Skip to main content

Advertisement

SpringerLink
Log in

Cerebral amyloid PET imaging in Alzheimer’s disease

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

The devastating effects of the still incurable Alzheimer’s disease (AD) project an ever increasing shadow of burden on the health care system and society in general. In this ominous context, amyloid (Aβ) imaging is considered by many of utmost importance for progress towards earlier AD diagnosis and for potential development of effective therapeutic interventions. Amyloid imaging positron emission tomography procedures offer the opportunity for accurate mapping and quantification of amyloid-Aβ neuroaggregate deposition in the living brain of AD patients. This review analyzes the perceived value of current Aβ imaging probes and their clinical utilization and, based on amyloid imaging results, offers a hypothesis on the effects of amyloid deposition on the biology of AD and its progression. It also analyzes lingering questions permeating the field of amyloid imaging on the apparent contradictions between imaging results and known neuropathology brain regional deposition of Aβ aggregates. As a result, the review also discusses literature evidence as to whether brain Aβ deposition is truly visualized and measured with these amyloid imaging agents, which would have significant implications in the understanding of the biological AD cascade and in the monitoring of therapeutic interventions with these surrogate Aβ markers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, Ziolko SK, James JA, Snitz BE, Houck PR, Bi W, Cohen AD, Lopresti BJ, DeKosky ST, Halligan EM, Klunk WE (2008) Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol 65:1509–1517

    PubMed  Google Scholar 

  2. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PC, Phelps CH (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging and Alzheimer’s Association Workgroup. Alzheimers Dement 7:270–279

    PubMed  Google Scholar 

  3. Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW (1991) The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease. Cereb Cortex 1:103–116

    PubMed  CAS  Google Scholar 

  4. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC (2012) Dominantly inherited Alzheimer network clinical and biomarker changes in dominantly inherited Alzheimer’s disease. New Engl J Med 367:795–804

    PubMed  CAS  Google Scholar 

  5. Bacskai BJ, Kajdasz ST, Christie RH, Carter C, Games D, Seubert P, Schenk D, Hyman BT (2001) Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nat Med 7:369–372

    PubMed  CAS  Google Scholar 

  6. Bacskai BJ, Frosch MP, Freeman SH, Raymond SB, Augustinack JC, Johnson KA, Irizarry MC, Klunk WE, Mathis CA, Dekosky ST, Greenberg SM, Hyman BT, Growdon JH (2007) Molecular imaging with Pittsburgh Compound B confirmed at autopsy: a case report. Arch Neurol 64:431–434

    PubMed  Google Scholar 

  7. Bengel FM, Minoshima S (2012) 2012 SNM highlights lectures. J Nucl Med 53:15N–31N

    PubMed  Google Scholar 

  8. Blennow K, Hampel H, Zetterberg H (2013) Biomarkers in β-amyloid immunotherapy trials in Alzheimer’s disease. Neuropsychopharmacology. doi:10.1038/npp.2013.154

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  10. Braak H, Braak E (1997) Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 18:351–357

    PubMed  CAS  Google Scholar 

  11. Burack MA, Hartlein J, Flores HP, Taylor-Reinwald L, Perlmutter JS, Cairns NJ (2010) In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia. Neurology 74:77–84

    PubMed  CAS  Google Scholar 

  12. Cairns NJ, Ikonomovic MD, Benzinger T, Storandt M, Fagan AM, Shah AR, Reinwald LT, Carter D, Felton A, Holtzman DM, Mintun MA, Klunk WE, Morris JC (2009) Absence of Pittsburgh compound B detection of cerebral amyloid beta in a patient with clinical, cognitive, and cerebrospinal fluid markers of Alzheimer disease: a case report. Arch Neurol 66:1557–1562

    PubMed  Google Scholar 

  13. Chetelat G, Villemagne VL, Pike KE, Ellis KA, Bourgeat P, Jones G, O’Keefe GJ, Salvado O, Szoeke C, Martins RN, Ames D, Masters CL, Rowe CC (2011) Independent contribution of temporal beta-amyloid deposition to memory decline in the pre-dementia phase of Alzheimer’s disease. Brain 134:798–807

    PubMed  Google Scholar 

  14. Chetelat G, Villemagne VL, Villain N, Jones G, Ellis KA, Ames D, Martins RN, Masters CL, Rowe CC (2012) Accelerated cortical atrophy in cognitively normal elderly with high beta-amyloid deposition. Neurology 78:477–484

    PubMed  CAS  Google Scholar 

  15. Chételat G, Villemagne VL, Pike KE, Ellis KA, Ames D, Masters CL, Rowe CC, Australian Imaging Biomarkers and Lifestyle Study of Ageing Research Group (2012) Relationship between memory performance and beta-amyloid deposition at different stages of Alzheimer’s disease. Neurodegener Dis 10:141–144

