Journal Mobile Options
Table of Contents
Vol. 16, No. 1, 2008
Issue release date: December 2007
Free Access
Neurosignals 2008;16:11–18
(DOI:10.1159/000109754)

Biomarkers for Early Detection of Alzheimer Pathology

Clark C.M.a, d-f · Davatzikos C.b · Borthakur A.b · Newberg A.b · Leight S.c, g · Lee V.M.-Y.c, f, g · Trojanowski J.Q.c-g
Departments of aNeurology, bRadiology and cPathology and Laboratory Medicine, dCenter of Excellence for Research on Neurodegenerative Diseases, eAlzheimer Disease Center, fInstitute on Aging, and gCenter for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pa., USA
email Corresponding Author

Abstract

The increasing prevalence of Alzheimer’s disease and the devastating consequences of late-life dementia motivates the drive to develop diagnostic biomarkers to reliably identify the pathology associated with this disorder. Strategies to accomplish this include the detection of altered levels of tau and amyloid in cerebrospinal fluid, the use of structural MRI to identify disease-specific patterns of regional atrophy and MRI T1ρ to detect disease-related macromolecular protein aggregation, and the direct imaging of amyloid deposits using positron emission tomography and single photon emission computerized tomography. Success will facilitate the ability to reliably diagnose Alzheimer’s disease while the symptoms of brain failure are mild and may provide objective measures of disease-modifying treatment efficacy.


 goto top of outline Key Words

  • Biomarkers
  • Alzheimer’s disease
  • Diagnosis
  • Neurodegenerative disease

 goto top of outline Abstract

The increasing prevalence of Alzheimer’s disease and the devastating consequences of late-life dementia motivates the drive to develop diagnostic biomarkers to reliably identify the pathology associated with this disorder. Strategies to accomplish this include the detection of altered levels of tau and amyloid in cerebrospinal fluid, the use of structural MRI to identify disease-specific patterns of regional atrophy and MRI T1ρ to detect disease-related macromolecular protein aggregation, and the direct imaging of amyloid deposits using positron emission tomography and single photon emission computerized tomography. Success will facilitate the ability to reliably diagnose Alzheimer’s disease while the symptoms of brain failure are mild and may provide objective measures of disease-modifying treatment efficacy.

Copyright © 2008 S. Karger AG, Basel


 goto top of outline References
  1. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M; Alzheimer’s Disease International: Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112–2117.
  2. Shaw LM, Korecka M, Clark CM, Lee VM, Trojanowski JQ: Biomarkers of neurodegeneration for diagnosis and monitoring therapeutics. Nat Rev Drug Discov 2007;6:295–303.
  3. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA: Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 2003;60:1119–1122.
  4. Blennow K: Cerebrospinal fluid protein biomarkers for Alzheimer’s disease. NeuroRx 2004;1:213–225.
  5. Blennow K, Hampel H: CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2003;2:605–613.
  6. Clark CM, Karlawish JH: Alzheimer disease: current concepts and emerging diagnostic and therapeutic strategies. Ann Intern Med 2003;138:400–410.
  7. Clark CM, Xie S, Chittams J, Ewbank D, Peskind E, Galasko D, Morris JC, McKeel DW Jr., Farlow M, Weitlauf SL, Quinn J, Kaye J, Knopman D, Arai H, Doody RS, DeCarli C, Leight S, Lee VM, Trojanowski JQ: Cerebrospinal fluid tau and β-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses? Arch Neurol 2003;60:1696–1702.
  8. Clark CM, Pratico D, Shaw LM, Leight S, Xie SX, Gu A, Lee VMY, Trojanowski JQ: Commentary on ‘Optimal design of clinical trials for drugs designed to slow the course of Alzheimer’s disease’. Biochemical biomarkers of late-life dementia. Alzheimers Dement 2006;2:287–293.
  9. Blennow K, Vanmechelen E, Hampel H: CSF total tau, Aβ42 and phosphorylated tau protein as biomarkers for Alzheimer’s disease. Mol Neurobiol 2001;24:87–97.
  10. Andreasen N, Vanmechelen E, Vanderstichele H, Davidsson P, Blennow K: Cerebrospinal fluid levels of total-tau, phospho-tau and Aβ 42 predicts development of Alzheimer’s disease in patients with mild cognitive impairment. Acta Neurol Scand 2003;179(suppl):47–51.

