Braak Heiko, Del Tredici Kelly
J Parkinsons Dis. 2017;7(s1):S71-S85. doi: 10.3233/JPD-179001.
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.
在人类中枢神经系统（CNS）、外周神经系统（PNS）和肠神经系统（ENS）的多个神经递质系统中，相对少数的特别易损神经细胞类型参与了散发性帕金森病（sPD）潜在的退行性病变过程。我们提出的与sPD相关的脑病理学六阶段模型（《神经生物学衰老》，2003年）是一项回顾性研究，研究对象是大量脑区非常规厚度（100μm）组织切片上的偶然发现病例和临床诊断病例。该分期模型强调了我们所认为的在解剖学上相互连接的区域中，路易体病理学程度逐渐加重的连续发展过程，以及蓝斑和黑质等部位（但不限于这些部位）中胺能投射神经元的丧失。轴突和体树突路易体病理学被赋予同等权重，嗅球首次被纳入sPD分期系统。经过多年研究，现在看来最早的病变可能发生在非黑质（对多巴胺激动剂无反应）部位，这些部位的周围环境可能具有潜在的不利因素：嗅球以及可能的肠神经系统。然而，目前对外周自主神经系统中路易体病理学发展的了解不足，这意味着不能忽视中枢神经系统以外的其他起源部位作为可能的候选部位。帕金森病分期系统不仅引发了争议，还为以下方面提供了一个框架：（1）评估脊髓、肠神经系统和外周神经系统中的病理学与大脑中病理学的关系；（2）定义前驱疾病和高危个体队列；（3）开发极早期疾病的潜在预后生物标志物；（4）测试α-突触核蛋白传播和疾病进展的新假设和实验模型；（5）找到在黑质受累之前进行干预的因果导向疗法。在分子和细胞水平上对新疾病机制的识别表明，易损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。
