Drugs & Aging

, Volume 20, Issue 10, pp 711–721 | Cite as

Potential Therapeutic Properties of Green Tea Polyphenols in Parkinson’s Disease

Leading Article

Abstract

Tea is one of the most frequently consumed beverages in the world. It is rich in polyphenols, a group of compounds that exhibit numerous biochemical activities. Green tea is not fermented and contains more catechins than black tea or oolong tea. Although clinical evidence is still limited, the circumstantial data from several recent studies suggest that green tea polyphenols may promote health and reduce disease occurrence, and possibly protect against Parkinson’s disease and other neurodegenerative diseases.

Green tea polyphenols have demonstrated neuroprotectant activity in cell cultures and animal models, such as the prevention of neurotoxin-induced cell injury. The biological properties of green tea polyphenols reported in the literature include antioxidant actions, free radical scavenging, iron-chelating properties, 3H-dopamine and 3H-methyl-4-phenylpyridine uptake inhibition, catechol-O-methyl-transferase activity reduction, protein kinase C or extracellular signal-regulated kinases signal pathway activation, and cell survival/cell cycle gene modulation. All of these biological effects may benefit patients with Parkinson’s disease.

Despite numerous studies in recent years, the understanding of the biological activities and health benefits of green tea polyphenols is still very limited. Further in-depth studies are needed to investigate the safety and efficacy of green tea in humans and to determine the different mechanisms of green tea in neuroprotection.

References

  1. 1.
    Yang CS. Tea and health. Nutrition 1999; 15: 946–9PubMedCrossRefGoogle Scholar
  2. 2.
    Shiota S, Shimizu M, Mizushima T, et al. Marked reduction in the minimum inhibitory concentration (MIC) of beta-lactams in methicillin-resistant Staphylococcus aureus produced by epicatechin gallate, an ingredient of green tea (Camellia sinensis). Biol Pharm Bull 1999; 22: 1388–90PubMedCrossRefGoogle Scholar
  3. 3.
    Yang CS, Wang ZY. Tea and cancer. J Natl Cancer Inst 1993; 85: 1038–49PubMedCrossRefGoogle Scholar
  4. 4.
    Muramatsu K, Fukuyo M, Hara Y. Effect of green tea catechins on plasma cholesterol level in cholesterol-fed rats. J Nutr Sci Vitaminol (Tokyo) 1986; 32: 613–22CrossRefGoogle Scholar
  5. 5.
    Matsumoto N, Ishigaki F, Ishigaki A, et al. Reduction of blood glucose levels by tea catechin. Biosci Biotechnol Biochem 1993; 57: 525–7CrossRefGoogle Scholar
  6. 6.
    Hertog M, Feskens E, Kromhout D. Antioxidant flavonols and coronary heart disease risk [letter]. Lancet 1997; 349: 699PubMedCrossRefGoogle Scholar
  7. 7.
    Sesso H, Gaziano J, Buring J, et al. Coffee and tea intake and the risk of myocardial infarction. Am J Epidemiol 1999; 149: 162–7PubMedCrossRefGoogle Scholar
  8. 8.
    Keli S, Hertog M, Feskens E, et al. Flavonoids, antiowciant vitamins and risk of stroke: the Zutphen Study. Arch Intern Med 1995; 155: 381–6CrossRefGoogle Scholar
  9. 9.
    Yang C, Chung J, Yang G, et al. Tea and tea polyphenols in cancer prevention. J Nutr 2000; 130: 472S–8SPubMedGoogle Scholar
  10. 10.
    Nakachi K, Matsuyama S, Miyake S, et al. Preventive effects of drinking green tea on cancer and cardiovascular disease: epidemiological evidence for multiple targeting prevention. Bio-factors 2000; 13: 49–54Google Scholar
  11. 11.
    Hegarty V, May H, Khaw K. Tea drinking and bone mineral density in older women. Am J Clin Nutr 2000; 71: 1003–7PubMedGoogle Scholar
  12. 12.
