Non-invasive assessment of Alzheimer’s disease neurofibrillary pathology using 18F-THK5105 PET

Abstract

Non-invasive imaging of tau pathology in the living brain would be useful for accurately diagnosing Alzheimer's disease, tracking disease progression, and evaluating the treatment efficacy of disease-specific therapeutics. In this study, we evaluated the clinical usefulness of a novel tau-imaging positron emission tomography tracer 18F-THK5105 in 16 human subjects including eight patients with Alzheimer's disease (three male and five females, 66-82 years) and eight healthy elderly controls (three male and five females, 63-76 years). All participants underwent neuropsychological examination and 3D magnetic resonance imaging, as well as both 18F-THK5105 and 11C-Pittsburgh compound B positron emission tomography scans. Standard uptake value ratios at 90-100 min and 40-70 min post-injection were calculated for 18F-THK5105 and 11C-Pittsburgh compound B, respectively, using the cerebellar cortex as the reference region. As a result, significantly higher 18F-THK5105 retention was observed in the temporal, parietal, posterior cingulate, frontal and mesial temporal cortices of patients with Alzheimer's disease compared with healthy control subjects. In patients with Alzheimer's disease, the inferior temporal cortex, which is an area known to contain high densities of neurofibrillary tangles in the Alzheimer's disease brain, showed prominent 18F-THK5105 retention. Compared with high frequency (100%) of 18F-THK5105 retention in the temporal cortex of patients with Alzheimer's disease, frontal 18F-THK5105 retention was less frequent (37.5%) and was only observed in cases with moderate-to-severe Alzheimer's disease. In contrast, 11C-Pittsburgh compound B retention was highest in the posterior cingulate cortex, followed by the ventrolateral prefrontal, anterior cingulate, and superior temporal cortices, and did not correlate with 18F-THK5105 retention in the neocortex. In healthy control subjects, 18F-THK5105 retention was ∼10% higher in the mesial temporal cortex than in the neocortex. Notably, unlike 11C-Pittsburgh compound B, 18F-THK5105 retention was significantly correlated with cognitive parameters, hippocampal and whole brain grey matter volumes, which was consistent with findings from previous post-mortem studies showing significant correlations of neurofibrillary tangle density with dementia severity or neuronal loss. From these results, 18F-THK5105 positron emission tomography is considered to be useful for the non-invasive assessment of tau pathology in the living brain. This technique would be applicable to the longitudinal evaluation of tau deposition and allow a better understanding of the pathophysiology of Alzheimer's disease.

Structure–Activity Relationship of 2-Arylquinolines as PET Imaging Tracers for Tau Pathology in Alzheimer Disease

“…Previously, we demonstrated the potential of THK compounds to image AD tau pathology in a PET study, although visual PET image inspection was complicated as a result of the relatively high nonspecific binding of the compounds in white matter (13,19). For further structural optimization of THK compounds, we synthesized 2-AQ derivatives including pyridine derivatives and evaluated the relationship between their structures and performance as a tau PET probe.…”

“…Similar to Ab probes, most tau probes are small molecules radiolabeled with 11 C or 18 F and have planar aromatic rings that enable them to bind to the b-sheet structure of tau aggregates. First-in-human PET studies in AD or other tauopathies of some tau probes have already been performed using novel tau tracers (11)(12)(13).…”

“…Since then, we have been developing 2-arylquinoline (2-AQ) derivatives for tau PET imaging (15-17) and 3 18 F-labeled derivatives, 18 F-THK-523, 18 F-THK-5105, and 18 F-THK-5117, have already been evaluated in clinical studies (13,18,19). In recent basic and clinical studies, 18 F-THK-5117 demonstrated high binding selectivity and affinity for tau over Ab pathology and better pharmacokinetics in the living brain than other THK probes (18).…”

Mind the gaps—advancing research into short-term and long-term neuropsychological outcomes of youth sports-related concussions

“…Early imaging results with 18 F-T807, 18 F-T808 and 18 F-THK5105 are proving to be useful in confirming the presence of tauopathy in various clinical situations, including AD. [178][179][180] In a recent AD study, the magnitude of tau tracer signal correlated positively with the stage of disease and severity of cognitive impairment. 180 A third tau PET tracer, 11 C-PBB3, has been tested in healthy individuals and patients with AD, and may be able to detect non-AD conformations of tau.…”

“…[178][179][180] In a recent AD study, the magnitude of tau tracer signal correlated positively with the stage of disease and severity of cognitive impairment. 180 A third tau PET tracer, 11 C-PBB3, has been tested in healthy individuals and patients with AD, and may be able to detect non-AD conformations of tau. 181 In addition, a recent report contains the first description of tauopathy imaging in a living person with suspected sports-associated CTE.…”