    PubMed  Google Scholar 

  16. Clark CM, Schneider JA, Bedell BJ, Beach TG, Bilker WB, Mintun MA, Pontecorvo MJ, Hefti F, Carpenter AP, Flitter ML, Krautkramer MJ, Kung HF, Coleman RE, Doraiswamy PM, Fleisher AS, Sabbagh MN, Sadowsky CH, Reiman PEM, Zehntner SP, Skovronsky DM (2011) Use of Florbetapir-PET for imaging β-amyloid pathology. JAMA 305:275–283

    PubMed  CAS  Google Scholar 

  17. Clark CM, Pontecorvo MJ, Beach TG, Bedell BJ, Coleman RE, Doraiswamy PM, Fleisher AS, Reiman EM, Sabbagh MN, Sadowsky CH, Schneider JA, Arora A, Carpenter AP, Flitter ML, Joshi AD, Krautkramer MJ, Lu M, Mintun MA, Skovronsky DM, AV-45-A16 Study Group (2012) Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-beta plaques: a prospective cohort study. Lancet Neurol 11:669–678

    PubMed  CAS  Google Scholar 

  18. Cole GB, Keum G, Liu J, Small GW, Satyamurthy N, Kepe V, Barrio JR (2010) Specific estrogen sulfotransferase (SULT1E1) substrates and molecular imaging probe candidates. Proc Natl Acad Sci USA 107:6222–6227

    PubMed  CAS  Google Scholar 

  19. Cupidi C, Capobianco R, Goffredo D, Marcon G, Ghetti B, Bugiani O, Tagliavini F, Giaccone G (2010) Neocortical variation of Abeta load in fully expressed, pure Alzheimer’s disease. J Alzheimers Dis 19:57–68

    PubMed  Google Scholar 

  20. DeCarli CS, Atack JR, Ball MJ, Kaye JA, Grady CL, Fewster P, Schapiro MB, Rapoport SI (1992) Postmortem regional neurofibrillary tangle densities, but not senile plaque densities, are related to regional cerebral metabolic rates for glucose during life in Alzheimer’s disease. Neurodegeneration 1:113–121

    Google Scholar 

  21. Driscoll I, Troncoso JC, Rudow G, Sojkova J, Pletnikova O, Zhou Y, Kraut MA, Ferrucci L, Mathis CA, Klunk WE, O’Brien RJ, Davatzikos C, Wong DF, Resnick SM (2012) Correspondence between in vivo (11)C-PiB-PET amyloid imaging and postmortem, region-matched assessment of plaques. Acta Neuropathol 124:823–831

    PubMed  Google Scholar 

  22. Drzezga A, Grimmer T, Henriksen G, Stangier I, Perneczky R, Diehl-Schmid J, Mathis CA, Klunk WE, Price J, DeKosky S, Wester HJ, Schwaiger M, Kurz A (2008) Imaging of amyloid plaques and cerebral glucose metabolism in semantic dementia and Alzheimer’s disease. Neuroimage 39:619–633

    PubMed  Google Scholar 

  23. Drzezga A, Grimmer T, Henriksen G, Muhlau M, Perneczky R, Miederer I, Praus C, Sorg C, Wohlschlager A, Riemenschneider M, Wester HJ, Foerstl H, Schwaiger M, Kurz A (2009) Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease. Neurology 72:1487–1494

    PubMed  CAS  Google Scholar 

  24. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O’Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P (2007) Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 6:734–746

    PubMed  Google Scholar 

  25. Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro K, O’Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, Stern Y, Visser PJ, Scheltens P (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 9:1118–1127

    PubMed  Google Scholar 

  26. Edison P, Archer HA, Hinz R, Hammers A, Pavese N, Tai YF, Hotton G, Cutler D, Fox N, Kennedy A, Rossor M, Brooks DJ (2007) Amyloid, hypometabolism, and cognition in Alzheimer disease: an [11C]PIB and [18F]FDG PET study. Neurology 68:501–508

    PubMed  CAS  Google Scholar 

  27. Eli Lilly and Company, Amyvid Prescribing Information. Lilly USA, LLC, Indianapolis, pp 1–10. http://pi.lilly.com/us/amyvid-uspi.pdf2012

  28. Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, LaRossa GN, Spinner ML, Klunk WE, Mathis CA, DeKosky ST, Morris JC, Holtzman DM (2006) Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol 59:512–519

    PubMed  CAS  Google Scholar 

  29. Fagan AM, Mintun MA, Shah AR, Aldea P, Roe CM, Mach RH, Marcus D, Morris JC, Holtzman DM (2009) Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer’s disease. EMBO Mol Med 1:371–380

