Rüb U, Del Tredici K, Schultz C, Thal D R, Braak E, Braak H
Department of Clinical Neuroanatomy, Johann Wolfgang Goethe University, Frankfurt/Main, Germany.
Neuropathol Appl Neurobiol. 2000 Dec;26(6):553-67. doi: 10.1046/j.0305-1846.2000.00291.x.
The cross-sectional analyses currently available show that the Alzheimer's disease (AD)-related cytoskeletal alterations within the human brain affect variously susceptible areas of the cerebral cortex in a uniform sequence with very little interpatient variability. This sequence has been divided for research and comparative purposes into six stages (cortical NFT/NT-stages I-VI). Among the subcortical nuclei affected in AD are those belonging to the raphe system. Efforts were focused on the lesions present in these nuclei to see in which of the six stages the AD-related cytoskeletal anomalies begin and whether a correlation exists between the AD-related pathology developing within the cerebral cortex and the cytoskeletal damage that occurs in the nuclei of the raphe system. To this end, serial sections from the brainstems of 27 post-mortem cases with stages I-VI of cortical cytoskeletal lesions were examined. The cytoskeletal pathology was visualized using the modified silver iodide-Gallyas staining technique and the antibody AT8. The latter is directed specifically against the abnormally phosphorylated cytoskeletal protein tau. The dorsal raphe nucleus manifests the cytoskeletal lesions early on (stages I-II). The central and linear raphe nuclei, by contrast, do so initially in stages III-IV, and the caudal raphe nuclei register the first changes in stages V-VI. In stages V and VI, the dorsal raphe nucleus displays the most severe cytoskeletal pathology within the raphe system, followed by the central and linear raphe nuclei, whereas the cytoskeletal anomalies in the caudal raphe nuclei are slight. The developing damage within the nuclei of the raphe system correlates with the stages I-VI and, furthermore, progresses in the oral raphe nuclei in close connection with the evolution of the pathological process in cortical projection destinations of these nuclei. As the source of the ascending serotonergic system, the involvement of the oral raphe nuclei may be partially responsible for the early manifestation of the non-cognitive and emotional deficiencies possibly traceable to dysfunctions within the ascending serotonergic system.
目前可得的横断面分析表明，人类大脑内与阿尔茨海默病（AD）相关的细胞骨架改变，以统一的顺序影响大脑皮层的不同易感区域，患者间的变异性很小。为了研究和比较的目的，这个顺序已被分为六个阶段（皮质神经原纤维缠结/神经原纤维阶段I - VI）。在AD中受影响的皮质下核团包括中缝系统的核团。研究重点关注这些核团中的病变，以了解与AD相关的细胞骨架异常在六个阶段中的哪个阶段开始，以及大脑皮层内发生的与AD相关的病理变化与中缝系统核团中发生的细胞骨架损伤之间是否存在相关性。为此，对27例死后病例的脑干连续切片进行了检查，这些病例具有皮质细胞骨架病变的I - VI阶段。使用改良的碘化银 - 加利亚斯染色技术和抗体AT8对细胞骨架病理进行可视化。后者特异性针对异常磷酸化的细胞骨架蛋白tau。背侧中缝核在早期（阶段I - II）就出现细胞骨架病变。相比之下，中央中缝核和线形中缝核最初在阶段III - IV出现病变，而尾侧中缝核在阶段V - VI出现首次变化。在阶段V和VI中，背侧中缝核在中缝系统中显示出最严重的细胞骨架病理，其次是中央中缝核和线形中缝核，而尾侧中缝核中的细胞骨架异常较轻。中缝系统核团内不断发展的损伤与阶段I - VI相关，此外，在口侧中缝核中，其损伤的进展与这些核团的皮质投射目的地的病理过程演变密切相关。作为上行5-羟色胺能系统的来源，口侧中缝核的受累可能部分导致了可能归因于上行5-羟色胺能系统功能障碍的非认知和情感缺陷的早期表现。
