Acta Neuropathologica

, Volume 123, Issue 1, pp 13–30 | Cite as

Mild cognitive impairment: pathology and mechanisms

  • Elliott J. Mufson
  • Lester Binder
  • Scott E. Counts
  • Steven T. DeKosky
  • Leyla deToledo-Morrell
  • Stephen D. Ginsberg
  • Milos D. Ikonomovic
  • Sylvia E. Perez
  • Stephen W. Scheff
Review

Abstract

Mild cognitive impairment (MCI) is rapidly becoming one of the most common clinical manifestations affecting the elderly. The pathologic and molecular substrate of people diagnosed with MCI is not well established. Since MCI is a human specific disorder and neither the clinical nor the neuropathological course appears to follow a direct linear path, it is imperative to characterize neuropathology changes in the brains of people who came to autopsy with a well-characterized clinical diagnosis of MCI. Herein, we discuss findings derived from clinical pathologic studies of autopsy cases who died with a clinical diagnosis of MCI. The heterogeneity of clinical MCI imparts significant challenges to any review of this subject. The pathologic substrate of MCI is equally complex and must take into account not only conventional plaque and tangle pathology but also a wide range of cellular, biochemical and molecular deficits, many of which relate to cognitive decline as well as compensatory responses to the progressive disease process. The multifaceted nature of the neuronal disconnection syndrome associated with MCI suggests that there is no single event which precipitates this prodromal stage of AD. In fact, it can be argued that neuronal degeneration initiated at different levels of the central nervous system drives cognitive decline as a final common pathway at this stage of the dementing disease process.

Keywords

Alzheimer’s disease Amyloid Cholinergic Dementia MCI Neurofibrillary tangles Neuropathology Molecular Neurotrophins Synapses 

Notes

Acknowledgments

This study was supported by NIA grants PO1 AG14999, PO1 AG09466, AG10688 and AG025204. We thank all our collaborators and the participants in each Alzheimer’s Disease Center, institute and organization without whom the information reviewed would not have been possible.

References

  1. 1.
    Abdul HM, Sama MA, Furman JL et al (2009) Cognitive decline in Alzheimer’s disease is associated with selective changes in calcineurin/NFAT signaling. J Neurosci 29:12957–12969PubMedCrossRefGoogle Scholar
  2. 2.
    Abner EL, Kryscio RJ, Schmitt FA et al (2011) “End-stage” neurofibrillary tangle pathology in preclinical Alzheimer’s disease: fact or fiction? J Alzheimers Dis 25:445–453PubMedGoogle Scholar
  3. 3.
    Adler CH, Caviness JN, Sabbagh MN et al (2010) Heterogeneous neuropathological findings in Parkinson’s disease with mild cognitive impairment. Acta Neuropathol 120:827–828PubMedCrossRefGoogle Scholar
  4. 4.
    Aizenstein HJ, Nebes RD, Saxton JA et al (2008) Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol 65:1509–1517PubMedCrossRefGoogle Scholar
  5. 5.
    Albert MS, DeKosky ST, Dickson D et al (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:270–279PubMedCrossRefGoogle Scholar
  6. 6.
    Andersen OM, Reiche J, Schmidt V et al (2005) Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci USA 102:13461–13466PubMedCrossRefGoogle Scholar
  7. 7.
    Andersen OM, Schmidt V, Spoelgen R et al (2006) Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11. Biochemistry 45:2618–2628PubMedCrossRefGoogle Scholar
  8. 8.
    Aoki C, Sekino Y, Hanamura K et al (2005) Drebrin A is a postsynaptic protein that localizes in vivo to the submembranous surface of dendritic sites forming excitatory synapses. J Comp Neurol 483:383–402PubMedCrossRefGoogle Scholar
  9. 9.
    Barbacid M (1995) Neurotrophic factors and their receptors. Curr Opin Cell Biol 7:148–155PubMedCrossRefGoogle Scholar
  10. 10.
    Barone E, Di Domenico F, Cenini G et al (2011) Oxidative and nitrosative modifications of biliverdin reductase-a in the brain of subjects with Alzheimer’s disease and amnestic mild cognitive impairment. J Alzheimers Dis 25:623–633PubMedGoogle Scholar
  11. 11.
    Bartus RT, Dean RL 3rd, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414PubMedCrossRefGoogle Scholar
  12. 12.
    Beach TG, McGeer EG (1992) Cholinergic fiber loss occurs in the absence of synaptophysin depletion in Alzheimer’s disease primary visual cortex. Neurosci Lett 142:253–256PubMedCrossRefGoogle Scholar
  13. 13.
    Beekly DL, Ramos EM, van Belle G et al (2004) The National Alzheimer’s Coordinating Center (NACC) Database: an Alzheimer disease database. Alzheimer Dis Assoc Disord 18:270–277PubMedGoogle Scholar
  14. 14.
    Bell KF, Ducatenzeiler A, Ribeiro-da-Silva A et al (2006) The amyloid pathology progresses in a neurotransmitter-specific manner. Neurobiol Aging 27:1644–1657PubMedCrossRefGoogle Scholar
  15. 15.
    Bennett DA, Wilson RS, Schneider JA et al (2002) Natural history of mild cognitive impairment in older persons. Neurology 59:198–205PubMedGoogle Scholar
  16. 16.
    Bettens K, Brouwers N, Engelborghs S et al (2008) SORL1 is genetically associated with increased risk for late-onset Alzheimer disease in the Belgian population. Hum Mutat 29:769–770PubMedCrossRefGoogle Scholar
  17. 17.
    Binder LI, Frankfurter A, Rebhun LI (1985) The distribution of tau in the mammalian central nervous system. J Cell Biol 101:1371–1378PubMedCrossRefGoogle Scholar
  18. 18.