    Mikuls TR, Cerhan JR, Criswell LA, et al. Coffee, tea, and caffeine consumption and risk of rheumatoid arthritis. Arthritis Rheum 2002; 46: 83–91PubMedCrossRefGoogle Scholar
  13. 13.
    Mukhtar H, Ahmad N. Tea polyphenols: prevention of cancer and optimizing health. Am J Clin Nutr 2000; 71 (6 Suppl.): 1698s–702sPubMedGoogle Scholar
  14. 14.
    Murase T, Nagasawa A, Suzuki J, et al. Beneficial effects of tea catechins on diet-induced obesity: stimulation of lipid catabolism in the liver. Int J Obes Relat Metab Disord 2002; 26: 1459–64PubMedCrossRefGoogle Scholar
  15. 15.
    Mack WJ, Preston-Martin S, Bernstein L, et al. Lifestyle and other risk factors for thyroid cancer in Los Angeles county females. Ann Epidemiol 2002; 12: 395–401PubMedCrossRefGoogle Scholar
  16. 16.
    Mckay DL, Blumberg JB. The role of tea in human health: an update. J Am Coll Nutr 2002; 21: 1–13PubMedGoogle Scholar
  17. 17.
    Kris-Etherton PM, Keen CL. Evidence that the antioxidant flavonoids in tea and cocoa are beneficial for cardiovascular health. Curr Opin Lipidol 2002; 13: 41–9PubMedCrossRefGoogle Scholar
  18. 18.
    Wang SJ, Fuh JL, Teng EL, et al. A door-to-door survey of Parkinson’s disease in a Chinese population in Kinmen. Arch Neurology 1996; 53: 66–71CrossRefGoogle Scholar
  19. 19.
    Chan DK, Woo J, Ho SC. Genetic and environmental risk factors for Parkinson’s disease in a Chinese population. J Neurol Neurosurg Psychiatry 1998; 65: 781–4PubMedCrossRefGoogle Scholar
  20. 20.
    Ascherio A, Zhang SM, Hernan MA, et al. Prospective study of caffeine consumption and risk of Parkinson’s disease in men and women. Ann Neurol 2001; 50(1): 56–63PubMedCrossRefGoogle Scholar
  21. 21.
    Levites Y, Weinreb O, Maor G, et al. Green tea polyphenol (−)-epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1,2,-3,6-tetrahydropyridine-induced dopaminergic neurodegeneration. J Neurochem 2001; 78(5): 1073–82PubMedCrossRefGoogle Scholar
  22. 22.
    Nie GJ, Jin CF, Cao YL, et al. Distinct effects of tea catechins on 6-hydroxydopamine-induced apoptosis in PC12 cells. Arch Biochem Biophys 2002; 397(1): 84–97PubMedCrossRefGoogle Scholar
  23. 23.
    Levites Y, Youdim MBH, Maor G, et al. Attenuation of 6-hydroxydopamine (6-OHDA)-induced nuclear factor-kappaB (NF-λB) activation and cell death by tea extracts in neuronal cultures. Biochem Pharmacol 2002; 63: 21–9PubMedCrossRefGoogle Scholar
  24. 24.
    Ruan J, Wu X, Hardter R. Effects of potassium and magnesium nutrition on the quality components of different types of tea. J Sci Food Agric 1999; 79: 47–52CrossRefGoogle Scholar
  25. 25.
    Lin YL, Juan IM, Chen Yl, et al. Composition of polyphenols in fresh tea leaves and associations of their oxygen-radical-absorbing capacity with antiproliferative actions in fibroblast cells. J Agric Food Chem 1996; 44: 1387–94CrossRefGoogle Scholar
  26. 26.
    Liao S, Kao YH, Hiipakka RA. Green tea: biochemical and biological basis for health benefits. Vitam Horm 2001; 62: 1–62PubMedCrossRefGoogle Scholar
  27. 27.
    Balentine DA, Wiseman SA, Bouwens LCM. The chemistry of tea flavonoids. Crit Rev Food Sci Nutr 1997; 37: 693–704PubMedCrossRefGoogle Scholar
  28. 28.
