Patterns of Distribution of 18F-THK5351 Positron Emission Tomography in Alzheimer’s Disease Continuum

Abstract

Background: Alzheimer’s disease (AD) is conceptualized as a biological continuum encompassing the preclinical (clinically asymptomatic but with evidence of AD pathology) and clinical (symptomatic) phases. Objective: Using 18F-THK5351 as a tracer that binds to both tau and MAO-B, we investigated the changes in 18F-THK5351 accumulation patterns in AD continuum individuals with positive amyloid PET consisting of cognitively normal individuals (CNp), amnestic mild cognitive impairment (aMCI), and AD and cognitively normal individuals (CNn) with negative amyloid PET. Methods: We studied 69 individuals (32 CNn, 11 CNp, 9 aMCI, and 17 AD) with structural magnetic resonance imaging, 11C-Pittsburgh compound-B (PIB) and 18F-THK5351 PET, and neuropsychological assessment. 18F-THK5351 accumulation was evaluated with visual analysis, voxel-based analysis and combined region of interest (ROI)-based analysis corresponding to Braak neurofibrillary tangle stage. Results: On visual analysis, 18F-THK5351 accumulation was increased with stage progression in the AD continuum. On voxel-based analysis, there was no statistical difference in 18F-THK5351 accumulation between CNp and CNn. However, a slight increase of the bilateral posterior cingulate gyrus in aMCI and definite increase of the bilateral parietal temporal association area and posterior cingulate gyrus/precuneus in AD were detected compared with CNn. On ROI-based analyses, 18F-THK5351 accumulation correlated positively with supratentorial 11C-PIB accumulation and negatively with the hippocampal volume and neuropsychological assessment. Conclusion: The AD continuum showed an increase in 18F-THK5351 with stage progression, suggesting that 18F-THK5351 has the potential to visualize the severity of tau deposition and neurodegeneration in accordance with the AD continuum.

The Use of Tau PET to Stage Alzheimer Disease According to the Braak Staging Framework

“…In another study, individuals classified as Aβ-negative CU, Aβ-positive CU, Aβ-positive MCI, and Aβ-positive AD showed a trend toward longitudinal tau accumulation predominantly in Braak I–II, I–III, IV–V, and V–VI ROIs, respectively ( 25 ). In Nihashi et al., 18 F-THK5351 binding in Braak ROIs did not differ between Aβ-positive and Aβ-negative CU individuals ( 23 ). MCI and AD individuals had higher binding than CU participants in Braak I–IV ROIs and in all Braak ROIs, respectively ( 23 ).…”

“…For stage VI, the topographic definition was relatively similar among studies, with the presence of the paracentral, postcentral, and precentral gyri highlighted in most descriptions ( 11 , 17 , 18 , 20 , 22 , 28 ). Divergence was found in the allocation of the cuneus: studies using second-generation ligands associated this structure with stage V ( 17 , 22 , 25 , 26 ), and those using first-generation ligands associated it with stage VI ( 11 , 18 , 20 , 21 , 23 , 28 ).…”

Evaluation of advanced, pathophysiologic new targets for imaging of CNS

“…THK5117 and THK523 were primary ligands of the THK group and for healthy control (HC) they exhibited large amount of white matter retention; it was continuously enhanced over the group and the final compound [ 18 F]THK5351 showed much improved results as compared with starting compounds. Maximum uptake in HC was observed for [ 18 F]AV‐1451 (Leuzy et al, 2022; Nihashi et al, 2022; Pascoal et al, 2020; S. Roy et al, 2021).…”

Amyloid and Tau Positron Emission Tomography Imaging in Alzheimer’s Disease and Other Tauopathies

“…Autoradiographic data from [ 18 F]THK5105 indicated selective recognition of NFTs and neuropil threads in the hippocampus of AD patients (Lemoine et al, 2017). Nonetheless, off-target binding of [ 18 F]THK5351 to monoamine oxidase B (MAO-B) in the basal ganglia and cortex remains a major drawback when interpreting PET images (Harada et al, 2016;Ng et al, 2017;Nihashi et al, 2021). First-generation tau tracers [ 18 F]THK5351, [ 11 C]PBB3 and [ 18 F] flortaucipir all bind to the 3R + 4R combination of tau as in AD (Table 1; Chien et al, 2013;Maruyama et al, 2013;Okamura et al, 2013;Xia et al, 2013;Harada et al, 2016;Betthauser et al, 2017;Ono et al, 2017).…”

“…Chiotis et al showed that [ 18 F]THK5317 accurately predicts the degree of cognitive decline in patients with AD (Chiotis et al, 2020). Nihashi et al (2021) suggested that the quantity of [ 18 F]THK5351 uptake in the brain of AD patients inversely correlated with hippocampal volume and neuropsychological assessment, implying that [ 18 F]THK5351 may be a candidate for monitoring AD disease progression. Ezura et al (2021) compared differential binding of [ 18 F]THK5351 to different tauopathies and found that high [ 18 F]THK5351 uptake was detected in the precentral and postcentral gyri of CBD patients, in the midbrain of PSP patients and in the parahippocampal gyri of AD patients compared to healthy controls, clearly distinguishing different tauopathies.…”