Skip to main content

Advertisement

Springer Nature Link
Log in

Tau PET Imaging in Alzheimer’s Disease

  • Neuroimaging (DJ Brooks, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

In several neurodegenerative diseases that are collectively called tauopathies, progressive accumulation of tau in the brain is closely associated with neurodegeneration and cognitive impairment. Noninvasive detection of tau protein deposits in the brain would be useful to diagnose tauopathies as well as to track and predict disease progression. Recently, several tau PET tracers including T807, THK-5117, and PBB3 have been developed and succeeded in imaging neurofibrillary pathology in vivo. For use of tau PET as a biomarker of tau pathology in Alzheimer’s disease, PET tracers should have high affinity to PHF-tau and high selectivity for tau over amyloid-β and other protein deposits. PET tau imaging enables the longitudinal assessment of the spatial pattern of tau deposition and its relation to amyloid-β pathology and neurodegeneration. This technology could also be applied to the pharmacological assessment of anti-tau therapy, thereby allowing preventive interventions.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297:353–6.

    Article  PubMed  CAS  Google Scholar 

  2. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. 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. 2011;7:280–92.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Citron M. Alzheimer’s disease: strategies for disease modification. Nat Rev Drug Discov. 2010;9:387–98.

    Article  PubMed  CAS  Google Scholar 

  4. Giacobini E, Gold G. Alzheimer disease therapy–moving from amyloid-beta to tau. Nat Rev Neurol. 2013;9:677–86.

    Article  PubMed  CAS  Google Scholar 

  5. Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 2007;8:663–72.

    Article  PubMed  CAS  Google Scholar 

  6. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986;83:4913–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem. 1986;261:6084–9.

    PubMed  CAS  Google Scholar 

  8. Price JL, Davis PB, Morris JC, White DL. The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease. Neurobiol Aging. 1991;12:295–312.

    Article  PubMed  CAS  Google Scholar 

  9. Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging. 1997;18:351–7.

    Article  PubMed  CAS  Google Scholar 

  10. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59.

    Article  PubMed  CAS  Google Scholar 

  11. Delacourte A, David JP, Sergeant N, Buee L, Wattez A, Vermersch P, et al. The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer’s disease. Neurology. 1999;52:1158–65.

    Article  PubMed  CAS  Google Scholar 

  12. Bierer LM, Hof PR, Purohit DP, Carlin L, Schmeidler J, Davis KL, et al. Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer’s disease. Arch Neurol. 1995;52:81–8.

    Article  PubMed  CAS  Google Scholar 

  13. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology. 1992;42:631–9.

    Article  PubMed  CAS  Google Scholar 

  14. Nordberg A, Rinne JO, Kadir A, Langstrom B. The use of PET in Alzheimer disease. Nat Rev Neurol. 2010;6:78–87.

    Article  PubMed  CAS  Google Scholar 

  15. Villemagne VL, Okamura N. In vivo tau imaging: obstacles and progress. Alzheimers Dement. 2014;10:S254–64.

    Article  PubMed  Google Scholar 

  16. Villemagne VL, Furumoto S, Fodero-Tavoletti MT, Harada R, Mulligan RS, Kudo Y, et al. The challenges of tau imaging. Futur Neurol. 2012;7:409–21.

    Article  CAS  Google Scholar 

  17. Shah M, Catafau AM. Molecular Imaging Insights into neurodegeneration: focus on Tau PET Radiotracers. J Nucl Med. 2014;55:871–4.

    Article  PubMed  CAS  Google Scholar 

  18. Fodero-Tavoletti MT, Smith DP, McLean CA, Adlard PA, Barnham KJ, Foster LE, et al. In vitro characterization of Pittsburgh compound-B binding to Lewy bodies. J Neurosci. 2007;27:10365–71.

  19. Fodero-Tavoletti MT, Mulligan RS, Okamura N, Furumoto S, Rowe CC, Kudo Y, et al. In vitro characterisation of BF227 binding to alpha-synuclein/Lewy bodies. Eur J Pharmacol. 2009;617:54–8.

    Article  PubMed  CAS  Google Scholar 

  20. Ni R, Gillberg PG, Bergfors A, Marutle A, Nordberg A. Amyloid tracers detect multiple binding sites in Alzheimer’s disease brain tissue. Brain. 2013;136:2217–27.