    Yang GY, Liao J, Li C, et al. Effect of black and green tea polyphenols on c-jun phosphorylation and H2O2 production in transformed and non-transformed human bronchial cell lines: possible mechanisms of cell growth inhibition and apoptosis induction. Carcinogenesis 2000; 21: 2035–9PubMedCrossRefGoogle Scholar
  29. 29.
    Borchers A, Keen CL, Hannum SM, et al. Cocoa and chocolate: composition, bioavailability, and health implications. J Med Food 2000; 3: 77–105CrossRefGoogle Scholar
  30. 30.
    Pan TH, Fei J, Zhou XD, et al. Effects of green tea polyphenols on dopamine uptake and on MPP+-induced dopamine neuron injury. Life Sci 2003; 72: 1073–83PubMedCrossRefGoogle Scholar
  31. 31.
    Yokogoshi H, Kobayashi M, Mochizuki M, et al. Effect of theanine, γ-glutamylethylamide, on brain monoamines and striatal dopamine release in conscious rats. Neurochem Res 1998; 23: 667–73PubMedCrossRefGoogle Scholar
  32. 32.
    Yamane T, Nakatani H, Kikuoka N, et al. Inhibitory effects and toxicity of green tea polyphenols for gastrointestinal carcinogenesis. Cancer 1996; 77: 1662–7PubMedGoogle Scholar
  33. 33.
    Li C, Lee MJ, Sheng S, et al. Structural identification of two metabolites of catechins and their kinetics in human urine and blood after tea ingestion. Chem Res Toxicol 2000; 13: 177–84PubMedCrossRefGoogle Scholar
  34. 34.
    Pietta PG, Simonetti P, Gardana C, et al. Catechin metabolites after intake of green tea infusions. Biofactors 1998; 8: 111–8PubMedCrossRefGoogle Scholar
  35. 35.
    Harada M, Kan Y, Naoki H, et al. Identification of the major antioxidative metabolites in biological fluids of the rat with ingested (+)-catechin an (−)-epicatechin. Biosci Biotechnol Biochem 1999; 63: 973–7PubMedCrossRefGoogle Scholar
  36. 36.
    Manal M, Mohsen AE, Kuhnle G, et al. Uptake and metabolixm of epicatechin and its access to the brain after oral ingestion. Free Radic Biol Med 2002; 33: 1693–702CrossRefGoogle Scholar
  37. 37.
    Datla KP, Christidou M, Widmer WW, et al. Tissue distribution and neuroprotective effects of citrus flavonoid tangeretin in a rat model of Parkinson’s disease. Neuroreport 2001; 12: 3871–5PubMedCrossRefGoogle Scholar
  38. 38.
    Katiyar SK, Mukhtar H. Tea antioxidants in cancer chemoprevention. J Cell Biochem Suppl 1998; 27: 59–67Google Scholar
  39. 39.
    Vinson J, Dabbagh Y, Serry M, et al. Plant flavonoids, especially tea flavonols, are powerful antioxidants using an in vitro oxidation model for heart disease. J Agric Food Chem 1995; 43: 2800–2CrossRefGoogle Scholar
  40. 40.
    Middleton Jr E. Effect of plant flavonoids on immune and inflammatory cell function. Adv Exp Med Biol 1998; 439: 175–82PubMedCrossRefGoogle Scholar
  41. 41.
    Eastwood MA. Interaction of dietary antioxidants in vivo: how fruit and vegetables prevent disease? QJM 1999; 92: 527–30PubMedCrossRefGoogle Scholar
  42. 42.
    Hollman PC, Katan MB. Health effects and bioavailability of dietary flavonols. Free Radic Res 1999; 31: S75–80PubMedCrossRefGoogle Scholar
  43. 43.
    Graham HN. Green tea composition, consumption, and polyphenol chemistry. Prev Med 1992; 21: 334–50PubMedCrossRefGoogle Scholar
  44. 44.
    Ichihashi M, Ahmed NU, Budiyanto A, et al. Preventive effect of antioxidant on ultraviolet-induced skin cancer in mice. J Dermatol Sci 2000; 23: S45–50PubMedCrossRefGoogle Scholar
  45. 45.
