Selective tau seeding assays and isoform-specific antibodies define neuroanatomic distribution of progressive supranuclear palsy pathology arising in Alzheimer's disease.
Selective tau seeding assays and isoform-specific antibodies define neuroanatomic distribution of progressive supranuclear palsy pathology arising in Alzheimer's disease.
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DOI：
10.1007/s00401-022-02480-x
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发表时间：
2022-10
影响因子：
12.7
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阿尔茨海默氏病神经病理改变 (ADNC) 背景下的早期进行性核上性麻痹 (PSP) 病理学很少有报道（有关重要的先前工作，请参阅补充表 1）[1]。这些工作表明，AD 相关 3R/4R tau 蛋白病和 PSP 相关 4R tau 蛋白病的刻板神经解剖学分布在这种情况下得以保留；然而，这还没有经过严格审查。最近，我们和其他人开发了异构体特异性 tau 抗体（RD3、RD4 和 AD 特异性 GT38）和异构体选择性 tau 播种测定（3R/4R 和 4R 实时震动诱导转换 [RT-QuIC]）（方法和参考文献在补充材料中），我们假设应该描绘出同时发生的 3R/4R 和 4R 的神经解剖学定位。 4R-tau 病理学。我们在 5 例伴有 PSP（“ADNC+ PSPi”）病理的高 ADNC 病例中测试了这一假设，结果发现，首先，4R PSP 和 3R/4R AD 病理的神经解剖学分布在 ADNC+ PSPi 中是保守的，其次，RT-QuIC 可以在混合 tau 病理的病例中强有力地区分 3R/4R 与 4R 病理的神经解剖学分布，这表明它可作为询问的工具。病理生理学。我们回顾了 1296 例中度或高度 ADNC 的尸检病例，并确定了 5 例 (0.3%) 偶然并发 PSP 病理（表 1 了解更多临床和病理信息）。发病年龄为 72±3.8 岁，病程为 11±2.1 年（平均值±SD）。 2例患有轻度帕金森症；一名患者在症状出现 5 年后出现步态障碍。没有病例符合可能或可能的 PSP 的 NINDS-SPSP 或 MDS 标准 [2]。病例3在整个大脑中存在广泛的与衰老相关的tau蛋白星形胶质细胞病（ARTAG，4R tau蛋白病）。对脑桥、中脑、海马、基底神经节、颞叶皮层、中额叶进行磷酸tau蛋白（AT8）、3R-tau蛋白（RD3）、4R-tau蛋白（RD4）和AD特异性tau蛋白（GT38）的免疫组织化学和免疫荧光检查皮质和枕叶皮质（方法见补充）。在 ADNC+ PSPi 中，我们可以通过包涵体的染色特征和形态来区分 AD 病理学和 PSP 病理学：所有病理性磷酸化 tau 包涵体均用 AT8 染色； AD 神经原纤维缠结 (NFT)，但不是用 GT38 和 RD3 染色的 PSP 病理学； PSP 病理学用 RD4 染色，但不用 GT38 染色。与每种病理学的神经解剖学分布一致，GT38阳性NFT在中额皮质和海马中丰富，而RD4阳性星形胶质细胞和少突胶质细胞在中额白质和基底神经节中突出（图1a，S1）。半定量区域评分表明，五例病例中 AD 与 PSP 病理学的神经解剖学分布相似（图 1 b 和补充结果）。
Incipient progressive supranuclear palsy (PSP) pathology in the setting of Alzheimer’s disease neuropathologic change (ADNC) has only rarely been reported (see Supplemental Table 1 for key prior works)[1]. These works suggest that the stereotyped neuroanatomic distribution of AD-related 3R/4R tauopathy and PSP-related 4R tauopathy are preserved in this setting; however, this has not been rigorously examined. Recently, isoform-specific tau antibodies (RD3, RD4, and AD-specific GT38) and isoform-selective tau seeding assays (3R/4R and 4R real-time quaking-induced conversion [RT-QuIC]) have been developed by us and others (methods and references in Supplement) that we hypothesized should delineate the neuroanatomic localization of co-occurring 3R/4R and 4R-tau pathology. We tested this hypothesis in five cases of high ADNC with incidental PSP (“ADNC+ PSPi”) pathology and found, first, that neuroanatomic distributions of 4R PSP and 3R/4R AD pathology are conserved in ADNC+ PSPi and, second, that RT-QuIC can robustly distinguish the neuroanatomic distribution of 3R/4R versus 4R pathology in cases with mixed tau pathology, suggesting its utility as a tool to interrogate pathophysiology. We reviewed 1296 autopsy cases with intermediate or high ADNC and identified 5 cases (0.3%) with incidental co-occurring PSP pathology (Table 1 for additional clinical and pathologic information). Age of onset was 72±3.8 years and disease duration was 11±2.1 years (mean±SD). Two cases had mild parkinsonism; one had gait disorder 5 years after symptom onset. No cases met NINDS-SPSP or MDS criteria for possible or probable PSP [2]. Case 3 had extensive aging-related tau astrogliopathy (ARTAG, 4R tauopathy) throughout the brain.Immunohistochemistry and immunofluorescence for phospho-tau (AT8), 3R-tau (RD3), 4R-tau (RD4), and AD-specific tau (GT38) was performed on pons, midbrain, hippocampus, basal ganglia, temporal cortex, midfrontal cortex, and occipital cortex (see Supplement for methods). In ADNC+ PSPi, we could distinguish AD pathology from PSP pathology by staining characteristics and morphology of inclusions: all pathological phospho-tau inclusions stained with AT8; AD neurofibrillary tangles (NFTs) but not PSP pathology stained with GT38 and RD3; PSP pathology stained with RD4 but not GT38. Consistent with the neuroanatomic distributions of each pathology in isolation, GT38-positive NFTs were abundant in midfrontal cortex and hippocampus, while RD4-positive astrocytes and oligodendroglia were prominent in midfrontal white matter and basal ganglia (Fig. 1 a, S1). Semi-quantitative regional scoring demonstrated similar neuroanatomic distribution of AD versus PSP pathology in the five cases (Fig. 1 b and Supplemental Results).