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

 描述(由申请人提供)：提高我们对癫痫猝死(SUDEP)的理解的能力严重依赖于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非癫痫患者的大脑对照的比较。我们试图更好地定义证据来支持或驳斥关于SUDEP病因的主要理论：脑干功能障碍的作用以及5-羟色胺和腺苷的作用。具体地说，我们假设与对照组相比，SUDEP患者重要的自主神经脑干结构中的中间神经元、嘌呤能和5-羟色胺能系统的变化增加。我们将使用先进的9.4T磁共振成像技术，辅以定量体视学和免疫组织化学技术来研究中央自主神经网络结构(如岛叶、扣带前皮质和杏仁核)中的神经元、神经元间和星形细胞密度，重点关注关键脑干区域(例如心肺和中缝正中核)以及神经递质5-羟色胺和腺苷。我们将利用世界上最大的福尔马林固定SUDEP脑集合，预期收集的冰冻和福尔马林固定的脑，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/自主神经病理分析将为SUDEP患者的组织病理学和生化自主神经系统异常提供最完整的对比图。对人脑组织和详细表型数据的联合研究将提供潜在生物标记物和活着患者的神经病理研究之间最强有力和最直接的联系，这些患者的神经病理结果来自SUDEP病例。我们活着的患者可以将发作期和其他表型标志物(例如MRI)与脑组织中5-羟色胺能(5-HT1A和5-HT1C受体，5-羟色胺转运体)和5-羟色胺合成酶(色氨酸羟基酶)和嘌呤能(腺苷激酶活性和腺苷受体结合)系统的活性联系起来。我们的SUDEP尸检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5-羟色胺能和嘌呤能活动。总而言之，这些研究将首次在详细的表型数据、皮质和脑干研究5-羟色胺能和嘌呤能活动之间架起桥梁。我们的研究还将与SuDEP的Sutra 5：遗传学和表观遗传学合作，研究5-羟色胺能和嘌呤能基因中非同义替换的潜在作用，以及这些作用与我们的定量体视学和免疫组织化学结果以及表型标记的关系。

 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.