Amyloid Imaging with PET in Alzheimer’s Disease, Mild Cognitive Impairment, and Clinically Unimpaired Subjects

  • William E. Klunk
  • Chester A. Mathis
  • Julie C. Price
  • Steven T. DeKosky
  • Brian J. Lopresti
  • Nicholas D. Tsopelas
  • Judith A. Saxton
  • Robert D. Nebes

Since 1900, the percentage of Americans aged 65 or over has more than tripled (4.1% in 1900 to 12.4% in 2000), and the number has increased 11 times (from 3.1 to 35.0 million). The older population itself is getting older. In 2000, the 65–74 age group (18.4 million) was eight times larger than in 1900, but the 75–84 age group (12.4 million) was 16 times larger, and the 85 and older group (4.2 million) was 34 times larger. Although aging is the major risk factor for Alzheimer’s disease (AD), most elderly do not meet clinical criteria for either dementia or mild cognitive impairment (MCI; see following discussion). In this chapter, we refer to these subjects as clinically unimpaired . Although they do not have AD or MCI, many clinically unimpaired elderly show decrements in cognitive performance in comparison with the young. Furthermore, a percentage of clinically unimpaired elderly (particularly those over 75 years) is found to have AD pathology after death; this has been termed pathologic aging. 1 These findings raise obvious questions: (1) Can we determine if the age-related cognitive decrements commonly found in clinically unimpaired elderly relate to the presence of varying amounts of amyloid pathology in these individuals? (2) Does the presence of amyloid pathology in clinically unimpaired elderly identify those who will develop a clinical diagnosis of AD? Determination of the nature, cause, and outcome of decreased cognitive performance in these elderly will be an essential component to improving the quality of life of our aging population


Amyloid Deposition Cerebral Amyloid Angiopathy Arterial Input Function Cognitive Reserve Amyloid Pathology 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors thank E. Halligan, the staff at the University of Pittsburgh Alzheimer’s Disease Research Center (C. McConaha, E. Eror, L. Macedonia, and M. Oakley) and PET facility (S. Hulland, J. Ruszkiewicz, P. McGeown, D. Ratica, K. Malone, S. Kendro, N. Flatt, and J. Gallo) for their efforts in conducting and analyzing these studies. We are indebted to our subjects and their families for their selfless contributions that made this work possible.

Financial support for this work was provided by grants from The National Institutes of Health (R01 AG018402, P50 AG005133, K02 AG001039, R01 AG020226, R01 MH070729, K01 MH001976, R37 AG025516, and P01 AG025204), The Alzheimer’s Association (TLL-01-3381), The US Department of Energy (DE-FD02-03 ER63590), and GE Healthcare, Inc.


  1. 1.
    1. Dickson DW, Crystal HA, Mattiace LA,. Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiol Aging 1992;13:179–189.PubMedGoogle Scholar
  2. 2.
    2. Goldman WP, Price JL, Storandt M,. Absence of cognitive impairment or decline in preclinical Alzheimer’s disease. Neurology 2001;56:361–367.PubMedGoogle Scholar
  3. 3.
    3. Terry RD, Masliah E, Salmon DP,. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991;30:572–580.PubMedGoogle Scholar
  4. 4.
    4. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992;256:184–185.PubMedGoogle Scholar
  5. 5.
    5. Rabbitt P. Does it all go together when it goes? The Nineteenth Bartlett Memorial Lecture. Q J Exp Psychol A 1993;46:385–434.PubMedGoogle Scholar
  6. 6.
    6. Price JL, Morris JC. Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol 1999;45:358–368.PubMedGoogle Scholar
  7. 7.
    7. Wolf DS, Gearing M, Snowdon DA,. Progression of regional neuropathology in Alzheimer disease and normal elderly: findings from the Nun study. Alzheim Dis Assoc Dis 1999;13:226–231.Google Scholar
  8. 8.
    8. Mirra SS, Heyman A, McKeel D, The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 1991;41:479–486.PubMedGoogle Scholar
  9. 9.
    9. Iwatsubo T, Odaka A, Suzuki N,. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 1994;13:45–53.PubMedGoogle Scholar
  10. 10.
