Study of the developing mechanism of dementia in non-Alzheimer-type degenerative dementias

在非阿尔茨海默型退行性痴呆的研究中，研究了弥漫性路易体病（DLBD）以及非典型皮克病和进行性核上性麻痹（PSP）。在对DLBD的首次研究中，海马中许多泛素阳性结构是由穿孔通路末端轴突变性引起的。这些结构也具有α-突触核蛋白免疫反应性，并且含有与路易小体（LB）相似的丝状成分，这表明α-突触核蛋白聚集成细胞骨架成分首先发生在终端轴突，在起源细胞形成LB之前经历了“死退”退化过程。在DLBD的第二项研究中，LB和神经原纤维缠结（NFT）经常共存于DLBD和阿尔茨海默病（AD）的边缘区域的同一神经元中。DLBD中α-synuclein阳性丝状成分与配对螺旋丝状成分（PHF）之间没有连续性，表明LB和NFT是分开发育的。而在AD中，α-synuclein和α-synuclein的聚集是继发于NFT的形成。在没有匹克体的非典型匹克病中，受影响的大脑皮层中存在泛素阳性的树突，齿状回颗粒细胞中存在泛素阳性的神经元内包涵体，这表明非典型匹克病与其他类型的额颞叶痴呆（FTD）具有共同的发病机制。在PSP中，根据tau阳性神经元中缠结的形成将PSP分为两组；典型PSP病理组和与皮质基底变性（CBD）相似的非典型PSP病理组，PSP中的NFT包括PSP-NFT而不是AD-NFT，即使在PSP和AD的共同易发部位也是如此。

In the study of non-Alzheimer-type degenerative dementias, diffuse Lewy body disease(DLBD) as well as atypical Pick's disease and progressive supranuclear palsy(PSP) were investigated. In the first study of DLBD, many of the ubiquitin-positive structures in the hippocampus were caused by degeneration of terminal axons of the perforant pathway. These structures were also α-synuclein- immunoreactive, and contained similar filamentous components to those of Lewy bodies(LB) immunoelectron microscopically, suggesting that the aggregation of α-synuclein into cytoskeletal components first occurs in the terminal axons by a "dying back" degenerating process before the formation of LB in the origin cells. In the second study of DLBD, LB and neurofibrillary tangles(NFT) frequently coexisted in the same neurons of the limbic areas of DLBD and Alzheimer's disease(AD). There was no continuity between α-synuclein-positive filamentous components and paired helical filaments(PHF) in DLBD, suggesting that LB and NFT are developed separately. In contrast, there was the close continuity between the two components in AD, suggesting that the aggregation of α-synuclein occurs secondary to the NFT formation. In atypical Pick's disease without Pick bodies, there were ubiquitin-positive dendrites in the affected cerebral cortex and ubiquitin-positive intraneuronal inclusions in the granular cells of the dentate gyrus, suggesting that atypical Pick's disease shares common pathomechanism to that of other types of frontotemporal dementia(FTD). In PSP, PSP was divided into two groups according to the tangle-formation in tau-positive neurons; the group with typical PSP pathology and the group with atypical PSP pathology similar to corticobasal degeneration(CBD), and NFT in PSP consisted of PSP-NFT but not AD-NFT even in the common predilection sites of PSP and AD.