Differences in gray and white matter 18F-THK5351 uptake between behavioral-variant frontotemporal dementia and other dementias

  • Hye Joo Son
  • Jungsu S. Oh
  • Jee Hoon Roh
  • Sang Won Seo
  • Minyoung Oh
  • Sang Ju Lee
  • Seung Jun Oh
  • Jae Seung KimEmail author
Original Article



We investigated the regional distribution of 18F-THK5351 uptake in gray (GM) and white matter (WM) in patients with behavioral-variant frontotemporal dementia (bvFTD) and compared it with that in patients with Alzheimer’s disease (AD) or semantic dementia (SD).


18F-THK-5351 positron emission tomography (PET), 18F-florbetaben PET, magnetic resonance imaging, and neuropsychological testing were performed in 103 subjects including 30, 24, 9, and 8 patients with mild cognitive impairment, AD, bvFTD, and SD, respectively, and 32 normal subjects. Standardized uptake value ratios (SUVRs) of 18F-THK-5351 PET images were measured from six GM and WM regions using cerebellar GM as reference. GM and WM SUVRs and WM/GM ratios, the relationship between GM SUVR and WM/GM ratio, and correlation between SUVR and cognitive function were compared.


In AD, both parietal GM (p < 0.001) and WM (p < 0.001) SUVRs were higher than in bvFTD. In AD and SD, the WM/GM ratio decreased as the GM SUVR increased, regardless of lobar region. In AD, memory function correlated with parietal GM (ρ = −0.74, p < 0.001) and WM (ρ = −0.53, p < 0.001) SUVR. In SD, language function correlated with temporal GM SUVR (ρ = −0.69, p = 0.006). The frontal WM SUVR was higher in bvFTD than in AD (p = 0.003) or SD (p = 0.017). The frontal WM/GM ratio was higher in bvFTD than in AD (p < 0.001). In bvFTD, the WM/GM ratio increased more prominently than the GM SUVR only in the frontal lobe (R2 = 0.026). In bvFTD, executive function correlated with frontal WM SUVR (ρ = −0.64, p = 0.014).


Frontal WM 18F-THK5351 uptake was higher in bvFTD than in other dementias. The increase in frontal WM uptake was greater than the increase in GM uptake and correlated with executive function. This suggests that frontal lobe WM 18F-THK5351 uptake reflects neuropathological differences between bvFTD and other dementias.


Behavioral-variant frontotemporal dementia 18F-THK-5351 PET White matter Tau 



This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (HI14C2768).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Written informed consent was obtained from all individual participants included in the study.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Supplementary material

259_2018_4125_MOESM1_ESM.pdf (1009 kb)
ESM 1 (PDF 1008 kb)


