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Mild cognitive impairment: pathology and mechanisms

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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.

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References

  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 29:12957–12969

    Article  PubMed  CAS  Google Scholar 

  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 25:445–453

    PubMed  Google Scholar 

  3. Adler CH, Caviness JN, Sabbagh MN et al (2010) Heterogeneous neuropathological findings in Parkinson’s disease with mild cognitive impairment. Acta Neuropathol 120:827–828

    Article  PubMed  Google Scholar 

  4. Aizenstein HJ, Nebes RD, Saxton JA et al (2008) Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol 65:1509–1517

    Article  PubMed  Google Scholar 

  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 7:270–279

    Article  PubMed  Google Scholar 

  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 102:13461–13466

    Article  PubMed  CAS  Google Scholar 

  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 45:2618–2628

    Article  PubMed  CAS  Google Scholar 

  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 483:383–402

    Article  PubMed  CAS  Google Scholar 

  9. Barbacid M (1995) Neurotrophic factors and their receptors. Curr Opin Cell Biol 7:148–155

    Article  PubMed  CAS  Google Scholar 

  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 25:623–633

    PubMed  CAS  Google Scholar 

  11. Bartus RT, Dean RL 3rd, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414

    Article  PubMed  CAS  Google Scholar 

  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 142:253–256

    Article  PubMed  CAS  Google Scholar 

  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 18:270–277

    PubMed  Google Scholar 

  14. Bell KF, Ducatenzeiler A, Ribeiro-da-Silva A et al (2006) The amyloid pathology progresses in a neurotransmitter-specific manner. Neurobiol Aging 27:1644–1657

    Article  PubMed  CAS  Google Scholar 

  15. Bennett DA, Wilson RS, Schneider JA et al (2002) Natural history of mild cognitive impairment in older persons. Neurology 59:198–205

    PubMed  CAS  Google Scholar 

  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 29:769–770

    Article  PubMed  Google Scholar 

  17. Binder LI, Frankfurter A, Rebhun LI (1985) The distribution of tau in the mammalian central nervous system. J Cell Biol 101:1371–1378

    Article  PubMed  CAS  Google Scholar 

  18. Binder LI, Guillozet-Bongaarts AL, Garcia-Sierra F, Berry RW (2005) Tau, tangles, and Alzheimer’s disease. Biochim Biophys Acta 1739:216–223

    PubMed  CAS  Google Scholar 

  19. Bonda DJ, Wang X, Perry G et al (2010) Oxidative stress in Alzheimer disease: a possibility for prevention. Neuropharmacology 59:290–294

    Article  PubMed  CAS  Google Scholar 

  20. Braak H, Braak E (1989) Cortical and subcortical argyrophilic grains characterize a disease associated with adult onset dementia. Neuropathol Appl Neurobiol 15:13–26

    Article  PubMed  CAS  Google Scholar 

  21. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259

    Article  PubMed  CAS  Google Scholar 

  22. Braak H, Del Tredici K (2011) Alzheimer’s pathogenesis: is there neuron-to-neuron propagation? Acta Neuropathol 121:589–595

    Article  PubMed  CAS  Google Scholar 

  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 103:6735–6740

    Article  PubMed  CAS  Google Scholar 

  24. Bruno MA, Mufson EJ, Wuu J, Cuello AC (2009) Increased matrix metalloproteinase 9 activity in mild cognitive impairment. J Neuropathol Exp Neurol 68:1309–1318

    Article  PubMed  CAS  Google Scholar 

  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 22:223–232

    Article  PubMed  CAS  Google Scholar 

  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 361:255–263

    Article  PubMed  CAS  Google Scholar 

  27. Caselli RJ, Walker D, Sue L, Sabbagh M, Beach T (2010) Amyloid load in nondemented brains correlates with APOE e4. Neurosci Lett 473:168–171

    Article  PubMed  CAS  Google Scholar 

  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 17:6142–6151

    PubMed  CAS  Google Scholar 

  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 88:10998–11002

    Article  PubMed  CAS  Google Scholar 

  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 157:277–286

    Article  PubMed  CAS  Google Scholar 

  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 164:916–921

    Article  PubMed  Google Scholar 

  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 261:921–923

    Article  PubMed  CAS  Google Scholar 

  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]

  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 64:1771–1776

    Article  PubMed  Google Scholar 

  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 56:520–531

    Article  PubMed  CAS  Google Scholar 

  36. D’Amato RJ, Zweig RM, Whitehouse PJ et al (1987) Aminergic systems in Alzheimer’s disease and Parkinson’s disease. Ann Neurol 22:229–236

