Biological Trace Element Research

, Volume 187, Issue 2, pp 341–356 | Cite as

Mercury Involvement in Neuronal Damage and in Neurodegenerative Diseases

  • Veronica Lanza Cariccio
  • Annalisa Samà
  • Placido Bramanti
  • Emanuela MazzonEmail author


Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis are characterized by a chronic and selective process of neuronal cell death. Although the causes of neurodegenerative diseases remain still unknown, it is now a well-established idea that more factors, such as genetic, endogenous, and environmental, are involved. Among environmental causes, the accumulation of mercury, a heavy metal considered a toxic agent, was largely studied as a probable factor involved in neurodegenerative disease course. Mercury exists in three main forms: elemental mercury, inorganic mercury, and organic mercury (methylmercury and ethylmercury). Sources of elemental mercury can be natural (volcanic emission) or anthropogenic (coal-fired electric utilities, waste combustion, hazardous-waste incinerators, and gold extraction). Moreover, mercury is still used as an antiseptic, as a medical preservative, and as a fungicide. Dental amalgam can emit mercury vapor. Mercury vapor, being highly volatile and lipid soluble, can cross the blood-brain barrier and the lipid cell membranes and can be accumulated into the cells in its inorganic forms. Also, methylmercury can pass through blood-brain and placental barriers, causing serious damage in the central nervous system. This review describes the toxic effects of mercury in cell cultures, in animal models, and in patients with neurodegenerative diseases. In vitro experiments showed that mercury exposure was principally involved in oxidative stress and apoptotic processes. Moreover, motor and cognitive impairment and neural loss have been confirmed in various studies performed in animal models. Finally, observational studies on patients with neurodegenerative diseases showed discordant data about a possible mercury involvement.


Methylmercury Multiple sclerosis Amyotrophic lateral sclerosis Alzheimer’s disease Parkinson’s disease In vivo/in vitro experiments 


Funding Information

This work was supported by the current research funds 2018 of IRCCS “Centro Neurolesi Bonino Pulejo.”


  1. 1.
    El Haj M, Roche J, Gallouj K, Gandolphe MC (2017) Autobiographical memory compromise in Alzheimer’s disease: a cognitive and clinical overview. Geriatrie et Psychologie Neuropsychiatrie du Vieillissement 15(4):443–451. CrossRefPubMedGoogle Scholar
  2. 2.
    Alves G, Wentzel-Larsen T, Aarsland D, Larsen JP (2005) Progression of motor impairment and disability in Parkinson disease: a population-based study. Neurology 65(9):1436–1441. CrossRefPubMedGoogle Scholar
  3. 3.
    Yang Y, Tang BS, Guo JF (2016) Parkinson’s disease and cognitive impairment. Park Dis 2016:6734678. CrossRefGoogle Scholar
  4. 4.
    Raggi A, Covelli V, Schiavolin S, Scaratti C, Leonardi M, Willems M (2016) Work-related problems in multiple sclerosis: a literature review on its associates and determinants. Disabil Rehabil 38(10):936–944. CrossRefPubMedGoogle Scholar
  5. 5.
    Tsuang DW, Bird TD (2017) Genetic factors in neurodegenerative diseases. Am J Med Genet Part B, Neuropsychiatr Genet: Off Publ Int Soc Psychiatr Genet 174(1):3–4. CrossRefGoogle Scholar
  6. 6.
    Monnet-Tschudi F, Zurich MG, Boschat C, Corbaz A, Honegger P (2006) Involvement of environmental mercury and lead in the etiology of neurodegenerative diseases. Rev Environ Health 21(2):105–117CrossRefGoogle Scholar
  7. 7.
    Mutter J, Naumann J, Sadaghiani C, Schneider R, Walach H (2004) Alzheimer disease: mercury as pathogenetic factor and apolipoprotein E as a moderator. Neuro Endocrinol Lett 25(5):331–339PubMedGoogle Scholar
  8. 8.
    Allen Reish HE, Standaert DG (2015) Role of alpha-synuclein in inducing innate and adaptive immunity in Parkinson disease. J Park Dis 5(1):1–19. CrossRefGoogle Scholar
  9. 9.
    Zheng M, Shi Y, Fan D (2013) Nuclear TAR DNA-binding protein 43: a new target for amyotrophic lateral sclerosis treatment. Neural Regen Res 8(35):3284–3295. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ramanan VK, Saykin AJ (2013) Pathways to neurodegeneration: mechanistic insights from GWAS in Alzheimer’s disease, Parkinson’s disease, and related disorders. Am J Neurodegenerative Dis 2(3):145–175Google Scholar
  11. 11.
    Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113):787–795. CrossRefPubMedGoogle Scholar
  12. 12.
    Liang P, Le W (2015) Role of autophagy in the pathogenesis of multiple sclerosis. Neurosci Bull 31(4):435–444. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Rivera-Mancia S, Perez-Neri I, Rios C, Tristan-Lopez L, Rivera-Espinosa L, Montes S (2010) The transition metals copper and iron in neurodegenerative diseases. Chem Biol Interact 186(2):184–199. CrossRefPubMedGoogle Scholar
  14. 14.