  1. 1.
    Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 2007;8:663–72. Scholar
  2. 2.
    Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998;51:1546–54.CrossRefGoogle Scholar
  3. 3.
    Siri S, Benaglio I, Frigerio A, Binetti G, Cappa SF. A brief neuropsychological assessment for the differential diagnosis between frontotemporal dementia and Alzheimer’s disease. Eur J Neurol. 2001;8:125–32.CrossRefGoogle Scholar
  4. 4.
    Beach TG, Monsell SE, Phillips LE, Kukull W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer disease centers, 2005-2010. J Neuropathol Exp Neurol. 2012;71:266–73. Scholar
  5. 5.
    Ossenkoppele R, Pijnenburg YA, Perry DC, Cohn-Sheehy BI, Scheltens NM, Vogel JW, et al. The behavioural/dysexecutive variant of Alzheimer’s disease: clinical, neuroimaging and pathological features. Brain. 2015;138:2732–49. Scholar
  6. 6.
    Rabinovici GD, Rosen HJ, Alkalay A, Kornak J, Furst AJ, Agarwal N, et al. Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD. Neurology. 2011;77:2034–42. Scholar
  7. 7.
    Borroni B, Brambati SM, Agosti C, Gipponi S, Bellelli G, Gasparotti R, et al. Evidence of white matter changes on diffusion tensor imaging in frontotemporal dementia. Arch Neurol. 2007;64:246–51. Scholar
  8. 8.
    Taipa R, Brochado P, Robinson A, Reis I, Costa P, Mann DM, et al. Patterns of microglial cell activation in Alzheimer disease and frontotemporal lobar degeneration. Neurodegener Dis. 2017;17:145–54. Scholar
  9. 9.
    Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol. 2014;14:463–77. Scholar
  10. 10.
    Leyns CEG, Holtzman DM. Glial contributions to neurodegeneration in tauopathies. Mol Neurodegener. 2017;12:50. Scholar
  11. 11.
    Sander K, Lashley T, Gami P, Gendron T, Lythgoe MF, Rohrer JD, et al. Characterization of tau positron emission tomography tracer [(18)F]AV-1451 binding to postmortem tissue in Alzheimer’s disease, primary tauopathies, and other dementias. Alzheimers Dement. 2016;12:1116–24. Scholar
  12. 12.
    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. 2016;57:208–14. Scholar
  13. 13.
    Ng KP, Pascoal TA, Mathotaarachchi S, Therriault J, Kang MS, Shin M, et al. Monoamine oxidase B inhibitor, selegiline, reduces (18)F-THK5351 uptake in the human brain. Alzheimers Res Ther. 2017;9:25. Scholar
  14. 14.
    Harada R, Ishiki A, Kai H, Sato N, Furukawa K, Furumoto S, et al. Correlations of (18)F-THK5351 PET with post-mortem burden of tau and astrogliosis in Alzheimer’s disease. J Nucl Med. 2017.
  15. 15.
    Kang Y, Na DL, Hahn S. Seoul Neuropsychological Screening Battery. Incheon: Human Brain Research & Consulting Co.; 2003.Google Scholar
  16. 16.
    McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:263–9. Scholar
  17. 17.
    Petersen RC, Smith GE, Waring SC, Ivnik RJ, Kokmen E, Tangelos EG. Aging, memory, and mild cognitive impairment. Int Psychogeriatr. 1997;9(Suppl 1):65–9.CrossRefGoogle Scholar
  18. 18.
    Knopman DS, Kramer JH, Boeve BF, Caselli RJ, Graff-Radford NR, Mendez MF, et al. Development of methodology for conducting clinical trials in frontotemporal lobar degeneration. Brain. 2008;131:2957–68. Scholar
  19. 19.
    Thomas BA, Erlandsson K, Modat M, Thurfjell L, Vandenberghe R, Ourselin S, et al. The importance of appropriate partial volume correction for PET quantification in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2011;38:1104–19. Scholar
  20. 20.
    Ossenkoppele R, Schonhaut DR, Scholl M, Lockhart SN, Ayakta N, Baker SL, et al. Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease. Brain. 2016;139:1551–67. Scholar
  21. 21.
    Schofield E, Kersaitis C, Shepherd CE, Kril JJ, Halliday GM. Severity of gliosis in Pick’s disease and frontotemporal lobar degeneration: tau-positive glia differentiate these disorders. Brain. 2003;126:827–40.CrossRefGoogle Scholar
  22. 22.
    Shi J, Shaw CL, Du Plessis D, Richardson AM, Bailey KL, Julien C, et al. Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation. Acta Neuropathol. 2005;110:501–12. Scholar
  23. 23.
    Serrano-Pozo A, Mielke ML, Gomez-Isla T, Betensky RA, Growdon JH, Frosch MP, et al. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am J Pathol. 2011;179:1373–84. Scholar
  24. 24.
