Department of Radiology, Mayo Clinic, Rochester, MN, USA.
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Acta Neuropathol Commun. 2016 Jun 13;4(1):58. doi: 10.1186/s40478-016-0315-6.
It is essential to determine the specificity of AV-1451 PET for tau in brain imaging by using pathological comparisons. We performed autoradiography in autopsy-confirmed Alzheimer disease and other neurodegenerative disorders to evaluate the specificity of AV-1451 binding for tau aggregates.
Tissue samples were selected that had a variety of dementia-related neuropathologies including Alzheimer disease, primary age-related tauopathy, tangle predominant dementia, non-Alzheimer disease tauopathies, frontotemporal dementia, parkinsonism, Lewy body disease and multiple system atrophy (n = 38). Brain tissue sections were stained for tau, TAR DNA-binding protein-43, and α-synuclein and compared to AV-1451 autoradiography on adjacent sections.
AV-1451 preferentially localized to neurofibrillary tangles, with less binding to areas enriched in neuritic pathology and less mature tau. The strength of AV-1451 binding with respect to tau isoforms in various neurodegenerative disorders was: 3R + 4R tau (e.g., AD) > 3R tau (e.g., Pick disease) or 4R tau. Only minimal binding of AV-1451 to TAR DNA-binding protein-43 positive regions was detected. No binding of AV-1451 to α-synuclein was detected. "Off-target" binding was seen in vessels, iron-associated regions, substantia nigra, calcifications in the choroid plexus, and leptomeningeal melanin.
Reduced AV-1451 binding in neuritic pathology compared to neurofibrillary tangles suggests that the maturity of tau pathology may affect AV-1451 binding and suggests complexity in AV-1451 binding. Poor association of AV-1451 with tauopathies that have preferential accumulation of either 4R tau or 3R tau suggests limited clinical utility in detecting these pathologies. In contrast, for disorders associated with 3R + 4R tau, such as Alzheimer disease, AV-1451 binds tau avidly but does not completely reflect the early stage tau progression suggested by Braak neurofibrillary tangle staging. AV-1451 binding to TAR DNA-binding protein-43 or TAR DNA-binding protein-43 positive regions can be weakly positive. Clinical use of AV-1451 will require a familiarity with distinct types of "off-target" binding.
通过病理学比较来确定 AV-1451 PET 对脑中 tau 的特异性是至关重要的。我们进行了尸检证实的阿尔茨海默病和其他神经退行性疾病的放射自显影，以评估 AV-1451 与 tau 聚集物结合的特异性。
选择了具有各种与痴呆相关的神经病理学的组织样本，包括阿尔茨海默病、原发性年龄相关性 tau 病、缠结为主的痴呆、非阿尔茨海默病 tau 病、额颞叶痴呆、帕金森病、路易体病和多系统萎缩（n=38）。对脑组织切片进行 tau、TAR DNA 结合蛋白-43 和 α-突触核蛋白染色，并与相邻切片的 AV-1451 放射自显影进行比较。
AV-1451 优先定位于神经纤维缠结，与富含神经原纤维病理和较不成熟 tau 的区域的结合较少。AV-1451 与各种神经退行性疾病中 tau 同工型的结合强度为：3R+4R tau（例如 AD）>3R tau（例如 Pick 病）或 4R tau。仅检测到 AV-1451 对 TAR DNA 结合蛋白-43 阳性区域的最小结合。未检测到 AV-1451 与 α-突触核蛋白的结合。在血管、铁相关区域、黑质、脉络丛钙化、软脑膜黑色素中观察到“脱靶”结合。
与神经纤维缠结相比，神经原纤维病理中 AV-1451 结合减少表明 tau 病理的成熟度可能影响 AV-1451 结合，并表明 AV-1451 结合的复杂性。AV-1451 与优先积累 4R tau 或 3R tau 的 tau 病的相关性差表明其在检测这些病变方面的临床应用有限。相比之下，对于与 3R+4R tau 相关的疾病，如阿尔茨海默病，AV-1451 强烈结合 tau，但不能完全反映 Braak 神经纤维缠结分期所提示的早期 tau 进展。AV-1451 与 TAR DNA 结合蛋白-43 或 TAR DNA 结合蛋白-43 阳性区域的结合可能呈弱阳性。AV-1451 的临床应用需要熟悉不同类型的“脱靶”结合。
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