Emerging concepts in alzheimer's disease

Annual Review of Pathology: Mechanisms of Disease

Volumn 10, Issue , 2015, Pages 291-319

  Vinters, Harry V ^a  

^a UCLA MEDICAL CENTER   (United States)

Author keywords

Alzheimer's disease; biomarkers; dementia; immunotherapy; ischemic vascular dementia; mixed dementia; neuropathology

Indexed keywords

AMYLOID BETA PROTEIN; BIOLOGICAL MARKER;

ALZHEIMER DISEASE; ARTICLE; BRAIN DYSFUNCTION; BRAIN TISSUE; CEREBROSPINAL FLUID; CEREBROVASCULAR DISEASE; COGNITIVE DEFECT; COMORBIDITY; DISEASE MARKER; HUMAN; IMMUNOHISTOCHEMISTRY; IMMUNOTHERAPY; MILD COGNITIVE IMPAIRMENT; NEUROFIBRILLARY TANGLE; NEUROIMAGING; NEUROPATHOLOGY; NONHUMAN; PRIORITY JOURNAL; SENILE DEMENTIA; SENILE PLAQUE; TREATMENT RESPONSE; VASCULAR AMYLOIDOSIS; AMYLOID PLAQUE; ANIMAL; BRAIN; DEMENTIA; METABOLISM; PATHOLOGY;

ALZHEIMER DISEASE; ANIMALS; BIOLOGICAL MARKERS; BRAIN; DEMENTIA; HUMANS; NEUROFIBRILLARY TANGLES; PLAQUE, AMYLOID;

EID: 84921895084     PISSN: 15534006     EISSN: 15534014     Source Type: Book Series    
DOI: 10.1146/annurev-pathol-020712-163927     Document Type: Article

References (186)

1. Dickson DW, Weller RO, eds. 2011. Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. Oxford, UK: Wiley-Blackwell. 2nd ed.
2. Ellison D, Love S, Chimelli L, Harding BN, Lowe JS, et al. 2013. Neuropathology: A Reference Text of CNS Pathology. Edinburgh/London: Mosby. 3rd ed.
3. Jagust W. 2013. Vulnerable neural systems and the borderland of brain aging and neurodegeneration. Neuron 77:219-34
4. Palop JJ, Mucke L. 2010. Amyloid-â-induced neuronal dysfunction inAlzheimer's disease: from synapses toward neural networks. Nat. Neurosci. 13:812-18
5. Vinters HV, Farrell MA, Mischel PS, Anders KH. 1998. Neurodegenerative diseases. In Diagnostic Neuropathology, pp. 453-507. New York: Marcel Dekker
6. Thompson PM, Vinters HV. 2012. Pathologic lesions in neurodegenerative diseases. Mol. Biol. Transl. Sci. 107:1-40
7. Nelson PT, Head E, Schmitt FA, Davis PR, Neltner JH, et al. 2011. Alzheimer's disease is not 'brain aging': neuropathological, genetic, and epidemiological human studies. Acta Neuropathol. 121:571-87
8. Kawas C, Gray S, Brookmeyer R, Fozard J, Zonderman A. 2000. Age-specific incidence rates of Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology 54:2072-77
9. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, et al. 1991. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 41:479-86
10. Jellinger KA. 2002. Alzheimer disease and cerebrovascular pathology: an update. J. Neural Transm. 109:813-36
11. Rahimi F, Bitan G, ed. 2012. Non-Fibrillar Amyloidogenic Protein Assemblies-Common Cytotoxins Underlying Degenerative Diseases. Dordrecht, Neth.: Springer
12. Mintun MA, LaRossa GN, Sheline YI, Dence CS, Lee SY. 2006. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 67:446-52
13. Small GW, Kepe V, Ercoli LM, Siddarth P, Bookheimer SY, et al. 2006. PET of brain amyloid and tau in mild cognitive impairment. N. Engl. J. Med. 355:2652-63
14. Small GW, Komo S, La Rue A, Saxena S, Phelps ME. 1996. Early detection of Alzheimer's disease by combining apolipoprotein E and neuroimaging. Ann. N.Y. Acad. Sci. 802:70-78
15. Vinters HV. 2007. Imaging cerebral microvascular amyloid. Ann. Neurol. 62:209-12
16. Goedert M, Ghetti B. 2007. Alois Alzheimer: his life and times. Brain Pathol. 17:57-62
17. Kovacs GG, Botond G, Budka H. 2010. Protein coding of neurodegenerative dementias: the neuropathological basis of biomarker diagnostics. Acta Neuropathol. 119:389-408
18. Querfurth HW, LaFerla FM. 2010. Alzheimer's disease. N. Engl. J. Med. 362:329-44
19. Armstrong RA, Ellis W, Hamilton RL, Mackenzie IRA, Hedreen J, et al. 2010. Neuropathological heterogeneity in frontotemporal lobar degeneration with TDP-43 proteinopathy: a quantitative study of 94 cases using principal components analysis. J. Neural Transm. 117:227-39
20. Bigio EH. 2008. Update on recent molecular and genetic advances in frontotemporal lobar degeneration. J. Neuropathol. Exp. Neurol. 67:635-48
21. Dickson DW, Rademakers R, Hutton ML. 2007. Progressive supranuclear palsy: pathology and genetics. Brain Pathol. 17:74-82
