Neuropathological Staging of Brain Pathology in Sporadic Parkinson's disease: Separating the Wheat from the Chaff.
Neuropathological Staging of Brain Pathology in Sporadic Parkinson's disease: Separating the Wheat from the Chaff.
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DOI：
10.3233/jpd-179001
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Del Tredici K
中科院分区：
文献类型：
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作者：
Braak H;Del Tredici K
在人类中枢、外周和肠神经系统（CNS、PNS、ENS）的多种神经递质系统中，相对少数的特别易感的神经细胞类型参与了散发性帕金森病（sPD）的退行性过程。我们提出的与sPD相关的脑病理学的六阶段模型（Neurobiol Aging 2003）是一项回顾性研究，在大量大脑区域的非常规厚组织切片（100 μm）上进行偶然病例和临床诊断病例的研究。分期模型强调了我们所认为的在解剖学上相互关联的区域路易病理程度增加的顺序发展，以及在蓝斑和黑质中（但不限于）胺能投射神经元的丧失。轴突和体树突Lewy病理被赋予相同的权重，嗅球首次被纳入sPD分期系统。经过多年的研究，现在看来，最早的病变可能发生在非黑质（多巴胺激动剂无反应）部位，周围环境可能是敌对的：嗅球，也可能是脑神经系统。然而，目前缺乏关于周围自主神经系统中路易病理发展的知识，这意味着不能忽视其他中枢神经系统外的起源部位。PD分期系统不仅引起了争议，而且为以下方面提供了一个框架：(1)评估脊髓、ENS和PNS的病理与大脑进化的关系，(2)定义前驱疾病和高危个体队列，(3)开发非常早期疾病的潜在预后生物标志物，(4)测试α-突触核蛋白增殖和疾病进展的新假设和实验模型。(5)寻找因果导向的治疗方法，在黑质受累之前进行干预。在分子和细胞水平上发现新的疾病机制表明，脆弱神经细胞之间的物理接触（跨突触）和跨神经元传递在某种程度上对sPD的发病机制至关重要。
A relatively small number of especially susceptible nerve cell types within multiple neurotransmitter systems of the human central, peripheral, and enteric nervous systems (CNS, PNS, ENS) become involved in the degenerative process underlying sporadic Parkinson’s disease (sPD). The six-stage model we proposed for brain pathology related to sPD (Neurobiol Aging 2003) was a retrospective study of incidental and clinically diagnosed cases performed on unconventionally thick tissue sections (100 μm) from a large number of brain regions.The staging model emphasized what we perceived to be a sequential development of increasing degrees of Lewy pathology in anatomically interconnected regions together with the loss of aminergic projection neurons in, but not limited to, the locus coeruleus and substantia nigra. The same weight was assigned to axonal and somatodendritic Lewy pathology, and the olfactory bulb was included for the first time in a sPD staging system. After years of research, it now appears that the earliest lesions could develop at nonnigral (dopamine agonist nonresponsive) sites, where the surrounding environment is potentially hostile: the olfactory bulb and, possibly, the ENS. The current lack of knowledge regarding the development of Lewy pathology within the peripheral autonomic nervous system, however, means that alternative extra-CNS sites of origin cannot be disregarded as possible candidates. The PD staging system not only caused controversy but contributed a framework for (1) assessing pathology in the spinal cord, ENS, and PNS in relationship to that evolving in the brain, (2) defining prodromal disease and cohorts of at-risk individuals, (3) developing potential prognostic biomarkers for very early disease, (4) testing novel hypotheses and experimental models of α-synuclein propagation and disease progression, and (5) finding causally-oriented therapies that intervene before the substantia nigra becomes involved. The identification of new disease mechanisms at the molecular and cellular levels indicates that physical contacts (transsynaptic) and transneuronal transmission between vulnerable nerve cells are somehow crucial to the pathogenesis of sPD.