    Article  PubMed  Google Scholar 

  37. Davies P, Maloney AJ (1976) Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 2:1403

    Article  PubMed  CAS  Google Scholar 

  38. Davis KL, Mohs RC, Marin D et al (1999) Cholinergic markers in elderly patients with early signs of Alzheimer disease. JAMA 281:1401–1406

    Article  PubMed  CAS  Google Scholar 

  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 51:145–155

    Article  PubMed  CAS  Google Scholar 

  40. Delacourte A, David JP, Sergeant N et al (1999) The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer’s disease. Neurology 52:1158–1165

    PubMed  CAS  Google Scholar 

  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 65:866–872

    Article  PubMed  CAS  Google Scholar 

  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 72:1487–1494

    Article  PubMed  CAS  Google Scholar 

  43. Dubois B, Feldman HH, Jacova C et al (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 9:1118–1127

    Article  PubMed  Google Scholar 

  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 90:404–412

    Article  PubMed  CAS  Google Scholar 

  45. Engler H, Forsberg A, Almkvist O et al (2006) Two-year follow-up of amyloid deposition in patients with Alzheimer’s disease. Brain 129:2856–2866

    Article  PubMed  Google Scholar 

  46. Forman MS, Mufson EJ, Leurgans S et al (2007) Cortical biochemistry in MCI and Alzheimer disease: lack of correlation with clinical diagnosis. Neurology 68:757–763

    Article  PubMed  CAS  Google Scholar 

  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 5:65–77

    PubMed  CAS  Google Scholar 

  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 32:1756–1764

    Google Scholar 

  49. Geula C, Mesulam MM (1996) Systematic regional variations in the loss of cortical cholinergic fibers in Alzheimer’s disease. Cereb Cortex 6:165–177

    Article  PubMed  CAS  Google Scholar 

  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 411:693–704

    Article  PubMed  CAS  Google Scholar 

  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 68:885–893

    Article  PubMed  CAS  Google Scholar 

  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 96:1401–1408

    Article  PubMed  CAS  Google Scholar 

  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 97:475–487

    Article  PubMed  CAS  Google Scholar 

  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 16:4491–4500

    PubMed  CAS  Google Scholar 

  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 20:7345–7352

    PubMed  CAS  Google Scholar 

  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 35:406–416

    Article  PubMed  CAS  Google Scholar 

  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 28:327–335

    Article  PubMed  CAS  Google Scholar 

  58. Guillozet AL, Weintraub S, Mash DC, Mesulam MM (2003) Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol 60:729–736

    Article  PubMed  Google Scholar 

  59. Haense C, Kalbe E, Herholz K et al (2010) Cholinergic system function and cognition in mild cognitive impairment. Neurobiol Aging

  60. Halliday GM, McCann HL, Pamphlett R et al (1992) Brain stem serotonin-synthesizing neurons in Alzheimer’s disease: a clinicopathological correlation. Acta Neuropathol 84:638–650

    Article  PubMed  CAS  Google Scholar 

  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 23:27–32

    PubMed  Google Scholar 

  62. Hanyu H, Shimizu S, Tanaka Y et al (2007) MR features of the substantia innominata and therapeutic implications in dementias. Neurobiol Aging 28:548–554

    Article  PubMed  Google Scholar 

  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 319:33–36

    Article  PubMed  CAS  Google Scholar 

  64. Haroutunian V, Hoffman LB, Beeri MS (2009) Is there a neuropathology difference between mild cognitive impairment and dementia? Dialogues Clin Neurosci 11:171–179

    PubMed  Google Scholar 

  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 58:637–643

    Article  PubMed  CAS  Google Scholar 

  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 16:7161–7170

    PubMed  CAS  Google Scholar 

  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 372:216–223

    Article  PubMed  CAS  Google Scholar 

  68. Honer WG, Dickson DW, Gleeson J, Davies P (1992) Regional synaptic pathology in Alzheimer’s disease. Neurobiol Aging 13:375–382

    Article  PubMed  CAS  Google Scholar 

  69. Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL (1984) Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science 225:1168–1170

    Article  PubMed  CAS  Google Scholar 

  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 64:1312–1317

    Article  PubMed  Google Scholar 

  71. Ikonomovic MD, Klunk WE, Abrahamson EE et al (2011) Precuneus amyloid burden is associated with reduced cholinergic activity in Alzheimer disease. Neurology 77:39–47

    Article  PubMed  CAS  Google Scholar 

  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 62:425–430

    Article  PubMed  Google Scholar 

  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 5:39–48

    PubMed  CAS  Google Scholar 

  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 66:646–651

    Article  PubMed  Google Scholar 

  75. Janvin CC, Larsen JP, Aarsland D, Hugdahl K (2006) Subtypes of mild cognitive impairment in Parkinson’s disease: progression to dementia. Mov Disord 21:1343–1349

