Large inter- and intra-case variability of first generation tau PET ligand binding in neurodegenerative dementias
Large inter- and intra-case variability of first generation tau PET ligand binding in neurodegenerative dementias
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DOI：
10.1186/s40478-018-0535-z
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发表时间：
2018-05-01
影响因子：
7.1
通讯作者：
Sander, Kerstin
中科院分区：
文献类型：
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作者：
Wren, Melissa C.;Lashley, Tammaryn;Sander, Kerstin
用正电子发射断层扫描(PET)对病理性tau进行成像，有可能在活体内早期诊断痴呆和监测疾病进展，包括评估治疗措施。第一代tau PET示踪剂，包括咔唑氟他西平和THK系列的2-芳基喹啉，现在被用于临床研究；然而，人们对靶外结合和低灵敏度提出了担忧。为了确定由结构不同的tau配体描述的tau病理的本质，我们在原发和继发性tau病患者的死后人脑组织中进行了显微神经病理学评估。咔唑和2-芳基喹啉结合仅在阿尔茨海默病和1例额颞痴呆和帕金森病患者中观察到，该患者与17号染色体连锁，显示R406W MAPT突变。在终末期阿尔茨海默病病例中，咔唑T726和2-芳基喹啉THK-5117的荧光成像显示示踪剂结合的病例间和病例内的变异性很高，这一点得到了PET示踪剂[F-18]THK-5117的定量磷成像的证实。病理包涵体的显微镜分析显示，荧光示踪剂优先与过早的tau聚集体结合。虽然T726结合仅限于神经元tau，但THK-5117另外描述了神经性tau。我们的结果突出了第一代tau PET示踪剂的局限性，特别是病理性tau负荷和示踪剂结合之间缺乏相关性，早期疾病对tau的敏感性有限，以及病例间和病例内示踪剂结合的高度变异性。人们仍然担心，这些限制也可能影响下一代示踪剂，因为它们针对的是相同的高亲和力结合位点。因此，在身体组织研究中评估示踪剂结合与病理tau负荷的受试者间和受试者内的相关性，并在将其转化为临床研究之前严格评估新的tau PET示踪剂是至关重要的。
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 [F-18]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.