Alteration of peripheral markers of copper homeostasis in Alzheimer's disease patients: Implications in aetiology and therapy

Journal of Nutrition, Health and Aging

Volumn 11, Issue 5, 2007, Pages 408-417

  Rossi, Luisa ^a   Squitti, R ^b   Calabrese, L ^c   Rotilio, G ^a   Rossini, P M ^b,d,e  

^a UNIVERSITY OF ROME TOR VERGATA   (Italy)

^b FATEBENEFRATELLI HOSPITAL   (Italy)

^c SAPIENZA UNIVERSITY OF ROME   (Italy)

^d UNIVERSITY CAMPUS BIO MEDICO   (Italy)

^e IRCCS ISTITUTO CENTRO SAN GIOVANNI DI DIO FATEBENEFRATELLI   (Italy)

Author keywords

Alzheimer's disease; Copper; Neurodegeneration; Oxidative stress; Serum

Indexed keywords

AMYLOID BETA PROTEIN; AMYLOID PRECURSOR PROTEIN; CLIOQUINOL; COPPER; DEFEROXAMINE; PENICILLAMINE; PLACEBO; BIOLOGICAL MARKER;

ALZHEIMER DISEASE; CELL MIGRATION; CLINICAL TRIAL; DIAGNOSTIC PROCEDURE; DISEASE MARKER; HOMEOSTASIS; HUMAN; LABORATORY TEST; NERVE DEGENERATION; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; REVIEW; UNSPECIFIED SIDE EFFECT; AGED; AGING; BLOOD; BRAIN; FEMALE; MALE; METABOLISM;

AGED; AGING; ALZHEIMER DISEASE; AMYLOID BETA-PROTEIN; BIOLOGICAL MARKERS; BRAIN; COPPER; FEMALE; HOMEOSTASIS; HUMANS; MALE; OXIDATIVE STRESS;

EID: 38349084395     PISSN: 12797707     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (94)