    Serafini M, Ghiselli A, Ferro-Luzzi A. In vivo antioxidant effect of green and black tea in man. Eur J Clin Nutr 1996; 50: 28–32PubMedGoogle Scholar
  46. 46.
    Sano M, Takahashi Y, Yoshino K, et al. Effect of tea (Camellia Sinensis L.) on lipid peroxidation in rat liver and kidney: a comparison of green tea and black tea feeding. Biol Pharm Bull 1995; 18: 1006–8PubMedCrossRefGoogle Scholar
  47. 47.
    Dreosti IE. Bioactive ingredients: antioxidants and polyphenols in tea. Nutr Rev 1996; 54: S51–8PubMedCrossRefGoogle Scholar
  48. 48.
    Grinberg LK, Newmark H, Kitrossky N, et al. Protective effects of tea polyphenols against oxidative damage to red blood cells. Biochem Pharmacol 1997; 54(9): 973–8PubMedCrossRefGoogle Scholar
  49. 49.
    Prystai EA, Kies CV, Driskell JA. Calcium, copper, iron, copper, iron magnesium and zinc utilization of humans as affected by consumption of black, decaffeinated black and green teas. Nutr Res 1999; 19: 167–77CrossRefGoogle Scholar
  50. 50.
    Hayakawa F, Kimura T, Hoshino N, et al. DNA cleavage activities of (−)-epigallocatechin, (−)-epicatechin, (+)-catechin, and (−)-epigallocatechin gallate with various kind of metal ions. Biosci Biotechnol Biochem 1999; 63: 1654–6PubMedCrossRefGoogle Scholar
  51. 51.
    Haslam E. Plant polyphenols-vegetable tannins revisited. Cambridge, UK: Cambridge University Press, 1989Google Scholar
  52. 52.
    No JK, Soung DY, Kim YJ, et al. Inhibition of tyrosinase by green tea components. Life Sci 1999; 65(21): PL241–6PubMedCrossRefGoogle Scholar
  53. 53.
    Akiyama K, Shimizu Y, Yokoi I, et al. Effects of epigallocatechin and epigallocatechin-3-O-gallate on catechol O-methyl-transferase. Neurosci 1989; 15: 262–4Google Scholar
  54. 54.
    Dulloo AG, Seydoux J, Girardier L, et al. Green tea and therogenesis: interactions between catechin-polyphenols, caffeine and sympathetic activity. Int J Obes Relat Metab Disord 2000; 24: 252–8PubMedCrossRefGoogle Scholar
  55. 55.
    Yoshizawa S, Horiuci T, Fujiki H, et al. Antitumor promoting activity of (−)-epigallocatechin gallate, the main constituent of “tannin” in green tea. Phytother Res 1987; 1: 44–7CrossRefGoogle Scholar
  56. 56.
    Yasokawa M, Sugimoto I, Fukuma M, et al. (−)-Epigallocatechin gallate inhibits mos activation-mediated xenopus oocyte maturation induced by progesterone. FEBS Lett 1999; 463: 317–20PubMedCrossRefGoogle Scholar
  57. 57.
    Levites Y, Amit T, Youdim MBH, et al. Involvement of protein kinase C activation and cell survival/cell cycle gene in green tea polyphenol (−)-Epigallocatechin-3-gallate neuroprotective action. J Biol Chem 2002; 277(34): 30574–80PubMedCrossRefGoogle Scholar
  58. 58.
    Liu Z, Zhang J, Fei J, et al. A novel mechanism of dopamine neurotoxicity involving the peripheral extracellular and the plasma membrane dopamine transporter. Neuroreport 2001; 12(15): 3293–7PubMedCrossRefGoogle Scholar
  59. 59.
    Pakkenberg B, Moller A, Gundersen HJ, et al. The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson’s disease estimated with an unbiased stereological method. J Neurol Neurosurg Psychiatry 1991; 54(1): 30–3PubMedCrossRefGoogle Scholar
  60. 60.