    Gaeta A, Hider RC (2005) The crucial role of metal ions in neurodegeneration: the basis for a promising therapeutic strategy. Br J Pharmacol 146(8):1041–1059. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Carocci A, Rovito N, Sinicropi MS, Genchi G (2014) Mercury toxicity and neurodegenerative effects. Rev Environ Contam Toxicol 229:1–18. CrossRefPubMedGoogle Scholar
  16. 16.
    Fung YK, Meade AG, Rack EP, Blotcky AJ (1997) Brain mercury in neurodegenerative disorders. J Toxicol Clin Toxicol 35(1):49–54CrossRefGoogle Scholar
  17. 17.
    Clarkson TW, Magos L (2006) The toxicology of mercury and its chemical compounds. Crit Rev Toxicol 36(8):609–662. CrossRefPubMedGoogle Scholar
  18. 18.
    Magos L, Clarkson TW (2006) Overview of the clinical toxicity of mercury. Ann Clin Biochem 43:257–268. CrossRefPubMedGoogle Scholar
  19. 19.
    Harada M (1995) Minamata disease: methylmercury poisoning in Japan caused by environmental pollution. Crit Rev Toxicol 25(1):1–24. CrossRefPubMedGoogle Scholar
  20. 20.
    Skerfving SB, Copplestone JF (1976) Poisoning caused by the consumption of organomercury-dressed seed in Iraq. Bull World Health Organ 54(1):101–112PubMedPubMedCentralGoogle Scholar
  21. 21.
    Xu F, Farkas S, Kortbeek S, Zhang FX, Chen L, Zamponi GW, Syed NI (2012) Mercury-induced toxicity of rat cortical neurons is mediated through N-methyl-D-aspartate receptors. Mol Brain 5:30. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kim SH, Johnson VJ, Sharma RP (2002) Mercury inhibits nitric oxide production but activates proinflammatory cytokine expression in murine macrophage: differential modulation of NF-kappaB and p38 MAPK signaling pathways. Nitric Oxide Biol Chem 7(1):67–74CrossRefGoogle Scholar
  23. 23.
    Ortega HG, Lopez M, Takaki A, Huang QH, Arimura A, Salvaggio JE (1997) Neuroimmunological effects of exposure to methylmercury forms in the Sprague-Dawley rats. Activation of the hypothalamic-pituitary-adrenal axis and lymphocyte responsiveness. Toxicol Ind Health 13(1):57–66CrossRefGoogle Scholar
  24. 24.
    Havarinasab S, Bjorn E, Nielsen JB, Hultman P (2007) Mercury species in lymphoid and non-lymphoid tissues after exposure to methyl mercury: correlation with autoimmune parameters during and after treatment in susceptible mice. Toxicol Appl Pharmacol 221(1):21–28. CrossRefPubMedGoogle Scholar
  25. 25.
    Kim MK, Zoh KD (2012) Fate and transport of mercury in environmental media and human exposure. J Prev Med Publ Health = Yebang Uihakhoe chi 45(6):335–343. CrossRefGoogle Scholar
  26. 26.
    Yokoo EM, Valente JG, Grattan L, Schmidt SL, Platt I, Silbergeld EK (2003) Low level methylmercury exposure affects neuropsychological function in adults. Environ Health: Global Access Sci Source 2(1):8. CrossRefGoogle Scholar
  27. 27.
    Drasch G, Schupp I, Hofl H, Reinke R, Roider G (1994) Mercury burden of human fetal and infant tissues. Eur J Pediatr 153(8):607–610CrossRefGoogle Scholar
  28. 28.
    Murcia M, Ballester F, Enning AM, Iniguez C, Valvi D, Basterrechea M, Rebagliato M, Vioque J, Maruri M, Tardon A, Riano-Galan I, Vrijheid M, Llop S (2016) Prenatal mercury exposure and birth outcomes. Environ Res 151:11–20. CrossRefPubMedGoogle Scholar
  29. 29.
    Prpic I, Milardovic A, Vlasic-Cicvaric I, Spiric Z, Nisevic JR, Vukelic P, Tratnik JS, Mazej D, Horvat M (2017) Prenatal exposure to low-level methylmercury alters the child’s fine motor skills at the age of 18 months. Environ Res 152:369–374. CrossRefPubMedGoogle Scholar
  30. 30.
    Castoldi AF, Barni S, Turin I, Gandini C, Manzo L (2000) Early acute necrosis, delayed apoptosis and cytoskeletal breakdown in cultured cerebellar granule neurons exposed to methylmercury. J Neurosci Res 59(6):775–787.<775::Aid-Jnr10>3.0.Co;2-T CrossRefPubMedGoogle Scholar
  31. 31.
    Zahir F, Rizwi SJ, Haq SK, Khan RH (2005) Low dose mercury toxicity and human health. Environ Toxicol Pharmacol 20(2):351–360. CrossRefPubMedGoogle Scholar
  32. 32.