1. Mattson MP. Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol Rev 1997;77:1081-1132.
2. 2. J Biol Chem 2002;277:40302-40308.
3. Atwood CS, Moir RD, Huang X, Scarpa RC, Bacarra NM, Romano DM, Hartshorn MA, Tanzi RE, Bush AI. Dramatic aggregation of Alzheimer Aβ by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem 1998;273:12817-12826.
4. Roher AE, Baudry J, Chaney MO, Kuo YM, Stine WB, Emmerling MR. Oligomerizaiton and fibril assembly of the amyloid-aβ protein. Biochim Biophys Acta 2000;150:31-43.
5. Sheng JG, Mrak RE, Griffin WS. Glial-neuronal interactions in Alzheimer disease: progressive association of IL-1a microglia and S100β astrocytes with neurofibrillary tangle stages. Neuropathol Exp Neurol 1997;56:285-290.
6. De Luigi A, Fragiacomo C, Lucca U, Quadri P, Tettamanti M, Grazia, P, De Simoni M. Inflammatory markers in Alzheimer's disease and multi-infarct dementia. Mech Ageing Dev 2001;122:1985-1995.
7. Hardy J. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci 1997;20:154-159.
8. Holtzman DM, Bayney RM, Li YW, Khosrovi H, Berger CN, Epstein CJ, Mobley WC. Dysregulation of gene expression in mouse trisomy 16, an animal model of Down syndrome. EMBO J 1992;11:619-662.
9. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993;261:921-923.
10. Wisniewski T, Frangione B. Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett 1992;135:235-238.
11. Sanan DA, Weisgraber KH, Russell SJ, Mahley RW, Huang D, Saunders A. Schmechel D, Wisniewski T, Frangione B, Roses AD, et al. Apolipoprotein E associates with β amyloid peptide of Alzheimer's disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3. J Clin Invest 1994;94:860-869.
12. Miyata M, Smith JD. Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and β-amyloid peptides. Nat Genet 1996;14:55-61.
13. Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol 2004;3:343-353.
14. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N, Schneider J, Wilson RS. Dietary fats and the risk of incident Alzheimer disease. Arch Neurol 2003;60: 194-200.
15. Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N, Porcellini E, Licastro F. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr 2005;82:636-643.
16. Puglielli L, Tanzi RE, Kovacs DM. Alzheimer's disease: the cholesterol connection. Nat Neurosci 2003;6:345-351.
17. Sparks DL, Schreurs BG. Trace amounts of copper in water induce β-amyloid plaques and learning deficits in a rabbit model of Alzheimer's disease. Proc Natl Acad Sci USA 2003;100:11065-11069.
18. Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, Runz H, Kuhl S, Bertsch T, von Bergmann K, Hennerici M, Beyreuther K, Hartmann T. Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ 42 and Aβ 40 in vitro and in vivo. Proc Natl Acad Sci USA 2001;98:5856-5861.
19. Cole SL, Grudzien A, Manhart IO, Kelly BL, Oakley H, Vassar R. Statins cause intracellular accumulation of amyloid precursor protein, β-secretase-cleaved fragments, and amyloid β-peptide via an isoprenoid-dependent mechanism. J Biol Chem 2005;280:18755-18757.
20. Behl C, Moosmann B. Antioxidant neuroprotection in Alzheimer's disease as preventive and therapeutic approach. Free Radic Biol Med 2002;33:182-191.
21. Zimmermann M, Gardoni F, Di Luca M. Molecular rationale for the pharmacological treatment of Alzheimer's disease. Drugs Aging. 2005;22 Suppl 1:27-37.
22. Wolozin B. Cholesterol and the biology of Alzheimer's disease. Neuron 2004;41:7-10.
23. Cordy JM, Hussain I, Dingwall C, Hooper NM, Turner AJ. Exclusively targeting β-secretase to lipid rafts by GPI-anchor addition up-regulates β-site processing of the amyloid precursor protein. Proc Natl Acad Sci U S A 2003;100:11735-11740.
24. Kalmijn S, Launer LJ, Ott A, Witteman JC, Hofman A, Breteler MM. Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol 1997;42: 776-782.
25. Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N Jr, Frautschy SA, Cole GM. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci 2005;25:3032-3040.
26. Maynard CJ, Bush AI, Masters CL, Cappai R, Li QX. Metals and amyloid-β in Alzheimer's disease. Int J Exp Pathol 2005;86: 147-159.
27. Nalbandyan RM. Copper in brain. Neurochem Res 1983;8:1211-1232.
