behavioral disinhibition. Neurotoxicol Teratol. 2007 Mar–Apr;29(2):181–187. PubMed PMID: 17079114.
  • Chan TJ, Gutierrez C, Ogunseitan OA. Metallic burden of deciduous teeth and childhood behavioral deficits. Int J Environ Res Public Health. 2015 Jun 15;12(6):6771–6787. PubMed PMID: 26084001; PubMed Central PMCID: PMCPMC4483729.
  • Lucchini RG, Zoni S, Guazzetti S, et al. Inverse association of intellectual function with very low blood lead but not with manganese exposure in Italian adolescents. Environ Res. 2012 Oct;118:65–71. PubMed PMID: 22925625; PubMed Central PMCID: PMCPMC3477579.
  • Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry. 2007 Mar;64(3):327–337. PubMed PMID: 17339521.
  • Andrews PW, Bharwani A, Lee KR, et al. Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response. Neurosci Biobehav Rev. 2015 Apr;51:164–188. PubMed PMID: 25625874.
  • Bowler RM, Gysens S, Diamond E, et al. Manganese exposure: neuropsychological and neurological symptoms and effects in welders. Neurotoxicology. 2006 May;27(3):315–326. PubMed PMID: 16343629.
  • Bouchard M, Mergler D, Baldwin M, et al. Neuropsychiatric symptoms and past manganese exposure in a ferro-alloy plant. Neurotoxicology. 2007 Mar;28(2):290–297. PubMed PMID: 16962176.
  • Bowler RM, Roels HA, Nakagawa S, et al. Dose-effect relationships between manganese exposure and neurological, neuropsychological and pulmonary function in confined space bridge welders. Occup Environ Med. 2007 Mar;64(3):167–177. PubMed PMID: 17018581; PubMed Central PMCID: PMCPMC2092523.
  • Yuan H, He S, He M, et al. A comprehensive study on neurobehavior, neurotransmitters and lymphocyte subsets alteration of Chinese manganese welding workers. Life Sci. 2006 Feb 16;78(12):1324–1328. PubMed PMID: 16243361.
  • Shiue I. Urinary heavy metals, phthalates and polyaromatic hydrocarbons independent of health events are associated with adult depression: USA NHANES, 2011-2012. Environ Sci Pollut Res Int. 2015 Nov;22(21):17095–17103. 10.1007/s11356-015-4944-2. PubMed PMID: 26126689.
  • Zheng W, Fu SX, Dydak U, et al. Biomarkers of manganese intoxication. Neurotoxicology. 2011 Jan;32(1):1–8. PubMed PMID: 20946915; PubMed Central PMCID: PMCPMC3030659.
  • Abdalian R, Saqui O, Fernandes G, et al. Effects of manganese from a commercial multi-trace element supplement in a population sample of Canadian patients on long-term parenteral nutrition. JPEN J Parenter Enteral Nutr. 2013 Jul;37(4):538–543. PubMed PMID: 22829428.
  • Hong SB, Kim JW, Choi BS, et al. Blood manganese levels in relation to comorbid behavioral and emotional problems in children with attention-deficit/hyperactivity disorder. Psychiatry Res. 2014 Dec 15;220(1–2):418–425. PubMed PMID: 25064383.
  • Rubio-Lopez N, Morales-Suarez-Varela M, Pico Y, et al. Nutrient intake and depression symptoms in spanish children: the ANIVA study. Int J Environ Res Public Health. 2016 Mar 22;13(3). PubMed PMID: 27011198; PubMed Central PMCID: PMCPMC4809015. DOI:10.3390/ijerph13030352
  • Miyake Y, Tanaka K, Okubo H, et al. Manganese intake is inversely associated with depressive symptoms during pregnancy in Japan: baseline data from the Kyushu Okinawa maternal and child health study. J Affect Disord. 2017 Mar 15;211:124–129. PubMed PMID: 28110159.
  • Rovira A, Alonso J, Cordoba J. MR imaging findings in hepatic encephalopathy. AJNR Am J Neuroradiol. 2008 Oct;29(9):1612–1621. PubMed PMID: 18583413.
  • Ciecko-Michalska I, Szczepanek M, Slowik A, et al. Pathogenesis of hepatic encephalopathy. Gastroenterol Res Pract. 2012;2012:642108. PubMed PMID: 23316223; PubMed Central PMCID: PMCPMC3534214.
  • Ferro JM, Oliveira S. Neurologic manifestations of gastrointestinal and liver diseases. Curr Neurol Neurosci Rep. 2014 Oct;14(10):487. PubMed PMID: 25171900.
  • Cordoba J. Hepatic encephalopathy: from the pathogenesis to the new treatments. ISRN Hepatol. 2014;2014:236268. PubMed PMID: 27335836; PubMed Central PMCID: PMCPMC4890879.
