Intra-individual correlations between quantitative THK-5351 PET and MRI-derived cortical volume in Alzheimer’s disease differ according to disease severity and amyloid positivity

Autoři: Ji Eun Park aff001;  Jessica Yun aff001;  Sang Joon Kim aff001;  Woo Hyun Shim aff001;  Jungsu S. Oh aff002;  Minyoung Oh aff002;  Jee Hoon Roh aff003;  Sang Won Seo aff004;  Seung Jun Oh aff002;  Jae Seung Kim aff002
Působiště autorů: Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea aff001;  Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea aff002;  Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea aff003;  Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-ro, Kangnam-ku, Seoul, South Korea aff004
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226265



To assess the in vivo whole-brain relationship between uptake of [18F]THK-5351 on PET and cortical atrophy on structural MRI according to the presence and severity of Alzheimer’s disease (AD).

Materials and methods

Sixty-five participants (21 normal controls, 32 mild cognitive impairment [MCI] subjects, and 12 AD patients) were enrolled from a prospective multicenter clinical trial (NCT02656498). Structural MRI and [18F]THK-5351 PET were performed within a 2-month interval. Cortical volume and standardized uptake value ratios (SUVR) were calculated from MRI and PET images, respectively, for 35 FreeSurfer-derived cortical regions. Pearson’s correlation coefficients between SUVR and cortical volume were calculated for the same regions, and correlated regions were compared according to disease severity and β-amyloid PET positivity.


No significantly correlated regions were found in the normal controls. Negative correlations between SUVR and cortical volume were found in the MCI and AD groups, mainly in limbic locations in MCI and isocortical locations in AD. The AD group exhibited stronger correlations (r = −0.576–0.781) than the MCI group (r = 0.368–0.571). Hippocampal atrophy did not show any correlation with SUVR in the β-amyloid PET-negative group, but negatively correlated with SUVR (r = −0.494, P = .012) in the β-amyloid PET-positive group.


Regional THK-5351 uptake correlated more strongly with cortical atrophy in AD compared with MCI, thereby demonstrating a close relationship between the neuro-pathologic process and cortical atrophy. Hippocampal atrophy was associated with both β-amyloid and THK-5351 uptake, possibly reflecting an interaction between β-amyloid and tau deposition in the neurodegeneration process.

Klíčová slova:

Alzheimer's disease – Atrophy – Autopsy – Cognitive impairment – Hippocampus – Magnetic resonance imaging – Positron emission tomography – Temporal lobe


1. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta neuropathologica. 1991; 82: 239–259. doi: 10.1007/bf00308809 1759558

2. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta neuropathologica. 2006; 112: 389–404. doi: 10.1007/s00401-006-0127-z 16906426

3. Okamura N, Harada R, Furumoto S, Arai H, Yanai K, Kudo Y. Tau PET imaging in Alzheimer's disease. Curr Neurol Neurosci Rep. 2014; 14: 500. doi: 10.1007/s11910-014-0500-6 25239654

4. 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: 1762–1771. doi: 10.1093/brain/awu064 24681664

5. 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: 743–749. doi: 10.1212/01.wnl.0000324924.91351.7d 18765650

6. Sone D, Imabayashi E, Maikusa N, Okamura N, Furumoto S, Kudo Y, et al. Regional tau deposition and subregion atrophy of medial temporal structures in early Alzheimer's disease: A combined positron emission tomography/magnetic resonance imaging study. Alzheimers Dement (Amst). 2017; 9: 35–40. doi: 10.1016/j.dadm.2017.07.001 28856235

7. Wang L, Benzinger TL, Su Y, Christensen J, Friedrichsen K, Aldea P, et al. Evaluation of Tau Imaging in Staging Alzheimer Disease and Revealing Interactions Between beta-Amyloid and Tauopathy. JAMA Neurol. 2016; 73: 1070–1077. doi: 10.1001/jamaneurol.2016.2078 27454922

8. 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: 208–214. doi: 10.2967/jnumed.115.164848 26541774

9. 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: 263–269. doi: 10.1016/j.jalz.2011.03.005 WOS:000291239600003 21514250

10. Barthel H, Luthardt J, Becker G, Patt M, Hammerstein E, Hartwig K, et al. Individualized quantification of brain beta-amyloid burden: results of a proof of mechanism phase 0 florbetaben PET trial in patients with Alzheimer's disease and healthy controls. Eur J Nucl Med Mol Imaging. 2011; 38: 1702–1714. doi: 10.1007/s00259-011-1821-1 21547601

11. Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, et al. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron. 2002; 33: 341–355. doi: 10.1016/s0896-6273(02)00569-x 11832223

12. Desikan RS, Segonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage. 2006; 31: 968–980. doi: 10.1016/j.neuroimage.2006.01.021 16530430

13. Scholl M, Lockhart SN, Schonhaut DR, O'Neil JP, Janabi M, Ossenkoppele R, et al. PET Imaging of Tau Deposition in the Aging Human Brain. Neuron. 2016; 89: 971–982. doi: 10.1016/j.neuron.2016.01.028 26938442

14. Hulette CM, Welsh-Bohmer KA, Murray MG, Saunders AM, Mash DC, McIntyre LM. Neuropathological and neuropsychological changes in "normal" aging: evidence for preclinical Alzheimer disease in cognitively normal individuals. Journal of neuropathology and experimental neurology. 1998; 57: 1168–1174. doi: 10.1097/00005072-199812000-00009 9862640

15. LaPoint MR, Chhatwal JP, Sepulcre J, Johnson KA, Sperling RA, Schultz AP. The association between tau PET and retrospective cortical thinning in clinically normal elderly. Neuroimage. 2017; 157: 612–622. doi: 10.1016/j.neuroimage.2017.05.049 28545932

16. Sepulcre J, Schultz AP, Sabuncu M, Gomez-Isla T, Chhatwal J, Becker A, et al. In Vivo Tau, Amyloid, and Gray Matter Profiles in the Aging Brain. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2016; 36: 7364–7374. doi: 10.1523/JNEUROSCI.0639-16.2016 27413148

17. 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: 631–639. doi: 10.1212/wnl.42.3.631 1549228

18. 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. Archives of neurology. 1995; 52: 81–88. doi: 10.1001/archneur.1995.00540250089017 7826280

19. Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cerebral cortex. 1991; 1: 103–116. doi: 10.1093/cercor/1.1.103 1822725

20. Jack CR Jr, Petersen RC, Xu YC, O'Brien PC, Smith GE, Ivnik RJ, et al. Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology. 1999; 52: 1397–1403. doi: 10.1212/wnl.52.7.1397 10227624

21. Henneman WJ, Sluimer JD, Barnes J, van der Flier WM, Sluimer IC, Fox NC, et al. Hippocampal atrophy rates in Alzheimer disease: added value over whole brain volume measures. Neurology. 2009; 72: 999–1007. doi: 10.1212/01.wnl.0000344568.09360.31 19289740

22. Devanand DP, Pradhaban G, Liu X, Khandji A, De Santi S, Segal S, et al. Hippocampal and entorhinal atrophy in mild cognitive impairment: prediction of Alzheimer disease. Neurology. 2007; 68: 828–836. doi: 10.1212/01.wnl.0000256697.20968.d7 17353470

23. Small SA, Duff K. Linking Abeta and tau in late-onset Alzheimer's disease: a dual pathway hypothesis. Neuron. 2008; 60: 534–542. doi: 10.1016/j.neuron.2008.11.007 19038212

24. Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. Journal of neuropathology and experimental neurology. 2012; 71: 362–381. doi: 10.1097/NEN.0b013e31825018f7 22487856

25. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med. 2011; 1: a006189. doi: 10.1101/cshperspect.a006189 22229116

26. 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. 2017; 9: 25. doi: 10.1186/s13195-017-0253-y 28359327

27. Jang YK, Lyoo CH, Park S, Oh SJ, Cho H, Oh M, et al. Head to head comparison of [(18)F] AV-1451 and [(18)F] THK5351 for tau imaging in Alzheimer's disease and frontotemporal dementia. Eur J Nucl Med Mol Imaging. 2018; 45: 432–442. doi: 10.1007/s00259-017-3876-0 29143870

28. Harada R, Ishiki A, Kai H, Sato N, Furukawa K, Furumoto S, et al. Correlations of (18)F-THK5351 PET with Postmortem Burden of Tau and Astrogliosis in Alzheimer Disease. J Nucl Med. 2018; 59: 671–674. doi: 10.2967/jnumed.117.197426 28864633

29. Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, et al. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology. 2004; 62: 925–931. doi: 10.1212/01.wnl.0000115115.98960.37 15037694

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