    Article  PubMed  Google Scholar 

  21. Choi SR, Golding G, Zhuang Z, Zhang W, Lim N, Hefti F, et al. Preclinical properties of 18 F-AV-45: a PET agent for Abeta plaques in the brain. J Nucl Med. 2009;50:1887–94.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Klunk WE, Wang Y, Huang GF, Debnath ML, Holt DP, Shao L, et al. The binding of 2-(4′-methylaminophenyl)benzothiazole to postmortem brain homogenates is dominated by the amyloid component. J Neurosci. 2003;23:2086–92.

  23. Mathis CA, Wang Y, Holt DP, Huang GF, Debnath ML, Klunk WE. Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. J Med Chem. 2003;46:2740–54.

    Article  PubMed  CAS  Google Scholar 

  24. Schafer KN, Kim S, Matzavinos A, Kuret J. Selectivity requirements for diagnostic imaging of neurofibrillary lesions in Alzheimer’s disease: a simulation study. Neuroimage. 2012;60:1724–33.

    Article  PubMed  Google Scholar 

  25. Choi SR, Golding G, Zhuang Z, Zhang W, Lim N, Hefti F, et al. Preclinical properties of 18 F-AV-45: a PET agent for Abeta plaques in the brain. J Neurosci. 2009;50:1887–94.

  26. Snellman A, Rokka J, Lopez-Picon FR, Eskola O, Wilson I, Farrar G, et al. Pharmacokinetics of [18F]flutemetamol in wild-type rodents and its binding to beta amyloid deposits in a mouse model of Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2012;39:1784–95.

  27. Dischino DD, Welch MJ, Kilbourn MR, Raichle ME. Relationship between lipophilicity and brain extraction of C-11-labeled radiopharmaceuticals. J Nucl Med. 1983;24:1030–8.

    CAS  Google Scholar 

  28. Herholz K, Ebmeier K. Clinical amyloid imaging in Alzheimer’s disease. Lancet Neurol. 2011;10:667–70.

    Article  PubMed  CAS  Google Scholar 

  29. Shoghi-Jadid K, Small GW, Agdeppa ED, Kepe V, Ercoli LM, Siddarth P, et al. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatr. 2002;10:24–35.

    Article  Google Scholar 

  30. Agdeppa ED, Kepe V, Liu J, Flores-Torres S, Satyamurthy N, Petric A, 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:RC189.

    PubMed  CAS  Google Scholar 

  31. Small GW, Kepe V, Ercoli LM, Siddarth P, Bookheimer SY, Miller KJ, et al. PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med. 2006;355:2652–63.

    Article  PubMed  CAS  Google Scholar 

  32. Shin J, Lee SY, Kim SH, Kim YB, Cho SJ. Multitracer PET imaging of amyloid plaques and neurofibrillary tangles in Alzheimer’s disease. Neuroimage. 2008;43:236–44.

    Article  PubMed  Google Scholar 

  33. Small GW, Kepe V, Siddarth P, Ercoli LM, Merrill DA, Donoghue N, et al. PET scanning of brain tau in retired national football league players: preliminary findings. Am J Geriatr Psychiatr. 2013;21:138–44.

    Article  Google Scholar 

  34. DeKosky ST, Blennow K, Ikonomovic MD, Gandy S. Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers. Nat Rev Neurol. 2013;9:192–200.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Kepe V, Bordelon Y, Boxer A, Huang SC, Liu J, Thiede FC, et al. PET imaging of neuropathology in tauopathies: progressive supranuclear palsy. J Alzheimers Dis. 2013;36:145–53.

    PubMed  CAS  PubMed Central  Google Scholar 

  36. Maruyama M, Shimada H, Suhara T, Shinotoh H, Ji B, Maeda J, et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron. 2013;79:1094–108. Maruyama et al. performed first-in-man PET studies of [ 11 C]PBB3 in 3 healthy controls and 3 AD patients. [ 11 C]PBB3 retention was observed in the hippocampus of AD patients, suggesting that this tracer binds to NFTs in vivo. In addition, [ 11 C]PBB3 binding to tau deposits was reported in the basal ganglia of CBD patient.

    Article  PubMed  CAS  Google Scholar 

  37. Hashimoto H, Kawamura K, Igarashi N, Takei M, Fujishiro T, Aihara Y, et al. Radiosynthesis, Photoisomerization, Biodistribution, and metabolite analysis of 11C-PBB3 as a clinically useful PET probe for imaging of Tau pathology. J Nucl Med. 2014;55:1532-8.