  • Rose C, Butterworth RF, Zayed J, et al. Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction. Gastroenterology. 1999 Sep;117(3):640–644. PubMed PMID: 10464140.
  • Zeron HM, Rodriguez MR, Montes S, et al. Blood manganese levels in patients with hepatic encephalopathy. J Trace Elem Med Biol. 2011 Dec;25(4):225–229. PubMed PMID: 21975221.
  • Burkhard PR, Delavelle J, Du Pasquier R, et al. Chronic parkinsonism associated with cirrhosis: a distinct subset of acquired hepatocerebral degeneration. Arch Neurol. 2003 Apr;60(4):521–528. PubMed PMID: 12707065.
  • Spahr L, Butterworth RF, Fontaine S, et al. Increased blood manganese in cirrhotic patients: relationship to pallidal magnetic resonance signal hyperintensity and neurological symptoms. Hepatology. 1996 Nov;24(5):1116–1120. PubMed PMID: 8903385.
  • Layrargues GP, Shapcott D, Spahr L, et al. Accumulation of manganese and copper in pallidum of cirrhotic patients: role in the pathogenesis of hepatic encephalopathy? Metab Brain Dis. 1995 Dec;10(4):353–356. PubMed PMID: 8847998.
  • Butterworth RF. Metal toxicity, liver disease and neurodegeneration. Neurotox Res. 2010 Jul;18(1):100–105. PubMed PMID: 20369313.
  • Alonso J, Cordoba J, Rovira A. Brain magnetic resonance in hepatic encephalopathy. Semin Ultrasound CT MR. 2014 Apr;35(2):136–152. PubMed PMID: 24745889.
  • Butterworth RF. Pathophysiology of hepatic encephalopathy: the concept of synergism. Hepatol Res. 2008 Nov;38(Suppl 1):S116–21. PubMed PMID: 19125942.
  • Salgado M, Cortes Y. Hepatic encephalopathy: etiology, pathogenesis, and clinical signs. Compend Contin Educ Vet. 2013 Jun;35(6):E1–8. quiz E9. PubMed PMID: 23677822.
  • Ahboucha S. Neurosteroids and hepatic encephalopathy: an update on possible pathophysiologic mechanisms. Curr Mol Pharmacol. 2011 Jan;4(1):1–13. PubMed PMID: 20825363.
  • Savlan I, Liakina V, Valantinas J. Concise review of current concepts on nomenclature and pathophysiology of hepatic encephalopathy. Medicina (Kaunas). 2014;502:75–81. PubMed PMID: 25172600.
  • Cichoz-Lach H, Michalak A. Current pathogenetic aspects of hepatic encephalopathy and noncirrhotic hyperammonemic encephalopathy. World J Gastroenterol. 2013 Jan 7;19(1):26–34. PubMed PMID: 23326159; PubMed Central PMCID: PMCPMC3545226.
  • Butterworth RF. Pathogenesis of hepatic encephalopathy in cirrhosis: the concept of synergism revisited. Metab Brain Dis. 2016 Dec;31(6):1211–1215. PubMed PMID: 26521983.
  • Prakash R, Mullen KD. Mechanisms, diagnosis and management of hepatic encephalopathy. Nat Rev Gastroenterol Hepatol. 2010 Sep;7(9):515–525. PubMed PMID: 20703237.
  • Aschner JL, Aschner M. Nutritional aspects of manganese homeostasis. Mol Aspects Med. 2005 Aug–Oct;26(4–5):353–362. PubMed PMID: 16099026.
  • Smith D, Gwiazda R, Bowler R, et al. Biomarkers of Mn exposure in humans. Am J Ind Med. 2007 Nov;50(11):801–811. PubMed PMID: 17924418.
  • Schroeter JD, Nong A, Yoon M, et al. Analysis of manganese tracer kinetics and target tissue dosimetry in monkeys and humans with multi-route physiologically based pharmacokinetic models. Toxicol Sci. 2011 Apr;120(2):481–498. PubMed PMID: 21205636.
  • Ntihabose R, Surette C, Foucher D, et al. Assessment of saliva, hair and toenails as biomarkers of low level exposure to manganese from drinking water in children. Neurotoxicology. 2018 Jan;64:126–133. PubMed PMID: 28867366.
  • Grashow R, Zhang J, Fang SC, et al. Toenail metal concentration as a biomarker of occupational welding fume exposure. J Occup Environ Hyg. 2014;11(6):397–405. PubMed PMID: 24372360; PubMed Central PMCID: PMCPMC4019688.