    External Resources

  11. Arai H, Ishiguro K, Ohno H, Moriyama M, Itoh N, Okamura N, Matsui T, Morikawa Y, Horikawa E, Kohno H, Sasaki H, Imahori K: CSF phosphorylated tau protein and mild cognitive impairment: a prospective study. Exp Neurol 2000;166:201–203.
  12. Buerger K, Teipel SJ, Zinkowski R, Blennow K, Arai H, Engel R, Hofmann-Kiefer K, McCulloch C, Ptok U, Heun R, Andreasen N, DeBernardis J, Kerkman D, Moeller H, Davies P, Hampel H: CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects. Neurology 2002;59:627–629.
  13. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L: Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006;5:228–234.
  14. Galasko D: Biological markers and the treatment of Alzheimer’s disease. J Mol Neurosci 2001;17:119–125.
  15. Csernansky JG, Wang L, Joshi S, Miller JP, Gado M, Kido D, McKeel D, Morris JC, Miller MI: Early DAT is distinguished from aging by high-dimensional mapping of the hippocampus. Neurology 2000;55:1636–1643.
  16. Dickerson BC, Goncharova I, Sullivan MP, Forchetti C, Wilson RS, Bennett DA, Beckett LA, deToledo-Morrell L: MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer’s disease. Neurobiol Aging 2001;22:747–754.
  17. Rosen AC, Prull MW, Gabrieli JD, Stoub T, O’Hara R, Friedman L, Yesavage JA, deToledo-Morrell L: Differential associations between entorhinal and hippocampal volumes and memory performance in older adults. Behav Neurosci 2003;117:1150–1160.
  18. Stoub TR, Bulgakova M, Leurgans S, Bennett DA, Fleischman D, Turner DA, deToledo-Morrell L: MRI predictors of risk of incident Alzheimer disease: a longitudinal study. Neurology 2005;64:1520–1524.
  19. Scheltens P, Pasquier F, Weerts JG, Barkhof F, Leys D: Qualitative assessment of cerebral atrophy on MRI: inter- and intra-observer reproducibility in dementia and normal aging. Eur Neurol 1997;37:95–99.
  20. Resnick SM, Goldszal A, Davatzikos C, Golski S, Kraut MA, Metter EJ, Bryan RN, Zonderman AB: One-year age changes in MRI brain volumes in older adults. Cereb Cortex 2000;10:464–472.
  21. Sullivan EV, Pfefferbaum A, Adalsteinsson E, Swan GE, Carmelli D: Differential rates of regional brain change in callosal and ventricular size: a 4-year longitudinal MRI study of elderly men. Cereb Cortex 2002;12:438–445.
  22. Liu T, Shen DG, Davatzikos C: Deformable registration of cortical structures via hybrid volumetric and surface warping. Neuroimage 2004;22:1790–1801.
  23. Chetelat G: Early diagnosis of Alzheimer’s disease: contribution of structural neuroimaging. Neuroimage 2003;18:525–541.
  24. Benveniste H, Einstein G, Kim KR, Hulette C, Johnson GA: Detection of neuritic plaques in Alzheimer’s disease by magnetic resonance microscopy. Proc Natl Acad Sci USA 1999;96:14079–14084.
  25. Borthakur A, Gur T, Wheaton AJ, Corbo M, Trojanowski JQ, Lee VM, Reddy R: In vivo measurement of plaque burden in a mouse model of Alzheimer’s disease. J Magn Reson Imaging 2006;24:1011–1017.
  26. Borthakur A, Wheaton AJ, Gougoutas AJ, Akella SV, Regatte RR, Charagundla SR, Reddy R: In vivo measurement of T1ρ dispersion in the human brain at 1.5 tesla. J Magn Reson Imaging 2004;19:403–409.
  27. Heidebrink JL, Barbas NR, Turner RS, Clark CM, Jagust WJ, Arnold SE, DeCarli CS, Koeppe RA, Higdon R, Foster NL: FDG-PET improves differential diagnosis of dementia when clinical history and examination are ambiguous. Neurobiol Aging 2004;25:370–371.

    External Resources

  28. Silverman DH, Small GW, Chang CY, Lu CS, Kung de Aburto MA, Chen W, Czernin J, Rapoport SI, Pietrini P, Alexander GE, Schapiro MB, Jagust WJ, Hoffman JM, Welsh-Bohmer KA, Alavi A, Clark CM, Salmon E, de Leon MJ, Mielke R, Cummings JL, Kowell AP, Gambhir SS, Hoh CK, Phelps ME: Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA 2001;286:2120–2127.
  29. Foster NL, Barbas NR, Heidebrink JL, Turner RS, Clark CM, Jagust WJ, Arnold SE, DeCarli CS, Koeppe RA, Higdon R: Adding FDG-PET to clinical history and examination improves the accuracy of dementia diagnosis. Neurobiol Aging 2004;25:372.