    Azevedo BF, Furieri LB, Pecanha FM, Wiggers GA, Vassallo PF, Simoes MR, Fiorim J, de Batista PR, Fioresi M, Rossoni L, Stefanon I, Alonso MJ, Salaices M, Vassallo DV (2012) Toxic effects of mercury on the cardiovascular and central nervous systems J Biomed Biotechnol doi:Artn 949,048
  33. 33.
    Clarkson TW (2002) The three modern faces of mercury. Environ Health Perspect 110(Suppl 1):11–23CrossRefGoogle Scholar
  34. 34.
    Clarkson TW, Vyas JB, Ballatorl N (2007) Mechanisms of mercury disposition in the body. Am J Ind Med 50(10):757–764. CrossRefPubMedGoogle Scholar
  35. 35.
    Pirrone N, Cinnirella S, Feng X, Finkelman RB, Friedli HR, Leaner J, Mason R, Mukherjee AB, Stracher GB, Streets DG, Telmer K (2010) Global mercury emissions to the atmosphere from anthropogenic and natural sources. Atmos Chem Phys 10(13):5951–5964. CrossRefGoogle Scholar
  36. 36.
    Bose-O’Reilly S, Lettmeier B, Gothe RM, Beinhoff C, Siebert U, Drasch G (2008) Mercury as a serious health hazard for children in gold mining areas. Environ Res 107(1):89–97. CrossRefPubMedGoogle Scholar
  37. 37.
    Mutter J, Naumann J, Guethlin C (2007) Comments on the article “the toxicology of mercury and its chemical compounds” by Clarkson and Magos (2006). Crit Rev Toxicol 37(6):537–549; discussion 551–532. CrossRefPubMedGoogle Scholar
  38. 38.
    Halbach S, Vogt S, Kohler W, Felgenhauer N, Welzl G, Kremers L, Zilker T, Melchart D (2008) Blood and urine mercury levels in adult amalgam patients of a randomized controlled trial: interaction of Hg species in erythrocytes. Environ Res 107(1):69–78. CrossRefPubMedGoogle Scholar
  39. 39.
    Rice KM, Walker EM Jr, Wu M, Gillette C, Blough ER (2014) Environmental mercury and its toxic effects. J Prev Med Publ Health = Yebang Uihakhoe chi 47(2):74–83. CrossRefGoogle Scholar
  40. 40.
    Mutter J, Curth A, Naumann J, Deth R, Walach H (2010) Does inorganic mercury play a role in Alzheimer’s disease? A systematic review and an integrated molecular mechanism. J Alzheim Dis 22(2):357–374.,705 CrossRefGoogle Scholar
  41. 41.
    Rooney JP (2007) The role of thiols, dithiols, nutritional factors and interacting ligands in the toxicology of mercury. Toxicology 234(3):145–156. CrossRefPubMedGoogle Scholar
  42. 42.
    Fonnum F, Lock EA (2004) The contributions of excitotoxicity, glutathione depletion and DNA repair in chemically induced injury to neurones: exemplified with toxic effects on cerebellar granule cells. J Neurochem 88(3):513–531CrossRefGoogle Scholar
  43. 43.
    Albrecht J, Matyja E (1996) Glutamate: a potential mediator of inorganic mercury neurotoxicity. Metab Brain Dis 11(2):175–184CrossRefGoogle Scholar
  44. 44.
    Hunter AM, Brown DL (2000) Effects of microtubule-associated protein (MAP) expression on methylmercury-induced microtubule disassembly. Toxicol Appl Pharmacol 166(3):203–213. CrossRefPubMedGoogle Scholar
  45. 45.
    Huel G, Sahuquillo J, Debotte G, Oury JF, Takser L (2008) Hair mercury negatively correlates with calcium pump activity in human term newborns and their mothers at delivery. Environ Health Perspect 116(2):263–267. CrossRefPubMedGoogle Scholar
  46. 46.
    Farina M, Rocha JB, Aschner M (2011) Mechanisms of methylmercury-induced neurotoxicity: evidence from experimental studies. Life Sci 89(15–16):555–563. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Ralston NV, Raymond LJ (2010) Dietary selenium’s protective effects against methylmercury toxicity. Toxicology 278(1):112–123. CrossRefPubMedGoogle Scholar
  48. 48.
    Farina M, Aschner M, Rocha JB (2011) Oxidative stress in MeHg-induced neurotoxicity. Toxicol Appl Pharmacol 256(3):405–417. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Zahir F, Rizvi SJ, Haq SK, Khan RH (2006) Effect of methyl mercury induced free radical stress on nucleic acids and protein: implications on cognitive and motor functions. Indian J Clin Biochem: IJCB 21(2):149–152. CrossRefPubMedGoogle Scholar
  50. 50.
    Sinha K, Das J, Pal PB, Sil PC (2013) Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol 87(7):1157–1180. CrossRefPubMedGoogle Scholar
  51. 51.
    Collins Y, Chouchani ET, James AM, Menger KE, Cocheme HM, Murphy MP (2012) Mitochondrial redox signalling at a glance. J Cell Sci 125(4):801–806. CrossRefPubMedGoogle Scholar
  52. 52.
    Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13. CrossRefPubMedGoogle Scholar
  53. 53.
    Kannan K, Jain SK (2000) Oxidative stress and apoptosis. Pathophysiol: Off J Int Soc Pathophysiol 7(3):153–163CrossRefGoogle Scholar
  54. 54.
    LeBel CP, Ali SF, McKee M, Bondy SC (1990) Organometal-induced increases in oxygen reactive species: the potential of 2′,7′-dichlorofluorescin diacetate as an index of neurotoxic damage. Toxicol Appl Pharmacol 104(1):17–24CrossRefGoogle Scholar
  55. 55.
    Parran DK, Mundy WR, Barone S Jr (2001) Effects of methylmercury and mercuric chloride on differentiation and cell viability in PC12 cells. Toxicoll Sci: Off J Soc Toxicol 59(2):278–290CrossRefGoogle Scholar
  56. 56.
    Schubert J, Riley EJ, Tyler SA (1978) Combined effects in toxicology—a rapid systematic testing procedure: cadmium, mercury, and lead. J Toxicol Environ Health 4(5–6):763–776. CrossRefPubMedGoogle Scholar
  57. 57.
    Papp A, Pecze L, Szabo A, Vezer T (2006) Effects on the central and peripheral nervous activity in rats elicited by acute administration of lead, mercury and manganese, and their combinations. J Appl Toxicol: JAT 26(4):374–380. CrossRefPubMedGoogle Scholar
  58. 58.
    Haley BE (2005) Mercury toxicity: genetic susceptibility and synergistic effects. Medical Veritas: The Journal of Medical Truth 2:535–542Google Scholar
  59. 59.
    Balmus IM, Strungaru SA, Ciobica A, Nicoara MN, Dobrin R, Plavan G, Stefanescu C (2017) Preliminary data on the interaction between some biometals and oxidative stress status in mild cognitive impairment and Alzheimer’s disease patients. Oxidative Med Cell Longev 2017:7156928. CrossRefGoogle Scholar
  60. 60.
    Bjorkblom B, Adilbayeva A, Maple-Grodem J, Piston D, Okvist M, Xu XM, Brede C, Larsen JP, Moller SG (2013) Parkinson disease protein DJ-1 binds metals and protects against metal-induced cytotoxicity. J Biol Chem 288(31):22809–22,820. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Liu S, Liu J, Wang XD, Shi Z, Zhou Y, Li J, Yu T, Ji Y (2017) Caregiver burden, sleep quality, depression, and anxiety in dementia caregivers: a comparison of frontotemporal lobar degeneration, dementia with Lewy bodies, and Alzheimer’s disease. Int Psychogeriatrics: 1–8. doi:
  62. 62.
    Jomova K, Vondrakova D, Lawson M, Valko M (2010) Metals, oxidative stress and neurodegenerative disorders. Mol Cell Biochem 345(1–2):91–104. CrossRefPubMedGoogle Scholar
  63. 63.
    Crespo AC, Silva B, Marques L, Marcelino E, Maruta C, Costa S, Timoteo A, Vilares A, Couto FS, Faustino P, Correia AP, Verdelho A, Porto G, Guerreiro M, Herrero A, Costa C, de Mendonca A, Costa L, Martins M (2014) Genetic and biochemical markers in patients with Alzheimer’s disease support a concerted systemic iron homeostasis dysregulation. Neurobiol Aging 35(4):777–785. CrossRefPubMedGoogle Scholar
  64. 64.
    De Simone U, Caloni F, Gribaldo L, Coccini T (2017) Human co-culture model of neurons and astrocytes to test acute cytotoxicity of neurotoxic compounds. Int J Toxicol 36(6):463–477CrossRefGoogle Scholar
  65. 65.
    Lu TH, Hsieh SY, Yen CC, Wu HC, Chen KL, Hung DZ, Chen CH, Wu CC, Su YC, Chen YW, Liu SH, Huang CF (2011) Involvement of oxidative stress-mediated ERK1/2 and p38 activation regulated mitochondria-dependent apoptotic signals in methylmercury-induced neuronal cell injury. Toxicol Lett 204(1):71–80. CrossRefPubMedGoogle Scholar
  66. 66.
    Olivieri G, Brack C, Muller-Spahn F, Stahelin HB, Herrmann M, Renard P, Brockhaus M, Hock C (2000) Mercury induces cell cytotoxicity and oxidative stress and increases beta-amyloid secretion and tau phosphorylation in SHSY5Y neuroblastoma cells. J Neurochem 74(1):231–236CrossRefGoogle Scholar
  67. 67.
    Herrmann M, Golombowski S, Krauchi K, Frey P, Mourton-Gilles C, Hulette C, Rosenberg C, Muller-Spahn F, Hock C (1999) ELISA-quantitation of phosphorylated tau protein in the Alzheimer’s disease brain. Eur Neurol 42(4):205–210. CrossRefPubMedGoogle Scholar
  68. 68.