  38. Chien DT, Bahri S, Szardenings AK, Walsh JC, Mu F, Su MY, et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J Alzheimers Dis. 2013;34:457–68. The first-in-man PET studies of [ 18 F]T807 demonstrated significant tracer retention in the frequent areas of PHF-tau in AD brain. [ 18 F]T807 retention was associated with increasing disease severity. In addition, [ 18 F]T807 shows very low non-specific binding of the tracer in the white matter.

    PubMed  CAS  Google Scholar 

  39. Chien DT, Szardenings AK, Bahri S, Walsh JC, Mu FR, Xia CF, et al. Early clinical PET imaging results with the Novel PHF-Tau radioligand [F18]-T808. J Alzheimers Dis. 2014;38:171–84.

    PubMed  Google Scholar 

  40. Xia CF, Arteaga J, Chen G, Gangadharmath U, Gomez LF, Kasi D, et al. [18F]T807, a novel tau positron emission tomography imaging agent for Alzheimer’s disease. Alzheimers Dement. 2013.

  41. Okamura N, Suemoto T, Furumoto S, Suzuki M, Shimadzu H, Akatsu H, et al. Quinoline and benzimidazole derivatives: candidate probes for in vivo imaging of tau pathology in Alzheimer’s disease. J Neurosci. 2005;25:10857–62.

    Article  PubMed  CAS  Google Scholar 

  42. Fodero-Tavoletti MT, Okamura N, Furumoto S, Mulligan RS, Connor AR, McLean CA, et al. 18 F-THK523: a novel in vivo tau imaging ligand for Alzheimer’s disease. Brain. 2011;134:1089–100.

    Article  PubMed  Google Scholar 

  43. Harada R, Okamura N, Furumoto S, Tago T, Maruyama M, Higuchi M, et al. Comparison of the binding characteristics of [18 F]THK-523 and other amyloid imaging tracers to Alzheimer’s disease pathology. Eur J Nucl Med Mol Imaging. 2013;40:125–32.

    Article  PubMed  CAS  Google Scholar 

  44. Okamura N, Furumoto S, Harada R, Tago T, Yoshikawa T, Fodero-Tavoletti M, et al. Novel 18 F-labeled arylquinoline derivatives for noninvasive imaging of tau pathology in Alzheimer disease. J Nucl Med. 2013;54:1420–7.

    Article  PubMed  CAS  Google Scholar 

  45. Villemagne VL, Furumoto S, Fodero-Tavoletti MT, Mulligan RS, Hodges J, Harada R, et al. In vivo evaluation of a novel tau imaging tracer for Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2014;41:816-26.

  46. Okamura N, Furumoto S, Fodero-Tavoletti MT, Mulligan RS, Harada R, Yates P, et al. Non-invasive assessment of Alzheimer’s disease neurofibrillary pathology using 18F-THK5105 PET. Brain. 2014;137:1762–71. The first-in man studies of [ 18 F]THK-5105 demonstrated tracer retention in the frequent areas of PHF-tau in AD brain. Tracer retention was associated with clinical severity of dementia and brain atrophy, which is consistent with the observation of postmortem studies.

    Article  PubMed  Google Scholar 

  47. Fodero-Tavoletti MT, Furumoto S, Taylor L, McLean CA, Mulligan RS, Birchall I, et al. Assessing THK523 selectivity for tau deposits in Alzheimer’s disease and non Alzheimer’s disease tauopathies. Alzheimers Res Ther. 2014;6:11.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Stein TD, Alvarez VE, McKee AC. Chronic traumatic encephalopathy: a spectrum of neuropathological changes following repetitive brain trauma in athletes and military personnel. Alzheimers Res Ther. 2014;6:4.

    Article  PubMed  Google Scholar 

  49. McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain. 2013;136:43–64.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Yamada M, Itoh Y, Sodeyama N, Suematsu N, Otomo E, Matsushita M, et al. Senile dementia of the neurofibrillary tangle type: a comparison with Alzheimer’s disease. Dement Geriatr Cogn Disord. 2001;12:117–26.

    Article  PubMed  CAS  Google Scholar 

  51. Saito Y, Ruberu NN, Sawabe M, Arai T, Tanaka N, Kakuta Y, et al. Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol. 2004;63:911–8.

    PubMed  Google Scholar 

  52. Takeuchi J, Shimada H, Ataka S, Kawabe J, Mori H, Mizuno K, et al. Clinical features of Pittsburgh compound-B-negative dementia. Dement Geriatr Cogn Disord. 2012;34:112–20.