    10. Goedert M. Tau protein and the neurofibrillary pathology of Alzheimer’s disease. Trends Neurosci 1993;16:460–465.PubMedGoogle Scholar
  11. 11.
    11. Thal DR, Rub U, Orantes M,. Phases of A β-deposition in the human brain and its relevance for the development of AD. Neurology 2002;58:1791–1800.PubMedGoogle Scholar
  12. 12.
    12. Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 1991;82:239–259.PubMedGoogle Scholar
  13. 13.
    13. Delacourte A, David JP, Sergeant N,. The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer’s disease. Neurology 1999;52:1158–1165.PubMedGoogle Scholar
  14. 14.
    14. Arnold SE, Hyman BT, Flory J,. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease. Cereb Cortex 1991;1:103–116.PubMedGoogle Scholar
  15. 15.
    15. Joachim CL, Morris JH, Selkoe DJ. Diffuse senile plaques occur commonly in the cerebellum in Alzheimer’s disease. Am J Pathol 1989;135:309–319.PubMedGoogle Scholar
  16. 16.
    16. Yamaguchi H, Hirai S, Morimatsu M,. Diffuse type of senile plaques in the cerebellum of Alzheimer-type dementia demonstrated by beta protein immunostain. Acta Neuropathol 1989;77:314–319.PubMedGoogle Scholar
  17. 17.
    17. Hardy J, Duff K, Hardy KG,. Genetic dissection of Alzheimer’s disease and related dementias: amyloid and its relationship to tau. Nat Neurosci 1998;1:355–358.PubMedGoogle Scholar
  18. 18.
    18. Tanzi RE, Kovacs DM, Kim TW,. The gene defects responsible for familial Alzheimer’s disease. Neurobiol Dis 1996;3:159–168.PubMedGoogle Scholar
  19. 19.
    19. Price DL, Sisodia SS. Mutant genes in familial Alzheimer’s disease and transgenic models. Ann Rev Neurosci 1998;21:479–505.PubMedGoogle Scholar
  20. 20.
    20. Xia W, Ostaszewski BL, Kimberly WT,. FAD mutations in presenilin-1 or amyloid precursor protein decrease the efficacy of a gamma-secretase inhibitor: evidence for direct involvement of PS1 in the gamma-secretase cleavage complex. Neurobiol Dis 2000;7:673–681.PubMedGoogle Scholar
  21. 21.
    21. Walsh DM, Klyubin I, Fadeeva JV,. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002;416:535–539.PubMedGoogle Scholar
  22. 22.
    22. Caughey B, Lansbury PT. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 2003;26:267–298.PubMedGoogle Scholar
  23. 23.
    23. Lesne S, Koh MT, Kotilinek L,. A specific amyloid-beta protein assembly in the brain impairs memory. Nature 2006;440:352–357.PubMedGoogle Scholar
  24. 24.
    24. Lue LF, Kuo YM, Roher AE,. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol 1999;155:853–862.PubMedGoogle Scholar
  25. 25.
    25. Glabe CG. Conformation-dependent antibodies target diseases of protein misfolding. Trends Biochem Sci 2004;29:542–547.PubMedGoogle Scholar
  26. 26.
    26. Zhou J, Fonseca MI, Glabe CG, Age-related decline in the clearance of plaques by A β-immunotherapy in murine model of Alzheimer’s disease using either fibrillar or a novel oligomeric A β as an immunogen. Society for Neuroscience Abstracts 2004, 716. 9.Google Scholar
  27. 27.
    27. Olson RE, Copeland RA, Seiffert D. Progress towards testing the amyloid hypothesis: inhibitors of APP processing. Curr Opin Drug Dis Dev 2001;4:390–401.Google Scholar
  28. 28.
    28. Nunan J, Small DH. Regulation of APP cleavage by alpha-, beta- and gamma-secretases. FEBS Lett 2000;483:6–10.PubMedGoogle Scholar
  29. 29.
    29. Dovey HF, John V, Anderson JP,. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem 2001;76:173–181.PubMedGoogle Scholar
  30. 30.
    30. Petit A, Pasini A, Alves Da Costa C,. JLK isocoumarin inhibitors: selective gamma-secretase inhibitors that do not interfere with notch pathway in vitro or in vivo. J Neurosci Res 2003;74:370–377.PubMedGoogle Scholar
  31. 31.