    Fujimura M, Usuki F, Sawada M, Takashima A (2009) Methylmercury induces neuropathological changes with tau hyperphosphorylation mainly through the activation of the c-jun-N-terminal kinase pathway in the cerebral cortex, but not in the hippocampus of the mouse brain. Neurotoxicology 30(6):1000–1007. CrossRefPubMedGoogle Scholar
  69. 69.
    Gerhardsson L, Lundh T, Minthon L, Londos E (2008) Metal concentrations in plasma and cerebrospinal fluid in patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 25(6):508–515. CrossRefPubMedGoogle Scholar
  70. 70.
    Hock C, Drasch G, Golombowski S, Muller-Spahn F, Willershausen-Zonnchen B, Schwarz P, Hock U, Growdon JH, Nitsch RM (1998) Increased blood mercury levels in patients with Alzheimer’s disease. J Neural Transm 105(1):59–68. CrossRefPubMedGoogle Scholar
  71. 71.
    Giacoppo S, Galuppo M, Calabro RS, D’Aleo G, Marra A, Sessa E, Bua DG, Potorti AG, Dugo G, Bramanti P, Mazzon E (2014) Heavy metals and neurodegenerative diseases: an observational study. Biol Trace Elem Res 161(2):151–160. CrossRefPubMedGoogle Scholar
  72. 72.
    Harris FM, Tesseur I, Brecht WJ, Xu Q, Mullendorff K, Chang S, Wyss-Coray T, Mahley RW, Huang Y (2004) Astroglial regulation of apolipoprotein E expression in neuronal cells. Implications for Alzheimer’s disease. J Biol Chem 279(5):3862–3868. CrossRefPubMedGoogle Scholar
  73. 73.
    Hendrie HC, Murrell J, Baiyewu O, Lane KA, Purnell C, Ogunniyi A, Unverzagt FW, Hall K, Callahan CM, Saykin AJ, Gureje O, Hake A, Foroud T, Gao S (2014) APOE ε4 and the risk for Alzheimer disease and cognitive decline in African Americans and Yoruba. Int Psychogeriatr 26(6):977–985. CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Godfrey ME, Wojcik DP, Krone CA (2003) Apolipoprotein E genotyping as a potential biomarker for mercury neurotoxicity. J Alzheimers Dis 5(3):189–195CrossRefGoogle Scholar
  75. 75.
    Laws SM, Hone E, Gandy S, Martins RN (2003) Expanding the association between the APOE gene and the risk of Alzheimer’s disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription. J Neurochem 84(6):1215–1236. CrossRefPubMedGoogle Scholar
  76. 76.
    Pendergrass JC, Haley BE, Vimy MJ, Winfield SA, Lorscheider FL (1997) Mercury vapor inhalation inhibits binding of GTP to tubulin in rat brain: similarity to a molecular lesion in Alzheimer diseased brain. Neurotoxicology 18(2):315–324PubMedGoogle Scholar
  77. 77.
    Morris MC, Brockman J, Schneider JA, Wang Y, Bennett DA, Tangney CC, van de Rest O (2016) Association of seafood consumption, brain mercury level, and APOE ε4 status with brain neuropathology in older adults. JAMA 315(5):489–497. CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Lee J-Y, Kim J-H, Choi D-W, Lee D-W, Park J-H, Yoon H-J, Pyo H-S, Kwon H-J, Park K-S (2012) The association of heavy metal of blood and serum in the Alzheimer’s diseases. Toxicol Res 28(2):93–98CrossRefGoogle Scholar
  79. 79.
    Pamphlett R, Kum Jew S (2015) Different populations of human locus ceruleus neurons contain heavy metals or hyperphosphorylated tau: implications for amyloid-beta and tau pathology in Alzheimer’s disease. J Alzheimers Dis 45(2):437–447CrossRefGoogle Scholar
  80. 80.
    Sun Y-H, Nfor ON, Huang J-Y, Liaw Y-P (2015) Association between dental amalgam fillings and Alzheimer’s disease: a population-based cross-sectional study in Taiwan. Alzheimers Res Ther 7(1):65CrossRefGoogle Scholar
  81. 81.
    Park J-H, Lee D-W, Park KS, Joung H (2014) Serum trace metal levels in Alzheimer’s disease and normal control groups. Am J Alzheimers Dis Other Demen 29(1):76–83CrossRefGoogle Scholar
  82. 82.
    Jadvar H, Colletti PM (2014) Competitive advantage of PET/MRI. Eur J Radiol 83(1):84–94. CrossRefPubMedGoogle Scholar
  83. 83.
    Zhang XY, Yang ZL, Lu GM, Yang GF, Zhang LJ (2017) PET/MR imaging: new frontier in Alzheimer’s disease and other dementias. Front Mol Neurosci 10:343. CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Gallegos S, Pacheco C, Peters C, Opazo CM, Aguayo LG (2015) Features of alpha-synuclein that could explain the progression and irreversibility of Parkinson’s disease. Front Neurosci 9:59CrossRefGoogle Scholar
  85. 85.
    Tysnes OB, Storstein A (2017) Epidemiology of Parkinson’s disease. J Neural Transm 124(8):901–905. CrossRefPubMedGoogle Scholar
  86. 86.
    de Lau LM, Breteler MM (2006) Epidemiology of Parkinson’s disease. Lancet Neurol 5(6):525–535. CrossRefPubMedGoogle Scholar
  87. 87.