22. Joachim CL, Morris JH, Selkoe DJ. 1988. Clinically diagnosed Alzheimer's disease: autopsy results in 150 cases. Ann. Neurol. 24:50-56
23. Brun A, Englund E. 1986. Awhite matter disorder in dementia of the Alzheimer type-A pathoanatomical study. Ann. Neurol. 19:253-62
24. Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, et al. 2012. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J. Neuropathol. Exp. Neurol. 71:362-81
25. Braak H, Braak E. 1991. Neuropathological staging of Alzheimer related changes. Acta Neuropathol. 82:239-59
26. Braak H, Duyckaerts C, Braak E, Piette F. 1993. Neuropathological staging ofAlzheimer-related changes with psychometrically assessed intellectual status. In Alzheimer's Disease: Advances in Clinical and Basic Research, ed. B Corain, K Iqbal, MNicolini, BWinblad, HWisniewski, P Zatta, pp. 131-37. Chichester, UK:Wiley
27. Braak H, Thal DR, Ghebremedhin E, Del Tredici K. 2011. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70:960-69
28. Masters CL, Simms G, WeinmanNA, Multhaup G, McDonald BL, Beyreuther K. 1985. Amyloid plaque core protein in Alzheimer disease and Down syndrome. PNAS 82:4245-49
29. Dickson DW. 1997. The pathogenesis of senile plaques. J. Neuropathol. Exp. Neurol. 56:321-39
30. Blessed G, Tomlinson BE, Roth M. 1968. The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br. J. Psychiatry 117:797-811
31. Berlau DJ, Kahle-Wrobleski K, Head E, Goodus M, Kim R, Kawas C. 2007. Dissociation of neuropathologic findings and cognition. Case report of an apolipoprotein E e2/e2 genotype. Arch. Neurol. 64:1193-96
32. Serrano-Pozo A, Mielke ML, Muzitansky A, Gomez-Isla T, Growdon JH, et al. 2012. Stable size distribution of amyloid plaques over the course of Alzheimer disease. J. Neuropathol. Exp. Neurol. 71:694-701
33. Thal DR, Rub U, Orantes M, Braak H. 2002. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791-800
34. Vinters HV, Secor DL, Read SL, Frazee JG, Tomiyasu U, et al. 1994. Microvasculature in brain biopsy specimens from patients with Alzheimer's disease: an immunohistochemical and ultrastructural study. Ultrastruct. Pathol. 18:333-48
35. Kidd M. 1963. Paired helical filaments in electron microscopy of Alzheimer's disease. Nature 197:192-93
36. Braak H, Braak E, Grundke-Iqbal I, Iqbal K. 1986. Occurrence of neuropil threads in the senile human brain and in Alzheimer's disease: a third location of paired helical filaments outside of neurofibrillary tangles and neuritic plaques. Neurosci. Lett. 65:351-55
37. Braak H, Braak E. 1988. Neuropil threads occur in the dendrites of tangle-bearing nerve cells. Neuropathol. Appl. Neurobiol. 14:39-44
38. Wisniewski K, Jervis GA, Moretz RC, Wisniewski HM. 1979. Alzheimer neurofibrillary tangles in disease other than senile and presenile dementia. Ann. Neurol. 5:288-94
39. Mischel PS, Nguyen LP, Vinters HV. 1995. Cerebral cortical dysplasia associated with pediatric epilepsy. Review of neuropathologic features and proposal for a grading system. J. Neuropathol. Exp. Neurol. 54:137-53
40. Duong T, DeRosa MJ, Poukens V, Vinters HV, Fisher RS. 1994. Neuronal cytoskeletal abnormalities in human cerebral cortical dysplasia. Acta Neuropathol. 87:493-503
41. Tai HC, Serrano-Pozo A, Hashimoto T, Frosch MP, Spires-Jones TL, Hyman BT. 2012. The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am. J. Pathol. 181:1426-35
42. Vinters HV. 1987. Cerebral amyloid angiopathy. A critical review. Stroke 18:311-24
43. Vinters HV, Gilbert JJ. 1983. Cerebral amyloid angiopathy: incidence and complications in the aging brain. II. The distribution of amyloid vascular changes. Stroke 14:924-28
44. Vinters HV, Wang ZZ, Secor DL. 1996. Brain parenchymal and microvascular amyloid in Alzheimer's disease. Brain Pathol. 6:179-95
45. Ellis RJ, Olichney JM, Thal LJ, Mirra SS, Morris JC, et al. 1996. Cerebral amyloid angiopathy in the brains of patients with Alzheimer's disease. The CERAD experience, part XV. Neurology 46:1592-96
46. Glenner GG, WongCW.1984. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120:885-890
47. Verbeek MM, de Waal RM, Vinters HV, eds. 2000. Cerebral Amyloid Angiopathy in Alzheimer's Disease and Related Disorders. Dordrecht, Neth.: Kluwer Acad.