    External Resources

  30. Archer HA, Edison P, Brooks DJ, Barnes J, Frost C, Yeatman T, Fox NC, Rossor MN: Amyloid load and cerebral atrophy in Alzheimer’s disease: an 11C-PIB positron emission tomography study. Ann Neurol 2006;60:145–147.
  31. Edison P, Archer HA, Hinz R, Hammers A, Pavese N, Tai YF, Hotton G, Cutler D, Fox N, Kennedy A, Rossor M, Brooks DJ: Amyloid, hypometabolism, and cognition in Alzheimer disease. An [11C]PIB and [18F]FDG PET study. Neurology 2007;68:501–508.
  32. Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I, Wall A, Ringheim A, Langstrom B, Nordberg A: Two-year follow-up of amyloid deposition in patients with Alzheimer’s disease. Brain 2006;129:2856–2866.
  33. Kemppainen NM, Aalto S, Wilson IA, Nagren K, Helin S, Bruck A, Oikonen V, Kailajarvi M, Scheinin M, Viitanen M, Parkkola R, Rinne JO: Voxel-based analysis of PET amyloid ligand [11C]PIB uptake in Alzheimer disease. Neurology 2006;67:1575–1580.
  34. Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, Klunk WE, Mathis CA, DeKosky ST, Morris JC: [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 2006;67:446–452.
  35. Zhang W, Oya S, Kung MP, Hou C, Maier DL, Kung HF: F-18 Polyethyleneglycol stilbenes as PET imaging agents targeting Aβ aggregates in the brain. Nucl Med Biol 2005;32:799–809.
  36. Jagust W, Thisted R, Devous MD Sr, Van Heertum R, Mayberg H, Jobst K, Smith AD, Borys N: SPECT perfusion imaging in the diagnosis of Alzheimer’s disease: a clinical-pathologic study. Neurology 2001;56:950–956.
  37. Kung MP, Hou C, Zhuang ZP, Skovronsky D, Kung HF: 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.

 goto top of outline Author Contacts

Chris M. Clark, MD
Penn – Ralston Center, University of Pennsylvania
3615 Chestnut Street
Philadelphia, PA 19104 (USA)
Tel. +1 215 662 7810, Fax +1 215 662 7812, E-Mail chris.clark@uphs.upenn.edu


 goto top of outline Article Information

Published online: December 5, 2007
Number of Print Pages : 8
Number of Figures : 4, Number of Tables : 2, Number of References : 37


 goto top of outline Publication Details

Neurosignals

Vol. 16, No. 1, Year 2008 (Cover Date: December 2007)

Journal Editor: Ip, N.Y. (Hong Kong)
ISSN: 1424–862X (print), 1424–8638 (Online)

For additional information: http://www.karger.com/NSG


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

The increasing prevalence of Alzheimer’s disease and the devastating consequences of late-life dementia motivates the drive to develop diagnostic biomarkers to reliably identify the pathology associated with this disorder. Strategies to accomplish this include the detection of altered levels of tau and amyloid in cerebrospinal fluid, the use of structural MRI to identify disease-specific patterns of regional atrophy and MRI T1ρ to detect disease-related macromolecular protein aggregation, and the direct imaging of amyloid deposits using positron emission tomography and single photon emission computerized tomography. Success will facilitate the ability to reliably diagnose Alzheimer’s disease while the symptoms of brain failure are mild and may provide objective measures of disease-modifying treatment efficacy.



 goto top of outline Author Contacts

Chris M. Clark, MD
Penn – Ralston Center, University of Pennsylvania
3615 Chestnut Street
Philadelphia, PA 19104 (USA)
Tel. +1 215 662 7810, Fax +1 215 662 7812, E-Mail chris.clark@uphs.upenn.edu


 goto top of outline Article Information

Published online: December 5, 2007
Number of Print Pages : 8
Number of Figures : 4, Number of Tables : 2, Number of References : 37


 goto top of outline Publication Details

Neurosignals

Vol. 16, No. 1, Year 2008 (Cover Date: December 2007)

Journal Editor: Ip, N.Y. (Hong Kong)
ISSN: 1424–862X (print), 1424–8638 (Online)