    Binder LI, Guillozet-Bongaarts AL, Garcia-Sierra F, Berry RW (2005) Tau, tangles, and Alzheimer’s disease. Biochim Biophys Acta 1739:216–223PubMedGoogle Scholar
  19. 19.
    Bonda DJ, Wang X, Perry G et al (2010) Oxidative stress in Alzheimer disease: a possibility for prevention. Neuropharmacology 59:290–294PubMedCrossRefGoogle Scholar
  20. 20.
    Braak H, Braak E (1989) Cortical and subcortical argyrophilic grains characterize a disease associated with adult onset dementia. Neuropathol Appl Neurobiol 15:13–26PubMedCrossRefGoogle Scholar
  21. 21.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedCrossRefGoogle Scholar
  22. 22.
    Braak H, Del Tredici K (2011) Alzheimer’s pathogenesis: is there neuron-to-neuron propagation? Acta Neuropathol 121:589–595PubMedCrossRefGoogle Scholar
  23. 23.
    Bruno MA, Cuello AC (2006) Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. Proc Natl Acad Sci USA 103:6735–6740PubMedCrossRefGoogle Scholar
  24. 24.
    Bruno MA, Mufson EJ, Wuu J, Cuello AC (2009) Increased matrix metalloproteinase 9 activity in mild cognitive impairment. J Neuropathol Exp Neurol 68:1309–1318PubMedCrossRefGoogle Scholar
  25. 25.
    Butterfield DA, Poon HF, St Clair D et al (2006) Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer’s disease. Neurobiol Dis 22:223–232PubMedCrossRefGoogle Scholar
  26. 26.
    Caselli RJ, Dueck AC, Osborne D et al (2009) Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. N Engl J Med 361:255–263PubMedCrossRefGoogle Scholar
  27. 27.
    Caselli RJ, Walker D, Sue L, Sabbagh M, Beach T (2010) Amyloid load in nondemented brains correlates with APOE e4. Neurosci Lett 473:168–171PubMedCrossRefGoogle Scholar
  28. 28.
    Cataldo AM, Barnett JL, Pieroni C, Nixon RA (1997) Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer’s disease: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis. J Neurosci 17:6142–6151PubMedGoogle Scholar
  29. 29.
    Cataldo AM, Paskevich PA, Kominami E, Nixon RA (1991) Lysosomal hydrolases of different classes are abnormally distributed in brains of patients with Alzheimer disease. Proc Natl Acad Sci USA 88:10998–11002PubMedCrossRefGoogle Scholar
  30. 30.
    Cataldo AM, Peterhoff CM, Troncoso JC et al (2000) Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer’s disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. Am J Pathol 157:277–286PubMedCrossRefGoogle Scholar
  31. 31.
    Chen K, Reiman EM, Alexander GE et al (2007) Correlations between apolipoprotein E epsilon4 gene dose and whole brain atrophy rates. Am J Psychiatry 164:916–921PubMedCrossRefGoogle Scholar
  32. 32.
    Corder EH, Saunders AM, Strittmatter WJ et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923PubMedCrossRefGoogle Scholar
  33. 33.
    Counts SE, He B, Nadeem M, Wuu J and Mufson EJ (2011) Hippocampal drebrin loss in mild cognitive impairment. Neurodeg Dis [Epub ahead of print]Google Scholar
  34. 34.
    Counts SE, He B, Che S et al (2007) Alpha7 nicotinic receptor up-regulation in cholinergic basal forebrain neurons in Alzheimer disease. Arch Neurol 64:1771–1776PubMedCrossRefGoogle Scholar
  35. 35.
    Counts SE, Nadeem M, Wuu J et al (2004) Reduction of cortical TrkA but not p75(NTR) protein in early-stage Alzheimer’s disease. Ann Neurol 56:520–531PubMedCrossRefGoogle Scholar
  36. 36.
    D’Amato RJ, Zweig RM, Whitehouse PJ et al (1987) Aminergic systems in Alzheimer’s disease and Parkinson’s disease. Ann Neurol 22:229–236PubMedCrossRefGoogle Scholar
  37. 37.
    Davies P, Maloney AJ (1976) Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 2:1403PubMedCrossRefGoogle Scholar
  38. 38.
    Davis KL, Mohs RC, Marin D et al (1999) Cholinergic markers in elderly patients with early signs of Alzheimer disease. JAMA 281:1401–1406PubMedCrossRefGoogle Scholar
  39. 39.
    DeKosky ST, Ikonomovic MD, Styren SD et al (2002) Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol 51:145–155PubMedCrossRefGoogle Scholar
  40. 40.
    Delacourte A, David JP, Sergeant N et al (1999) The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer’s disease. Neurology 52:1158–1165PubMedGoogle Scholar
  41. 41.
    Dodson SE, Gearing M, Lippa CF et al (2006) LR11/SorLA expression is reduced in sporadic Alzheimer disease but not in familial Alzheimer disease. J Neuropathol Exp Neurol 65:866–872PubMedCrossRefGoogle Scholar
  42. 42.
    Drzezga A, Grimmer T, Henriksen G et al (2009) Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease. Neurology 72:1487–1494PubMedCrossRefGoogle Scholar
  43. 43.
    Dubois B, Feldman HH, Jacova C et al (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 9:1118–1127PubMedCrossRefGoogle Scholar
  44. 44.
    Ellis JR, Villemagne VL, Nathan PJ et al (2008) Relationship between nicotinic receptors and cognitive function in early Alzheimer’s disease: a 2-[18F]fluoro-A-85380 PET study. Neurobiol Learn Mem 90:404–412PubMedCrossRefGoogle Scholar
  45. 45.
