PET Biomarkers for Tau Pathology

  • Antoine Leuzy
  • Kerstin Heurling
  • Michael SchöllEmail author


The aggregation and accumulation of pathologic forms of the microtubule-associated tau protein into fibrils, eventually forming characteristic tangle pathology, hallmarks the majority of all dementia disorders which constitute the most prevalent family of neurodegenerative disorders. These so-called tauopathies are difficult to identify and diagnose, especially at early disease stages. The relatively recent development of positron emission tomography tracers to visualize, map, and quantify tau pathology in the living brain has already provided substantial information about the temporal and spatial characteristics of tau accumulation during disease development, holding promise to serve as a highly valuable diagnostic tool in research and clinical settings. This chapter describes the current state of research employing tau biomarkers derived from neuroimaging with PET as well as recent technical developments in this field.


Positron emission tomography Tau Tauopathies β-Amyloid Neurodegenerative diseases Dementia Alzheimer’s disease 


  1. 1.
    Weingarten MD, Lockwood AH, Hwo SY. A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A. 1975;72(5):1858–62.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Sotiropoulos I, Galas MC, Silva JM, et al. Atypical, non-standard functions of the microtubule associated tau protein. Acta Neuropathol Commun. 2017;5(1):91.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Kopke E, Tung YC, Shaikh S, et al. Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem. 1993;268(32):24374–84.PubMedGoogle Scholar
  4. 4.
    Lindwall G, Cole RD. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem. 1984;259(8):5301–5.PubMedGoogle Scholar
  5. 5.
    Maas T, Eidenmuller J, Brandt R. Interaction of tau with the neural membrane cortex is regulated by phosphorylation at sites that are modified in paired helical filaments. J Biol Chem. 2000;275(21):15733–40.PubMedCrossRefGoogle Scholar
  6. 6.
    Hernandez F, Avila J. Tauopathies. Cell Mol Life Sci. 2007;64(17):2219–33.PubMedCrossRefGoogle Scholar
  7. 7.
    Schöll M, Maass A, Mattsson N, et al. Biomarkers for tau pathology. Mol Cell Neurosci. 2019;97:18–33.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Shoghi-Jadid K, Small G, Agdeppa E, et al. Localization of neurofibrillary tangles and betaamyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry. 2002;10:24–35.PubMedCrossRefGoogle Scholar
  9. 9.
    Shoup TM, Yokell DL, Rice PA, et al. A concise radiosynthesis of the tau radiopharmaceutical, [(18) F]T807. J Labelled Comp Radiopharm. 2013;56(14):736–40.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Xia CF, Arteaga J, Chen G, et al. [(18)F]T807, a novel tau positron emission tomography imaging agent for Alzheimer’s disease. Alzheimers Dement. 2013;9(6):666–76.PubMedCrossRefGoogle Scholar
  11. 11.
    Holt DP, Ravert HT, Dannals RF. Synthesis and quality control of [(18) F]T807 for tau PET imaging. J Labelled Comp Radiopharm. 2016;59(10):411–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Mossine AV, Brooks AF, Henderson BD. An updated radiosynthesis of [(18)F]AV1451 for tau PET imaging. EJNMMI Radiopharm Chem. 2017;2(1):7.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Collier TL, Yokell DL, Livni E, et al. cGMP production of the radiopharmaceutical [(18) F]MK-6240 for PET imaging of human neurofibrillary tangles. J Labelled Comp Radiopharm. 2017;60(5):263–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Saint-Aubert L, Lemoine L, Chiotis K, et al. Tau PET imaging: present and future directions. Mol Neurodegener. 2017;12(1):19.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Ono M, Sahara N, Kumata K, Ji B, Ni R, Koga S, et al. Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies. Brain. 2017;140:764–80.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Marquie M, Normandin MD, Meltzer AC, Siao Tick Chong M, Andrea NV, Anton-Fernandez A, et al. Pathological correlations of [F-18]-AV-1451 imaging in non-Alzheimer tauopathies. Ann Neurol. 2017;81:117–28.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Lemoine L, Leuzy A, Chiotis K, et al. Tau positron emission tomography imaging in tauopathies: the added hurdle of off-target binding. Alzheimers Dement (Amst). 2018;10:232–6.Google Scholar
  18. 18.