48. Wang Z, Natte R, Berliner JA, Van Duinen SG, Vinters HV. 2000. Toxicity of Dutch (E22Q) and Flemish (A21G) mutant amyloid β proteins to human cerebral microvessel and aortic smooth muscle cells. Stroke 31:534-38
49. Wang ZZ, WuDF, Vinters HV. 2002. Hypoxia and reoxygenation of brain microvascular smoothmuscle cells in vitro: cellular responses and expression of cerebral amyloid angiopathy-Associated proteins. Acta Pathol. Microbiol. Immunol. Scand. 110:423-34
50. Soontornniyomkij V, Choi C, Pomakian J, Vinters HV. 2010. High-definition characterization of cerebral â-Amyloid angiopathy in Alzheimer's disease. Hum. Pathol. 41:1601-8
51. Miyakawa T, Katsuragi S, Watanabe K, Shimoji A, Ikeuchi Y. 1986. Ultrastructural studies of amyloid fibrils and senile plaques in human brain. Acta Neuropathol. 70:202-8
52. Attems J, Yamaguchi H, Saido TC, Thal DR. 2010. Capillary CAA and perivascular Aβ-deposition: two distinct features of Alzheimer's disease pathology. J. Neurol. Sci. 299:155-62
53. Zabel M, Schrag M, Crofton A, Tung S, Beaufond P, et al. 2013. A shift in microglial â-Amyloid binding in Alzheimer's disease is associated with cerebral amyloid angiopathy. Brain Pathol. 23:390-401
54. Weller RO, Yow HY, Preston SD, Mazanti I, Nicoll JAR. 2002. Cerebrovascular disease is a major factor in the failure of elimination of Aâfrom the aging human brain: implications for therapy of Alzheimer's disease. Ann. N.Y. Acad. Sci. 977:162-68
55. Herzig MC, Van Nostrand WE, Jucker M. 2006. Mechanism of cerebral β-Amyloid angiopathy: murine and cellular models. Brain Pathol. 16:40-54
56. Zhang-Nunes SX, Maat-Schieman MLC, Van Duinen SG, Roos RAC, Frosch MP, Greenberg SM. 2006. The cerebral β-Amyloid angiopathies: hereditary and sporadic. Brain Pathol. 16:30-39
57. Haglund M, Passant U, Sjobeck E, Ghebremedhin E, Englund E. 2006. Cerebral amyloid angiopathy and cortical microinfarcts as putative substrates of vascular dementia. Int. J. Geriatr. Psychiatry 21:681-87
58. Soontornniyomkij V, Lynch MD, Mermash S, Pomakian J, Badkoobehi H, et al. 2010. Cerebral microinfarcts associated with severe cerebral β-Amyloid angiopathy. Brain Pathol. 20:459-67
59. Anders KH, Wang ZZ, Kornfeld M, Gray V, Soontornniyomkij V, et al. 1997. Giant cell arteritis in association with cerebral amyloid angiopathy: immunohistochemical andmolecular studies. Hum. Pathol. 28:1237-46
60. Arvanitakis Z, Leurgans SE, Wang Z, Wilson RS, Bennett DA, Schneider JA. 2011. Cerebral amyloid angiopathy pathology and cognitive domains in older persons. Ann. Neurol. 69:320-27
61. Ball MJ. 1977. Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia: a quantitative study. Acta Neuropathol. 37:111-18
62. Ball MJ. 1978. Topographic distribution of neurofibrillary tangles and granulovacuolar degeneration in hippocampal cortex of aging and demented patients: a quantitative study. Acta Neuropathol. 42:73-80
63. Clare R, King VG, Wirenfeldt M, Vinters HV. 2010. Synapse loss in dementias. J. Neurosci. Res. 88:2083-90
64. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, et al. 1991. Physical basis of cognitive alterations in Alzheimer's disease: Synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30:572-80
65. Davidsson P, Blennow K. 1998. Neurochemical dissection of synaptic pathology in Alzheimer's disease. Int. Psychogeriatr. 10:11-23
66. Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, et al. 2005. Natural oligomers of the amyloid-βprotein specifically disrupt cognitive function. Nat. Neurosci. 8:79-84
67. Selkoe DJ. 2008. Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior. Behav. Brain Res. 192:106-13
68. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, et al. 2002. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-Term potentiation in vivo. Nature 416:535-39