    PubMed  CAS  Google Scholar 

  30. Fleisher AS, Chen K, Quiroz YT, Jakimovich LJ, Gomez MG, Langois CM, Langbaum JB, Ayutyanont N, Roontiva A, Thiyyagura P, Lee W, Mo H, Lopez L, Moreno S, Acosta-Baena N, Giraldo M, Garcia G, Reiman RA, Huentelman MJ, Kosik KS, Tariot PN, Lopera F, Reiman EM (2012) Florbetapir PET analysis of amyloid-beta deposition in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross-sectional study. Lancet Neurol 11:1057–1065

    PubMed  CAS  Google Scholar 

  31. Fleisher AS, Chen K, Liu X, Roontiva A, Thiyyagura P, Ayutyanont N, Joshi AD, Clark CM, Mintun MA, Pontecorvo MJ, Doraiswamy PM, Johnson KA, Skovronsky DM, Reiman EM (2011) Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease. Arch Neurol 68:1404–1411

    PubMed  Google Scholar 

  32. Forsberg A, Engler H, Almkvist O, Blomquist G, Hagman G, Wall A, Ringheim A, Långström B, Nordberg A (2008) PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging 29:1456–1465

    PubMed  CAS  Google Scholar 

  33. Grimmer T, Riemenschneider M, Förstl H, Henriksen G, Klunk WE, Mathis CA, Shiga T, Wester HJ, Kurz A, Drzezga A (2009) Beta amyloid in Alzheimer’s disease: increased deposition in brain is reflected in reduced concentration in cerebrospinal fluid. Biol Psychiatry 65:927–934

    PubMed  CAS  Google Scholar 

  34. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    PubMed  CAS  Google Scholar 

  35. Hedden T, Van Dijk KR, Becker JA, Mehta A, Sperling RA, Johnson KA, Buckner RL (2009) Disruption of functional connectivity in clinically normal older adults harboring amyloid burden. J Neurosci 29:12686–12694

    PubMed  CAS  Google Scholar 

  36. Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski JQ, Vinters HV, Montine TJ (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8:1–13

    PubMed  Google Scholar 

  37. Ikonomovic MD, Klunk WE, Abrahamson EE, Mathis CA, Price JC, Tsopelas ND, Lopresti BJ, Ziolko S, Bi W, Paljug WR, Debnath ML, Hope CE, Isanski BA, Hamilton RL, DeKosky ST (2008) Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease. Brain 131:1630–1645

    PubMed  Google Scholar 

  38. Ikonomovic MD, Abrahamson EE, Price JC, Hamilton RL, Mathis CA, Paljug WR, Debnath ML, Cohen AD, Mizukami K, DeKosky ST, Lopez OL, Klunk WE (2012) Early AD pathology in a [C-11]PiB-negative case: a PiB-amyloid imaging, biochemical, and immunohistochemical study. Acta Neuropathol 123:433–447

    PubMed  CAS  Google Scholar 

  39. Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC (2004) Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62:925–931

    PubMed  CAS  Google Scholar 

  40. Jack CR Jr, Lowe VJ, Senjem ML, Weigand SD, Kemp BJ, Shiung MM, Knopman DS, Boeve BF, Klunk WE, Mathis CA, Petersen RC (2008) 11C PiB and structural MRI provide complementary information in imaging of Alzheimer’s disease and amnestic mild cognitive impairment. Brain 131:665–680

    PubMed  Google Scholar 

  41. Jack CR Jr, Lowe VJ, Weigand SD, Wiste HJ, Senjem ML, Knopman DS, Shiung MM, Gunter JL, Boeve BF, Kemp BJ, Weiner M, Petersen RC (2009) Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer’s disease: implications for sequence of pathological events in Alzheimer’s disease. Brain 132:1355–1365

    PubMed  Google Scholar 

  42. Jack CR Jr, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, Bernstein MA, Gunter JL, Pankratz VS, Aisen PS, Weiner MW, Petersen RC, Shaw LM, Trojanowski JQ, Knopman DS, Alzheimer’s Disease Neuroimaging Initiative (2010) Brain beta-amyloid measure and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer’s disease. Brain 133:3336–3348

    PubMed  Google Scholar 

  43. Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 9:119–128

    PubMed  CAS  Google Scholar 

  44. Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, Thies B, Phelps CH (2011) Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:257–262

    PubMed  Google Scholar 

  45. Jack CR Jr, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Lowe V, Kantarci K, Bernstein MA, Senjem ML, Gunter JL, Boeve BF, Trojanowski JQ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Knopman DS, Alzheimer’s Disease Neuroimaging Initiative (2012) Shapes of the trajectories of 5 major biomarkers of Alzheimer disease. Arch Neurol 69:856–867

    PubMed  Google Scholar 

  46. Jack CR Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue MC, Trojanowski JQ (2013) Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 12:207–216

    PubMed  CAS  Google Scholar 

  47. Jack CR Jr, Wiste HJ, Lesnick TG, Weigand SD, Knopman DS, Vemuri P, Pankratz VS, Senjem ML, Gunter JL, Mielke MM, Lowe VJ, Boeve BF, Petersen RC (2013) Brain beta-amyloid load approaches a plateau. Neurology 80:890–896

