An autoradiographic evaluation of AV-1451 Tau PET in dementia.
An autoradiographic evaluation of AV-1451 Tau PET in dementia.
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DOI：
10.1186/s40478-016-0315-6
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发表时间：
2016-06-13
影响因子：
7.1
通讯作者：
Murray ME
中科院分区：
文献类型：
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作者：
Lowe VJ;Curran G;Fang P;Liesinger AM;Josephs KA;Parisi JE;Kantarci K;Boeve BF;Pandey MK;Bruinsma T;Knopman DS;Jones DT;Petrucelli L;Cook CN;Graff-Radford NR;Dickson DW;Petersen RC;Jack CR Jr;Murray ME
通过使用病理学比较来确定AV-1451 PET对脑成像中tau的特异性是至关重要的。我们对尸检证实的阿尔茨海默病和其他神经退行性疾病进行了放射自显影，以评估AV-1451与tau聚集体结合的特异性。选择具有多种痴呆相关神经病理学的组织样品，包括阿尔茨海默病、原发性年龄相关tau蛋白病、缠结主导型痴呆、非阿尔茨海默病tau蛋白病、额颞叶痴呆、帕金森综合征、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，并与相邻切片上的AV-1451放射自显影进行比较。AV-1451优先定位于神经元缠结，与神经炎病理学富集的区域结合较少，tau成熟度较低。AV-1451与各种神经退行性疾病中tau亚型的结合强度为：3R +4 R tau（例如，AD）> 3R tau（例如，Pick病）或4 R tau。仅检测到AV-1451与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、脉络丛钙化和软脑膜黑色素中观察到“脱靶”结合。与神经纤维缠结相比，神经炎病理学中AV-1451结合减少表明tau病理学的成熟可能影响AV-1451结合，并表明AV-1451结合的复杂性。AV-1451与具有4 R tau或3R tau的优先积累的tau蛋白病的不良关联表明在检测这些病理中的有限临床效用。相反，对于与3R +4 R tau相关的疾病，例如阿尔茨海默病，AV-1451强烈结合tau，但不能完全反映Braak神经元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阳性区域的结合可为弱阳性。AV-1451的临床使用需要熟悉不同类型的“脱靶”结合。本文的在线版本（doi：10.1186/s40478-016-0315-6）包含补充材料，可供授权用户使用。
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. The online version of this article (doi:10.1186/s40478-016-0315-6) contains supplementary material, which is available to authorized users.