69. Ihara M, Kalaria RN. 2007. Amyloid-βand synaptic activity in mice and men. NeuroReport 18:1205-6
70. Matsuyama S, Teraoka R, Mori H, Tomiyama T. 2007. Inverse correlation between amyloid precursor protein and synaptic plasticity in transgenic mice. NeuroReport 18:1083-87
71. Fu C, Chute DJ, Farag ES, Garakian J, Cummings JL, Vinters HV. 2004. Comorbidity in dementia: an autopsy study. Arch. Pathol. Lab. Med. 128:32-38
72. Gearing M, Mirra SS, Hedreen JC, Sumi SM, Hansen LA, Heyman A. 1995. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part X. Neuropathology confirmation of the clinical diagnosis of Alzheimer's disease. Neurology 45:461-66
73. Selnes OA, Vinters HV. 2006. Vascular cognitive impairment. Nat. Clin. Pract. Neurol. 2:538-47
74. Vinters HV, Ellis WG, Zarow C, Zaias BW, Jagust WJ, et al. 2000. Neuropathologic substrates of ischemic vascular dementia. J. Neuropathol. Exp. Neurol. 59:931-45
75. Woodhouse A, Dickson TC, Vickers JC. 2007. Vaccination strategies for Alzheimer's disease: a new hope?. Drugs Aging 24:107-19
76. Karran E, Hardy J. 2014. Antiamyloid therapy for Alzheimer's disease-Are we on the right road?. N. Engl. J. Med. 370:377-78
77. Vinters HV, Pardridge WM, Yang J. 1988. Immunohistochemical study of cerebral amyloid angiopathy: use of an antiserum to a synthetic 28-Amino-Acid peptide fragment of the Alzheimer's disease amyloid precursor. Hum. Pathol. 19:214-22
78. Vinters HV, Nishimura GS, Secor DL, Pardridge WM. 1990. Immunoreactive A4 and gamma-Trace peptide co-localization in amyloidotic arteriolar lesions in the brains of patients with Alzheimer's disease. Am. J. Pathol. 137:233-40
79. Galasko D, Hansen LA, Katzman R, Wiederholt W, Masliah E, et al. 1994. Clinical-neuropathological correlations in Alzheimer's disease and related dementias. Arch. Neurol. 51:888-95
80. Di Patre PL, Read SL, Cummings JL, Tomiyasu U, Vartavarian LM, et al. 1999. Progression of clinical deterioration and pathological changes in patientswithAlzheimer disease evaluated at biopsy and autopsy. Arch. Neurol. 56:1254-61
81. Khachaturian ZS. 1985. Diagnosis of Alzheimer's disease. Arch. Neurol. 42:1097-105
82. Newell KL, Hyman BT, Growdon JH, Hedley-Whyte ET. 1999. Application of the National Institute on Aging (NIA)-Reagan Institute criteria for the neuropathological diagnosis of Alzheimer disease. J. Neuropathol. Exp. Neurol. 58:1147-55
83. Postupna N, Rose SE, Bird TD, Gonzalez-Cuyar LF, Sonnen JA, et al. 2012. Novel antibody capture assay for paraffin-embedded tissue detects wide-ranging amyloid beta and paired helical filament-Tau accumulation in cognitively normal older adults. Brain Pathol. 22:472-84
84. Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, et al. 2012. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimer's Dement. 8:1-13
85. Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, et al. 2012. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathol. 123:1-11
86. Ritchie K, Touchon J. 2000. Mild cognitive impairment: conceptual basis and current nosological status. Lancet 355:225-28
87. Petersen RC, Parisi JE, Dickson DW, Johnson KA, Knopman DS, et al. 2006. Neuropathologic features of amnestic mild cognitive impairment. Arch. Neurol. 63:665-72
88. Vinters HV. 2006. Neuropathology of amnestic mild cognitive impairment. Arch. Neurol. 63:645-46
89. Jicha GA, Parisi JE, Dickson DW, Johnson K, Cha R, et al. 2006. Neuropathologic outcome of mild cognitive impairment following progression to clinical dementia. Arch. Neurol. 63:674-81
90. Schneider JA, Arvanitakis Z, Leurgans SE, Bennett DA. 2009. The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann. Neurol. 66:200-8
91. Shepherd C, McCann H, Halliday GM. 2009. Variations in the neuropathology of familial Alzheimer's disease. Acta Neuropathol. 118:37-52
92. Jonsson T, Atwal JK, Steinberg S, Snaedel J, Jonsson PV, et al. 2012. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488:96-99