  • Viana GF, de Carvalho CF, Nunes LS, et al. Noninvasive biomarkers of manganese exposure and neuropsychological effects in environmentally exposed adults in Brazil. Toxicol Lett. 2014 Dec 1;231(2):169–178. PubMed PMID: 24992226.
  • Menezes-Filho JA, Paes CR, Pontes AM, et al. High levels of hair manganese in children living in the vicinity of a ferro-manganese alloy production plant. Neurotoxicology. 2009 Nov;30(6):1207–1213. PubMed PMID: 19393689; PubMed Central PMCID: PMCPMC2789903.
  • Reiss B, Simpson CD, Mg B, et al. Hair manganese as an exposure biomarker among welders. Ann Occup Hyg. 2016 Mar;60(2):139–149. PubMed PMID: 26409267; PubMed Central PMCID: PMCPMC4834832.
  • Cowan DM, Fan Q, Zou Y, et al. Manganese exposure among smelting workers: blood manganese-iron ratio as a novel tool for manganese exposure assessment. Biomarkers. 2009 Feb;14(1):3–16. PubMed PMID: 19283519; PubMed Central PMCID: PMCPMC3980868.
  • Cowan DM, Zheng W, Zou Y, et al. Manganese exposure among smelting workers: relationship between blood manganese-iron ratio and early onset neurobehavioral alterations. Neurotoxicology. 2009 Nov;30(6):1214–1222. PubMed PMID: 19963104; PubMed Central PMCID: PMCPMC3983997.
  • Tutkun E, Abusoglu S, Yilmaz H, et al. Prolactin levels in manganese-exposed male welders. Pituitary. 2014 Dec;17(6):564–568. PubMed PMID: 24337778.
  • Montes S, Schilmann A, Riojas-Rodriguez H, et al. Serum prolactin rises in Mexican school children exposed to airborne manganese. Environ Res. 2011 Nov;111(8):1302–1308. PubMed PMID: 22001219.
  • Smargiassi A, Mutti A. Peripheral biomarkers and exposure to manganese. Neurotoxicology. 1999 Apr–Jun;20(2–3):401–406. PubMed PMID: 10385899.
  • Montes S, Riojas-Rodriguez H, Sabido-Pedraza E, et al. Biomarkers of manganese exposure in a population living close to a mine and mineral processing plant in Mexico. Environ Res. 2008 Jan;106(1):89–95. PubMed PMID: 17915211.
  • Kim EA, Cheong HK, Joo KD, et al. Effect of manganese exposure on the neuroendocrine system in welders. Neurotoxicology. 2007 Mar;28(2):263–269. PubMed PMID: 16950514.
  • Freeman ME, Kanyicska B, Lerant A, et al. Prolactin: structure, function, and regulation of secretion. Physiol Rev. 2000 Oct;80(4):1523–1631. PubMed PMID: 11015620.
  • Kim HY, Lee CK, Lee JT, et al. Effects of manganese exposure on dopamine and prolactin production in rat. Neuroreport. 2009 Jan 7;20(1):69–73. PubMed PMID: 19057282.
  • Crossgrove J, Zheng W. Manganese toxicity upon overexposure. NMR Biomed. 2004 Dec;17(8):544–553. PubMed PMID: 15617053; PubMed Central PMCID: PMCPMC3980863.
  • Fell JM, Reynolds AP, Meadows N, et al. Manganese toxicity in children receiving long-term parenteral nutrition. Lancet. 1996 May 4;347(9010):1218–1221. PubMed PMID: 8622451.
  • Bowler RM, Yeh CL, Adams SW, et al. Association of MRI T1 relaxation time with neuropsychological test performance in manganese- exposed welders. Neurotoxicology. 2018 Jan;64:19–29. PubMed PMID: 28587807; PubMed Central PMCID: PMCPMC5905426.
  • Criswell SR, Perlmutter JS, Huang JL, et al. Basal ganglia intensity indices and diffusion weighted imaging in manganese-exposed welders. Occup Environ Med. 2012 Jun;69(6):437–443. PubMed PMID: 22447645.
  • Krieger D, Krieger S, Jansen O, et al. Manganese and chronic hepatic encephalopathy. Lancet. 1995 Jul 29;346(8970):270–274. PubMed PMID: 7630246.
  • Jiang Y, Zheng W, Long L, et al. Brain magnetic resonance imaging and manganese concentrations in red blood cells of smelting workers: search for biomarkers of manganese exposure. Neurotoxicology. 2007 Jan;28(1):126–135. PubMed PMID: 16978697; PubMed Central PMCID: PMCPMC3983995.
  • Long Z, Jiang YM, Li XR, et al. Vulnerability of welders to manganese exposure–a neuroimaging study. Neurotoxicology. 2014 Dec;45:285–292. PubMed PMID: 24680838; PubMed Central PMCID: PMCPMC4177505.
