慢性创伤性脑病(CTE)是与重复性头部创伤相关的tau病。没有经过验证的CTE体内生物标志物,只能在尸检时做出明确的诊断。最近的研究表明,正电子发射断层扫描(PET)示踪剂AV-1451(Flortaucipir)对阿尔茨海默氏症(AD)大脑中的成对螺旋丝(PHF)-tau聚集体具有高结合亲和力,但对其他tau病变的亲和力相对较低,如颞叶变性(FTLD)-tau,进行性核上性麻痹(PSP)或皮质基底变性(CBD)。鲜为人知,然而,关于该配体与CTE含tau病变的结合谱。
研究[18F]-AV-1451在病理证实的CTE死后脑组织样品上的结合特性。
我们进行了[18F]-AV-1451荧光屏和高分辨率放射自显影,通过免疫组织化学和蛋白质印迹以及含有海马的脑块中的tau接种活性测定进行定量tau测量,颞叶上皮质,额叶上皮质,5例CTE患者的下顶叶皮质和枕叶皮质,跨越疾病阶段:II-III期(n=1),阶段III(n=3),和阶段IV(n=1)。重要的是,这些大脑中存在低或无伴随的经典AD病理。
尽管在所有CTE大脑的多个区域都存在丰富的tau聚集体,通过放射自显影只能检测到微弱或没有[18F]-AV-1451结合信号。唯一的例外是在五例中的两例中,存在仅限于脉络丛和脑膜区域的强信号。Tau免疫染色和硫黄素-S染色排除了这些区域中tau聚集体的存在。高分辨率核乳剂放射自显影显示,软脑膜黑素细胞的存在是这种脱靶结合的组织学来源。异常高度磷酸化tau物种的水平,通过Western印迹检测,与AD相比,发现CTE病例的提取物和tau播种活性均较低。
AV-1451对于体内选择性和可靠地检测CTE中的tau聚集体可能具有有限的效用。疾病特异性tau构象的存在可能解释了该示踪剂对不同tau病变中tau病变的差异结合亲和力。
Chronic traumatic encephalopathy (CTE) is a tauopathy associated to repetitive head trauma. There are no validated in vivo biomarkers of CTE and a definite diagnosis can only be made at autopsy. Recent studies have shown that positron emission tomography (PET) tracer AV-1451 (Flortaucipir) exhibits high binding affinity for paired helical filament (PHF)-tau aggregates in Alzheimer (AD) brains but relatively low affinity for tau lesions in other tauopathies like temporal lobal degeneration (FTLD)-tau, progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). Little is known, however, about the binding profile of this ligand to the tau-containing lesions of CTE.
To study the binding properties of [18F]-AV-1451 on pathologically confirmed CTE postmortem brain tissue samples.
We performed [18F]-AV-1451 phosphor screen and high resolution
autoradiography, quantitative tau measurements by immunohistochemistry and Western blot and tau seeding activity assays in brain blocks containing hippocampus, superior temporal cortex, superior frontal cortex, inferior parietal cortex and occipital cortex from 5 cases of CTE, across the stages of disease: stage II-III (n = 1), stage III (n = 3), and stage IV (n = 1). Importantly, low or no concomitant classic AD pathology was present in these brains.
Despite the presence of abundant tau aggregates in multiple regions in all CTE brains, only faint or no [18F]-AV-1451 binding signal could be detected by
autoradiography. The only exception was the presence of a strong signal confined to the region of the choroid plexus and the meninges in two of the five cases. Tau immunostaining and Thioflavin-S staining ruled out the presence of tau aggregates in those regions. High resolution nuclear emulsion
autoradiography revealed the presence of leptomeningeal melanocytes as the histologic source of this off-target binding. Levels of abnormally hyperphosphorylated tau species, as detected by Western Blotting, and tau seeding activity were both found to be lower in extracts from cases CTE when compared to AD.
AV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in CTE. The existence of disease-specific tau conformations may likely explain the differential binding affinity of this tracer for tau lesions in different tauopathies.