    Engler H, Forsberg A, Almkvist O et al (2006) Two-year follow-up of amyloid deposition in patients with Alzheimer’s disease. Brain 129:2856–2866PubMedCrossRefGoogle Scholar
  46. 46.
    Forman MS, Mufson EJ, Leurgans S et al (2007) Cortical biochemistry in MCI and Alzheimer disease: lack of correlation with clinical diagnosis. Neurology 68:757–763PubMedCrossRefGoogle Scholar
  47. 47.
    Garcia-Sierra F, Ghoshal N, Quinn B, Berry RW, Binder LI (2003) Conformational changes and truncation of tau protein during tangle evolution in Alzheimer’s disease. J Alzheimers Dis 5:65–77PubMedGoogle Scholar
  48. 48.
    George S, Mufson EJ, Leurgans S et al (2009) MRI-based volumetric measurement of the substantia innominata in amnestic MCI and mild AD. Neurobiol Aging 32:1756–1764Google Scholar
  49. 49.
    Geula C, Mesulam MM (1996) Systematic regional variations in the loss of cortical cholinergic fibers in Alzheimer’s disease. Cereb Cortex 6:165–177PubMedCrossRefGoogle Scholar
  50. 50.
    Gilmor ML, Erickson JD, Varoqui H et al (1999) Preservation of nucleus basalis neurons containing choline acetyltransferase and the vesicular acetylcholine transporter in the elderly with mild cognitive impairment and early Alzheimer’s disease. J Comp Neurol 411:693–704PubMedCrossRefGoogle Scholar
  51. 51.
    Ginsberg SD, Alldred MJ, Counts SE et al (2010) Microarray analysis of hippocampal CA1 neurons implicates early endosomal dysfunction during Alzheimer’s disease progression. Biol Psychiatry 68:885–893PubMedCrossRefGoogle Scholar
  52. 52.
    Ginsberg SD, Che S, Counts SE, Mufson EJ (2006) Shift in the ratio of three-repeat tau and four-repeat tau mRNAs in individual cholinergic basal forebrain neurons in mild cognitive impairment and Alzheimer’s disease. J Neurochem 96:1401–1408PubMedCrossRefGoogle Scholar
  53. 53.
    Ginsberg SD, Che S, Wuu J, Counts SE, Mufson EJ (2006) Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer’s disease. J Neurochem 97:475–487PubMedCrossRefGoogle Scholar
  54. 54.
    Gomez-Isla T, Price JL, McKeel DW Jr et al (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci 16:4491–4500PubMedGoogle Scholar
  55. 55.
    Greeve I, Hermans-Borgmeyer I, Brellinger C et al (2000) The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer’s disease-associated neurodegeneration and oxidative stress. J Neurosci 20:7345–7352PubMedGoogle Scholar
  56. 56.
    Grinberg LT, Rub U, Ferretti RE et al (2009) The dorsal raphe nucleus shows phospho-tau neurofibrillary changes before the transentorhinal region in Alzheimer’s disease. A precocious onset? Neuropathol Appl Neurobiol 35:406–416PubMedCrossRefGoogle Scholar
  57. 57.
    Grudzien A, Shaw P, Weintraub S et al (2007) Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging 28:327–335PubMedCrossRefGoogle Scholar
  58. 58.
    Guillozet AL, Weintraub S, Mash DC, Mesulam MM (2003) Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol 60:729–736PubMedCrossRefGoogle Scholar
  59. 59.
    Haense C, Kalbe E, Herholz K et al (2010) Cholinergic system function and cognition in mild cognitive impairment. Neurobiol AgingGoogle Scholar
  60. 60.
    Halliday GM, McCann HL, Pamphlett R et al (1992) Brain stem serotonin-synthesizing neurons in Alzheimer’s disease: a clinicopathological correlation. Acta Neuropathol 84:638–650PubMedCrossRefGoogle Scholar
  61. 61.
    Hanyu H, Asano T, Sakurai H et al (2002) MR analysis of the substantia innominata in normal aging, Alzheimer disease, and other types of dementia. AJNR Am J Neuroradiol 23:27–32PubMedGoogle Scholar
  62. 62.
    Hanyu H, Shimizu S, Tanaka Y et al (2007) MR features of the substantia innominata and therapeutic implications in dementias. Neurobiol Aging 28:548–554PubMedCrossRefGoogle Scholar
  63. 63.
    Hanyu H, Tanaka Y, Sakurai H, Takasaki M, Abe K (2002) Atrophy of the substantia innominata on magnetic resonance imaging and response to donepezil treatment in Alzheimer’s disease. Neurosci Lett 319:33–36PubMedCrossRefGoogle Scholar
  64. 64.
    Haroutunian V, Hoffman LB, Beeri MS (2009) Is there a neuropathology difference between mild cognitive impairment and dementia? Dialogues Clin Neurosci 11:171–179PubMedGoogle Scholar
  65. 65.
    Hatanpaa K, Isaacs KR, Shirao T, Brady DR, Rapoport SI (1999) Loss of proteins regulating synaptic plasticity in normal aging of the human brain and in Alzheimer disease. J Neuropathol Exp Neurol 58:637–643PubMedCrossRefGoogle Scholar
  66. 66.
    Hayashi K, Ishikawa R, Ye LH et al (1996) Modulatory role of drebrin on the cytoskeleton within dendritic spines in the rat cerebral cortex. J Neurosci 16:7161–7170PubMedGoogle Scholar
  67. 67.
    Holmes C, Boche D, Wilkinson D et al (2008) Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216–223PubMedCrossRefGoogle Scholar
  68. 68.