    Choi JY, Cho H, Ahn SJ, et al. Off-Target (18)F-AV-1451 binding in the basal ganglia correlates with age-related iron accumulation. J Nucl Med. 2018;59:117–20.PubMedCrossRefGoogle Scholar
  19. 19.
    Marquie M, Normandin MD, Vanderburg CR, et al. Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann Neurol. 2015;78:787–800.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Vermeiren C, Motte P, Viot D, et al. The tau positron-emission tomography tracer AV-1451 binds with similar affinities to tau fibrils and monoamine oxidases. Mov Disord. 2018;33(2):273–81.PubMedCrossRefGoogle Scholar
  21. 21.
    Lemoine L, Gillberg PG, Svedberg M, et al. Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains. Alzheimers Res Ther. 2017;9(1):96.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Betthauser TJ, Cody KA, Zammit MD, et al. In vivo characterization and quantification of neurofibrillary tau PET radioligand (18)F-MK-6240 in humans from Alzheimer disease dementia to young controls. J Nucl Med. 2019;60(1):93–9.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Wong DF, Comley RA, Kuwabara H, et al. Characterization of 3 novel tau radiopharmaceuticals, (11)C-RO-963, (11)C-RO-643, and (18)F-RO-948, in healthy controls and in Alzheimer subjects. J Nucl Med. 2018;59(12):1869–76.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Hahn A, Schain M, Erlandsson M, et al. Modeling strategies for quantification of in vivo (18)F-AV-1451 binding in patients with tau pathology. J Nucl Med. 2017;58(4):623–31.PubMedCrossRefGoogle Scholar
  25. 25.
    Jonasson M, Wall A, Chiotis K, et al. Tracer kinetic analysis of (S)-(1)(8)F-THK5117 as a PET tracer for assessing tau pathology. J Nucl Med. 2016;57(4):574–81.PubMedCrossRefGoogle Scholar
  26. 26.
    Kuwabara H, Comley RA, Borroni E, Honer M, Kitmiller K, Roberts J, et al. Evaluation of (18)F-RO-948 PET for quantitative assessment of tau accumulation in the human brain. J Nucl Med. 2018;59(12):1877–84.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Kimura Y, Ichise M, Ito H, et al. PET quantification of tau pathology in human brain with 11C-PBB3. J Nucl Med. 2015;56(9):1359–65.PubMedCrossRefGoogle Scholar
  28. 28.
    Barret O, Alagille D, Sanabria S, et al. Kinetic modeling of the tau PET tracer (18)F-AV-1451 in human healthy volunteers and Alzheimer disease subjects. J Nucl Med. 2017;58(7):1124–31.PubMedCrossRefGoogle Scholar
  29. 29.
    Baker SL, Lockhart SN, Price JC, et al. Reference tissue-based kinetic evaluation of 18F-AV-1451 for tau imaging. J Nucl Med. 2017;58(2):332–8.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Heurling K, Smith R, Strandberg OT, et al. Regional times to equilibria and their impact on semi-quantification of [(18)F]AV-1451 uptake. J Cereb Blood Flow Metab. 2018:271678X18791430.Google Scholar
  31. 31.
    Schöll M, Lockhart SN, Schonhaut DR, et al. PET imaging of tau deposition in the aging human brain. Neuron. 2016;89(5):971–82.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Cho H, Choi JY, Hwang MS, et al. In vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum. Ann Neurol. 2016;80(2):247–58.PubMedCrossRefGoogle Scholar
  33. 33.
    Jack CR Jr, Wiste HJ, Schwarz CG, et al. Longitudinal tau PET in ageing and Alzheimer’s disease. Brain. 2018;141(5):1517–28.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Jones DT, Graff-Radford J, Lowe VJ, et al. Tau, amyloid, and cascading network failure across the Alzheimer’s disease spectrum. Cortex. 2017;97:143–59.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Cho H, Choi JY, Lee HS, et al. Progressive tau accumulation in Alzheimer’s disease: two-year follow-up study. J Nucl Med. 2019. pii: jnumed.118.221697Google Scholar
  36. 36.
    Brier MR, Gordon B, Friedrichsen K, et al. Tau and Abeta imaging, CSF measures, and cognition in Alzheimer’s disease. Sci Transl Med. 2016;8(338):338ra66.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Lowe VJ, Wiste HJ, Senjem ML, et al. Widespread brain tau and its association with ageing, Braak stage and Alzheimer’s dementia. Brain. 2018;141(1):271–87.PubMedCrossRefGoogle Scholar
  38. 38.
