[18F]THK5317 imaging as a tool for predicting prospective cognitive decline in Alzheimer’s disease

Abstract

Cross-sectional studies have indicated potential for positron emission tomography (PET) in imaging tau pathology in Alzheimer’s disease (AD); however, its prognostic utility remains unproven. In a longitudinal, multi-modal, prognostic study of cognitive decline, 20 patients with a clinical biomarker-based diagnosis in the AD spectrum (mild cognitive impairment or dementia and a positive amyloid-beta PET scan) were recruited from the Cognitive Clinic at Karolinska University Hospital. The participants underwent baseline neuropsychological assessment, PET imaging with [18F]THK5317, [11C]PIB and [18F]FDG, magnetic resonance imaging, and in a subgroup cerebrospinal fluid (CSF) sampling, with clinical follow-up after a median 48 months (interquartile range = 32:56). In total, 11 patients declined cognitively over time, while 9 remained cognitively stable. The accuracy of baseline [18F]THK5317 binding in temporal areas was excellent at predicting future cognitive decline (area under the receiver operating curve 0.84–1.00) and the biomarker levels were strongly associated with the rate of cognitive decline (β estimate −33.67 to −31.02, p < 0.05). The predictive accuracy of the other baseline biomarkers was poor (area under the receiver operating curve 0.58–0.77) and their levels were not associated with the rate of cognitive decline (β estimate −4.64 to 15.78, p > 0.05). Baseline [18F]THK5317 binding and CSF tau levels were more strongly associated with the MMSE score at follow-up than at baseline (p < 0.05). These findings support a temporal dissociation between tau deposition and cognitive impairment, and suggest that [18F]THK5317 predicts future cognitive decline better than other biomarkers. The use of imaging markers for tau pathology could prove useful for clinical prognostic assessment and screening before inclusion in relevant clinical trials.

Clinical validity of increased cortical binding of tau ligands of the THK family and PBB3 on PET as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework

“…The ligands of the THK family have been the only ones from all developed tau PET ligands that were tested longitudinally in a phase 3 study at the time of writing this review [69]. The generalizability of these promising results is, however, subject to several gaps that remain to be filled as research priorities for assessing the clinical validity of the THK ligands: namely, the assessment of (1) the discriminative ability of the assay in pathology confirmed AD and HC samples for phase 2; (2) the accuracy of the biomarker to discriminate between AD and non-AD neurodegenerative disease in adequately powered studies; (3) the consistency of the antemortem and the histopathological measurements of tau pathology, which remains, so far, inconclusive; (4) covariates that are associated with the biomarker status in patients with AD and HCs; (5) the replicability of the available evidence about the biomarker's diagnostic performance at the MCI stage; (6) criteria of biomarker positivity.…”

“…Phase 3: primary aim 1: to evaluate the biomarker ability in the detection of the disease at the earliest clinical stage (MCI due to AD) using conversion to AD dementia as the reference standard A single small-scale monocentric study has, so far, investigated the accuracy of THK5317 in discriminating between amyloid-β positive cognitively impaired patients that will remain cognitively stable (considered being non-AD-related cognitive impairment) from those who deteriorated further cognitively to clinical AD dementia, with an average followup interval of 4 years [69]. According to the latter study, the accuracy of THK5317 in temporal regions of interest was excellent, up to 100%.…”

“…The only available study comparing the prognostic accuracy of THK5317 with that of FDG PET, tau assessment in the CSF, clinical atrophy rating on MRI, and neuropsychological measures reported that the THK5317 showed far greater accuracy than all other markers [69]. To the best of our knowledge, no study has yet attempted to assess the accuracy of the other ligands of the THK family or PBB3.…”

Clinical validity of second-generation tau PET tracers as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework

“…Phase 3. Secondary aim 4: To determine an interval able to detect a meaningful change of biomarker status or level in progressing MCI While longitudinal studies for the firstgeneration tau PET tracer have been examined up to f4 year follow-up in MCI patients [52,53], longitudinal studies for the second-generation tau PET tracers including prodromal disease stages are still underway.…”

Assessment of Tau Pathology as Measured by 18F-THK5317 and 18F-Flortaucipir PET and Their Relation to Brain Atrophy and Cognition in Alzheimer’s Disease

“…The same image processing protocol was applied to image data from both tracers. For all participants from both the KI and the ADNI cohorts, we segmented the T1-weighted MRI images into grey and white matter (GM and WM, respectively) tissue classes using SPM8 software's unified segmentation, using a corroborated pipeline from our group [24,29,30]. We then used the inverse non-linear transformation from the T1-weighted MRI segmentation step to warp the Hammers probabilistic atlas [31] from the Montreal Neurological Institute (MNI) space to each individual's native T1-weighted MRI space.…”