Abstract
Imaging of pathological tau with positron emission tomography (PET) has the potential to allow early diagnosis of the dementias and monitoring of disease progression, including assessment of therapeutic interventions, in vivo. The first generation of tau PET tracers, including the carbazole flortaucipir and the 2-arylquinolines of the THK series, are now used in clinical research; however, concerns have been raised about off-target binding and low sensitivity.With the aim to determine the nature of tau pathology depicted by structurally distinct tau ligands we carried out a microscopic neuropathological evaluation in post-mortem human brain tissue of cases with primary and secondary tauopathies. Carbazole and 2-arylquinoline binding was only observed in cases with Alzheimer’s disease and one case with frontotemporal dementia and parkinsonism linked to chromosome 17 exhibiting a R406W MAPT mutation. In end stage Alzheimer’s disease cases, fluorescent imaging with the carbazole T726 and the 2-arylquinoline THK-5117 revealed high inter- and intra-case variability of tracer binding, and this was corroborated by quantitative phosphorimaging with the PET tracer [18F]THK-5117. Microscopic analysis of the pathological inclusions revealed that the fluorescent tracers preferentially bind to premature tau aggregates. Whilst T726 binding was limited to neuronal tau, THK-5117 additionally depicted neuritic tau. Neither tracer depicted tau in pre-symptomatic disease.Our results highlight limitations of the first generation of tau PET tracers, in particular lack of correlation between pathological tau load and tracer binding, limited sensitivity to tau in early disease, and high variability in tracer binding between and within cases. Concerns remain that these limitations may also affect the next generation tracers as they target the same high affinity binding site. Therefore, it is crucial to assess inter- and intra-subject correlation of tracer binding with pathological tau load in post-mortem tissue studies, and to rigorously assess novel tau PET tracers before translation into clinical studies.
Highlights
Dementia represents one of the most pressing public health challenges worldwide
We aimed to answer the following questions: 1) what is the nature of tau pathology that the first generation tau ligands depict in vivo; 2) do carbazoles and 2-arylquinolines differ in their binding profiles; 3) is the T808 binding site an appropriate target for the development of tau positron emission tomography (PET) tracers?
Alzheimer’s disease cases were classified as Braak & Braak stage VI and had pronounced tau pathology in the grey matter accounting for 25–35% of the surface of the respective flash frozen tissue sections (Fig. 1)
Summary
Dementia represents one of the most pressing public health challenges worldwide. A clinical diagnosis of the underlying disease causing the dementia remains challenging, at the early stages, and a definite confirmation is usually only obtained post-mortem through histopathological examination of the brain.Approximately 80% of dementia cases are associated with structural changes of the microtubule associatedWren et al Acta Neuropathologica Communications (2018) 6:34The first generation of tau selective ligands for noninvasive imaging with positron emission tomography (PET) have recently entered clinical studies. PET tracers from both compound classes have been reported to be suitable for staging of Alzheimer’s disease [30, 39, 40], and for differential diagnosis of Alzheimer’s disease and progressive supranuclear palsy [33, 47]. Some of these findings, in particular tracer binding to primary tauopathies, remain controversial, and are not supported by ex vivo studies on post-mortem brain tissue [13, 16, 22, 23, 29, 31, 37]. This highlights the importance of elucidating the interplay between the T808 binding site [50] and tau pathology
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