    Maral Mouradian M. Recent advances in the genetics and pathogenesis of Parkinson disease. Neurology 2002; 58: 179–85PubMedCrossRefGoogle Scholar
  61. 61.
    Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997; 276(5321): 2045–7PubMedCrossRefGoogle Scholar
  62. 62.
    Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998; 392(6676): 605–8PubMedCrossRefGoogle Scholar
  63. 63.
    Leroy E, Boyer R, Auburger G, et al. The ubiquitin pathway in Parkinson’s disease. Nature 1998; 395(6701): 451–2PubMedCrossRefGoogle Scholar
  64. 64.
    Gorell JM, Johnson CC, Rybicki BA, et al. The risk of Parkinson’s disease with exposure to pesticides, farming, well water, and rural living. Neurology 1998; 50: 1346–50PubMedCrossRefGoogle Scholar
  65. 65.
    Gerlach M, Gotz M, Dirr A, et al. Acute MPTP treatment produces no changes in mitochondrial complex activities and indices of oxidative damage in the common marmoset ex vivo one week after exposure to the toxin. Neurochem Int 1996; 28(1): 41–9PubMedCrossRefGoogle Scholar
  66. 66.
    Singer TP, Castagnoli Jr N, Ramsay RR, et al. Biochemical events in the development of parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Neurochem 1987; 49(1): 1–8PubMedCrossRefGoogle Scholar
  67. 67.
    Javitch JA, D’Amato RJ, Strittmatter SM, et al. Parkinsonism-inducing neurtotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahy-dropyridine: uptake of the metabolite N-methyl-4-phenylpyri-dine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci U S A 1985; 82: 2173–7PubMedCrossRefGoogle Scholar
  68. 68.
    Nicklas WJ, Vyas I, Heikkila RE. Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyri-dine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,-5,6-tetrahydropyridine. Life Sci 1985; 36(26): 2503–8PubMedCrossRefGoogle Scholar
  69. 69.
    Bezard E, Gross CE, Fournier MC, et al. Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter. Exp Neurol 1999; 155: 268–73PubMedCrossRefGoogle Scholar
  70. 70.
    Jenner P, Olanow CW. Understanding cell death in Parkinson’s disease. Ann Neurol 1998; 44 (3 Suppl. 1): S72–84PubMedGoogle Scholar
  71. 71.
    Olanow CW, Tatton WG. Etiology and pathogenesis of Parkinson’s disease. Annu Rev Neurosci 1999; 22: 123–44PubMedCrossRefGoogle Scholar
  72. 72.
    Le WD, Jankovic J. Are dopamine receptor agonists neuroprotective in Parkinson’s disease? Drugs Aging 2001; 18: 389–96PubMedCrossRefGoogle Scholar
  73. 73.
    Halliwell B, Gutteridge JM. The importance of free radicals and catalytic metal ions in human diseases. Mol Aspects Med 1985; 8(2): 89–193PubMedCrossRefGoogle Scholar
  74. 74.
    Olanow CW. A radical hypothesis for neurodegeneration. Trends Neurosci 1993; 16(11): 439–44PubMedCrossRefGoogle Scholar
  75. 75.
    Sofic E, Lange KW, Jellinger K, et al. Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson’s disease. Neurosci Lett 1992 Aug 17; 142(2): 128–30PubMedCrossRefGoogle Scholar
  76. 76.
    Sian J, Dexter DT, Lees AJ, et al. Glutathione-related enzymes in brain in Parkinson’s disease. Ann Neurol 1994; 36(3): 356–61PubMedCrossRefGoogle Scholar
  77. 77.
    Alam ZI, Jenner A, Daniel SE, et al. Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J Neurochem 1997; 69(3): 1196–203PubMedCrossRefGoogle Scholar
  78. 78.
    Jenner P, Olanow CW. Oxidative stress and the pathogenesis of Parkinson’s disease. Neurology 1996; 47 (6 Suppl. 3): S161–70PubMedCrossRefGoogle Scholar
  79. 79.