93. Arnold SE, Vega IE, Karlawish JH, Wolk DA, Nunez J, et al. 2013. Frequency and clinicopathological characterization of presenilin 1 Gly206Ala mutation in Puerto Rican Hispanics with dementia. J. Alzheimer's Dis. 33:1089-95
94. Holton P, Ryten M, Nalls M, Trabzuni D, Weale ME, et al. 2013. Initial assessment of the pathogenic mechanisms of the recently identified Alzheimer risk loci. Ann. Hum. Genet. 77:85-105
95. Neumann H, Daly MJ. 2013. Variant TREM2 as risk factor for Alzheimer's disease. N. Engl. J. Med. 368:182-84
96. Reitz C, Mayeux R. 2013. TREM2 and neurodegenerative disease. N. Engl. J. Med. 369:1564-65
97. Bertram L, Parrado AR, Tanzi RE. 2013. Letter to the editor. N. Engl. J. Med. 369:1565
98. Jellinger KA, Attems J. 2007. Neuropathological evaluation of mixed dementia. J. Neurol. Sci. 257:80-87
99. Robinson JL, Geser F, Corrada MM, Berlau DJ, Arnold SE, et al. 2011. Neocortical and hippocampal amyloid-βand tau measures associate with dementia in the oldest-old. Brain 134:3708-15
100. Sonnen JA, Larson EB, Haneuse S, Woltjer R, Crane PK, et al. 2009. Neuropathology in the Adult Changes in Thought study: a review. J. Alzheimer's Dis. 18:703-11
101. Schneider JA, Aggarwal NT, Barnes L, Boyle P, Bennett DA. 2009. The neuropathology of older persons with and without dementia from community versus clinic cohorts. J. Alzheimer's Dis. 18:691-701
102. Schneider JA, Bennett DA. 2010. Where vascular meets neurodegenerative disease. Stroke 41(Suppl. 1):S144-46
103. Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis D, et al. 2006. National Institute ofNeurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 37:2220-41
104. Jack Jr. CR. 2011. Alliance for Aging Research AD Biomarkers Work Group: structural MRI. Neurobiol. Aging 32:S48-57
105. Jagust W. 2013. Biomarkers and brain connectivity. JAMA Neurol. 70:1233-34
106. Schott JM, Fox NC, Frost C, Scahill RI, Janssen JC, et al. 2003. Assessing the onset of structural change in familial Alzheimer's disease. Ann. Neurol. 53:181-88
107. Chan D, Fox NC, Jenkins R, Scahill RI, Crum WR, et al. 2001. Rates of global and regional cerebral atrophy in AD and frontotemporal dementia. Neurology 57:1756-63
108. Erten-Lyons D, Dodge HH, Woltjer R, Silbert LC, Howleson DB, et al. 2013. Neuropathologic basis of age-Associated brain atrophy. JAMA Neurol. 70:616-22
109. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, et al. 2004. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann. Neurol. 55:306-19
110. Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, et al. 2012. The Alzheimer's disease Neuroimaging Initiative: a review of papers published since its inception. Alzheimer's Dement. 9:e111-94
111. Wirth M, Madison CM, Rabinovici GD, Oh H, Landau SM, Jagust WJ. 2013. Alzheimer's disease neurodegenerative biomarkers are associated with decreased cognitive function but not β-Amyloid in cognitively normal older individuals. J. Neurosci. 33:5553-63
112. Wolk DA, Price JC, Madeira C, Saxton JA, Snitz BE, et al. 2012. Amyloid imaging in dementias with atypical presentation. Alzheimer's Dement. 8:389-98
113. Sanchez-Juan P, Ghosh PM, Hagen J, Gesierich B, Henry M, et al. 2014. Practical utility of amyloid and FDG-PET in an academic dementia center. Neurology 82:230-38
114. Reiman EM, Jagust WJ. 2012. Brain imaging in the study of Alzheimer's disease. NeuroImage 61:505-16
115. Oh H, Madison C, Villeneuve S, Markley C, Jagust WJ. 2014. Association of gray matter atrophy with age, β-Amyloid, and cognition in aging. Cereb. Cortex 24:1609-18
116. Ikonomovic MD, Abrahamson EE, Price JC, Hamilton RL, Mathis CA, et al. 2012. Early AD pathology in a [C-11]PiB-negative case: a PiB-Amyloid imaging, biochemical and immunohistochemical study. Acta Neuropathol. 123:433-47