    PubMed  CAS  Google Scholar 

  48. Jagust WJ, Landau SM, Shaw LM, Trojanowski JQ, Koeppe RA, Reiman EM, Foster NL, Petersen RC, Weiner MW, Price JC, Mathis CA, Alzheimer’s Disease Neuroimaging Initiative (2009) Relationships between biomarkers in aging and dementia. Neurology 73:1193–1199

    PubMed  CAS  Google Scholar 

  49. Jagust WJ, Bandy D, Chen K, Foster NL, Landau SM, Mathis CA, Price JC, Reiman EM, Skovronsky D, Koeppe RA (2010) The Alzheimer’s Disease Neuroimaging Initiative positron emission tomography core. Alzheimers Dement 6:221–229

    PubMed  Google Scholar 

  50. Jicha GA, Parisi JE, Dickson DW, Johnson K, Cha R, Ivnik RJ, Tangalos EG, Boeve BF, Knopman DS, Braak H, Petersen RC (2006) Neuropathologic outcome of mild cognitive impairment following progression to clinical dementia. Arch Neurol 63:674–681

    PubMed  Google Scholar 

  51. Johnson KA, Gregas M, Becker JA, Kinnecom C, Salat DH, Moran EK, Smith EE, Rosand J, Rentz DM, Klunk WE, Mathis CA, Price JC, Dekosky ST, Fischman AJ, Greenberg SM (2007) Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. Ann Neurol 62:229–234

    PubMed  Google Scholar 

  52. Johnson G, Nathan M, Parisi J, Lingle W, Hunt C, Peller P, Fauq A, Maharvi G, Mathis CA, Lowe V (2012) PiB PET/CT identification of meningiomas is not due to presence of amyloid-beta within tumors. J Nucl Med 53(Supplement 1):253

    Google Scholar 

  53. Johnson KA, Minoshima S, Bohnen NI, Donohoe KJ, Foster NL, Herscovitch P, Karlawish JH, Rowe CC, Carrillo MC, Hartley DM, Hedrick S, Pappas V, Thies WH (2013) Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Alzheimers Dement 9:e-1–e-16

    Google Scholar 

  54. Kadir A, Marutle A, Gonzalez D, Scholl M, Almkvist O, Mousavi M, Mustafiz T, Darreh-Shori T, Nennesmo I, Nordberg A (2011) Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer’s disease. Brain 134:301–317

    PubMed  Google Scholar 

  55. Kantarci K, Yang C, Schneider JA, Senjem ML, Reyes DA, Lowe VJ, Barnes LL, Aggarwal NT, Bennett DA, Smith GE, Petersen RC, Jack CR Jr, Boeve BF (2012) Antemortem amyloid imaging and beta-amyloid pathology in a case with dementia with Lewy bodies. Neurobiol Aging 33:878–885

    PubMed  CAS  Google Scholar 

  56. Kemppainen NM, Aalto S, Wilson IA, Någren K, Helin S, Brück A, Oikonen V, Kailajärvi M, Scheinin M, Viitanen M, Parkkola R, Rinne JO (2006) Voxel-based analysis of PET amyloid ligand [11C]PIB uptake in Alzheimer disease. Neurology 67:1575–1580

    PubMed  CAS  Google Scholar 

  57. Kim HY, Kim J, Lee JH (2012) Incidental finding of meningioma on C11-PIB PET. Clin Nucl Med 37:e36–e37

    PubMed  Google Scholar 

  58. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergstrom M, Savitcheva I, Huang GF, Estrada S, Ausen B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni A, Mathis CA, Langstrom B (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55:306–319

    PubMed  CAS  Google Scholar 

  59. Klunk WE, Lopresti BJ, Ikonomovic MD, Lefterov IM, Koldamova RP, Abrahamson EE, Debnath ML, Holt DP, Huang GF, Shao L, DeKosky ST, Price JC, Mathis CA (2005) 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 25:10598–10606

    PubMed  CAS  Google Scholar 

  60. Klunk WE (2013) Standardization of quantitative amyloid imaging data: the centiloid project. 7th Human Amyloid Imaging, Miami, Florida; January 16–18, 2013. Abstract available on page 31 of the on-line Book of Abstracts at http://www.worldeventsforum.com/hai/xhtml-css/past-programs/HAI_2013_ConferenceBook%20A.pdf

  61. Koivunen J, Scheinin N, Virta JR, Aalto S, Vahlberg T, Någren K, Helin S, Parkkola R, Viitanen M, Rinne JO (2011) Amyloid PET imaging in patients with mild cognitive impairment: a 2-year follow-up study. Neurology 76:1085–1090

    PubMed  CAS  Google Scholar 

  62. Knopman DS, Parisi JE, Salviati A, Floriach-Robert M, Boeve BF, Ivnik RJ, Smith GE, Dickson DW, Johnson KA, Petersen LE, McDonald WC, Braak H, Petersen RC (2003) Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol 62:1087–1095