    Reeve A, Simcox E, Turnbull D (2014) Ageing and Parkinson’s disease: why is advancing age the biggest risk factor? Ageing Res Rev 14:19–30. CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Kuzis G, Sabe L, Tiberti C, Leiguarda R, Starkstein SE (1997) Cognitive functions in major depression and Parkinson disease. Arch Neurol 54(8):982–986CrossRefGoogle Scholar
  89. 89.
    Goldman SM (2014) Environmental toxins and Parkinson’s disease. Annu Rev Pharmacol Toxicol 54:141–164.,937 CrossRefPubMedGoogle Scholar
  90. 90.
    Bjorklund G, Stejskal V, Urbina MA, Dadar M, Chirumbolo S, Mutter J (2017) Metals and Parkinson’s disease: mechanisms and biochemical processes. Curr Med Chem.
  91. 91.
    Bjorklund G (1995) Parkinson disease, mercury and other heavy metals. Tidsskrift for den Norske laegeforening: tidsskrift for praktisk medicin, ny raekke 115(6):757Google Scholar
  92. 92.
    Forte G, Alimonti A, Pino A, Stanzione P, Brescianini S, Brusa L, Sancesario G, Violante N, Bocca B (2005) Metals and oxidative stress in patients with Parkinson’s disease. Annali dell’Istituto Superiore di Sanita 41(2):189–195PubMedGoogle Scholar
  93. 93.
    Dantzig PI (2006) Parkinson’s disease, macular degeneration and cutaneous signs of mercury toxicity. J Occup Environ Med 48(7):656. CrossRefPubMedGoogle Scholar
  94. 94.
    Miller K, Ochudlo S, Opala G, Smolicha W, Siuda J (2003) Parkinsonism in chronic occupational metallic mercury intoxication. Neurologia Neurochirurgia Polska 37(Suppl 5):31–38Google Scholar
  95. 95.
    Hsu Y-C, Chang C-W, Lee H-L, Chuang C-C, Chiu H-C, Li W-Y, Horng J-T, Fu E (2016) Association between history of dental amalgam fillings and risk of Parkinson’s disease: a population-based retrospective cohort study in Taiwan. PLoS One 11(12):e0166552CrossRefGoogle Scholar
  96. 96.
    Palacios N, Fitzgerald K, Roberts AL, Hart JE, Weisskopf MG, Schwarzschild MA, Ascherio A, Laden F (2014) A prospective analysis of airborne metal exposures and risk of Parkinson disease in the nurses’ health study cohort. Environ Health Perspect 122(9):933–938. CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Wijesekera LC, Leigh PN (2009) Amyotrophic lateral sclerosis. Orphanet J Rare Dis 4:3. CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW (2008) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11(3):251–253CrossRefGoogle Scholar
  99. 99.
    Chio A, Calvo A, Mazzini L, Cantello R, Mora G, Moglia C, Corrado L, D’Alfonso S, Majounie E, Renton A, Pisano F, Ossola I, Brunetti M, Traynor BJ, Restagno G, Parals (2012) Extensive genetics of ALS: a population-based study in Italy. Neurology 79(19):1983–1989. CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Talbott EO, Malek AM, Lacomis D (2016) The epidemiology of amyotrophic lateral sclerosis. Handb Clin Neurol 138:225–238.,973-2.00013-6 CrossRefPubMedGoogle Scholar
  101. 101.
    Takeuchi R, Tada M, Shiga A, Toyoshima Y, Konno T, Sato T, Nozaki H, Kato T, Horie M, Shimizu H, Takebayashi H, Onodera O, Nishizawa M, Kakita A, Takahashi H (2016) Heterogeneity of cerebral TDP-43 pathology in sporadic amyotrophic lateral sclerosis: evidence for clinico-pathologic subtypes. Acta Neuropathologica Commun 4(1):61. CrossRefGoogle Scholar
  102. 102.
    Strong MJ, Abrahams S, Goldstein LH, Woolley S, McLaughlin P, Snowden J, Mioshi E, Roberts-South A, Benatar M, HortobaGyi T, Rosenfeld J, Silani V, Ince PG, Turner MR (2017) Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): revised diagnostic criteria. Amyotroph Lateral Scler Frontotempl Degen 18(3–4):153–174. CrossRefGoogle Scholar
  103. 103.
    Henstridge CM, Sideris DI, Carroll E, Rotariu S, Salomonsson S, Tzioras M, McKenzie C-A, Smith C, von Arnim CAF, Ludolph AC, Lule D, Leighton D, Warner J, Cleary E, Newton J, Swingler R, Chandran S, Gillingwater TH, Abrahams S, Spires-Jones TL (2018) Synapse loss in the prefrontal cortex is associated with cognitive decline in amyotrophic lateral sclerosis. Acta Neuropathol 135(2):213–226CrossRefGoogle Scholar
  104. 104.