117. Ikonomovic MD, Klunk WE, Abrahamson EE, Mathis CA, Price JC, et al. 2008. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain 131:1630-45
118. Clark CM, Pontecorvo MJ, Beach TG, Bedell BJ, Coleman RE, et al. 2012. CerebralPETwith florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-β plaques: a prospective cohort study. Lancet Neurol. 11:669-78
119. Lo RY, Jagust WJ, Alzheimer's Dis. Neuroimaging Initiat. 2013. Effect of cognitive reserve markers on Alzheimer pathologic progression. Alzheimer Dis. Assoc. Disord. 27:343-50
120. Irwin DJ, Trojanowski JQ, Grossman M. 2013. Cerebrospinal fluid biomarkers for differentiation of frontotemporal lobar degeneration from Alzheimer's disease. Front. Aging Neurosci. 5:6
121. Ghidoni R, Benussi L, Paterlini A, Albertini V, Binetti G, Emanuele E. 2011. Cerebrospinal fluid biomarkers for Alzheimer's disease: the present and future. Neurodegener. Dis. 8:413-20
122. Landau SM, Lu M, Joshi AD, Pontecorvo M, Mintun MA, et al. 2013. Comparing positron emission tomography imaging and cerebrospinal fluid measurements of β-Amyloid. Ann. Neurol. 74:826-36
123. Graff-Radford NR, Crook JE, Lucas J, Boeve BF, Knopman DS, et al. 2007. Association of low plasma Aβ42/Aβ40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch. Neurol. 64:354-62
124. Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, et al. 2007. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat. Med. 13:1359-62
125. Sunderland T, Hampel H, Takeda M, Putnam KT, Cohen RM. 2006. Biomarkers in the diagnosis of Alzheimer's disease: Are we ready?. J. Geriatr. Psychiatry Neurol. 19:172-79
126. Freeman SH, Raju S, Hyman BT, Frosch MP, Irizarry MC. 2007. Plasma Aβlevels do not reflect brain Aβlevels. J. Neuropathol. Exp. Neurol. 66:264-71
127. Nicoll JAR, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. 2003. Neuropathology of human Alzheimer disease after immunization with amyloid-βpeptide: a case report. Nat. Med. 9:448-52
128. Ferrer I, Rovira MB, Guerra MLS, Rey MJ, Costa-Jussa F. 2004. Neuropathology and pathogenesis of encephalitis following amyloid-âimmunization in Alzheimer's disease. Brain Pathol. 14:11-20
129. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, et al. 2008. Long-Term effects of Aâ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216-23
130. Nicoll JAR, Barton E, Boche D, Neal JW, Ferrer I, et al. 2006. Aβspecies removal after Aβ42 immunization. J. Neuropathol. Exp. Neurol. 65:1040-48
131. Boche D, Denham N, Holmes C, Nicoll JAR. 2010. Neuropathology after active Aβ42 immunotherapy: implications for Alzheimer's disease pathogenesis. Acta Neuropathol. 120:369-84
132. Boche D, Zotova E, Weller RO, Love S, Neal JW, et al. 2008. Consequence of Aâ immunization on the vasculature of human Alzheimer's disease brain. Brain 131:3299-310
133. Maarouf CL, Daugs ID, Kokjohn TA, Kalback WM, Patton RL, et al. 2010. The biochemical aftermath of anti-Amyloid immunotherapy. Mol. Neurodegener. 5:39
134. Zotova E, Bharambe V, Cheaveau M, Morgan W, Holmes C, et al. 2013. Inflammatory components in human Alzheimer's disease and after active amyloid-β42 immunization. Brain 136:2677-96
135. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, et al. 2014. Phase 3 trials of solanezumab for mild-To-moderate Alzheimer's disease. N. Engl. J. Med. 370:311-21
136. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, et al. 2014. Two phase 3 trials of bapineuzumab in mild-To-moderate Alzheimer's disease. N. Engl. J. Med. 370:322-33
137. Klyubin I, Walsh DM, Lemere CA, Cullen WK, Shankar GM, et al. 2005. Amyloid β protein immunotherapy neutralizes Aβoligomers that disrupt synaptic plasticity in vivo. Nat. Med. 11:556-61
138. Miners JS, Barua N, Kehoe PG, Gill S, Love S. 2011. Aβ-degrading enzymes: potential for treatment of Alzheimer disease. J. Neuropathol. Exp. Neurol. 70:944-59