For additional information: http://www.karger.com/NSG


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M; Alzheimer’s Disease International: Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112–2117.
  2. Shaw LM, Korecka M, Clark CM, Lee VM, Trojanowski JQ: Biomarkers of neurodegeneration for diagnosis and monitoring therapeutics. Nat Rev Drug Discov 2007;6:295–303.
  3. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA: Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 2003;60:1119–1122.
  4. Blennow K: Cerebrospinal fluid protein biomarkers for Alzheimer’s disease. NeuroRx 2004;1:213–225.
  5. Blennow K, Hampel H: CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2003;2:605–613.
  6. Clark CM, Karlawish JH: Alzheimer disease: current concepts and emerging diagnostic and therapeutic strategies. Ann Intern Med 2003;138:400–410.
  7. Clark CM, Xie S, Chittams J, Ewbank D, Peskind E, Galasko D, Morris JC, McKeel DW Jr., Farlow M, Weitlauf SL, Quinn J, Kaye J, Knopman D, Arai H, Doody RS, DeCarli C, Leight S, Lee VM, Trojanowski JQ: Cerebrospinal fluid tau and β-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses? Arch Neurol 2003;60:1696–1702.
  8. Clark CM, Pratico D, Shaw LM, Leight S, Xie SX, Gu A, Lee VMY, Trojanowski JQ: Commentary on ‘Optimal design of clinical trials for drugs designed to slow the course of Alzheimer’s disease’. Biochemical biomarkers of late-life dementia. Alzheimers Dement 2006;2:287–293.
  9. Blennow K, Vanmechelen E, Hampel H: CSF total tau, Aβ42 and phosphorylated tau protein as biomarkers for Alzheimer’s disease. Mol Neurobiol 2001;24:87–97.
  10. Andreasen N, Vanmechelen E, Vanderstichele H, Davidsson P, Blennow K: Cerebrospinal fluid levels of total-tau, phospho-tau and Aβ 42 predicts development of Alzheimer’s disease in patients with mild cognitive impairment. Acta Neurol Scand 2003;179(suppl):47–51.

    External Resources

  11. Arai H, Ishiguro K, Ohno H, Moriyama M, Itoh N, Okamura N, Matsui T, Morikawa Y, Horikawa E, Kohno H, Sasaki H, Imahori K: CSF phosphorylated tau protein and mild cognitive impairment: a prospective study. Exp Neurol 2000;166:201–203.
  12. Buerger K, Teipel SJ, Zinkowski R, Blennow K, Arai H, Engel R, Hofmann-Kiefer K, McCulloch C, Ptok U, Heun R, Andreasen N, DeBernardis J, Kerkman D, Moeller H, Davies P, Hampel H: CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects. Neurology 2002;59:627–629.
  13. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L: Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006;5:228–234.
  14. Galasko D: Biological markers and the treatment of Alzheimer’s disease. J Mol Neurosci 2001;17:119–125.
  15. Csernansky JG, Wang L, Joshi S, Miller JP, Gado M, Kido D, McKeel D, Morris JC, Miller MI: Early DAT is distinguished from aging by high-dimensional mapping of the hippocampus. Neurology 2000;55:1636–1643.
  16. Dickerson BC, Goncharova I, Sullivan MP, Forchetti C, Wilson RS, Bennett DA, Beckett LA, deToledo-Morrell L: MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer’s disease. Neurobiol Aging 2001;22:747–754.
  17. Rosen AC, Prull MW, Gabrieli JD, Stoub T, O’Hara R, Friedman L, Yesavage JA, deToledo-Morrell L: Differential associations between entorhinal and hippocampal volumes and memory performance in older adults. Behav Neurosci 2003;117:1150–1160.
  18. Stoub TR, Bulgakova M, Leurgans S, Bennett DA, Fleischman D, Turner DA, deToledo-Morrell L: MRI predictors of risk of incident Alzheimer disease: a longitudinal study. Neurology 2005;64:1520–1524.
  19. Scheltens P, Pasquier F, Weerts JG, Barkhof F, Leys D: Qualitative assessment of cerebral atrophy on MRI: inter- and intra-observer reproducibility in dementia and normal aging. Eur Neurol 1997;37:95–99.
  20. Resnick SM, Goldszal A, Davatzikos C, Golski S, Kraut MA, Metter EJ, Bryan RN, Zonderman AB: One-year age changes in MRI brain volumes in older adults. Cereb Cortex 2000;10:464–472.
  21. Sullivan EV, Pfefferbaum A, Adalsteinsson E, Swan GE, Carmelli D: Differential rates of regional brain change in callosal and ventricular size: a 4-year longitudinal MRI study of elderly men. Cereb Cortex 2002;12:438–445.
  22. Liu T, Shen DG, Davatzikos C: Deformable registration of cortical structures via hybrid volumetric and surface warping. Neuroimage 2004;22:1790–1801.
  23. Chetelat G: Early diagnosis of Alzheimer’s disease: contribution of structural neuroimaging. Neuroimage 2003;18:525–541.
  24. Benveniste H, Einstein G, Kim KR, Hulette C, Johnson GA: Detection of neuritic plaques in Alzheimer’s disease by magnetic resonance microscopy. Proc Natl Acad Sci USA 1999;96:14079–14084.
  25. Borthakur A, Gur T, Wheaton AJ, Corbo M, Trojanowski JQ, Lee VM, Reddy R: In vivo measurement of plaque burden in a mouse model of Alzheimer’s disease. J Magn Reson Imaging 2006;24:1011–1017.
  26. Borthakur A, Wheaton AJ, Gougoutas AJ, Akella SV, Regatte RR, Charagundla SR, Reddy R: In vivo measurement of T1ρ dispersion in the human brain at 1.5 tesla. J Magn Reson Imaging 2004;19:403–409.
  27. Heidebrink JL, Barbas NR, Turner RS, Clark CM, Jagust WJ, Arnold SE, DeCarli CS, Koeppe RA, Higdon R, Foster NL: FDG-PET improves differential diagnosis of dementia when clinical history and examination are ambiguous. Neurobiol Aging 2004;25:370–371.