    Article  PubMed  CAS  Google Scholar 

  53. Jack Jr CR, Knopman DS, Weigand SD, Wiste HJ, Vemuri P, Lowe V, et al. An operational approach to National Institute on Aging-Alzheimer’s association criteria for preclinical Alzheimer disease. Ann Neurol. 2012;71:765–75.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Morris JC, Price JL. Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer’s disease. J Mol Neurosci. 2001;17:101–18.

    Article  PubMed  CAS  Google Scholar 

  55. Jack Jr CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12:207–16.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  56. Perrin RJ, Fagan AM, Holtzman DM. Multimodal techniques for diagnosis and prognosis of Alzheimer’s disease. Nature. 2009;461:916–22.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  57. Rabinovici GD, Jagust WJ. Amyloid imaging in aging and dementia: testing the amyloid hypothesis in vivo. Behav Neurol. 2009;21:117–28.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  58. Jack Jr CR, Lowe VJ, Weigand SD, Wiste HJ, Senjem ML, Knopman DS, et al. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer’s disease: implications for sequence of pathological events in Alzheimer’s disease. Brain. 2009;132:1355–65.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Whitwell JL, Josephs KA, Murray ME, Kantarci K, Przybelski SA, Weigand SD, et al. MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study. Neurology. 2008;71:743–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  60. Hof PR, Bierer LM, Perl DP, Delacourte A, Buee L, Bouras C, et al. Evidence for early vulnerability of the medial and inferior aspects of the temporal lobe in an 82-year-old patient with preclinical signs of dementia. Regional and laminar distribution of neurofibrillary tangles and senile plaques. Arch Neurol. 1992;49:946–53.

    Article  PubMed  CAS  Google Scholar 

  61. Csernansky JG, Hamstra J, Wang L, McKeel D, Price JL, Gado M, et al. Correlations between antemortem hippocampal volume and postmortem neuropathology in AD subjects. Alzheimer Dis Assoc Disord. 2004;18:190–5.

    PubMed  Google Scholar 

  62. Csernansky JG, Wang L, Swank J, Miller JP, Gado M, McKeel D, et al. Preclinical detection of Alzheimer’s disease: hippocampal shape and volume predict dementia onset in the elderly. Neuroimage. 2005;25:783–92.

    Article  PubMed  CAS  Google Scholar 

  63. Delacourte A, Sergeant N, Wattez A, Maurage CA, Lebert F, Pasquier F, et al. Tau aggregation in the hippocampal formation: an ageing or a pathological process? Exp Gerontol. 2002;37:1291–6.

    Article  PubMed  CAS  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Ryuichi Harada, Hiroyuki Arai, and Kazuhiko Yanai declare that they have no conflict of interest.

Nobuyuki Okamura, Shozo Furumoto, and Yukitsuka Kudo were funded by a grant to study tau PET imaging from GE Healthcare, the SEI (Sumitomo Electric Industries, Ltd.) Group, CSR Foundation, Health and Labor Sciences Research Grants from the Ministry of Health, Labor, and Welfare of Japan, and Grant-in-Aid for Exploratory Research (25670524) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Tohoku University School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, 9808575, Japan

    Nobuyuki Okamura & Kazuhiko Yanai

  2. Division of Neuro-imaging, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-machi, Aoba-ku, Sendai, 9808575, Japan

    Nobuyuki Okamura, Ryuichi Harada & Yukitsuka Kudo

  3. Frontier Research Institute for Interdisciplinary Science, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, 9808578, Japan

    Shozo Furumoto

  4. Cyclotron and Radioisotope Center, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, 9808578, Japan

    Shozo Furumoto

  5. Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-machi, Aoba-ku, Sendai, 9808575, Japan

    Hiroyuki Arai

Authors
  1. Nobuyuki Okamura
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Ryuichi Harada
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Shozo Furumoto
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Hiroyuki Arai
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Kazuhiko Yanai
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Yukitsuka Kudo
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Nobuyuki Okamura.

Additional information

This article is part of the Topical Collection on Neuroimaging

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Okamura, N., Harada, R., Furumoto, S. et al. Tau PET Imaging in Alzheimer’s Disease. Curr Neurol Neurosci Rep 14, 500 (2014). https://doi.org/10.1007/s11910-014-0500-6

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-014-0500-6

Keywords