    31. Roberds SL, Anderson J, Basi G,. BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum Mol Genet 2001;10:1317–1324.PubMedGoogle Scholar
  32. 32.
    32. Dewachter I, Van Leuven F. Secretases as targets for the treatment of Alzheimer’s disease: the prospects. Lancet Neurol 2002;1:409–416.PubMedGoogle Scholar
  33. 33.
    33. Wang W, Reichert P, Beyer BM,. Crystallization of glycosylated human BACE protease domain expressed in Trichoplusia ni . Biochim Biophys Acta 2004;1698:255–259.PubMedGoogle Scholar
  34. 34.
    34. Siemers E, Skinner M, Dean RA,. Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin Neuropharmacol 2005;28:126–132.PubMedGoogle Scholar
  35. 35.
    35. Orgogozo JM, Gilman S, Dartigues JF,. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003;61:46–54.PubMedGoogle Scholar
  36. 36.
    36. Gilman S, Koller M, Black RS,. Clinical effects of A β immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005;64:1553–1562.PubMedGoogle Scholar
  37. 37.
    37. Gandy S, Walker L. Toward modeling hemorrhagic and encephalitic complications of Alzheimer amyloid-beta vaccination in nonhuman primates. Curr Opin Immunol 2004;16:607–615.PubMedGoogle Scholar
  38. 38.
    38. Hock C, Konietzko U, Streffer JR,. Antibodies against β-amyloid slow cognitive decline in Alzheimer’s disease. Neuron 2003;38:547–554.PubMedGoogle Scholar
  39. 39.
    39. Fox NC, Black RS, Gilman S,. Effects of A β immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology 2005;64:1563–1572.PubMedGoogle Scholar
  40. 40.
    40. Nicoll JA, Wilkinson D, Holmes C,. Neuropathology of human Alzheimer disease after immunization with amyloid- β peptide: a case report. Nat Med 2003;9:448–452.PubMedGoogle Scholar
  41. 41.
    41. Ferrer I, Boada R, Sanchez G,. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathol 2004;14:11–20.PubMedGoogle Scholar
  42. 42.
    42. Masliah E, Hansen L, Adame A,. A β vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 2005;64:129–131.PubMedGoogle Scholar
  43. 43.
    43. DeMattos RB, Bales KR, Cummins DJ,. Peripheral anti-A β antibody alters CNS and plasma A β clearance and decreases brain A β burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 2001;98:8850–8855.PubMedGoogle Scholar
  44. 44.
    44. Bard F, Barbour R, Cannon C,. Epitope and isotype specificities of antibodies to beta-amyloid peptide for protection against Alzheimer’s disease-like neuropathology. Proc Natl Acad Sci USA 2003;100:2023–2028.PubMedGoogle Scholar
  45. 45.
    45. Lee EB, Leng LZ, Lee VM,. Meningoencephalitis associated with passive immunization of a transgenic murine model of Alzheimer’s amyloidosis. FEBS Lett 2005;579:2564–2568.PubMedGoogle Scholar
  46. 46.
    46. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256:183–194.PubMedGoogle Scholar
  47. 47.
    47. Lopez OL, Jagust WJ, DeKosky ST,. Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study Cognition Study. Arch Neurol 2003;60:1385–1389.PubMedGoogle Scholar
  48. 48.
    48. Larrieu S, Letenneur L, Orgogozo JM,. Incidence and outcome of mild cognitive impairment in a population-based prospective cohort. Neurology 2002;59:1594–1599.PubMedGoogle Scholar
  49. 49.
    49. Morris JC, Price AL. Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer’s disease. J Mol Neurosci 2001;17:101–118.PubMedGoogle Scholar
  50. 50.
    50. Morris JC, Storandt M, Miller JP,. Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 2001;58:397–405.PubMedGoogle Scholar
  51. 51.
    51. Petersen RC, Stevens JC, Ganguli M, Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1133–1142.PubMedGoogle Scholar
  52. 52.
    52. Folstein M, Folstein S, McHugh PR. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatry Res 1975;12:189–198.Google Scholar
  53. 53.
    53. Davis DG, Schmitt FA, Wekstein DR,. Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol 1999;58:376–388.PubMedGoogle Scholar
  54. 54.