    Sepulcre J, Sabuncu MR, Li Q, et al. Tau and amyloid beta proteins distinctively associate to functional network changes in the aging brain. Alzheimers Dement. 2017;13(11):1261–9.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Mishra S, Gordon BA, Su Y, et al. AV-1451 PET imaging of tau pathology in preclinical Alzheimer disease: defining a summary measure. Neuroimage. 2017;161:171–8.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Whitwell JL, Graff-Radford J, Tosakulwong N, et al. [(18) F]AV-1451 clustering of entorhinal and cortical uptake in Alzheimer’s disease. Ann Neurol. 2018a;83(2):248–57.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Jack CR Jr. PART and SNAP. Acta Neuropathol. 2014;128(6):773–6.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Schöll M, Ossenkoppele R, Strandberg O, et al. Distinct 18F-AV-1451 tau PET retention patterns in early- and late-onset Alzheimer’s disease. Brain. 2017;140(9):2286–94.PubMedCrossRefGoogle Scholar
  43. 43.
    Chiotis K, Saint-Aubert L, Savitcheva I, et al. Imaging in-vivo tau pathology in Alzheimer’s disease with THK5317 PET in a multimodal paradigm. Eur J Nucl Med Mol Imaging. 2016;43(9):1686–99.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Leuzy A, Chiotis K, Lemoine L, et al. Tau PET imaging in neurodegenerative tauopathies-still a challenge. Mol Psychiatry. 2019;Google Scholar
  45. 45.
    Smith R, Schöll M, Honer M, et al. Tau neuropathology correlates with FDG-PET, but not AV-1451-PET, in progressive supranuclear palsy. Acta Neuropathol. 2017a;133(1):149–51.PubMedCrossRefGoogle Scholar
  46. 46.
    Smith R, Schöll M, Widner H, et al. In vivo retention of (18)F-AV-1451 in corticobasal syndrome. Neurology. 2017b;89(8):845–53.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Rafii MS, Lukic AS, Andrews RD, et al. PET imaging of tau pathology and relationship to amyloid, longitudinal MRI, and cognitive change in down syndrome: results from the down syndrome biomarker initiative (DSBI). J Alzheimers Dis. 2017;60(2):439–50.PubMedCrossRefGoogle Scholar
  48. 48.
    Smith R, Schöll M, Londos E, et al. (18)F-AV-1451 in Parkinson’s disease with and without dementia and in dementia with Lewy bodies. Sci Rep. 2018;8(1):4717.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Ossenkoppele R, Rabinovici GD, Smith R, et al. Discriminative accuracy of [18F]flortaucipir positron emission tomography for Alzheimer disease vs other neurodegenerative disorders. JAMA. 2018;320(11):1151–62.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Ossenkoppele R, Schonhaut DR, Baker SL, et al. Tau, amyloid, and hypometabolism in a patient with posterior cortical atrophy. Ann Neurol. 2015;77(2):338–42.PubMedCrossRefGoogle Scholar
  51. 51.
    Whitwell JL, Graff-Radford J, Tosakulwong N, et al. Imaging correlations of tau, amyloid, metabolism, and atrophy in typical and atypical Alzheimer’s disease. Alzheimers Dement. 2018b;14(8):1005–14.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Chiotis K, Saint-Aubert L, Rodriguez-Vieitez E, et al. Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer’s disease dementia. Mol Psychiatry. 2018;23(7):1666–73.PubMedCrossRefGoogle Scholar
  53. 53.
    Bejanin A, Schonhaut DR, La Joie R, et al. Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease. Brain. 2017;140(12):3286–300.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Jacobs HIL, Hedden T, Schultz AP, et al. Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals. Nat Neurosci. 2018;21(3):424–31.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Mattsson N, Schöll M, Strandberg O, et al. (18)F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer’s disease. EMBO Mol Med. 2017;9(9):1212–23.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Mattsson N, Smith R, Strandberg O, et al. Comparing (18)F-AV-1451 with CSF t-tau and p-tau for diagnosis of Alzheimer disease. Neurology. 2018;90(5):e388–e95.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Villemagne VL, Fodero-Tavoletti MT, Masters CL. Tau imaging: early progress and future directions. Lancet Neurol. 2015;14(1):114–24.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Antoine Leuzy
    • 1
    • 2
  • Kerstin Heurling
    • 2
  • Michael Schöll
    • 1
    • 2
    • 3
    Email author
  1. 1.Clinical Memory Research Unit, Department of Clinical SciencesLund UniversityMalmöSweden
  2. 2.Wallenberg Centre for Molecular and Translational Medicine and The Department for Psychiatry and Neurochemistry, The Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
  3. 3.Department of Neurodegenerative Disease, Dementia Research CentreUCL Institute of NeurologyLondonUK

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