    PubMed  CAS  Google Scholar 

  63. Knopman DS, Jack CR, Wiste HJ, Weigand SD, Vemuri P, Lowe VJ, Kantarci K, Gunter JL, Senjem ML, Mielke MM, Roberts RO, Boeve BF, Petersen RC (2013) Selective worsening of brain injury biomarker abnormalities in cognitively normal elderly persons with β-amyloidosis. JAMA Neurology. doi:10.1001/jamaneurol.2013.182

    Google Scholar 

  64. Leinonen V, Alafuzoff I, Aalto S, Suotunen T, Savolainen S, Någren K, Tapiola T, Pirttilä T, Rinne J, Jääskeläinen JE, Soininen H, Rinne JO (2008) Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron emission tomography with carbon 11-labeled Pittsburgh Compound B. Arch Neurol 65:1304–1309

    PubMed  Google Scholar 

  65. Leinonen V, Rinne JO, Virtanen KA, Eskola O, Rummukainen J, Huttunen J, von Und Zu, Fraunberg M, Nerg O, Koivisto AM, Rinne J, Jääskeläinen JE, Buckley C, Smith A, Jones PA, Sherwin P, Farrar G, McLain R, Kailajärvi M, Heurling K, Grachev ID (2013) Positron emission tomography with [(18) F]flutemetamol and [(11) C]PiB for in vivo detection of cerebral cortical amyloid in normal pressure hydrocephalus patients. Eur J Neurol 20:1043–1052

    PubMed  CAS  Google Scholar 

  66. Lockhart A, Lamb JR, Osredkar T, Sue LI, Joyce JN, Ye L, Libri V, Leppert D, Beach TG (2007) PIB is a non-specific imaging marker of amyloid-beta (Abeta) peptide-related cerebral amyloidosis. Brain 130:2607–2615

    PubMed  CAS  Google Scholar 

  67. Lopresti BJ, Klunk WE, Mathis CA, Hoge JA, Ziolko SK, Lu X, Meltzer CC, Schimmel K, Tsopelas ND, DeKosky ST, Price JC (2005) Simplified quantification of Pittsburgh Compound B amyloid imaging PET studies: a comparative analysis. J Nucl Med 46:1959–1972

    PubMed  CAS  Google Scholar 

  68. Lowe VJ, Kemp BJ, Jack CR Jr, Senjem M, Weigand S, Shiung M, Smith G, Knopman D, Boeve B, Mullan B, Petersen RC (2009) Comparison of 18F-FDG and PiB PET in cognitive impairment. J Nucl Med 50:878–886

    PubMed  Google Scholar 

  69. Ly JV, Rowe CC, Villemagne VL, Zavala JA, Ma H, Sahathevan R, O’Keefe G, Gong SJ, Gunawan R, Churilov L, Saunder T, Ackerman U, Tochon-Danguy H, Donnan GA (2012) Subacute ischemic stroke is associated with focal 11C PiB positron emission tomography retention but not with global neocortical Abeta deposition. Stroke 43:1341–1346

    PubMed  CAS  Google Scholar 

  70. McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136:43–64

    PubMed  Google Scholar 

  71. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (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 

  72. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging and the Alzheimer’s Association Workgroup. Alzheimers Dement 7:263–269

    PubMed  Google Scholar 

  73. McNamee RL, Yee SH, Price JC, Klunk WE, Rosario B, Weissfeld L, Ziolko S, Berginc M, Lopresti B, Dekosky S, Mathis CA (2009) Consideration of optimal time window for Pittsburgh compound B PET summed uptake measurements. J Nucl Med 50:348–355

    PubMed  CAS  Google Scholar 

  74. Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, Klunk WE, Mathis CA, DeKosky ST, Morris JC (2006) [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 67:446–452

    PubMed  CAS  Google Scholar 

  75. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486

    PubMed  CAS  Google Scholar 

  76. Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Trojanowski JQ, Vinters HV, Hyman BT (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

    PubMed  CAS  Google Scholar 

  77. Mormino EC, Kluth JT, Madison CM, Rabinovici GD, Baker SL, Miller BL, Koeppe RA, Mathis CA, Weiner MW, Jagust WJ, Alzheimer’s Disease Neuroimaging Initiative (2009) Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects. Brain 132:1310–1323

    PubMed  CAS  Google Scholar 

  78. Morris JC, Roe CM, Grant EA, Head D, Storandt M, Goate AM, Fagan AM, Holtzman DM, Mintun MA (2009) Pittsburgh Compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. Arch Neurol 66:1469–1475

    PubMed  Google Scholar 

  79. Morris JC, Roe CM, Xiong C, Fagan AM, Goate AM, Holtzman DM, Mintun MA (2010) APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol 67:122–131