    Honer WG, Dickson DW, Gleeson J, Davies P (1992) Regional synaptic pathology in Alzheimer’s disease. Neurobiol Aging 13:375–382PubMedCrossRefGoogle Scholar
  69. 69.
    Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL (1984) Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science 225:1168–1170PubMedCrossRefGoogle Scholar
  70. 70.
    Ikonomovic MD, Abrahamson EE, Isanski BA et al (2007) Superior frontal cortex cholinergic axon density in mild cognitive impairment and early Alzheimer disease. Arch Neurol 64:1312–1317PubMedCrossRefGoogle Scholar
  71. 71.
    Ikonomovic MD, Klunk WE, Abrahamson EE et al (2011) Precuneus amyloid burden is associated with reduced cholinergic activity in Alzheimer disease. Neurology 77:39–47PubMedCrossRefGoogle Scholar
  72. 72.
    Ikonomovic MD, Mufson EJ, Wuu J, Bennett DA, DeKosky ST (2005) Reduction of choline acetyltransferase activity in primary visual cortex in mild to moderate Alzheimer’s disease. Arch Neurol 62:425–430PubMedCrossRefGoogle Scholar
  73. 73.
    Ikonomovic MD, Mufson EJ, Wuu J et al (2003) Cholinergic plasticity in hippocampus of individuals with mild cognitive impairment: correlation with Alzheimer’s neuropathology. J Alzheimers Dis 5:39–48PubMedGoogle Scholar
  74. 74.
    Ikonomovic MD, Wecker L, Abrahamson EE et al (2009) Cortical alpha7 nicotinic acetylcholine receptor and beta-amyloid levels in early Alzheimer disease. Arch Neurol 66:646–651PubMedCrossRefGoogle Scholar
  75. 75.
    Janvin CC, Larsen JP, Aarsland D, Hugdahl K (2006) Subtypes of mild cognitive impairment in Parkinson’s disease: progression to dementia. Mov Disord 21:1343–1349PubMedCrossRefGoogle Scholar
  76. 76.
    Johnson JK, Pa J, Boxer AL et al (2010) Baseline predictors of clinical progression among patients with dysexecutive mild cognitive impairment. Dement Geriatr Cogn Disord 30:344–351PubMedCrossRefGoogle Scholar
  77. 77.
    Kalus P, Slotboom J, Gallinat J et al (2006) Examining the gateway to the limbic system with diffusion tensor imaging: the perforant pathway in dementia. Neuroimage 30:713–720PubMedCrossRefGoogle Scholar
  78. 78.
    Kataturian Z (2011) Revised criteria for diagnosis of Alzheimer’s disease: National Institute of Aging Alzheimer’s Association diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:253–256CrossRefGoogle Scholar
  79. 79.
    Keller JN, Schmitt FA, Scheff SW et al (2005) Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology 64:1152–1156PubMedCrossRefGoogle Scholar
  80. 80.
    Kendziorra K, Wolf H, Meyer PM et al (2011) Decreased cerebral alpha4beta2* nicotinic acetylcholine receptor availability in patients with mild cognitive impairment and Alzheimer’s disease assessed with positron emission tomography. Eur J Nucl Med Mol Imaging 38:515–525PubMedCrossRefGoogle Scholar
  81. 81.
    Killiany RJ, Hyman BT, Gomez-Isla T et al (2002) MRI measures of entorhinal cortex vs hippocampus in preclinical AD. Neurology 58:1188–1196PubMedGoogle Scholar
  82. 82.
    King ME, Gamblin TC, Kuret J, Binder LI (2000) Differential assembly of human tau isoforms in the presence of arachidonic acid. J Neurochem 74:1749–1757PubMedCrossRefGoogle Scholar
  83. 83.
    Klein WL, Stine WB Jr, Teplow DB (2004) Small assemblies of unmodified amyloid beta-protein are the proximate neurotoxin in Alzheimer’s disease. Neurobiol Aging 25:569–580PubMedCrossRefGoogle Scholar
  84. 84.
    Klunk WE, Engler H, Nordberg A et al (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55:306–319PubMedCrossRefGoogle Scholar
  85. 85.
    Kok E, Haikonen S, Luoto T et al (2009) Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Ann Neurol 65:650–657PubMedCrossRefGoogle Scholar
  86. 86.
    Kolsch H, Jessen F, Wiltfang J et al (2009) Association of SORL1 gene variants with Alzheimer’s disease. Brain Res 1264:1–6PubMedCrossRefGoogle Scholar
  87. 87.
    Kordower JH, Chu Y, Stebbins GT et al (2001) Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment. Ann Neurol 49:202–213PubMedCrossRefGoogle Scholar
  88. 88.
    Lee HG, Perry G, Moreira PI et al (2005) Tau phosphorylation in Alzheimer’s disease: pathogen or protector? Trends Mol Med 11:164–169PubMedCrossRefGoogle Scholar
  89. 89.
    Lilja AM, Porras O, Storelli E, Nordberg A, Marutle A (2011) Functional interactions of fibrillar and oligomeric amyloid-beta with alpha7 nicotinic receptors in Alzheimer’s disease. J Alzheimers Dis 23:335–347PubMedGoogle Scholar
  90. 90.
    Lopez OL, Jagust WJ, DeKosky ST et al (2003) Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 1. Arch Neurol 60:1385–1389PubMedCrossRefGoogle Scholar
  91. 91.
    Lopez OL, Jagust WJ, Dulberg C et al (2003) Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. Arch Neurol 60:1394–1399PubMedCrossRefGoogle Scholar
  92. 92.
    Mamidipudi V, Wooten MW (2002) Dual role for p75(NTR) signaling in survival and cell death: can intracellular mediators provide an explanation? J Neurosci Res 68:373–384PubMedCrossRefGoogle Scholar
  93. 93.