  • Dorman DC, Struve MF, Wong BA, et al. Correlation of brain magnetic resonance imaging changes with pallidal manganese concentrations in rhesus monkeys following subchronic manganese inhalation. Toxicol Sci. 2006 Jul;92(1):219–227. PubMed PMID: 16638924.
  • Lee EY, Flynn MR, Du G, et al. T1 relaxation rate (R1) indicates nonlinear mn accumulation in brain tissue of welders with low-level exposure. Toxicol Sci. 2015 Aug;146(2):281–289. PubMed PMID: 25953701; PubMed Central PMCID: PMCPMC4607746.
  • Choi DS, Kim EA, Cheong HK, et al. Evaluation of MR signal index for the assessment of occupational manganese exposure of welders by measurement of local proton T1 relaxation time. Neurotoxicology. 2007 Mar;28(2):284–289. PubMed PMID: 16828869.
  • Sikk K, Haldre S, Aquilonius SM, et al. Manganese-induced parkinsonism due to ephedrone abuse. Parkinsons Dis. 2011;2011:865319. PubMed PMID: 21403909; PubMed Central PMCID: PMC3043321.
  • Kim Y, Kim KS, Yang JS, et al. Increase in signal intensities on T1-weighted magnetic resonance images in asymptomatic manganese-exposed workers. Neurotoxicology. 1999 Dec;20(6):901–907. PubMed PMID: 10693971.
  • Kim Y. Neuroimaging in manganism. Neurotoxicology. 2006 May;27(3):369–372. PubMed PMID: 16442160.
  • Kim EA, Cheong HK, Choi DS, et al. Effect of occupational manganese exposure on the central nervous system of welders: 1H magnetic resonance spectroscopy and MRI findings. Neurotoxicology. 2007 Mar;28(2):276–283. PubMed PMID: 16824604.
  • Chang Y, Woo ST, Lee JJ, et al. Neurochemical changes in welders revealed by proton magnetic resonance spectroscopy. Neurotoxicology. 2009 Nov;30(6):950–957. PubMed PMID: 19631686.
  • Dydak U, Jiang YM, Long LL, et al. In vivo measurement of brain GABA concentrations by magnetic resonance spectroscopy in smelters occupationally exposed to manganese. Environ Health Perspect. 2011 Feb;119(2):219–224. PubMed PMID: 20876035; PubMed Central PMCID: PMCPMC3040609.
  • O’Neal SL, Zheng W. Manganese toxicity upon overexposure: a decade in review. Curr Environ Health Rep. 2015 Sep;2(3):315–328. PubMed PMID: 26231508; PubMed Central PMCID: PMCPMC4545267.
  • Walter E, Alsaffar S, Livingstone C, et al. Manganese toxicity in critical care: case report, literature review and recommendations for practice. J Intensive Care Soc. 2016 Aug;17(3):252–257. PubMed PMID: 28979499; PubMed Central PMCID: PMCPMC5606512.
  • Koller WC, Lyons KE, Truly W. Effect of levodopa treatment for parkinsonism in welders: a double-blind study. Neurology. 2004 Mar 9;62(5):730–733. PubMed PMID: 15007122.
  • Discalzi G, Pira E, Herrero Hernandez E, et al. Occupational Mn parkinsonism: magnetic resonance imaging and clinical patterns following CaNa2-EDTA chelation. Neurotoxicology. 2000 Oct;21(5):863–866. PubMed PMID: 11130292.
  • Ono K, Komai K, Yamada M. Myoclonic involuntary movement associated with chronic manganese poisoning. J Neurol Sci. 2002 Jul 15;199(1–2):93–96. PubMed PMID: 12084450.
  • Quadri M, Federico A, Zhao T, et al. Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease. Am J Hum Genet. 2012 Mar 9;90(3):467–477. PubMed PMID: 22341971; PubMed Central PMCID: PMCPMC3309204.
  • Jiang YM, Mo XA, Du FQ, et al. Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: a case of 17-year follow-up study. J Occup Environ Med. 2006 Jun;48(6):644–649. PubMed PMID: 16766929; PubMed Central PMCID: PMCPMC4180660.
  • Zheng W, Jiang YM, Zhang Y, et al. Chelation therapy of manganese intoxication with para-aminosalicylic acid (PAS) in Sprague-Dawley rats. Neurotoxicology. 2009 Mar;30(2):240–248. PubMed PMID: 19150464; PubMed Central PMCID: PMCPMC2677987.
  • Tuschl K, Mills PB, Parsons H, et al. Hepatic cirrhosis, dystonia, polycythaemia and hypermanganesaemia–a new metabolic disorder. J Inherit Metab Dis. 2008 Apr;31(2):151–163. PubMed PMID: 18392750.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.