    Pamphlett R, Kum Jew S (2013) Uptake of inorganic mercury by human locus ceruleus and corticomotor neurons: implications for amyotrophic lateral sclerosis. Acta Neuropathologica Commun 1:13CrossRefGoogle Scholar
  105. 105.
    Chuu J-J, Liu S-H, Lin-Shiau S-Y (2007) Differential neurotoxic effects of methylmercury and mercuric sulfide in rats. Toxicol Lett 169(2):109–120CrossRefGoogle Scholar
  106. 106.
    Praline J, Guennoc AM, Limousin N, Hallak H, de Toffol B, Corcia P (2007) ALS and mercury intoxication: a relationship? Clin Neurol Neurosurg 109(10):880–883. CrossRefPubMedGoogle Scholar
  107. 107.
    Mangelsdorf I, Walach H, Mutter J (2017) Healing of amyotrophic lateral sclerosis: a case report. Complement Med Res 24(3):175–181. CrossRefPubMedGoogle Scholar
  108. 108.
    Kotelnikova E, Kiani NA, Abad E, Martinez-Lapiscina EH, Andorra M, Zubizarreta I, Pulido-Valdeolivas I, Pertsovskaya I, Alexopoulos LG, Olsson T, Martin R, Paul F, Tegner J, Garcia-Ojalvo J, Villoslada P (2017) Dynamics and heterogeneity of brain damage in multiple sclerosis. PLoS Comput Biol 13(10):e1005757. CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Leray E, Moreau T, Fromont A, Edan G (2016) Epidemiology of multiple sclerosis. Rev Neurol 172(1):3–13. CrossRefPubMedGoogle Scholar
  110. 110.
    Crabtree-Hartman E (2018) Advanced symptom management in multiple sclerosis. Neurol Clin 36 (1):197-+.
  111. 111.
    Patsopoulos NA (2018) Genetics of multiple sclerosis: an overview and new directions. Cold Spring Harbor perspectives in medicine doi:
  112. 112.
    Visconti A, Cotichini R, Cannoni S, Bocca B, Forte G, Ghazaryan A, Santucci S, D’Ippolito C, Stazi MA, Salvetti M, Alimonti A, Ristori G (2005) Concentration of elements in serum of patients affected by multiple sclerosis with first demyelinating episode: a six-month longitudinal follow-up study. Annali dell’Istituto Superiore di Sanita 41(2):217–222PubMedGoogle Scholar
  113. 113.
    Attar AM, Kharkhaneh A, Etemadifar M, Keyhanian K, Davoudi V, Saadatnia M (2012) Serum mercury level and multiple sclerosis. Biol Trace Elem Res 146(2):150–153. CrossRefPubMedGoogle Scholar
  114. 114.
    Dulamea AO, Boscaiu V, Sava MM (2015) Disability status and dental pathology in multiple sclerosis patients. Mult Scler Relat Disord 4(6):567–571. CrossRefPubMedGoogle Scholar
  115. 115.
    Casetta I, Invernizzi M, Granieri E (2001) Multiple sclerosis and dental amalgam: case-control study in Ferrara, Italy. Neuroepidemiology 20(2):134–137. CrossRefPubMedGoogle Scholar
  116. 116.
    Bates MN, Fawcett J, Garrett N, Cutress T, Kjellstrom T (2004) Health effects of dental amalgam exposure: a retrospective cohort study. Int J Epidemiol 33(4):894–902. CrossRefPubMedGoogle Scholar
  117. 117.
    Ceccatelli S, Dare E, Moors M (2010) Methylmercury-induced neurotoxicity and apoptosis. Chem Biol Interact 188(2):301–308. CrossRefPubMedGoogle Scholar
  118. 118.
    Kakita A, Wakabayashi K, Su M, Yoneoka Y, Sakamoto M, Ikuta F, Takahashi H (2000) Intrauterine methylmercury intoxication. Consequence of the inherent brain lesions and cognitive dysfunction in maturity. Brain Res 877(2):322–330CrossRefGoogle Scholar
  119. 119.
    Sakaue M, Mori N, Makita M, Fujishima K, Hara S, Arishima K, Yamamoto M (2009) Acceleration of methylmercury-induced cell death of rat cerebellar neurons by brain-derived neurotrophic factor in vitro. Brain Res 1273:155–162. CrossRefPubMedGoogle Scholar
  120. 120.
    Yee S, Choi BH (1996) Oxidative stress in neurotoxic effects of methylmercury poisoning. Neurotoxicology 17(1):17–26PubMedGoogle Scholar
  121. 121.
    Shanker G, Aschner JL, Syversen T, Aschner M (2004) Free radical formation in cerebral cortical astrocytes in culture induced by methylmercury. Brain Res Mol Brain Res 128(1):48–57. CrossRefPubMedGoogle Scholar
  122. 122.
    Aschner M, Allen JW (2000) Astrocytes in methylmercury, ammonia, methionine sulfoximine and alcohol-induced neurotoxicity. Neurotoxicology 21(4):573–579PubMedGoogle Scholar
  123. 123.