    PubMed  CAS  Google Scholar 

  80. Musiek ES, Holtzman DM (2012) Origins of Alzheimer’s disease: reconciling cerebrospinal fluid biomarker and neuropathology data regarding the temporal sequence of amyloid-beta and tau involvement. Curr Opin Neurol 25:715–720

    PubMed  CAS  Google Scholar 

  81. Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, Duyckaerts C, Frosch MP, Haroutunian V, Hof PR, Hulette CM, Hyman BT, Iwatsubo T, Jellinger KA, Jicha GA, Kövari E, Kukull WA, Leverenz JB, Love S, Mackenzie IR, Mann DM, Masliah E, McKee AC, Montine TJ, Morris JC, Schneider JA, Sonnen JA, Thal DR, Trojanowski JQ, Troncoso JC, Wisniewski T, Woltjer RL, Beach TG (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71:362–381

    PubMed  Google Scholar 

  82. Niedowicz DM, Beckett TL, Matveev S, Weidner AM, Baig I, Kryscio RJ, Mendiondo MS, LeVine H 3rd, Keller JN, Murphy MP (2012) Pittsburgh compound B and the postmortem diagnosis of Alzheimer disease. Ann Neurol 72:564–570

    PubMed  CAS  Google Scholar 

  83. Okello A, Koivunen J, Edison P, Archer HA, Turkheimer FE, Någren K, Bullock R, Walker Z, Kennedy A, Fox NC, Rossor MN, Rinne JO, Brooks DJ (2009) Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study. Neurology 73:754–760

    PubMed  CAS  Google Scholar 

  84. Perrin RJ, Fagan AM, Holtzman DM (2009) Multimodal techniques for diagnosis and prognosis of Alzheimer’s disease. Nature 461:916–922

    PubMed  CAS  Google Scholar 

  85. Price JC, Klunk WE, Lopresti BJ, Lu X, Hoge JA, Ziolko SK, Holt DP, Meltzer CC, DeKosky ST, Mathis CA (2005) Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B. J Cereb Blood Flow Metab 25:1528–1547

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  87. Price JL, McKeel DW Jr, Buckles VD, Roe CM, Xiong C, Grundman M, Hansen LA, Petersen RC, Parisi JE, Dickson DW, Smith CD, Davis DG, Schmitt FA, Markesbery WR, Kaye J, Kurlan R, Hulette C, Kurland BF, Higdon R, Kukull W, Morris JC (2009) Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging 30:1026–1036

    PubMed  Google Scholar 

  88. Rabinovici GD, Furst AJ, O’Neil JP, Racine CA, Mormino EC, Baker SL, Chetty S, Patel P, Pagliaro TA, Klunk WE, Mathis CA, Rosen HJ, Miller BL, Jagust WJ (2007) 11C-PIB PET imaging in Alzheimer disease and frontotemporal lobar degeneration. Neurology 68:1205–1212

    PubMed  CAS  Google Scholar 

  89. Rabinovici GD, Jagust WJ, Furst AJ, Ogar JM, Racine CA, Mormino EC, O’Neil JP, Lal RA, Dronkers NF, Miller BL, Gorno-Tempini ML (2008) Abeta amyloid and glucose metabolism in three variants of primary progressive aphasia. Ann Neurol 64:388–401

    PubMed  Google Scholar 

  90. Rabinovici GD, Jagust WJ (2009) Amyloid imaging in aging and dementia: testing the amyloid hypothesis in vivo. Behav Neurol 21:117–128

    PubMed  CAS  Google Scholar 

  91. Rabinovici GD, Furst AJ, Alkalay A, Racine CA, O’Neil JP, Janabi M, Baker SL, Agarwal N, Bonasera SJ, Mormino EC, Weiner MW, Gorno-Tempini ML, Rosen HJ, Miller BL, Jagust WJ (2010) Increased metabolic vulnerability in early-onset Alzheimer’s disease is not related to amyloid burden. Brain 133:512–528

    PubMed  Google Scholar 

  92. Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, Ayutyanont N, Keppler J, Reeder SA, Langbaum JB, Alexander GE, Klunk WE, Mathis CA, Price JC, Aizenstein HJ, DeKosky ST, Caselli RJ (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

    PubMed  CAS  Google Scholar 

  93. Ringman JM, Teplow DB, Villemagne VL (2012) The exception makes the rule: not all Abeta plaques are created equal. Neurology 79:206–207

    PubMed  Google Scholar 

  94. Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, Mathis CA, Blennow K, Barakos J, Okello AA, Rodriguez Martinez de Liano S, Liu E, Koller M, Gregg KM, Schenk D, Black R, Grundman M (2010) 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol 9:363–372

