The Neuropathology of SUDEP : The central autonomic network, Serotonin and adenosine

 描述（由申请人提供）：提高我们对癫痫突然意外死亡（SUDEP）的理解的能力，关键取决于SUDEP病例的死后大脑与其他原因死亡的癫痫患者和突然死亡的无癫痫患者的对照大脑的比较。我们试图更好地定义证据来支持或反驳关于SUDEP原因的主要理论：脑干功能障碍的作用以及5-羟色胺和腺苷的作用。具体来说，我们假设，改变的中间神经元，嘌呤能和多巴胺能系统在重要的自主脑干结构增加SUDEP相比，控制。我们将使用先进的9.4T MRI成像，辅以定量体视学和免疫组织化学技术，研究中枢自主神经网络结构（如小脑、前扣带皮层和杏仁核）中的神经元、神经元间和星形胶质细胞密度，重点关注关键脑干区域（例如，心肺和中缝核）和神经递质5-羟色胺和腺苷。我们将利用世界上最大的福尔马林固定的SUDEP大脑，冷冻和福尔马林固定的大脑的前瞻性收集，以及癫痫手术病例的组织来研究我们的假设。我们系统的脑干/自主神经病理学分析将提供SUDEP中改变的组织病理学和生化自主神经系统异常的最完整的比较图。人脑组织和详细表型数据的联合研究将提供潜在生物标志物与SUDEP病例神经病理学发现的活患者的神经病理学研究之间最强和最直接的联系。我们活着的患者可以将发作和其他表型标记（例如，MRI）对脑组织中腺苷能（5-HT 1A和5-HT 1C受体，5-HT转运蛋白）和5-羟色胺合成酶（色氨酸羟化酶）和嘌呤能（腺苷激酶活性和腺苷受体结合）系统的活性的影响。我们的SUDEP死后研究将连接整个大脑的9.4T图像，以及皮质，皮质下和脑干区域的多巴胺能和嘌呤能活动。总之，这些研究将首次将详细的表型数据、皮质和脑干的多巴胺能和嘌呤能活性研究联系起来。我们的研究还将与SUTRA 5：SUDEP的遗传学和表观遗传学合作，研究非同义取代在多巴胺能和嘌呤能基因中的潜在作用，以及这些与我们的定量体视学和免疫组化结果和表型标记的关系。

 DESCRIPTION (provided by applicant): The ability to advance our understanding of sudden unexpected death in epilepsy (SUDEP) is critically dependent on the comparison of postmortem brains from SUDEP cases to control brains from patients with epilepsy who died from other causes and patients without epilepsy who died suddenly. We seek to better define the evidence to support or refute leading theories about the causes of SUDEP: the role of brainstem dysfunction and the role of serotonin and adenosine. Specifically, we hypothesize that alterations of interneurons, purinergic and serotonergic systems in vital autonomic brainstem structures are increased in SUDEP compared to controls. We will use advanced 9.4T MRI imaging complemented by quantitative stereological and immunohistochemical techniques to study the neuronal, interneuronal and astrocytic densities in the central autonomic network structures such as the insula, anterior cingulate cortex, and amygdala, with a focus on critical brainstem regions (e.g., cardiorespiratory and median raphe nuclei) and the neurotransmitters serotonin and adenosine. We will leverage the world's largest collection of formalin fixed SUDEP brains, prospective collection of frozen and formalin fixed brains, and tissue from epilepsy surgery cases to study our hypotheses. Our systematic brainstem/autonomic neuropathological analysis will provide the most complete comparative map of the histopathological and biochemical autonomic system abnormalities that are altered in SUDEP. The combined study of human brain tissue and detailed phenotypic data will provide the strongest and most direct link between potential biomarkers and neuropathological studies in living patients with neuropathological findings from SUDEP cases. Our living patients can link ictal and other phenotypic markers (e.g., MRI) to activity in serotonergic (5-HT1A and 5-HT1C receptors, 5-HT transporter) and the enzyme of serotonin synthesis tryptophan hydroxylases) and purinergic (adenosine kinase activity and adenosine receptor binding) systems in their brain tissue. Our SUDEP postmortem studies will link 9.4T images of the entire brain, as well as serotonergic and purinergic activity in cortical, subcortical and brainstem regions. Together, these studies will, for the first time, bridge detailed phenotypic data, cortical and brainstem studies of serotonergic and purinergic activity. Our study will also work with SUTRA 5: Genetics and Epigenetics of SUDEP to study the potential role of nonsynonymous substitutions in serotonergic and purinergic genes, and how these relate to our quantitative stereological and immunohistochemical findings and phenotypic markers.