    54. Green MS, Kaye JA, Ball MJ. The Oregon brain aging study: neuropathology accompanying healthy aging in the oldest old. Neurology 2000;54:105–113.PubMedGoogle Scholar
  55. 55.
    55. Schmand B, Smit JH, Geerlings MI, The effects of intelligence and education on the development of dementia. A test of the brain reserve hypothesis. Psychol Med 1997;27:1337–1344.PubMedGoogle Scholar
  56. 56.
    56. Stern Y, Albert S, Tang MX Rate of memory decline in AD is related to education and occupation: cognitive reserve. Neurology 1999;53:1942–1947.PubMedGoogle Scholar
  57. 57.
    57. Satz P. Brain reserve capacity on symptom onset after brain injury: a formulation and review of evidence for threshold theory. Neuropsychology 1993;7:273–295.Google Scholar
  58. 58.
    58. Stern Y. What is cognitive reserve? Theory and research application of the reserve concept. J Int Neuropsychol Soc 2002;8:448–460.PubMedGoogle Scholar
  59. 59.
    59. Bennett DA, Wilson RS, Schneider JA,. Education modifies the relation of AD pathology to level of cognitive function in older persons. Neurology 2003;60:1909–1915.PubMedGoogle Scholar
  60. 60.
    60. Stern Y, Alexander GE, Prohovnik I,. Inverse relationship between education and parietotemporal perfusion deficit in Alzheimer’s disease. Ann Neurol 1992;32:371–375.PubMedGoogle Scholar
  61. 61.
    61. Coffey CE, Saxton JA, Ratcliff G,. Relation of education to brain size in normal aging: implications for the reserve hypothesis. Neurology 1999;53:189–196.PubMedGoogle Scholar
  62. 62.
    62. Haroutunian V, Perl D, Purohit D,. Regional distribution of neuritic plaques in the nondemented elderly and subjects with very mild Alzheimer’s disease. Arch Neurol 1998;55:1185–1191.PubMedGoogle Scholar
  63. 63.
    63. Morris JC, Storandt M, McKeel DW Jr,. Cerebral amyloid deposition and diffuse plaques in “normal” aging: evidence for presymptomatic and very mild Alzheimer’s disease. Neurology 1996;46:707–719.PubMedGoogle Scholar
  64. 64.
    64. Hyman BT. Down syndrome and Alzheimer disease. Prog Clin Biol Res 1992;379:123–142.PubMedGoogle Scholar
  65. 65.
    65. Hyman BT, West HL, Rebeck GW, Neuropathological changes in Down’s syndrome hippocampal formation. Effect of age and apolipoprotein E genotype. Arc Neurol 1995;52:373–378.Google Scholar
  66. 66.
    66. Morse CK. Does variability increase with age? An archival study of cognitive measures. Psychol Aging 1993;8:156–164.PubMedGoogle Scholar
  67. 67.
    67. Hulette CM, Welsh-Bohmer KA, Murray MG,. Neuropathological and neuropsychological changes in “normal” aging. J Neuropathol Exp Neurol 1998;57:1168–1174.PubMedGoogle Scholar
  68. 68.
    68. Price JL. Diagnostic criteria for Alzheimer’s disease. Neurobiol Aging 1997;18:S67–S70.PubMedGoogle Scholar
  69. 69.
    69. Klunk WE, Debnath ML, Pettegrew JW. Development of small molecule probes for the beta-amyloid protein of Alzheimer’s disease. Neurobiol Aging 1994;15:691–698.PubMedGoogle Scholar
  70. 70.
    70. Klunk WE. Biological markers of Alzheimer’s disease. Neurobiol Aging 1998;19:145–147.PubMedGoogle Scholar
  71. 71.
    71. Mathis CA, Wang Y, Klunk WE. Imaging beta-amyloid plaques and neurofibrillary tangles in the aging human brain. Curr Pharm Des 2004;10:1469–1492.PubMedGoogle Scholar
  72. 72.
    72. Klunk WE, Debnath ML, Pettegrew JW. Chrysamine-G binding to Alzheimer and control brain: autopsy study of a new amyloid probe. Neurobiol Aging 1995;16:541–548.PubMedGoogle Scholar
  73. 73.