    External Resources

  28. Silverman DH, Small GW, Chang CY, Lu CS, Kung de Aburto MA, Chen W, Czernin J, Rapoport SI, Pietrini P, Alexander GE, Schapiro MB, Jagust WJ, Hoffman JM, Welsh-Bohmer KA, Alavi A, Clark CM, Salmon E, de Leon MJ, Mielke R, Cummings JL, Kowell AP, Gambhir SS, Hoh CK, Phelps ME: Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA 2001;286:2120–2127.
  29. Foster NL, Barbas NR, Heidebrink JL, Turner RS, Clark CM, Jagust WJ, Arnold SE, DeCarli CS, Koeppe RA, Higdon R: Adding FDG-PET to clinical history and examination improves the accuracy of dementia diagnosis. Neurobiol Aging 2004;25:372.

    External Resources

  30. Archer HA, Edison P, Brooks DJ, Barnes J, Frost C, Yeatman T, Fox NC, Rossor MN: Amyloid load and cerebral atrophy in Alzheimer’s disease: an 11C-PIB positron emission tomography study. Ann Neurol 2006;60:145–147.
  31. Edison P, Archer HA, Hinz R, Hammers A, Pavese N, Tai YF, Hotton G, Cutler D, Fox N, Kennedy A, Rossor M, Brooks DJ: Amyloid, hypometabolism, and cognition in Alzheimer disease. An [11C]PIB and [18F]FDG PET study. Neurology 2007;68:501–508.
  32. Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I, Wall A, Ringheim A, Langstrom B, Nordberg A: Two-year follow-up of amyloid deposition in patients with Alzheimer’s disease. Brain 2006;129:2856–2866.
  33. Kemppainen NM, Aalto S, Wilson IA, Nagren K, Helin S, Bruck A, Oikonen V, Kailajarvi M, Scheinin M, Viitanen M, Parkkola R, Rinne JO: Voxel-based analysis of PET amyloid ligand [11C]PIB uptake in Alzheimer disease. Neurology 2006;67:1575–1580.
  34. Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, Klunk WE, Mathis CA, DeKosky ST, Morris JC: [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 2006;67:446–452.
  35. Zhang W, Oya S, Kung MP, Hou C, Maier DL, Kung HF: F-18 Polyethyleneglycol stilbenes as PET imaging agents targeting Aβ aggregates in the brain. Nucl Med Biol 2005;32:799–809.
  36. Jagust W, Thisted R, Devous MD Sr, Van Heertum R, Mayberg H, Jobst K, Smith AD, Borys N: SPECT perfusion imaging in the diagnosis of Alzheimer’s disease: a clinical-pathologic study. Neurology 2001;56:950–956.
  37. Kung MP, Hou C, Zhuang ZP, Skovronsky D, Kung HF: 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.