    PubMed  CAS  Google Scholar 

  95. Rinne JO, Wong DF, Wolk DA, Leinonen V, Arnold SE, Buckley C, Smith A, McLain R, Sherwin PF, Farrar G, Kailajärvi M, Grachev ID (2012) [(18)F]Flutemetamol PET imaging and cortical biopsy histopathology for fibrillar amyloid beta detection in living subjects with normal pressure hydrocephalus: pooled analysis of four studies. Acta Neuropathol 124:833–845

    PubMed  CAS  Google Scholar 

  96. Roher AE, Cribbs DH, Kim RC, Maarouf CL, Whiteside CM, Kokjohn TA, Daugs ID, Head E, Liebsack C, Serrano G, Belden C, Sabbagh MN, Beach TG (2013) Bapineuzumab alters aβ composition: implications for the amyloid cascade hypothesis and anti-amyloid immunotherapy. PLoS One 8:e59735

    PubMed  CAS  Google Scholar 

  97. Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, Cowie TF, Dickinson KL, Maruff P, Darby D, Smith C, Woodward M, Merory J, Tochon-Danguy H, O’Keefe G, Klunk WE, Mathis CA, Price JC, Masters CL, Villemagne VL (2007) Imaging beta-amyloid burden in aging and dementia. Neurology 68:1718–1725

    PubMed  CAS  Google Scholar 

  98. Rowe CC, Ellis KA, Rimajova M, Bourgeat P, Pike KE, Jones G, Fripp J, Tochon-Danguy H, Morandeau L, O’Keefe G, Price R, Raniga P, Robins P, Acosta O, Lenzo N, Szoeke C, Salvado O, Head R, Martins R, Masters CL, Ames D, Villemagne VL (2010) Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol Aging 31:1275–1283

    PubMed  Google Scholar 

  99. Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C, Medical Research Council Cognitive Function and Ageing Study (2009) Age, neuropathology, and dementia. N Engl J Med 360:2302–2309

    PubMed  CAS  Google Scholar 

  100. Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, Blennow K, Soares H, Simon A, Lewczuk P, Dean R, Siemers E, Potter W, Lee VM, Trojanowski JQ, Alzheimer’s Disease Neuroimaging Initiative (2009) Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol 65:403–413

    PubMed  CAS  Google Scholar 

  101. Shin J, Lee SY, Kim SH, Kim YB, Cho SJ (2008) Multitracer PET imaging of amyloid plaques and neurofibrillary tangles in Alzheimer’s disease. Neuroimage 43:236–244

    PubMed  Google Scholar 

  102. Shin J, Kepe V, Small GW, Phelps ME, Barrio JR (2011) Multimodal imaging of Alzheimer pathophysiology in the brain’s default mode network. Int J Alzheimers Dis 2011:687945

    PubMed  Google Scholar 

  103. Sojkova J, Driscoll I, Iacono D, Zhou Y, Codispoti KE, Kraut MA, Ferrucci L, Pletnikova O, Mathis CA, Klunk WE, O’Brien RJ, Wong DF, Troncoso JC, Resnick SM (2011) In vivo fibrillar beta-amyloid detected using [11C]PiB positron emission tomography and neuropathologic assessment in older adults. Arch Neurol 68:232–240

    PubMed  Google Scholar 

  104. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH (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

    PubMed  Google Scholar 

  105. Stankoff B, Freeman L, Aigrot MS, Chardain A, Dollé F, Williams A, Galanaud D, Armand L, Lehericy S, Lubetzki C, Zalc B, Bottlaender M (2011) Imaging central nervous system myelin by positron emission tomography in multiple sclerosis using [methyl-(1)(1)C]-2-(4′-methylaminophenyl)-6-hydroxybenzothiazole. Ann Neurol 69:673–680

    PubMed  CAS  Google Scholar 

  106. Thal DR, Rüb U, Schultz C, Sassin I, Ghebremedhin E, Del Tredici K, Braak E, Braak H (2000) Sequence of Abeta-protein deposition in the human medial temporal lobe. J Neuropathol Exp Neurol 59:733–748

    PubMed  CAS  Google Scholar 

  107. Thal DR, Rüb 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 

  108. Tolboom N, van der Flier WM, Yaqub M, Boellaard R, Verwey NA, Blankenstein MA, Windhorst AD, Scheltens P, Lammertsma AA, van Berckel BN (2009) Relationship of cerebrospinal fluid markers to 11C-PiB and 18F-FDDNP binding. J Nucl Med 50:1464–1470

    PubMed  CAS  Google Scholar 

  109. Tolboom N, Yaqub M, Boellaard R, Luurtsema G, Windhorst AD, Scheltens P, Lammertsma AA, van Berckel BN (2009) Test-retest variability of quantitative [11C]PIB studies in Alzheimer’s disease. Eur J Nucl Med Mol Imaging 36:1629–1638