    73. Mathis CA, Mahmood K, Debnath ML,. Synthesis of a lipophilic radioiodinated ligand with high affinity to amyloid protein in Alzheimer’s disease brain tissue. J Label Comp Radiopharm 1997;40:94–95.Google Scholar
  74. 74.
    74. Dezutter NA, Dom RJ, de Groot TJ,. 99mTc-MAMA-chrysamine G, a probe for beta-amyloid protein of Alzheimer’s disease. Eur J Nucl Med 1999;26:1392–1399.PubMedGoogle Scholar
  75. 75.
    75. Styren SD, Hamilton RL, Styren GC,. X-34, a fluorescent derivative of Congo red: a novel histochemical stain for Alzheimer’s disease pathology. J Histochem Cytochem 2000;48:1223–1232.PubMedGoogle Scholar
  76. 76.
    76. Klunk WE, Bacskai BJ, Mathis CA,. Imaging Abeta plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered Congo red derivative. J Neuropathol Exp Neurol 2002;61:797–805.PubMedGoogle Scholar
  77. 77.
    77. Wang Y, Mathis CA, Huang G-F,. Synthesis and 11C-labelling of (E,E)-1-(3′,4′-dihydroxystyryl)-4-(3′-methoxy-4′-hydroxystyryl) benzene for PET imaging of amyloid deposits. J Label Comp Radiopharm 2002;45:647–664.Google Scholar
  78. 78.
    78. Klunk WE, Wang Y, Huang GF,. Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain. Life Sci 2001;69:1471–1484.PubMedGoogle Scholar
  79. 79.
    79. Mathis CA, Bacskai BJ, Kajdasz ST,. A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg Med Chem Lett 2002;12:295–298.PubMedGoogle Scholar
  80. 80.
    80. Wang Y, Mathis CA, Huang G-F,. Synthesis and evaluation of 2-(3′-iodo-4′-amino)-6-hydroxy-benzothiazole for in vivo quantitation of amyloid deposits in Alzheimer’s disease. J Mol Neurosci 2002;19:11–16.PubMedGoogle Scholar
  81. 81.
    81. Mathis CA, Wang Y, Holt DP,. Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. J Med Chem 2003;46:2740–2754.PubMedGoogle Scholar
  82. 82.
    82. Engler H, Nordberg A, Blomqvist G,. First human study with a benzothiazole amyloid-imaging agent in Alzheimer’s disease and control subjects. Neurobiol Aging 2002;23(1S):S429.Google Scholar
  83. 83.
    83. Bacskai BJ, Hickey GA, Skoch J,. Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice. Proc Natl Acad Sci USA 2003;100:12462–12467.PubMedGoogle Scholar
  84. 84.
    84. Trojanowski JQ, Mattson MP. Overview of protein aggregation in single, double, and triple neurodegenerative brain amyloidoses. Neuromusc Disord 2003;4:1–6.Google Scholar
  85. 85.
    85. Klunk WE, Wang Y, Huang GF,. The binding of 2-(4′-methylaminophenyl)benzothiazole to postmortem brain homogenates is dominated by the amyloid component. J Neurosci 2003;23:2086–2092.PubMedGoogle Scholar
  86. 86.
    86. Klunk WE, Lopresti BJ, Ikonomovic MD,. Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer’s disease brain but not in transgenic mouse brain. J Neurosci 2005;25:10598–10606.PubMedGoogle Scholar
  87. 87.
    87. Zhuang ZP, Kung MP, Hou C,. IBOX(2-(4′-dimethylaminophenyl)-6-iodobenzoxazole): a ligand for imaging amyloid plaques in the brain. Nucl Med Biol 2001;28:887–894.PubMedGoogle Scholar
  88. 88.
    88. Zhuang ZP, Kung MP, Hou C,. Radioiodinated styrylbenzenes and thioflavins as probes for amyloid aggregates. J Med Chem 2001;44:1905–1914.PubMedGoogle Scholar
  89. 89.
    89. Ono M, Wilson A, Nobrega J,. 11C-labeled stilbene derivatives as Abeta-aggregate-specific PET imaging agents for Alzheimer’s disease. Nucl Med Biol 2003;30:565–571.PubMedGoogle Scholar
  90. 90.