    Markesbery WR (2010) Neuropathologic alterations in mild cognitive impairment: a review. J Alzheimers Dis 19:221–228PubMedGoogle Scholar
  94. 94.
    Markesbery WR, Schmitt FA, Kryscio RJ et al (2006) Neuropathologic substrate of mild cognitive impairment. Arch Neurol 63:38–46PubMedCrossRefGoogle Scholar
  95. 95.
    Masliah E, Mallory M, Alford M et al (2001) Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 56:127–129PubMedGoogle Scholar
  96. 96.
    Masliah E, Terry RD, DeTeresa RM, Hansen LA (1989) Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease. Neurosci Lett 103:234–239PubMedCrossRefGoogle Scholar
  97. 97.
    Masliah E, Terry RD, Mallory M, Alford M, Hansen LA (1990) Diffuse plaques do not accentuate synapse loss in Alzheimer’s disease. Am J Pathol 137:1293–1297PubMedGoogle Scholar
  98. 98.
    McKhann G, Drachman D, Folstein M et al (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944PubMedGoogle Scholar
  99. 99.
    Mesulam M, Shaw P, Mash D, Weintraub S (2004) Cholinergic nucleus basalis tauopathy emerges early in the aging-MCI-AD continuum. Ann Neurol 55:815–828PubMedCrossRefGoogle Scholar
  100. 100.
    Mesulam MM, Mufson EJ, Levey AI, Wainer BH (1983) Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. J Comp Neurol 214:170–197PubMedCrossRefGoogle Scholar
  101. 101.
    Meyer JS, Xu G, Thornby J, Chowdhury MH, Quach M (2002) Is mild cognitive impairment prodromal for vascular dementia like Alzheimer’s disease? Stroke 33:1981–1985PubMedCrossRefGoogle Scholar
  102. 102.
    Minster RL, DeKosky ST, Kamboh MI (2008) No association of dynamin binding protein (DNMBP) gene SNPs and Alzheimer’s disease. Neurobiol Aging 29:1602–1604PubMedCrossRefGoogle Scholar
  103. 103.
    Mitchell TW, Mufson EJ, Schneider JA et al (2002) Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer’s disease. Ann Neurol 51:182–189PubMedCrossRefGoogle Scholar
  104. 104.
    Mitsis EM, Reech KM, Bois F et al (2009) 123I-5-IA-85380 SPECT imaging of nicotinic receptors in Alzheimer disease and mild cognitive impairment. J Nucl Med 50:1455–1463PubMedCrossRefGoogle Scholar
  105. 105.
    Morris JC (1993) The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 43:2412–2414PubMedGoogle Scholar
  106. 106.
    Morris JC, Price AL (2001) Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer’s disease. J Mol Neurosci 17:101–118PubMedCrossRefGoogle Scholar
  107. 107.
    Morris JC, Roe CM, Xiong C et al (2010) APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol 67:122–131PubMedCrossRefGoogle Scholar
  108. 108.
    Morsch G, Maywald F, Wanner C (1995) In vitro and in vivo studies with different precipitate filter cartridges for H.E.L.P.-LDL-apheresis. Optimization of precipitate filter cartridges. Bioseparation 5:11–18PubMedGoogle Scholar
  109. 109.
    Mufson EJ, Chen EY, Cochran EJ et al (1999) Entorhinal cortex beta-amyloid load in individuals with mild cognitive impairment. Exp Neurol 158:469–490PubMedCrossRefGoogle Scholar
  110. 110.
    Mufson EJ, Counts SE, Perez SE, Ginsberg SD (2008) Cholinergic system during the progression of Alzheimer’s disease: therapeutic implications. Expert Rev Neurother 8:1703–1718PubMedCrossRefGoogle Scholar
  111. 111.
    Mufson EJ, Ginsberg SD, Ikonomovic MD, DeKosky ST (2003) Human cholinergic basal forebrain: chemoanatomy and neurologic dysfunction. J Chem Neuroanat 26:233–242PubMedCrossRefGoogle Scholar
  112. 112.
    Mufson EJ, Ikonomovic MD, Styren SD et al (2003) Preservation of brain nerve growth factor in mild cognitive impairment and Alzheimer disease. Arch Neurol 60:1143–1148PubMedCrossRefGoogle Scholar
  113. 113.
    Mufson EJ, Ma SY, Cochran EJ et al (2000) Loss of nucleus basalis neurons containing trkA immunoreactivity in individuals with mild cognitive impairment and early Alzheimer’s disease. J Comp Neurol 427:19–30PubMedCrossRefGoogle Scholar
  114. 114.
    Mufson EJ, Ma SY, Dills J et al (2002) Loss of basal forebrain P75(NTR) immunoreactivity in subjects with mild cognitive impairment and Alzheimer’s disease. J Comp Neurol 443:136–153PubMedCrossRefGoogle Scholar
  115. 115.
    Mufson EJ, Wuu J, Counts SE, Nykjaer A (2010) Preservation of cortical sortilin protein levels in MCI and Alzheimer’s disease. Neurosci Lett 471:129–133PubMedCrossRefGoogle Scholar
  116. 116.
    Muth K, Schonmeyer R, Matura S et al (2010) Mild cognitive impairment in the elderly is associated with volume loss of the cholinergic basal forebrain region. Biol Psychiatry 67:588–591Google Scholar
  117. 117.
    Nagele RG, D’Andrea MR, Anderson WJ, Wang HY (2002) Intracellular accumulation of beta-amyloid(1–42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer’s disease. Neuroscience 110:199–211PubMedCrossRefGoogle Scholar
  118. 118.