    PubMed  Google Scholar 

  110. Vemuri P, Wiste HJ, Weigand SD, Shaw LM, Trojanowski JQ, Weiner MW, Knopman DS, Petersen RC, Jack CR Jr, Alzheimer’s Disease Neuroimaging Initiative (2009) MRI and CSF biomarkers in normal, MCI, and AD subjects: diagnostic discrimination and cognitive correlations. Neurology 73:287–293

    PubMed  CAS  Google Scholar 

  111. Vemuri P, Wiste HJ, Weigand SD, Knopman DS, Shaw LM, Trojanowski JQ, Aisen PS, Weiner M, Petersen RC, Jack CR Jr, Alzheimer’s Disease Neuroimaging Initiative (2010) Effect of apolipoprotein E on biomarkers of amyloid load and neuronal pathology in Alzheimer disease. Ann Neurol 67:308–316

    PubMed  CAS  Google Scholar 

  112. Villain N, Chételat G, Grassiot B, Bourgeat P, Jones G, Ellis KA, Ames D, Martins RN, Eustache F, Salvado O, Masters CL, Rowe CC, Villemagne VL, AIBL Research Group (2012) Regional dynamics of amyloid-beta deposition in healthy elderly, mild cognitive impairment and Alzheimer’s disease: a voxelwise PiB-PET longitudinal study. Brain 135:2126–2139

    PubMed  Google Scholar 

  113. Villemagne VL, Pike KE, Darby D, Maruff P, Savage G, Ng S, Ackermann U, Cowie TF, Currie J, Chan SG, Jones G, Tochon-Danguy H, O’Keefe G, Masters CL, Rowe CC (2008) Abeta deposits in older non-demented individuals with cognitive decline are indicative of preclinical Alzheimer’s disease. Neuropsychologia 46:1688–1697

    PubMed  CAS  Google Scholar 

  114. Villemagne VL, McLean CA, Reardon K, Boyd A, Lewis V, Klug G, Jones G, Baxendale D, Masters CL, Rowe CC, Collins SJ (2009) 11C-PiB PET studies in typical sporadic Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 80:998–1001

    PubMed  CAS  Google Scholar 

  115. Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, Szoeke C, Macaulay SL, Martins R, Maruff P, Ames D, Rowe CC, Masters CL, Australian Imaging Biomarkers and Lifestyle (AIBL) Research Group (2013) Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol 12:357–367

    PubMed  CAS  Google Scholar 

  116. Weigand SD, Vemuri P, Wiste HJ, Senjem ML, Pankratz VS, Aisen PS, Weiner MW, Petersen RC, Shaw LM, Trojanowski JQ, Knopman DS, Jack CR Jr, Alzheimer’s Disease Neuroimaging Initiative (2011) Transforming cerebrospinal fluid Abeta42 measures into calculated Pittsburgh compound B units of brain Abeta amyloid. Alzheimers Dement 7:133–141

    PubMed  CAS  Google Scholar 

  117. Wolk DA, Klunk W (2009) Update on amyloid imaging: from healthy aging to Alzheimer’s disease. Curr Neurol Neurosci Rep 9:345–352

    PubMed  Google Scholar 

  118. Wolk DA, Grachev ID, Buckley C, Kazi H, Grady MS, Trojanowski JQ, Hamilton RH, Sherwin P, McLain R, Arnold SE (2011) Association between in vivo fluorine 18-labeled flutemetamol amyloid positron emission tomography imaging and in vivo cerebral cortical histopathology. Arch Neurol 68:1398–1403

    PubMed  Google Scholar 

  119. Wong DF, Moghekar AR, Rigamonti D, Brašić JR, Rousset O, Willis W, Buckley C, Smith A, Gok B, Sherwin P, Grachev ID (2013) An in vivo evaluation of cerebral cortical amyloid with [18F]flutemetamol using positron emission tomography compared with parietal biopsy samples in living normal pressure hydrocephalus patients. Mol Imaging Biol 15:230–237

    PubMed  Google Scholar 

Download references

Acknowledgments

JRB and VK work was partially supported by the UCLA ADRC (NIH grant P50 AG 16570). JRB and VK did not receive support from any for-profit entity, including licensing agreements. CRJ was supported by RO1 AG011378 and RO1 AG041851 and the Alexander Family Professorship of Alzheimers disease research, Mayo Clinic.

Author information

Authors and Affiliations

  1. Department of Radiology, Mayo Clinic, Rochester, USA

    Clifford R. Jack Jr.

  2. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine University of California, Los Angeles, USA

    Jorge R. Barrio & Vladimir Kepe

Authors
  1. Clifford R. Jack Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jorge R. Barrio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vladimir Kepe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Clifford R. Jack Jr. or Jorge R. Barrio.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jack, C.R., Barrio, J.R. & Kepe, V. Cerebral amyloid PET imaging in Alzheimer’s disease. Acta Neuropathol 126, 643–657 (2013). https://doi.org/10.1007/s00401-013-1185-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-013-1185-7

Keywords

Search

Navigation