    Lu PH, Lee GJ, Shapira J, Jimenez E, Mather MJ, Thompson PM, et al. Regional differences in white matter breakdown between frontotemporal dementia and early-onset Alzheimer’s disease. J Alzheimers Dis. 2014;39:261–9. Scholar
  25. 25.
    Zhang Y, Schuff N, Du AT, Rosen HJ, Kramer JH, Gorno-Tempini ML, et al. White matter damage in frontotemporal dementia and Alzheimer’s disease measured by diffusion MRI. Brain. 2009;132:2579–92. Scholar
  26. 26.
    Hardy J, Revesz T. The spread of neurodegenerative disease. N Engl J Med. 2012;366:2126–8. Scholar
  27. 27.
    Tartaglia MC, Zhang Y, Racine C, Laluz V, Neuhaus J, Chao L, et al. Executive dysfunction in frontotemporal dementia is related to abnormalities in frontal white matter tracts. J Neurol. 2012;259:1071–80. Scholar
  28. 28.
    Avants BB, Cook PA, Ungar L, Gee JC, Grossman M. Dementia induces correlated reductions in white matter integrity and cortical thickness: a multivariate neuroimaging study with sparse canonical correlation analysis. NeuroImage. 2010;50:1004–16. Scholar
  29. 29.
    Fowler JS, Volkow ND, Wang GJ, Logan J, Pappas N, Shea C, et al. Age-related increases in brain monoamine oxidase B in living healthy human subjects. Neurobiol Aging. 1997;18:431–5.CrossRefGoogle Scholar
  30. 30.
    Hodges JR, Mitchell J, Dawson K, Spillantini MG, Xuereb JH, McMonagle P, et al. Semantic dementia: demography, familial factors and survival in a consecutive series of 100 cases. Brain. 2010;133:300–6. Scholar
  31. 31.
    Spinelli EG, Mandelli ML, Miller ZA, Santos-Santos MA, Wilson SM, Agosta F, et al. Typical and atypical pathology in primary progressive aphasia variants. Ann Neurol. 2017;81:430–43. Scholar
  32. 32.
    Josephs KA, Hodges JR, Snowden JS, Mackenzie IR, Neumann M, Mann DM, et al. Neuropathological background of phenotypical variability in frontotemporal dementia. Acta Neuropathol. 2011;122:137–53. Scholar
  33. 33.
    Brettschneider J, Del Tredici K, Irwin DJ, Grossman M, Robinson JL, Toledo JB, et al. Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD). Acta Neuropathol. 2014;127:423–39. Scholar
  34. 34.
    Lee H, Seo S, Lee SY, Jeong HJ, Woo SH, Lee KM, et al. [18F]-THK5351 PET imaging in patients with semantic variant primary progressive aphasia. Alzheimer Dis Assoc Disord. 2018;32(1):62–9. Scholar
  35. 35.
    Bevan-Jones WR, Cope TE, Jones PS, Passamonti L, Hong YT, Fryer TD, et al. [(18)F]AV-1451 binding in vivo mirrors the expected distribution of TDP-43 pathology in the semantic variant of primary progressive aphasia. J Neurol Neurosurg Psychiatry. 2017.
  36. 36.
    Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol. 2007;114:5–22. Scholar
  37. 37.
    Downey LE, Mahoney CJ, Buckley AH, Golden HL, Henley SM, Schmitz N, et al. White matter tract signatures of impaired social cognition in frontotemporal lobar degeneration. Neuroimage Clin. 2015;8:640–51. Scholar
  38. 38.
    Zhou J, Greicius MD, Gennatas ED, Growdon ME, Jang JY, Rabinovici GD, et al. Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer’s disease. Brain. 2010;133:1352–67.CrossRefGoogle Scholar
  39. 39.
    Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H, et al. Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci. 2007;27:2349–56. Scholar
  40. 40.
    Spina S, Schonhaut DR, Boeve BF, Seeley WW, Ossenkoppele R, O’Neil JP, et al. Frontotemporal dementia with the V337M MAPT mutation: tau-PET and pathology correlations. Neurology. 2017;88(8):758–66. Scholar
  41. 41.
    Jang YK, Lyoo CH, Park S, Oh SJ, Cho H, Oh M, et al. Head to head comparison of [18F] AV-1451 and [18F] THK5351 for tau imaging in Alzheimer’s disease and frontotemporal dementia. Eur J Nucl Med Mol Imaging. 2018;45(3):432–42. Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Hye Joo Son
    • 1
  • Jungsu S. Oh
    • 1
  • Jee Hoon Roh
    • 2
  • Sang Won Seo
    • 3
  • Minyoung Oh
    • 1
  • Sang Ju Lee
    • 1
  • Seung Jun Oh
    • 1
  • Jae Seung Kim
    • 1
    Email author
  1. 1.Department of Nuclear Medicine, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
  2. 2.Department of Neurology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
  3. 3.Department of Neurology, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulRepublic of Korea

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