    Nelson PT, Braak H, Markesbery WR (2009) Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J Neuropathol Exp Neurol 68:1–14PubMedCrossRefGoogle Scholar
  119. 119.
    Nixon RA (2005) Endosome function and dysfunction in Alzheimer’s disease and other neurodegenerative diseases. Neurobiol Aging 26:373–382PubMedCrossRefGoogle Scholar
  120. 120.
    Nixon RA, Cataldo AM, Mathews PM (2000) The endosomal–lysosomal system of neurons in Alzheimer’s disease pathogenesis: a review. Neurochem Res 25:1161–1172PubMedCrossRefGoogle Scholar
  121. 121.
    Nixon RA, Wegiel J, Kumar A et al (2005) Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 64:113–122PubMedGoogle Scholar
  122. 122.
    Nordberg A (2001) Nicotinic receptor abnormalities of Alzheimer’s disease: therapeutic implications. Biol Psychiatry 49:200–210PubMedCrossRefGoogle Scholar
  123. 123.
    Offe K, Dodson SE, Shoemaker JT et al (2006) The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments. J Neurosci 26:1596–1603PubMedCrossRefGoogle Scholar
  124. 124.
    Overk CR, Felder CC, Tu Y et al (2010) Cortical M1 receptor concentration increases without a concomitant change in function in Alzheimer’s disease. J Chem Neuroanat 40:63–70PubMedCrossRefGoogle Scholar
  125. 125.
    Parvizi J, Van Hoesen GW, Damasio A (2001) The selective vulnerability of brainstem nuclei to Alzheimer’s disease. Ann Neurol 49:53–66PubMedCrossRefGoogle Scholar
  126. 126.
    Peng S, Garzon DJ, Marchese M et al (2009) Decreased brain-derived neurotrophic factor depends on amyloid aggregation state in transgenic mouse models of Alzheimer’s disease. J Neurosci 29:9321–9329PubMedCrossRefGoogle Scholar
  127. 127.
    Peng S, Wuu J, Mufson EJ, Fahnestock M (2004) Increased proNGF levels in subjects with mild cognitive impairment and mild Alzheimer disease. J Neuropathol Exp Neurol 63:641–649PubMedGoogle Scholar
  128. 128.
    Perry A, Cai DX, Scheithauer BW et al (2000) Merlin, DAL-1, and progesterone receptor expression in clinicopathologic subsets of meningioma: a correlative immunohistochemical study of 175 cases. J Neuropathol Exp Neurol 59:872–879PubMedGoogle Scholar
  129. 129.
    Petersen R (2003) Conceptual overview. In: Petersen R (ed) Mild cognitive impairment aging to Alzheimer’s disease. Oxford University Press, New YorkGoogle Scholar
  130. 130.
    Petersen RC (2003) Mild cognitive impairment clinical trials. Nat Rev Drug Discov 2:646–653PubMedCrossRefGoogle Scholar
  131. 131.
    Petersen RC (2004) Mild cognitive impairment as a diagnostic entity. J Intern Med 256:183–194PubMedCrossRefGoogle Scholar
  132. 132.
    Petersen RC, Parisi JE, Dickson DW et al (2006) Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 63:665–672PubMedCrossRefGoogle Scholar
  133. 133.
    Petersen RC, Smith GE, Waring SC et al (1999) Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 56:303–308PubMedCrossRefGoogle Scholar
  134. 134.
    Pham E, Crews L, Ubhi K et al (2010) Progressive accumulation of amyloid-beta oligomers in Alzheimer’s disease and in amyloid precursor protein transgenic mice is accompanied by selective alterations in synaptic scaffold proteins. FEBS J 277:3051–3067PubMedCrossRefGoogle Scholar
  135. 135.
    Potter PE, Rauschkolb PK, Pandya Y et al (2011) Pre- and post-synaptic cortical cholinergic deficits are proportional to amyloid plaque presence and density at preclinical stages of Alzheimer’s disease. Acta Neuropathol 122:49–60PubMedCrossRefGoogle Scholar
  136. 136.
    Price JL, Ko AI, Wade MJ et al (2001) Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch Neurol 58:1395–1402PubMedCrossRefGoogle Scholar
  137. 137.
    Price JL, McKeel DW Jr, Buckles VD et al (2009) Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging 30:1026–1036PubMedCrossRefGoogle Scholar
  138. 138.
    Price JL, Morris JC (1999) Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol 45:358–368PubMedCrossRefGoogle Scholar
  139. 139.
    Reiman EM, Chen K, Liu X et al (2009) Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease. Proc Natl Acad Sci USA 106:6820–6825PubMedCrossRefGoogle Scholar
  140. 140.
    Riley KP, Snowdon DA, Markesbery WR (2002) Alzheimer’s neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study. Ann Neurol 51:567–577PubMedCrossRefGoogle Scholar
  141. 141.
    Rinne JO, Kaasinen V, Jarvenpaa T et al (2003) Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer’s disease. J Neurol Neurosurg Psychiatry 74:113–115PubMedCrossRefGoogle Scholar
  142. 142.
    Robakis NK (2011) Mechanisms of AD neurodegeneration may be independent of Abeta and its derivatives. Neurobiol Aging 32:372–379PubMedCrossRefGoogle Scholar
  143. 143.
    Rogalski EJ, Murphy CM, de Toledo-Morrell L et al (2009) Changes in parahippocampal white matter integrity in amnestic mild cognitive impairment: a diffusion tensor imaging study. Behav Neurol 21:51–61PubMedGoogle Scholar
  144. 144.
    Roux PP, Barker PA (2002) Neurotrophin signaling through the p75 neurotrophin receptor. Prog Neurobiol 67:203–233PubMedCrossRefGoogle Scholar
  145. 145.