    Ramanathan G, Atchison WD (2011) Ca2+ entry pathways in mouse spinal motor neurons in culture following in vitro exposure to methylmercury. Neurotoxicology 32(6):742–750. CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Amonpatumrat S, Sakurai H, Wiriyasermkul P, Khunweeraphong N, Nagamori S, Tanaka H, Piyachaturawat P, Kanai Y (2008) L-glutamate enhances methylmercury toxicity by synergistically increasing oxidative stress. J Pharmacol Sci 108(3):280–289CrossRefGoogle Scholar
  125. 125.
    Wang X, Yan M, Zhao L, Wu Q, Wu C, Chang X, Zhou Z (2016) Low-dose methylmercury-induced apoptosis and mitochondrial DNA mutation in human embryonic neural progenitor cells. Oxidative Med Cell Longev 2016:5137042. CrossRefGoogle Scholar
  126. 126.
    Szumanska G, Gadamski R, Albrecht J (1993) Changes of the Na/K ATPase activity in the cerebral cortical microvessels of rat after single intraperitoneal administration of mercuric chloride: histochemical demonstration with light and electron microscopy. Acta Neuropathol 86(1):65–70CrossRefGoogle Scholar
  127. 127.
    Teixeira FB, Fernandes RM, Farias PMA, Costa NMM, Fernandes LMP, Santana LNS, Silva AF, Silva MCF, Maia CSF, Lima RR (2014) Evaluation of the effects of chronic intoxication with inorganic mercury on memory and motor control in rats. Int J Env Res Pub He 11(9):9171–9185. CrossRefGoogle Scholar
  128. 128.
    Goering PL, Morgan DL, Ali SF (2002) Effects of mercury vapor inhalation on reactive oxygen species and antioxidant enzymes in rat brain and kidney are minimal. J Appl Toxicol: JAT 22(3):167–172. CrossRefPubMedGoogle Scholar
  129. 129.
    Cooper JF, Kusnecov AW (2007) Methylmercuric chloride induces activation of neuronal stress circuitry and alters exploratory behavior in the mouse. Neuroscience 148(4):1048–1064. CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Rice D, Barone S Jr (2000) Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 108(Suppl 3):511–533CrossRefGoogle Scholar
  131. 131.
    Manfroi CB, Schwalm FD, Cereser V, Abreu F, Oliveira A, Bizarro L, Rocha JBT, Frizzo MES, Souza DO, Farina M (2004) Maternal milk as methylmercury source for suckling mice: neurotoxic effects involved with the cerebellar glutamatergic system. Toxicol Sci 81(1):172–178. CrossRefPubMedGoogle Scholar
  132. 132.
    Sakamoto M, Kakita A, Wakabayashi K, Takahashi H, Nakano A, Akagi H (2002) Evaluation of changes in methylmercury accumulation in the developing rat brain and its effects: a study with consecutive and moderate dose exposure throughout gestation and lactation periods. Brain Res 949(1–2):51–59CrossRefGoogle Scholar
  133. 133.
    Antonelli MC, Pallares ME, Ceccatelli S, Spulber S (2017) Long-term consequences of prenatal stress and neurotoxicants exposure on neurodevelopment. Prog Neurobiol 155:21–35. CrossRefPubMedGoogle Scholar
  134. 134.
    Boomhower SR, Newland MC (2016) Adolescent methylmercury exposure affects choice and delay discounting in mice. Neurotoxicology 57:136–144. CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Pope DA, Newland MC, Hutsell BA (2015) Delay-specific stimuli and genotype interact to determine temporal discounting in a rapid-acquisition procedure. J Exp Anal Behav 103(3):450–471. CrossRefPubMedGoogle Scholar
  136. 136.
    Fujimura M, Usuki F (2017) In situ different antioxidative systems contribute to the site-specific methylmercury neurotoxicity in mice. Toxicology 392:55–63. CrossRefPubMedGoogle Scholar
  137. 137.
    Fujimura M, Usuki F (2017) Site-specific neural hyperactivity via the activation of MAPK and PKA/CREB pathways triggers neuronal degeneration in methylmercury-intoxicated mice. Toxicol Lett 271:66–73. CrossRefPubMedGoogle Scholar
  138. 138.
    Agrawal M, Bhaskar AS, Lakshmana Rao PV (2015) Involvement of mitogen-activated protein kinase pathway in T-2 toxin-induced cell cycle alteration and apoptosis in human neuroblastoma cells. Mol Neurobiol 51(3):1379–1394. CrossRefPubMedGoogle Scholar
  139. 139.
    Venkatesan RS, Sadiq AM (2017) Effect of morin-5′-sulfonic acid sodium salt on the expression of apoptosis related proteins caspase 3, Bax and Bcl 2 due to the mercury induced oxidative stress in albino rats. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 85:202–208. CrossRefGoogle Scholar
  140. 140.
    Shen AN, Cummings C, Hoffman D, Pope D, Arnold M, Newland MC (2016) Aging, motor function, and sensitivity to calcium channel blockers: an investigation using chronic methylmercury exposure. Behav Brain Res 315:103–114. CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.IRCCS Centro Neurolesi “Bonino Pulejo”MessinaItaly

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