    Oliver CN, Starke-Reed PE, Stadtman ER, et al. Oxidative damage to brain proteins, loss of glutamine synthetase activity, and production of free radicals during ischemia/reperfusion-induced injury to gerbil brain. Proc Natl Acad Sci U S A 1990; 87: 5144–7PubMedCrossRefGoogle Scholar
  80. 80.
    Matsuoka Y, Hasegawa H, Okuda S, et al. Ameliorative effects of tea catechins on active oxygen-related nerve cell injuries. J Pharmacol Exp Ther 1995; 274: 602–8PubMedGoogle Scholar
  81. 81.
    Lee SR, Suhb SI, Kimc SP. Protective effect of the green tea polyphenol (−)- epigallocatechin gallate against hippocampal neuronal damage after transient global ischemia in gerbils. Neurosci Lett 2000; 287: 191–4PubMedCrossRefGoogle Scholar
  82. 82.
    Guo Q, Zhao B, Li M, et al. Studies on protective mechanisms of four components of green tea polyphenols against lipid peroxidation in synaptosomes. Biochim Biophys Acta 1996; 1304(3): 210–22PubMedCrossRefGoogle Scholar
  83. 83.
    Weinreb O, Mandel S, Youdim MBH. cDNA gene expression profile homology of antioxidants and their antiapoptotic and proapoptotic activities in human neuroblastoma cells. FASEB J 2003 May; 17(8): 935–7PubMedGoogle Scholar
  84. 84.
    Halliwell B. Vitamin C antioxidant or pro-oxidant in vivo. Free Radic Res 1996; 25: 439–54PubMedCrossRefGoogle Scholar
  85. 85.
    Ricaurte GA, Langston JW, Delanney LE, et al. Dopamine uptake blockers protect against the dopamine depleting effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse striatum. Neurosci Lett 1985; 59: 259–64PubMedCrossRefGoogle Scholar
  86. 86.
    Kitayama S, Wang JB, Uhl GR. Dopamine transporter mutants selectively enhance MPP+ transport. Synapses 1993; 15: 58–62CrossRefGoogle Scholar
  87. 87.
    Jaber M, Jones S, Giros B, et al. The dopamine transporter: a crucial component regulating dopamine transmission. Mov Disord 1997; 12: 629–33PubMedCrossRefGoogle Scholar
  88. 88.
    Yokozawa T, Dong E, Nakagawa T, et al. In vitro and in vivo studies on the radical-scavenging activity of tea. J Agric Food Chem 1998; 46: 2143–50CrossRefGoogle Scholar
  89. 89.
    Langley-Evans S. Antioxidant potential of green and black tea determined using the ferric reducing power (FRAP) assay. Int J Food Sci Nutr 2000; 51: 181–8PubMedCrossRefGoogle Scholar
  90. 90.
    Nakagawa K, Miyazawa T. Absorption and distribution of tea catechin, (−)-Epigallocatechin-3-Gallate, in the rat. J Nutr Sci Vitaminol (Tokyo) 1997; 43: 679–84CrossRefGoogle Scholar
  91. 91.
    Suganuma M, Okabe S, Oniyama M, et al. Wide distribution of [3H] (−)-epigallocatechin gallate, a cancer preventive tea polyphenol, in mouse tissue. Carcinogenesis 1998; 19: 1771–6PubMedCrossRefGoogle Scholar
  92. 92.
    Ebadi M, Srinivasan SK, Baxi MD. Oxidative stress and antioxidant therapy in Parkinson’s disease. Prog Neurobiol 1996; 48: 1–19PubMedCrossRefGoogle Scholar
  93. 93.
    Nutt JG, Fellman JH. Pharmacokinetics of L-DOPA. Clin Neuropharmacol 1984; 7: 35–49PubMedCrossRefGoogle Scholar
  94. 94.
    Giros B, Jaber M, Jones SR, et al. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 1996; 379: 606–12PubMedCrossRefGoogle Scholar
  95. 95.
    Pifl C, Giros B, Caron MG. Dopamine transporter -expression confers cytotoxicity to low dosed of the Parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium. J Neurosci 1993; 13: 4246–53PubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Department of NeurologyBaylor College of MedicineHoustonUSA

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