139. Hulette C, Nochlin D, McKeel D, Morris JC, Mirra SS, et al. 1997. Clinical-neuropathologic findings in multi-infarct dementia: a report of six autopsied cases. Neurology 48:668-72
140. Jellinger KA. 2007. The enigma of vascular cognitive disorder and vascular dementia. Acta Neuropathol. 113:349-88
141. Jellinger KA. 2008. The pathology of 'vascular dementia': a critical update. J. Alzheimer's Dis. 14:107-23
142. Knopman DS. 2007. Cerebrovascular disease and dementia. Br. J. Radiol. 80:S121-27
143. Chui HC, Zarow C, Mack WJ, Ellis WG, Zheng L, et al. 2006. Cognitive impact of subcortical vascular and Alzheimer's disease pathology. Ann. Neurol. 60:677-87
144. Gorelick PB, Scuteri A, Black SE, DeCarli C, Greenberg SM, et al. 2011. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42:2672-713
145. Iadecola C. 2010. The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol. 120:287-96
146. Jellinger KA, Attems J. 2010. Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathol. 119:421-33
147. Langa KM, Foster NL, Larson EB. 2004. Mixed dementia: emerging concepts and therapeutic implications. JAMA 292:2901-8
148. Kovari E, Herrmann FR, Hof PR, Bouras C. 2013. The relationship between cerebral amyloid angiopathy and cortical microinfarcts in brain aging and Alzheimer's disease. Neuropathol. Appl. Neurobiol. 39:498-509
149. Thal DR, Ghebremedhin E, Orantes M, Wiestler OD. 2003. Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J. Neuropathol. Exp. Neurol. 62:1287-301
150. Thal DR, Grinberg LT, Attems J. 2012. Vascular dementia: Different forms of vessel disorders contribute to the development of dementia in the elderly brain. Exp. Gerontol. 47:816-24
151. Arvanitakis Z, Leurgans SE, Barnes LL, Bennett DA, Schneider JA. 2011. Microinfarct pathology, dementia, and cognitive systems. Stroke 42:722-27
152. Longstreth WT, Sonnen JA, Koepsell TD, Kukull WA, Larson EB, Montine TJ. 2009. Associations between microinfarcts and other macroscopic vascular findings on neuropathologic examination in 2 databases. Alzheimer's Dis. Assoc. Disord. 23:291-94
153. Dickson DW, Davies P, Bevona C, Van Hoeven KH, Factor SM, et al. 1994. Hippocampal sclerosis: a common pathological feature of dementia in very old (80 years of age) humans. Acta Neuropathol. 88:212-21
154. Rauramaa T, Pikkarainen M, Englund E, Ince PG, Jellinger K, et al. 2011. Cardiovascular diseases and hippocampal infarcts. Hippocampus 21:281-87
155. Zarow C, Sitzer TE, Chui HC. Understanding hippocampal sclerosis in the elderly: epidemiology, characterization, and diagnostic issues. Curr. Neurol. Neurosci. Rep. 8:363-70
156. Amador-Ortiz C, Ahmed Z, Zehr C, Dickson DW. 2007. Hippocampal sclerosis dementia differs from hippocampal sclerosis in frontal lobe degeneration. Acta Neuropathol. 113:245-52
157. Zarow C, Vinters HV, Ellis WG, Weiner MW, Mungas D, et al. 2005. Correlates of hippocampal neuron number in Alzheimer's disease and ischemic vascular dementia. Ann. Neurol. 57:896-903
158. Ball MJ, Fisman M, Hachinski V, Blume W, Fox A, et al. 1985. A new definition of Alzheimer's disease: a hippocampal dementia. Lancet 325:14-16
159. Deane R, Zlokovic BV. 2007. Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease. Curr. Alzheimer Res. 4:191-97
160. Zlokovic BV. 2005. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci. 28:202-8
161. Jeynes B, Provias J. 2011. The case for blood-brain barrier dysfunction in the pathogenesis of Alzheimer's disease. J. Neurosci. Res. 89:22-28
162. Stewart PA, Hayakawa K, Akers MA, Vinters HV. 1992. A morphometric study of the blood-brain barrier in Alzheimer's disease. Lab. Investig. 67:734-42
163. Beach TG, Wilson JR, Sue LI, Newell A, Poston M, et al. 2007. Circle of Willis atherosclerosis: association with Alzheimer's disease, neuritic plaques and neurofibrillary tangles. Acta Neuropathol. 113:13-21