28. Lee J, Petris MJ, Thiele DJ. Characterization of mouse embryonic cells deficient in the Ctr1 high affinity copper transporter. Identification of a Ctr1-independent copper transport system. J Biol Chem 2002;277:40253-40259.
29. Peña MM, Lee J, Thiele DJ. A delicate balance: homeostatic control of copper uptake and distribution. J Nutr 1999;129: 1251-1260.
30. Halliwell B, Gutteridge JM. Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol 1990;186:1-85.
31. Smith MA, Taneda S, Richey PL, Miyata S, Yan SD, Stern D, Sayre LM, Monnier VM, Perry G. Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Proc Natl Acad Sci USA 1994; 91: 5710-5714.
32. Smith MA, Rottkamp CA, Nunomura A, Raina AK, Perry G. Oxidative stress in Alzheimer's disease. Biochim Biophys Acta 2000;1502:139-144.
33. Sayre LM, Zelasko DA, Harris PL, Perry G, Salomon RG, Smith MA 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer's disease. J Neurochem 1997;68:2092-2097.
34. Praticò D, Clark CM, Lee VM, Trojanowski JQ, Rokach J, FitzGerald GA. Increased 8,12-iso-iPF2a-VI in Alzheimer's disease: correlation of a noninvasive index of lipid peroxidation with disease severity. Ann Neurol 2000;48:809-812.
35. Tuppo EE, Forman LJ, Spur BW, Chan-Ting RE, Chopra A, Cavalieri TA. Sign of lipid peroxidation as measured in the urine of patients with probable Alzheimer's disease. Brain Res Bull 2001;54:565-568.
36. Mattson MP, Fu W, Waeg G, Uchida K. 4-Hydroxynonenal, a product of lipid peroxidation, inhibits dephosphorylation of the microtubule-associated protein tau. Neuroreport 1997;8:2275-2287.
37. Perez M, Hernandez F, Gomez-Ramos A, Smith M, Perry G, Avila J. Formation of aberrant phosphotau fibrillar polymers in neural cultured cells. Eur J Biochem 2002;269:1484-1489.
38. Floyd RA. Antioxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med 1999;222:236-245.
39. Spina MB, Cohen G. Dopamine turnover and glutathione oxidation: implications for Parkinson disease. Proc Natl Acad Sci USA 1989;86:1398-4000.
40. Harris ED. Cellular copper transport and metabolism. Annu Rev Nutr 2000;20:291-310.
41. Bielli P, Calabrese L. Structure to function relationships in ceruloplasmin: a 'moonlighting' protein. Cell Mol Life Sci 2002;59: 1413-1427.
42. Salzer JL, Lovejoy L, Linder MC, Rosen C. Ran-2, a glial lineage marker, is a GPI-anchored form of ceruloplasmin. J Neurosci Res 1998;54:147-157.
43. Patel BN, David S. A novel glycosylphosphatidylinositol-anchored form of ceruloplasmin is expressed by mammalian astrocytes. J Biol Chem 1997;272:20185-20190.
44. Loeffler DA, Sima AA, LeWitt PA. Ceruloplasmin immunoreactivity in neurodegenerative disorders. Free Radic Res 2001;35:111-118.
45. Patel BN, Dunn RJ, David SA. Alternative RNA splicing generates a glycosylphosphatidylinositol-anchored form of ceruloplasmin in mammalian brain. J Biol Chem 2000;275:4305-4310.
46. Loeffler DA, LeWitt PA, Juneau PL, Sima AA, Nguyen HU, DeMaggio AJ, Brickman CM, Brewer GJ, Dick RD, Troyer MD, Kanaley L. Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders. Brain Res 1996;738:265-274.
47. Harris ZL, Klomp LW, Gitlin JD. Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis. Am J Clin Nutr 1998;67:972S-977S.
48. Hochstrasser H, Tomiuk J, Walter U, Behnke S, Spiegel J, Kruger R, Becker G, Riess O, Berg D. Functional relevance of ceruloplasmin mutations in Parkinson's disease. FASEB J 2005;13:1851-1853.
49. Jeong SY, David S. Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J Biol Chem 2003; 278:27144-27148.
50. Miyajima H, Kono S, Takahashi Y, Sugimoto M. Increased lipid peroxidation and mitochondrial dysfunction in aceruloplasminemia brains. Blood Cells Mol Dis 2002;29:433-438.
51. Patel BN, Dunn RJ, Jeong SY, Zhu Q, Julien JP, David S. Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury. J Neurosci 2002;22:6578-6586.
52. Petris MJ, Mercer JF. The Menkes protein (ATP7A; MNK) cycles via the plasma membrane both in basal and elevated extracellular copper using a C-terminal dileucine endocytic signal. Hum Mol Genet 1999; 8: 2107-1215.
53. Palmiter RD. Regulation of metallothionein genes by heavy metals appears to be mediated by a zinc-sensitive inhibitor that interacts with a constitutively active transcription factor, MTF-1. Proc Natl Acad Sci USA 1994; 91: 1219-1223.