    Article  PubMed  Google Scholar 

  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 30:344–351

    Article  PubMed  Google Scholar 

  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 30:713–720

    Article  PubMed  Google Scholar 

  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 7:253–256

    Article  Google Scholar 

  79. Keller JN, Schmitt FA, Scheff SW et al (2005) Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology 64:1152–1156

    Article  PubMed  CAS  Google Scholar 

  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 38:515–525

    Article  PubMed  CAS  Google Scholar 

  81. Killiany RJ, Hyman BT, Gomez-Isla T et al (2002) MRI measures of entorhinal cortex vs hippocampus in preclinical AD. Neurology 58:1188–1196

    PubMed  CAS  Google Scholar 

  82. King ME, Gamblin TC, Kuret J, Binder LI (2000) Differential assembly of human tau isoforms in the presence of arachidonic acid. J Neurochem 74:1749–1757

    Article  PubMed  CAS  Google Scholar 

  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 25:569–580

    Article  PubMed  CAS  Google Scholar 

  84. Klunk WE, Engler H, Nordberg A et al (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55:306–319

    Article  PubMed  CAS  Google Scholar 

  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 65:650–657

    Article  PubMed  CAS  Google Scholar 

  86. Kolsch H, Jessen F, Wiltfang J et al (2009) Association of SORL1 gene variants with Alzheimer’s disease. Brain Res 1264:1–6

    Article  PubMed  CAS  Google Scholar 

  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 49:202–213

    Article  PubMed  CAS  Google Scholar 

  88. Lee HG, Perry G, Moreira PI et al (2005) Tau phosphorylation in Alzheimer’s disease: pathogen or protector? Trends Mol Med 11:164–169

    Article  PubMed  CAS  Google Scholar 

  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 23:335–347

    PubMed  CAS  Google Scholar 

  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 60:1385–1389

    Article  PubMed  Google Scholar 

  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 60:1394–1399

    Article  PubMed  Google Scholar 

  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 68:373–384

    Article  PubMed  CAS  Google Scholar 

  93. Markesbery WR (2010) Neuropathologic alterations in mild cognitive impairment: a review. J Alzheimers Dis 19:221–228

    PubMed  Google Scholar 

  94. Markesbery WR, Schmitt FA, Kryscio RJ et al (2006) Neuropathologic substrate of mild cognitive impairment. Arch Neurol 63:38–46

    Article  PubMed  Google Scholar 

  95. Masliah E, Mallory M, Alford M et al (2001) Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 56:127–129

    PubMed  CAS  Google Scholar 

  96. Masliah E, Terry RD, DeTeresa RM, Hansen LA (1989) Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease. Neurosci Lett 103:234–239

    Article  PubMed  CAS  Google Scholar 

  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 137:1293–1297

    PubMed  CAS  Google Scholar 

  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 34:939–944

    PubMed  CAS  Google Scholar 

  99. Mesulam M, Shaw P, Mash D, Weintraub S (2004) Cholinergic nucleus basalis tauopathy emerges early in the aging-MCI-AD continuum. Ann Neurol 55:815–828

    Article  PubMed  CAS  Google Scholar 

  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 214:170–197

    Article  PubMed  CAS  Google Scholar 

  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 33:1981–1985

    Article  PubMed  Google Scholar 

  102. Minster RL, DeKosky ST, Kamboh MI (2008) No association of dynamin binding protein (DNMBP) gene SNPs and Alzheimer’s disease. Neurobiol Aging 29:1602–1604

    Article  PubMed  CAS  Google Scholar 

  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 51:182–189

    Article  PubMed  Google Scholar 

  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 50:1455–1463

    Article  PubMed  CAS  Google Scholar 

  105. Morris JC (1993) The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 43:2412–2414

    PubMed  CAS  Google Scholar 

  106. Morris JC, Price AL (2001) Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer’s disease. J Mol Neurosci 17:101–118

    Article  PubMed  CAS  Google Scholar 

  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 67:122–131

    Article  PubMed  CAS  Google Scholar 

  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 5:11–18

    PubMed  CAS  Google Scholar 

  109. Mufson EJ, Chen EY, Cochran EJ et al (1999) Entorhinal cortex beta-amyloid load in individuals with mild cognitive impairment. Exp Neurol 158:469–490