164. Honig LS, Kukull W, Mayeux R. 2005. Atherosclerosis and AD: analysis of data from the US National Alzheimer's Coordinating Center. Neurology 64:494-500
165. Luoto TM, Haikonen S, Haapasalo H, Goebeler S, Huhtala H, et al. 2009. Large vessel atherosclerosis is not in direct association with neuropathological lesions of Alzheimer's disease. Eur. Neurol. 62:93-98
166. Yarchoan M, Xie SX, Kling MA, Toledo JB, Wolk DA, et al. 2012. Cerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias. Brain 135:3749-56
167. Dolan H, Crain B, Troncoso J, Resnick SM, Zonderman AB, O'Brien RJ. 2010. Atherosclerosis, dementia, and Alzheimer disease in the Baltimore Longitudinal Study of Aging cohort. Ann. Neurol. 68:231-40
168. Chui HC, Zheng L, Reed BR, Vinters HV, Mack WJ. 2012. Vascular risk factors and Alzheimer's disease: Are these risk factors for plaques and tangles or for concomitant vascular pathology that increases the likelihood of dementia?. An evidence-based review. Alzheimer's Res. Ther. 4:1
169. Zheng L, Vinters HV, Mack WJ, Zarow C, Ellis WG, Chui HC. 2013. Cerebral atherosclerosis is associated with cystic infarcts and microinfarcts but not Alzheimer pathologic changes. Stroke 44:2835-41
170. Rockenstein E, Crews L, Masliah E. 2007. Transgenic animal models of neurodegenerative diseases and their application to treatment development. Adv. Drug Deliv. Rev. 59:1093-102
171. Schellenberg GD, Montine TJ. 2012. The genetics and neuropathology of Alzheimer's disease. Acta Neuropathol. 124:305-23
172. Huang Y, Mucke L. 2012. Alzheimer mechanisms and therapeutic strategies. Cell 148:1204-22
173. Ball MJ, Lukiw WJ, Kammerman EM, Hill JM. 2013. Intracerebral propagation of Alzheimer's disease: strengthening evidence of a herpes simplex virus etiology. Alzheimer's Dement. 9:169-75
174. Aguzzi A, Rajendran L. 2009. The transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron 64:783-90
175. Stohr J, Watts JC, Mensinger ZL, Oehler A, Grillo SK, et al. 2012. Purified and synthetic Alzheimer's amyloid beta (Aβ) prions. PNAS 109:11025-30
176. Hamaguchi T, Eisele YS, Varvel NH, Lamb BT, Walker LC, Jucker M. 2012. The presence of Aβseeds, and not age per se, is critical to the initiation of Aβdeposition in the brain. Acta Neuropathol. 123:31-37
177. Harris JA, Devidze N, Verret L, Ho K, Halabisky B, et al. 2010. Transsynaptic progression of amyloid-β-induced neuronal dysfunction within the entorhinal-hippocampal network. Neuron 68:428-41
178. Braak H, Del Tredici K. 2011. Alzheimer's pathogenesis: Is there neuron-To-neuron propagation?. Acta Neuropathol. 121:589-95
179. Clavaguera F, Bolmont T, Crowther A, Abramowski D, Frank S, et al. 2009. Transmission and spread of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11:909-14
180. Castellani RJ, Perry G. 2014. The complexities of the pathology-pathogenesis relationship in Alzheimer disease. Biochem. Pharmacol. 88:671-76
181. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, et al. 2001. Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60:759-67
182. Kovacs GG, Budka H. 2010. Current concepts of neuropathological diagnostics in practice: neurodegenerative diseases. Clin. Neuropathol. 29:271-88
183. Kumar-Singh S, Van Broeckhoven C. 2007. Frontotemporal lobar degeneration: current concepts in the light of recent advances. Brain Pathol. 17:104-13
184. McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, et al. 2005. Diagnosis and management of dementia with Lewy bodies: third report of the DLB consortium. Neurology 65:1863-72
185. Wilson RS, Leurgans SE, Boyle PA, Schneider JA, Bennett DA. 2010. Neurodegenerative basis of agerelated cognitive decline. Neurology 75:1070-78
186. van Swieten J, Spillantini MG. 2007. Hereditary frontotemporal dementia caused by Tau gene mutations. Brain Pathol. 17:63-73.