54. Rossi L, Ciriolo MR, Marchese E, De Martino A, Giorgi M, Rotilio G. Differential decrease of copper content and of copper binding to superoxide dismutase in liver, heart and brain of copper-deficient rats. Biochem Biophys Res Commun 1994; 203:1028-1034.
55. Maynard CJ, Cappai R, Volitakis I, Cherny RA, White AR, Beyreuther K, Masters CL, Bush AI, Li QX. Overexpression of Alzheimer's disease amyloid-β opposes the age-dependent elevations of brain copper and iron. J Biol Chem 2002;277:44670-44676.
56. Deibel MA, Ehmann WD, Markesbery WR. Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress. J Neurol Sci 1996; 143: 137-142.
57. Loeffler DA, DeMaggio AJ, Juneau PL, Brickman CM, Mashour GA, Finkelman JH, Pomara N, LeWitt PA. Ceruloplasmin is increased in cerebrospinal fluid in Alzheimer's disease but not Parkinson's disease. Alzheimer Dis Assoc Disord 1994;8:190-197.
58. Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR. Copper, iron and zinc in Alzheimer's disease senile plaques. J Neurol Sci 1998;158:47-52.
59. Qian Y, Tiffany-Castiglioni E, Welsh J, Harris ED. Copper efflux from murine microvascular cells requires expression of the Menkes disease Cu-ATPase. J Nutr 1998;128:1276-82.
60. Hamza I, Faisst A, Prohaska J, Chen J, Gruss P, Gitlin JD. The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis. Proc Natl Acad Sci USA 2001;98:6848-6852.
61. Lee J, Prohaska JR, Thiele DJ. Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development. Proc Natl Acad Sci USA 2001;98:6842-6847.
62. Kuo YM, Zhou B, Cosco D, Gitschier J. The copper transporter CTR1 provides an essential function in mammalian embryonic development. Proc Natl Acad Sci USA 2001;98:6836-41.
63. Castellani RJ, Smith MA, Nunomura A, Harris PL, Perry G. Is increased redox-active iron in Alzheimer disease a failure of the copper-binding protein ceruloplasmin? Free Radic Biol Med 1999;26: 1508-1512.
64. Connor JR, Tucker P, Johnson M, Snyder B. Ceruloplasmin levels in the human superior temporal gyrus in aging and Alzheimer's disease. Neurosci Lett 1993;159:88-90.
65. Yu WH, Lukiw WJ, Bergeron C, Niznik HB, Fraser PE. Metallothionein III is reduced in Alzheimer's disease. Brain Res 2001;894:37-45.
66. Barnham KJ, McKinstry WJ, Multhaup G, Galatis D, Morton CJ, Curtain CC, Williamson NA, White AR, Hinds MG, Norton RS, Beyreuther K, Masters CL, Parker MW, Cappai R. Structure of the Alzheimer's disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis. J Biol Chem 2003;278:17401-17407.
67. Phinney AL, Drisaldi B, Schmidt SD, Lugowski S, Coronado V, Liang Y, Horne P, Yang J, Sekoulidis J, Coomaraswamy J, Chishti MA, Cox DW, Mathews PM, Nixon RA, Carlson GA, St George-Hyslop P, Westaway D. In vivo reduction of amyloid-β by a mutant copper transporter. Proc Natl Acad Sci USA 2003;100:14193-14198.
68. White AR, Reyes R, Mercer JF, Camakaris J, Zheng H, Bush AI, Multhaup G, Beyreuther K, Masters CL, Cappai R. Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice. Brain Res 1999;842:439-444.
69. Bellingham SA, Lahiri DK, Maloney B, La Fontaine S, Multhaup G, Camakaris J. Copper depletion down-regulates expression of the Alzheimer's disease amyloid-β precursor protein gene. J Biol Chem 2004;279:20378-20386.
70. Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JD, Hanson GR, Stokes KC, Leopold M, Multhaup G, Goldstein LE, Scarpa RC, Saunders AJ, Lim J, Moir RD, Glabe C, Bowden EF, Masters CL, Fairlie DP, Tanzi RE, Bush AI. Cu(II) potentiation of Alzheimer Aβ neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem 1999; 274:37111-37116.
71. Crouch PJ, Blake R, Duce JA, Ciccotosto GD, Li QX, Barnham KJ, Curtain CC, Cherny RA, Cappai R, Dyrks T, Masters CL, Trounce IA. Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-β1-42. J Neurosci 2005;25:672-679.
72. Mutisya EM, Bowling AC, Beal MF. Cortical cytochrome oxidase activity is reduced in Alzheimer's disease. J Neurochem 1994;63:2179-2184.
73. Parker WD Jr, Filley CM, Parks JK. Cytochrome oxidase deficiency in Alzheimer's disease. Neurology 1990;40:1302-1303.
