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European Journal of Nuclear Medicine and Molecular Imaging

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Open Access 01-08-2016 | Original Article

Imaging in-vivo tau pathology in Alzheimer’s disease with THK5317 PET in a multimodal paradigm

Authors: Konstantinos Chiotis, Laure Saint-Aubert, Irina Savitcheva, Vesna Jelic, Pia Andersen, My Jonasson, Jonas Eriksson, Mark Lubberink, Ove Almkvist, Anders Wall, Gunnar Antoni, Agneta Nordberg

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 9/2016

Abstract

Purpose

The aim of this study was to explore the cerebral distribution of the tau-specific PET tracer [¹⁸F]THK5317 (also known as (S)-[¹⁸F]THK5117) retention in different stages of Alzheimer’s disease; and study any associations with markers of hypometabolism and amyloid-beta deposition.

Methods

Thirty-three individuals were enrolled, including nine patients with Alzheimer’s disease dementia, thirteen with mild cognitive impairment (MCI), two with non-Alzheimer’s disease dementia, and nine healthy controls (five young and four elderly). In a multi-tracer PET design [¹⁸F]THK5317, [¹¹C] Pittsburgh compound B ([¹¹C]PIB), and [¹⁸F]FDG were used to assess tau pathology, amyloid-beta deposition and cerebral glucose metabolism, respectively. The MCI patients were further divided into MCI [¹¹C]PIB-positive (n = 11) and MCI [¹¹C]PIB-negative (n = 2) groups.

Results

Test-retest variability for [¹⁸F]THK5317-PET was very low (1.17–3.81 %), as shown by retesting five patients. The patients with prodromal (MCI [¹¹C]PIB-positive) and dementia-stage Alzheimer’s disease had significantly higher [¹⁸F]THK5317 retention than healthy controls (p = 0.002 and p = 0.001, respectively) in areas exceeding limbic regions, and their discrimination from this control group (using the area under the curve) was >98 %. Focal negative correlations between [¹⁸F]THK5317 retention and [¹⁸F]FDG uptake were observed mainly in the frontal cortex, and focal positive correlations were found between [¹⁸F]THK5317 and [¹¹C]PIB retentions isocortically. One patient with corticobasal degeneration syndrome and one with progressive supranuclear palsy showed no [¹¹C]PIB but high [¹⁸F]THK5317 retentions with a different regional distribution from that in Alzheimer’s disease patients.

Conclusions

The tau-specific PET tracer [¹⁸F]THK5317 images in vivo the expected regional distribution of tau pathology. This distribution contrasts with the different patterns of hypometabolism and amyloid-beta deposition.

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Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2013;12:357–67. doi:10.1016/S1474-4422(13)70044-9.CrossRefPubMed

Jack Jr CR, Wiste HJ, Lesnick TG, Weigand SD, Knopman DS, Vemuri P, et al. Brain beta-amyloid load approaches a plateau. Neurology. 2013;80:890–6. doi:10.1212/WNL.0b013e3182840bbe.CrossRefPubMedPubMedCentral

Braak H, Del Tredici K. The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol. 2011;121:171–81. doi:10.1007/s00401-010-0789-4.CrossRefPubMed

Giannakopoulos P, Herrmann FR, Bussiere T, Bouras C, Kovari E, Perl DP, et al. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology. 2003;60:1495–500.CrossRefPubMed

Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev. 2000;33:95–130.CrossRefPubMed

Johnson KA, Schultz A, Betensky RA, Becker JA, Sepulcre J, Rentz D, et al. Tau PET imaging in aging and early Alzheimer’s disease. Ann Neurol. 2015;79(1):110-9. doi:10.1002/ana.24546.CrossRefPubMed

Dani M, Brooks DJ, Edison P. Tau imaging in neurodegenerative diseases. Eur J Nucl Med Mol Imaging. 2015. doi:10.1007/s00259-015-3231-2.PubMedPubMedCentral

Villemagne VL, Fodero-Tavoletti MT, Masters CL, Rowe CC. Tau imaging: early progress and future directions. Lancet Neurol. 2015;14:114–24. doi:10.1016/S1474-4422(14)70252-2.CrossRefPubMed

Harada R, Okamura N, Furumoto S, Furukawa K, Ishiki A, Tomita N, et al. [(18)F]THK-5117 PET for assessing neurofibrillary pathology in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2015;42:1052–61. doi:10.1007/s00259-015-3035-4.CrossRefPubMed

10.

Lemoine L, Saint-Aubert L, Marutle A, Antoni G, Eriksson JP, Ghetti B, et al. Visualization of regional tau deposits using H-THK5117 in Alzheimer brain tissue. Acta Neuropathol Commun. 2015;3:40. doi:10.1186/s40478-015-0220-4.CrossRefPubMedPubMedCentral

11.

Jonasson M, Wall A, Chiotis K, Saint-Aubert L, Wilking H, Sprycha M, et al. Tracer kinetic analysis of (S)-18F-THK5117 as a PET tracer for assessing tau pathology. J Nucl Med: Off Publ, Soc Nucl Med. 2016. doi:10.2967/jnumed.115.158519.

12.

McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. 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. 1984;34:939–44.CrossRefPubMed

13.

Diagnostic and statistical manual of mental disorders: DSM-IV. 4th ed. ed. Washington, D.C.: American Psychiatric Association; 1995.

14.

Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303–8.CrossRefPubMed

15.

Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, et al. Mild cognitive impairment--beyond controversies, towards a consensus: report of the international working group on mild cognitive impairment. J Intern Med. 2004;256:240–6. doi:10.1111/j.1365-2796.2004.01380.x.CrossRefPubMed

16.

Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 2014;13:614–29. doi:10.1016/S1474-4422(14)70090-0.CrossRefPubMed

17.

Armstrong MJ, Litvan I, Lang AE, Bak TH, Bhatia KP, Borroni B, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013;80:496–503. doi:10.1212/WNL.0b013e31827f0fd1.CrossRefPubMedPubMedCentral

18.

Litvan I. Diagnosis and management of progressive supranuclear palsy. Semin Neurol. 2001;21:41–8.CrossRefPubMed

19.

Bergman I, Blomberg M, Almkvist O. The importance of impaired physical health and age in normal cognitive aging. Scand J Psychol. 2007;48:115–25. doi:10.1111/j.1467-9450.2007.00594.x.CrossRefPubMed

20.

Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55:306–19. doi:10.1002/ana.20009.CrossRefPubMed

21.

Hammers A, Allom R, Koepp MJ, Free SL, Myers R, Lemieux L, et al. Three-dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe. Hum Brain Mapp. 2003;19:224–47. doi:10.1002/hbm.10123.CrossRefPubMed

22.

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

23.

Steele JC, Richardson JC, Progressive OJ, Palsy S. A Heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and Pseudobulbar Palsy, Nuchal Dystonia and Dementia. Arch Neurol. 1964;10:333–59.CrossRefPubMed

24.

Nordberg A, Carter SF, Rinne J, Drzezga A, Brooks DJ, Vandenberghe R, et al. A European multicentre PET study of fibrillar amyloid in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2013;40:104–14. doi:10.1007/s00259-012-2237-2.CrossRefPubMed

25.

Nichols TE, Holmes AP. Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp. 2002;15:1–25.CrossRefPubMed

26.

Casanova R, Srikanth R, Baer A, Laurienti PJ, Burdette JH, Hayasaka S, et al. Biological parametric mapping: a statistical toolbox for multimodality brain image analysis. NeuroImage. 2007;34:137–43. doi:10.1016/j.neuroimage.2006.09.011.CrossRefPubMed

27.

Muller R, Buttner P. A critical discussion of intraclass correlation coefficients. Stat Med. 1994;13:2465–76.CrossRefPubMed

28.

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.CrossRefPubMed

29.

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. doi:10.1016/j.neuron.2013.07.037.CrossRefPubMed

30.

Chien DT, Szardenings AK, Bahri S, Walsh JC, Mu F, Xia C, et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F18]-T808. J Alzheimer’s Dis: JAD. 2014;38:171–84. doi:10.3233/JAD-130098.PubMed

31.

Braak H, Braak E. Alzheimer’s disease: striatal amyloid deposits and neurofibrillary changes. J Neuropathol Exp Neurol. 1990;49:215–24.CrossRefPubMed

32.

Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimer’s Dement: J Alzheimer’s Assoc. 2012;8:1–13. doi:10.1016/j.jalz.2011.10.007.CrossRef

33.

Forman MS, Zhukareva V, Bergeron C, Chin SS, Grossman M, Clark C, et al. Signature tau neuropathology in gray and white matter of corticobasal degeneration. Am J Pathol. 2002;160:2045–53. doi:10.1016/S0002-9440(10)61154-6.CrossRefPubMedPubMedCentral

34.

Josephs KA, Dickson DW. Diagnostic accuracy of progressive supranuclear palsy in the Society for Progressive Supranuclear Palsy brain bank. Mov Disord: Off J Mov Disord Soc. 2003;18:1018–26. doi:10.1002/mds.10488.CrossRef

35.

Boeve BF, Maraganore DM, Parisi JE, Ahlskog JE, Graff-Radford N, Caselli RJ, et al. Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology. 1999;53:795–800.CrossRefPubMed

36.

Mesulam MM, Weintraub S, Rogalski EJ, Wieneke C, Geula C, Bigio EH. Asymmetry and heterogeneity of Alzheimer’s and frontotemporal pathology in primary progressive aphasia. Brain: J Neurol. 2014;137:1176–92. doi:10.1093/brain/awu024.CrossRef

37.

Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76:1006–14. doi:10.1212/WNL.0b013e31821103e6.CrossRefPubMedPubMedCentral

38.

Nguyen LA, He H, Pham-Huy C. Chiral drugs: an overview. Int J Biomed Sci: IJBS. 2006;2:85–100.PubMedPubMedCentral

39.

Harada R, Okamura N, Furumoto S, Furukawa K, Ishiki A, Tomita N, et al. 18F-THK5351: a novel PET radiotracer for imaging neurofibrillary pathology in Alzheimer disease. J Nucl Med: Off Publ, Soc Nucl Med. 2016;57:208–14. doi:10.2967/jnumed.115.164848.CrossRef

40.

Tago T, Furumoto S, Okamura N, Harada R, Adachi H, Ishikawa Y, et al. Preclinical evaluation of [F]THK-5105 enantiomers: effects of chirality on its effectiveness as a Tau imaging radiotracer. Mol Imaging Biol: MIB: Off Publ Acad Mol Imaging. 2015. doi:10.1007/s11307-015-0879-8.

Title: Imaging in-vivo tau pathology in Alzheimer’s disease with THK5317 PET in a multimodal paradigm
Authors: Konstantinos Chiotis
Laure Saint-Aubert
Irina Savitcheva
Vesna Jelic
Pia Andersen
My Jonasson
Jonas Eriksson
Mark Lubberink
Ove Almkvist
Anders Wall
Gunnar Antoni
Agneta Nordberg
Publication date: 01-08-2016
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 9/2016
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-016-3363-z

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Springer Medicine

Imaging in-vivo tau pathology in Alzheimer’s disease with THK5317 PET in a multimodal paradigm

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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