    Article  PubMed  CAS  Google Scholar 

  110. Mufson EJ, Counts SE, Perez SE, Ginsberg SD (2008) Cholinergic system during the progression of Alzheimer’s disease: therapeutic implications. Expert Rev Neurother 8:1703–1718

    Article  PubMed  CAS  Google Scholar 

  111. Mufson EJ, Ginsberg SD, Ikonomovic MD, DeKosky ST (2003) Human cholinergic basal forebrain: chemoanatomy and neurologic dysfunction. J Chem Neuroanat 26:233–242

    Article  PubMed  CAS  Google Scholar 

  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 60:1143–1148

    Article  PubMed  Google Scholar 

  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 427:19–30

    Article  PubMed  CAS  Google Scholar 

  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 443:136–153

    Article  PubMed  CAS  Google Scholar 

  115. Mufson EJ, Wuu J, Counts SE, Nykjaer A (2010) Preservation of cortical sortilin protein levels in MCI and Alzheimer’s disease. Neurosci Lett 471:129–133

    Article  PubMed  CAS  Google Scholar 

  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 67:588–591

    Google Scholar 

  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 110:199–211

    Article  PubMed  CAS  Google Scholar 

  118. Nelson PT, Braak H, Markesbery WR (2009) Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J Neuropathol Exp Neurol 68:1–14

    Article  PubMed  CAS  Google Scholar 

  119. Nixon RA (2005) Endosome function and dysfunction in Alzheimer’s disease and other neurodegenerative diseases. Neurobiol Aging 26:373–382

    Article  PubMed  CAS  Google Scholar 

  120. Nixon RA, Cataldo AM, Mathews PM (2000) The endosomal–lysosomal system of neurons in Alzheimer’s disease pathogenesis: a review. Neurochem Res 25:1161–1172

    Article  PubMed  CAS  Google Scholar 

  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 64:113–122

    PubMed  Google Scholar 

  122. Nordberg A (2001) Nicotinic receptor abnormalities of Alzheimer’s disease: therapeutic implications. Biol Psychiatry 49:200–210

    Article  PubMed  CAS  Google Scholar 

  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 26:1596–1603

    Article  PubMed  CAS  Google Scholar 

  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 40:63–70

    Article  PubMed  CAS  Google Scholar 

  125. Parvizi J, Van Hoesen GW, Damasio A (2001) The selective vulnerability of brainstem nuclei to Alzheimer’s disease. Ann Neurol 49:53–66

    Article  PubMed  CAS  Google Scholar 

  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 29:9321–9329

    Article  PubMed  CAS  Google Scholar 

  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 63:641–649

    PubMed  CAS  Google Scholar 

  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 59:872–879

    PubMed  CAS  Google Scholar 

  129. Petersen R (2003) Conceptual overview. In: Petersen R (ed) Mild cognitive impairment aging to Alzheimer’s disease. Oxford University Press, New York

    Google Scholar 

  130. Petersen RC (2003) Mild cognitive impairment clinical trials. Nat Rev Drug Discov 2:646–653

    Article  PubMed  CAS  Google Scholar 

  131. Petersen RC (2004) Mild cognitive impairment as a diagnostic entity. J Intern Med 256:183–194

    Article  PubMed  CAS  Google Scholar 

  132. Petersen RC, Parisi JE, Dickson DW et al (2006) Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 63:665–672

    Article  PubMed  Google Scholar 

  133. Petersen RC, Smith GE, Waring SC et al (1999) Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 56:303–308

    Article  PubMed  CAS  Google Scholar 

  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 277:3051–3067

    Article  PubMed  Google Scholar 

  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 122:49–60

    Article  PubMed  CAS  Google Scholar 

  136. Price JL, Ko AI, Wade MJ et al (2001) Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch Neurol 58:1395–1402

    Article  PubMed  CAS  Google Scholar 

  137. Price JL, McKeel DW Jr, Buckles VD et al (2009) Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging 30:1026–1036

    Article  PubMed  Google Scholar 

  138. Price JL, Morris JC (1999) Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol 45:358–368

    Article  PubMed  CAS  Google Scholar 

  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 106:6820–6825

    Article  PubMed  CAS  Google Scholar 

  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 51:567–577

    Article  PubMed  Google Scholar 

  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 74:113–115

    Article  PubMed  CAS  Google Scholar 

  142. Robakis NK (2011) Mechanisms of AD neurodegeneration may be independent of Abeta and its derivatives. Neurobiol Aging 32:372–379