    90. Zhuang ZP, Kung MP, Wilson A,. Structure-activity relationship of imidazo[1,2-a]pyridines as ligands for detecting beta-amyloid plaques in the brain. J Med Chem 2003;46:237–243.PubMedGoogle Scholar
  91. 91.
    91. Barrio JR, Huang SC, Cole GM,. PET imaging of tangles and plaques in Alzheimer’s disease with a highly hydrophilic probe. J Label Comp Radiopharm 1999;42:S194–S195.Google Scholar
  92. 92.
    92. Barrio JR, Huang SC, Cole GM, PET imaging of tangles and plaques in Alzheimer’s disease. J Nucl Med 1999;40(S):70P.Google Scholar
  93. 93.
    . Agdeppa ED, Kepe V, Liu J, et al. Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for beta-amyloid plaques in Alzheimer’s disease. J Neurosci 2001;21:RC18995.Google Scholar
  94. 94.
    94. Majocha RE, Reno JM, Friedland RP,. Development of a monoclonal antibody specific for beta/A4 amyloid in Alzheimer’s disease brain for application to in vivo imaging of amyloid angiopathy. J Nucl Med 1992;33:2184–2189.PubMedGoogle Scholar
  95. 95.
    95. Bickel U, Lee VM, Trojanowski JQ,. Development and in vitro characterization of a cationized monoclonal antibody against beta A4 protein: a potential probe for Alzheimer’s disease. Bioconjugate Chem 1994;5:119–125.Google Scholar
  96. 96.
    96. Friedland RP, Majocha RE, Reno JM,. Development of an anti-A beta monoclonal antibody for in vivo imaging of amyloid angiopathy in Alzheimer’s disease. Mol Neurobiol 1994;9:107–113.PubMedGoogle Scholar
  97. 97.
    97. Friedland RP, Kalaria R, Berridge M,. Neuroimaging of vessel amyloid in Alzheimer’s disease. Ann NY Acad Sci 1997;826:242–247.PubMedGoogle Scholar
  98. 98.
    98. Maggio JE, Stimson ER, Ghilardi JR,. Reversible in vitro growth of Alzheimer disease beta-amyloid plaques by deposition of labeled amyloid peptide. Proc Natl Acad Sci USA 1992;89:5462–5466.PubMedGoogle Scholar
  99. 99.
    99. Saito Y, Buciak J, Yang J,. Vector-mediated delivery of 125I-labeled beta-amyloid peptide A beta 1–40 through the blood-brain barrier and binding to Alzheimer disease amyloid of the A beta 1–40/vector complex. Proc Natl Acad Sci USA 1995;95:10227–10231.Google Scholar
  100. 100.
    100. Ghilardi JR, Catton M, Stimson ER,. Intra-arterial infusion of [125I]A beta 1–40 labels amyloid deposits in the aged primate brain in vivo. Neuroreport 1996;7:2607–2611.PubMedGoogle Scholar
  101. 101.
    101. Wengenack TM, Curran GL, Poduslo JF. Targeting Alzheimer amyloid plaques in vivo. Nat Biotechnol 2000;18:868–872.PubMedGoogle Scholar
  102. 102.
    102. Shoghi-Jadid K, Small GW, Agdeppa ED,. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry 2002;10:24–35.PubMedGoogle Scholar
  103. 103.
    103. Dishino DD, Welch MJ, Kilbourn MR,. Relationship between lipophilicity and brain extraction of C-11-labeled radiopharmaceuticals. J Nucl Med 1983;24:1030–1038.PubMedGoogle Scholar
  104. 104.
    104. Gupta SP. QSAR studies on drugs acting at the central nervous system. Chem Rev 1989;89:1765–1800.Google Scholar
  105. 105.
    105. Verhoeff NP, Wilson AA, Takeshita S,. In-vivo imaging of Alzheimer disease beta-amyloid with [11C]SB-13 PET. Am J Geriatr Psychiatry 2004;12:584–595.PubMedGoogle Scholar
  106. 106.
    106. Kung MP, Hou C, Zhuang ZP,. Binding of two potential imaging agents targeting amyloid plaques in postmortem brain tissues of patients with Alzheimer’s disease. Brain Res 2004;1025:98–105.PubMedGoogle Scholar
  107. 107.
    107. Klunk WE, Engler H, Nordberg A,. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 2004;55:306–319.PubMedGoogle Scholar
  108. 108.