    Rub U, Del Tredici K, Schultz C et al (2000) The evolution of Alzheimer’s disease-related cytoskeletal pathology in the human raphe nuclei. Neuropathol Appl Neurobiol 26:553–567PubMedCrossRefGoogle Scholar
  146. 146.
    Sabbagh MN, Shah F, Reid RT et al (2006) Pathologic and nicotinic receptor binding differences between mild cognitive impairment, Alzheimer disease, and normal aging. Arch Neurol 63:1771–1776PubMedCrossRefGoogle Scholar
  147. 147.
    Sager KL, Wuu J, Leurgans SE et al (2007) Neuronal LR11/sorLA expression is reduced in mild cognitive impairment. Ann Neurol 62:640–647PubMedCrossRefGoogle Scholar
  148. 148.
    Saito Y, Murayama S (2007) Neuropathology of mild cognitive impairment. Neuropathol 27:578–584CrossRefGoogle Scholar
  149. 149.
    Salehi A, Verhaagen J, Dijkhuizen PA, Swaab DF (1996) Co-localization of high-affinity neurotrophin receptors in nucleus basalis of Meynert neurons and their differential reduction in Alzheimer’s disease. Neuroscience 75:373–387PubMedCrossRefGoogle Scholar
  150. 150.
    Sasaki M, Ehara S, Tamakawa Y et al (1995) MR anatomy of the substantia innominata and findings in Alzheimer disease: a preliminary report. AJNR Am J Neuroradiol 16:2001–2007PubMedGoogle Scholar
  151. 151.
    Scheff SW, DeKosky ST, Price DA (1990) Quantitative assessment of cortical synaptic density in Alzheimer’s disease. Neurobiol Aging 11:29–37PubMedCrossRefGoogle Scholar
  152. 152.
    Scheff SW, Ginsberg S, Counts SE and Mufson EJ (2011) Synaptic integrity in mild cognitive impairment and Alzheimer’s disease. In: Sun M (ed) Research progress in Alzheimer’s disease and dementia. NOVA Scientific Publisher, New York (in press)Google Scholar
  153. 153.
    Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ (2007) Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68:1501–1508PubMedCrossRefGoogle Scholar
  154. 154.
    Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27:1372–1384PubMedCrossRefGoogle Scholar
  155. 155.
    Scheff SW, Price DA, Schmitt FA, Scheff MA, Mufson EJ (2011) Synaptic loss in the inferior temporal gyrus in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 24:547–557PubMedGoogle Scholar
  156. 156.
    Schipper HM (2004) Heme oxygenase expression in human central nervous system disorders. Free Radic Biol Med 37:1995–2011PubMedCrossRefGoogle Scholar
  157. 157.
    Schipper HM, Bennett DA, Liberman A et al (2006) Glial heme oxygenase-1 expression in Alzheimer disease and mild cognitive impairment. Neurobiol Aging 27:252–261PubMedCrossRefGoogle Scholar
  158. 158.
    Schmidt ML, DiDario AG, Otvos L Jr et al (1994) Plaque-associated neuronal proteins: a recurrent motif in neuritic amyloid deposits throughout diverse cortical areas of the Alzheimer’s disease brain. Exp Neurol 130:311–322PubMedCrossRefGoogle Scholar
  159. 159.
    Schneider JA, Arvanitakis Z, Leurgans SE, Bennett DA (2009) The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann Neurol 66:200–208PubMedCrossRefGoogle Scholar
  160. 160.
    Shimohama S, Kamiya S, Taniguchi T, Akagawa K, Kimura J (1997) Differential involvement of synaptic vesicle and presynaptic plasma membrane proteins in Alzheimer’s disease. Biochem Biophys Res Commun 236:239–242PubMedCrossRefGoogle Scholar
  161. 161.
    Shirao T, Inoue HK, Kano Y, Obata K (1987) Localization of a developmentally regulated neuron-specific protein S54 in dendrites as revealed by immunoelectron microscopy. Brain Res 413:374–378PubMedCrossRefGoogle Scholar
  162. 162.
    Small GW, Mazziotta JC, Collins MT et al (1995) Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA 273:942–947PubMedCrossRefGoogle Scholar
  163. 163.
    Smith MA, Nunomura A, Lee HG et al (2005) Chronological primacy of oxidative stress in Alzheimer disease. Neurobiol Aging 26:579–580PubMedCrossRefGoogle Scholar
  164. 164.
    Snowdon DA, Gross MD, Butler SM (1996) Antioxidants and reduced functional capacity in the elderly: findings from the Nun Study. J Gerontol A Biol Sci Med Sci 51:M10–M16PubMedCrossRefGoogle Scholar
  165. 165.
    Snowdon DA, Kemper SJ, Mortimer JA et al (1996) Linguistic ability in early life and cognitive function and Alzheimer’s disease in late life. Findings from the Nun Study. JAMA 275:528–532PubMedCrossRefGoogle Scholar
  166. 166.
    Sojkova J, Zhou Y, An Y et al (2011) Longitudinal patterns of beta-amyloid deposition in nondemented older adults. Arch Neurol 68:644–649PubMedCrossRefGoogle Scholar
  167. 167.
    Soscia SJ, Kirby JE, Washicosky KJ et al (2010) The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PloS One 5:e9505PubMedCrossRefGoogle Scholar
  168. 168.
    Sperling RA, Aisen PS, Beckett LA et al (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:280–292PubMedCrossRefGoogle Scholar
  169. 169.
    Stoub TR, Bulgakova M, Leurgans S et al (2005) MRI predictors of risk of incident Alzheimer disease: a longitudinal study. Neurology 64:1520–1524PubMedCrossRefGoogle Scholar
  170. 170.