    Article  PubMed  CAS  Google Scholar 

  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 21:51–61

    PubMed  CAS  Google Scholar 

  144. Roux PP, Barker PA (2002) Neurotrophin signaling through the p75 neurotrophin receptor. Prog Neurobiol 67:203–233

    Article  PubMed  CAS  Google Scholar 

  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 26:553–567

    Article  PubMed  CAS  Google Scholar 

  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 63:1771–1776

    Article  PubMed  Google Scholar 

  147. Sager KL, Wuu J, Leurgans SE et al (2007) Neuronal LR11/sorLA expression is reduced in mild cognitive impairment. Ann Neurol 62:640–647

    Article  PubMed  Google Scholar 

  148. Saito Y, Murayama S (2007) Neuropathology of mild cognitive impairment. Neuropathol 27:578–584

    Article  Google Scholar 

  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 75:373–387

    Article  PubMed  CAS  Google Scholar 

  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 16:2001–2007

    PubMed  CAS  Google Scholar 

  151. Scheff SW, DeKosky ST, Price DA (1990) Quantitative assessment of cortical synaptic density in Alzheimer’s disease. Neurobiol Aging 11:29–37

    Article  PubMed  CAS  Google Scholar 

  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)

  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 68:1501–1508

    Article  PubMed  CAS  Google Scholar 

  154. Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27:1372–1384

    Article  PubMed  CAS  Google Scholar 

  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 24:547–557

    PubMed  Google Scholar 

  156. Schipper HM (2004) Heme oxygenase expression in human central nervous system disorders. Free Radic Biol Med 37:1995–2011

    Article  PubMed  CAS  Google Scholar 

  157. Schipper HM, Bennett DA, Liberman A et al (2006) Glial heme oxygenase-1 expression in Alzheimer disease and mild cognitive impairment. Neurobiol Aging 27:252–261

    Article  PubMed  CAS  Google Scholar 

  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 130:311–322

    Article  PubMed  CAS  Google Scholar 

  159. Schneider JA, Arvanitakis Z, Leurgans SE, Bennett DA (2009) The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann Neurol 66:200–208

    Article  PubMed  Google Scholar 

  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 236:239–242

    Article  PubMed  CAS  Google Scholar 

  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 413:374–378

    Article  PubMed  CAS  Google Scholar 

  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 273:942–947

    Article  PubMed  CAS  Google Scholar 

  163. Smith MA, Nunomura A, Lee HG et al (2005) Chronological primacy of oxidative stress in Alzheimer disease. Neurobiol Aging 26:579–580

    Article  PubMed  CAS  Google Scholar 

  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–M16

    Article  PubMed  CAS  Google Scholar 

  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 275:528–532

    Article  PubMed  CAS  Google Scholar 

  166. Sojkova J, Zhou Y, An Y et al (2011) Longitudinal patterns of beta-amyloid deposition in nondemented older adults. Arch Neurol 68:644–649

    Article  PubMed  Google Scholar 

  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:e9505

    Article  PubMed  CAS  Google Scholar 

  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 7:280–292

    Article  PubMed  Google Scholar 

  169. Stoub TR, Bulgakova M, Leurgans S et al (2005) MRI predictors of risk of incident Alzheimer disease: a longitudinal study. Neurology 64:1520–1524

    Article  PubMed  CAS  Google Scholar 

  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 103:10041–10045

    Article  PubMed  CAS  Google Scholar 

  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 31:1089–1098

    Article  PubMed  CAS  Google Scholar 

  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 88:469–477

    PubMed  CAS  Google Scholar 

  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 289:2094–2103

    Article  PubMed  Google Scholar 

  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 Behav

  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 23:6586–6595

    PubMed  CAS  Google Scholar 

  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 29:31–38

    Article  PubMed  Google Scholar 

  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 41:207–211

    Article  PubMed  Google Scholar 

  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 31:1885–1893

    Article  PubMed  CAS  Google Scholar 

  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 30:572–580

    Article  PubMed  CAS  Google Scholar 

  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:re1

  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 163:98–110

    Article  PubMed  CAS  Google Scholar 

  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 58:1791–1800

    PubMed  Google Scholar 

  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 12:377–390

    PubMed  CAS  Google Scholar 

  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 27:1216–1223

    Article  PubMed  CAS  Google Scholar 

  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)

  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 359:104–108

    Article  PubMed  CAS  Google Scholar 

  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 10:122–126

    Article  PubMed  CAS  Google Scholar 

  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 256:240–246

    Article  PubMed  CAS  Google Scholar 

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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.

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Mufson, E.J., Binder, L., Counts, S.E. et al. Mild cognitive impairment: pathology and mechanisms. Acta Neuropathol 123, 13–30 (2012). https://doi.org/10.1007/s00401-011-0884-1

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  • DOI: https://doi.org/10.1007/s00401-011-0884-1

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