74. Angeletti B, Waldron KJ, Freeman KB, Bawagan H, Hussain I, Miller CC, Lau KF, Tennant ME, Dennison C, Robinson NJ, Dingwall C. BACE1 cytoplasmic domain interacts with the copper chaperone for superoxide dismutase-1 and binds copper. J Biol Chem 2005;280:17930-17937.
75. Ma QF, Li YM, Du JT, Kanazawa K, Nemoto T, Nakanishi H, Zhao YF. Binding of copper(II) ion to an Alzheimer's tau peptide as revealed by MALDI-TOF MS, CD, and NMR. Biopolymers 2005;79:74-85.
76. Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA 2004;291:2947-2958.
77. Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, Hsia J, Margolis KL, Hogan PE, Wallace R, Dailey M, Freeman R, Hays J. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004;291:2959-2968.
78. Casadesus G, Atwood CS, Zhu X, Hartzler AW, Webber KM, Perry G, Bowen RL, Smith MA. Evidence for the role of gonadotropin hormones in the development of Alzheimer disease. Cell Mol Life Sci 2005;62:293-298.
79. Hartter DE, Barnea A. Brain tissue accumulates 67copper by two ligand-dependent saturable processes. A high affinity, low capacity and a low affinity, high capacity process. J Biol Chem 1988;263:799-805.
80. Squitti R, Lupoi D, Pasqualetti P, Dal Forno G, Vernieri F, Chiovenda P, Rossi L, Cortesi M, Cassetta E, Rossini PM. Elevation of serum copper levels in Alzheimer's disease. Neurology 2002;59:1153-1161.
81. Rossi L, Squitti R, Pasqualetti P, Marchese E, Cassetta E, Forastiere E, Rotilio G, Rossini PM, Finazzi-Agrò A. Red blood cell copper, zinc superoxide dismutase activity is higher in Alzheimer's disease and is decreased by D-penicillamine. Neurosci Lett 2002;329:137-140.
82. Joseph JA, Denisova NA, Bielinski D, Fisher DR, Shukitt-Hale B. Oxidative stress protection and vulnerability in aging: putative nutritional implications for intervention. Mech Ageing Dev 2000;116:141-153.
83. Squitti R, Rossini PM, Cassetta E, Moffa F, Pasqualetti P, Cortesi M, Colloca A, Rossi L, Finazzi-Agrò A. D-penicillamine reduces serum oxidative stress in Alzheimer's disease patients. Eur J Clin Invest 2002;32:51-59.
84. Brewer GJ. Practical recommendations and new therapies for Wilson's disease. Drugs 1995;50:240-249.
85. Cuajungco MP, Faget KY, Huang X, Tanzi RE, Bush AI. Metal chelation as a potential therapy for Alzheimer's disease. Ann NY Acad Sci 2000;920:292-304.
86. Crapper McLachlan DR, Dalton AJ, Kruck TP, Bell MY, Smith WL, Kalow W, Andrews DF. Intramuscular desferrioxamine in patients with Alzheimer's disease. Lancet 1991;337:1304-1308.
87. Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, Kiers L, Cherny R, Li QX, Tammer A, Carrington D, Mavros C, Volitakis I, Xilinas M, Ames D, Davis S, Beyreuther K, Tanzi RE, Masters CL. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 2003;60:1685-1691.
88. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y, Huang X, Goldstein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL, Bush AI. Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 2001;30:665-676.
89. Brewer GJ, Johnson V, Dick RD, Kluin KJ, Fink JK, Brunberg JA. Treatment of Wilson disease with ammonium tetrathiomolybdate. II. Initial therapy in 33 neurologically affected patients and follow-up with zinc therapy. Arch Neurol 1996;53:1017-1025.
90. Pan Q, Kleer CG, van Golen KL, Irani J, Bottema KM, Bias C, De Carvalho M, Mesri EA, Robins DM, Dick RD, Brewer GJ, Merajver SD. Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis. Cancer Res 2002;62:4854-4859.
91. Squitti R, Pasqualetti P, Dal Forno G, Moffa F, Cassetta E, Lupoi D, Vernieri F, Rossi L, Baldassini M, Rossini PM. Excess of serum copper not related to ceruloplasmin in Alzheimer disease. Neurology 2005;64: 1040-1046.
92. Gitlin JD. Transcriptional regulation of ceruloplasmin gene expression during inflammation. J Biol Chem 1988;263:6281-6287.
93. Wirth PL, Linder MC. Distribution of copper among components of human serum. J Natl Cancer Inst 1985;75:277-284.
94. Squitti R, Barbati G, Rossi L, Ventriglia M, Dal Forno G, Cesaretti S, Moffa F, Caridi I, Cassetta E, Pasqualetti P, Calabrese L, Lupoi D, Rossini PM. Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF β-amyloid, and h-tau. Neurology 2006;67:76-82.