    108. Braak H, Braak E. Alzheimer’s disease: striatal amyloid deposits and neurofibrillary changes. J Neuropathol Exp Neurol 1990;49:215–224.PubMedGoogle Scholar
  109. 109.
    109. Suenaga T, Hirano A, Llena JF,. Modified Bielschowsky stain and immunohistochemical studies on striatal plaques in Alzheimer’s disease. Acta Neuropathol 1990;80:280–286.PubMedGoogle Scholar
  110. 110.
    110. Brilliant MJ, Elble RJ, Ghobrial M,. The distribution of amyloid beta protein deposition in the corpus striatum of patients with Alzheimer’s disease. Neuropathol Appl Neurobiol 1997;23:322–325.PubMedGoogle Scholar
  111. 111.
    111. Schmitt FA, Davis DG, Wekstein DR,. “Preclinical” AD revisited: neuropathology of cognitively normal older adults. Neurology 2000;55:370–376.PubMedGoogle Scholar
  112. 112.
    112. Lopez OL, Becker JT, Klunk W,. Research evaluation and diagnosis of probable Alzheimer’s disease over the last two decades: I. Neurology 2000;55:1854–1862.PubMedGoogle Scholar
  113. 113.
    113. Price JC, Klunk WE, Lopresti BJ,. Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B. J Cereb Blood Flow Metab 2005;25:1528–1547.PubMedGoogle Scholar
  114. 114.
    114. Lopresti BJ, Klunk WE, Mathis CA,. Simplified quantification of Pittsburgh compound B amyloid imaging PET studies: a comparative analysis. J Nucl Med 2005;46:1959–1972.PubMedGoogle Scholar
  115. 115.
    Price JC, Ziolko SK, Weissfeld LA, et al. [O-15]Water and PIB PET imaging in Alzheimer’s disease and mild cognitive impairment. 53rd Annual Meeting of the Society of Nuclear Medicine, 2006.Google Scholar
  116. 116.
    116. Ziolko SK, Weissfeld LA, Klunk WE, Evaluation of voxel-based methods for the statistical analysis of PIB PET amyloid imaging studies in Alzheimer’s disease. Neuroimage 2006;15;33:94–102.PubMedGoogle Scholar
  117. 117.
    117. Fagan AM, Mintun MA, Mach RH,. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta(42) in humans. Ann Neurol 2006;59:512–519.PubMedGoogle Scholar
  118. 118.
    118. Villemagne VL, Rowe CC, Macfarlane S,. Imaginem oblivionis: the prospects of neuroimaging for early detection of Alzheimer’s disease. J Clin Neurosci 2005;12:221–230.PubMedGoogle Scholar
  119. 119.
    119. Mintun MA, LaRossa GA, Sheline YI, [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 2006;67:446–452PubMedGoogle Scholar
  120. 120.
    Rentz DM, Becker JA, Moran EK, et al. Amyloid imaging with Pittsburgh compound-B (PIB) in AD, MCI, and highly intelligent older adults. AAN Abstracts 58th Annual Meeting, 2006:S21.002.Google Scholar
  121. 121.
    Aizenstein HJ, Nebes RD, Saxton JA, et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 2008;65:1509–1517.PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2009

Authors and Affiliations

  • William E. Klunk
    • 1
  • Chester A. Mathis
    • 2
  • Julie C. Price
    • 3
  • Steven T. DeKosky
    • 4
  • Brian J. Lopresti
    • 5
  • Nicholas D. Tsopelas
    • 6
  • Judith A. Saxton
    • 7
  • Robert D. Nebes
    • 8
  1. 1.Department of PsychiatryUniversity of PittsburghPA
  2. 2.Department of RadiologyUniversity of PittsburghPA
  3. 3.Department of RadiologyUniversity of PittsburghPA
  4. 4.Department of NeurologyUniversity of PittsburghPA
  5. 5.Department of RadiologyUniversity of PittsburghPA
  6. 6.Department of PsychiatryWestern Psychiatric Institute and Clinic, University of PittsburghPA
  7. 7.Department of NeurologyUniversity of PittsburghPA
  8. 8.Department of PsychiatryUniversity of Pittsburgh Medical CenterPA

Personalised recommendations