    Stoub TR, de Toledo-Morrell L, Stebbins GT et al (2006) Hippocampal disconnection contributes to memory dysfunction in individuals at risk for Alzheimer’s disease. Proc Natl Acad Sci USA 103:10041–10045PubMedCrossRefGoogle Scholar
  171. 171.
    Stoub TR, Rogalski EJ, Leurgans S, Bennett DA, de Toledo-Morrell L (2010) Rate of entorhinal and hippocampal atrophy in incipient and mild AD: relation to memory function. Neurobiol Aging 31:1089–1098PubMedCrossRefGoogle Scholar
  172. 172.
    Sultana R, Banks WA, Butterfield DA (2010) Decreased levels of PSD95 and two associated proteins and increased levels of BCl2 and caspase 3 in hippocampus from subjects with amnestic mild cognitive impairment: insights into their potential roles for loss of synapses and memory, accumulation of Abeta, and neurodegeneration in a prodromal stage of Alzheimer’s disease. J Neurosci Res 88:469–477PubMedGoogle Scholar
  173. 173.
    Sunderland T, Linker G, Mirza N et al (2003) Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA 289:2094–2103PubMedCrossRefGoogle Scholar
  174. 174.
    Swaminathan S, Shen L, Risacher SL et al (2011) Amyloid pathway-based candidate gene analysis of [(11)C]PiB-PET in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Brain Imag BehavGoogle Scholar
  175. 175.
    Takahashi H, Sekino Y, Tanaka S et al (2003) Drebrin-dependent actin clustering in dendritic filopodia governs synaptic targeting of postsynaptic density-95 and dendritic spine morphogenesis. J Neurosci 23:6586–6595PubMedGoogle Scholar
  176. 176.
    Tapiola T, Pennanen C, Tapiola M et al (2008) MRI of hippocampus and entorhinal cortex in mild cognitive impairment: a follow-up study. Neurobiol Aging 29:31–38PubMedCrossRefGoogle Scholar
  177. 177.
    Teaktong T, Graham A, Court J et al (2003) Alzheimer’s disease is associated with a selective increase in alpha7 nicotinic acetylcholine receptor immunoreactivity in astrocytes. Glia 41:207–211PubMedCrossRefGoogle Scholar
  178. 178.
    Terriere E, Dempsey MF, Herrmann LL et al (2010) 5-(123)I-A-85380 binding to the alpha4beta2-nicotinic receptor in mild cognitive impairment. Neurobiol Aging 31:1885–1893PubMedCrossRefGoogle Scholar
  179. 179.
    Terry RD, Masliah E, Salmon DP et al (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580PubMedCrossRefGoogle Scholar
  180. 180.
    Thal DR, Capetillo-Zarate E, Del Tredici K, Braak H (2006) The development of amyloid beta protein deposits in the aged brain. Sci Aging Knowledge Environ 2006:re1Google Scholar
  181. 181.
    Thal DR, Holzer M, Rub U et al (2000) Alzheimer-related tau-pathology in the perforant path target zone and in the hippocampal stratum oriens and radiatum correlates with onset and degree of dementia. Exp Neurol 163:98–110PubMedCrossRefGoogle Scholar
  182. 182.
    Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800PubMedGoogle Scholar
  183. 183.
    Tremblay C, Pilote M, Phivilay A et al (2007) Biochemical characterization of Abeta and tau pathologies in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 12:377–390PubMedGoogle Scholar
  184. 184.
    Tsang SW, Lai MK, Kirvell S et al (2006) Impaired coupling of muscarinic M1 receptors to G-proteins in the neocortex is associated with severity of dementia in Alzheimer’s disease. Neurobiol Aging 27:1216–1223PubMedCrossRefGoogle Scholar
  185. 185.
    Vana L, Kanaan NM, Ugwu IC et al (2011) Progression of tau pathology in cholinergic basal forebrain neurons in MCI and AD. Am J Pathol (in press)Google Scholar
  186. 186.
    Wang DS, Bennett DA, Mufson E, Cochran E, Dickson DW (2004) Decreases in soluble alpha-synuclein in frontal cortex correlate with cognitive decline in the elderly. Neurosci Lett 359:104–108PubMedCrossRefGoogle Scholar
  187. 187.
    Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR (1981) Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol 10:122–126PubMedCrossRefGoogle Scholar
  188. 188.
    Winblad B, Palmer K, Kivipelto M et al (2004) Mild cognitive impairment—beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med 256:240–246PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Elliott J. Mufson
    • 1
  • Lester Binder
    • 2
  • Scott E. Counts
    • 1
  • Steven T. DeKosky
    • 3
  • Leyla deToledo-Morrell
    • 1
  • Stephen D. Ginsberg
    • 4
  • Milos D. Ikonomovic
    • 5
  • Sylvia E. Perez
    • 1
  • Stephen W. Scheff
    • 6
  1. 1.Department of Neurological SciencesRush University Medical CenterChicagoUSA
  2. 2.Department of Cell and Molecular BiologyFeinberg School of Medicine, Northwestern UniversityChicagoUSA
  3. 3.University of Virginia School of MedicineCharlottesvilleUSA
  4. 4.Departments of Psychiatry, Physiology and NeuroscienceCenter for Dementia Research, Nathan Kline Institute, New York University Langone Medical CenterOrangeburgUSA
  5. 5.Departments of Neurology, Psychiatry, and Geriatric Research Educational and Clinical CenterUniversity of Pittsburgh and VA Pittsburgh Healthcare SystemPittsburghUSA
  6. 6.Sanders Brown Center on AgingUniversity of KentuckyLexingtonUSA

Personalised recommendations