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

SUDEP 的神经病理学：中枢自主网络、血清素和腺苷

• 批准号: 8820861
• 负责人: Maura Boldrini
• 金额: $ 40.05万
• 依托单位: UNIVERSITY COLLEGE LONDON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8820861
• 关键词: Acute; Adenosine; Adenosine Kinase; Age; Amygdaloid structure; Animal Model; Anterior; Arousal; Astrocytes; Autonomic nervous system; Autopsy; Autoreceptors; Biochemical; Biological Markers; Brain; Brain Injuries; Brain Stem; Brain region; Categories; Cause of Death; Cell Nucleus; Cereals; Cerebellum; Cessation of life; Chronic; Clinical; Collaborations; Collection; Complement; Confocal Microscopy; Control Groups; Data; Densitometry; Development; Electroencephalography; Enzymes; Epigenetic Process; Epilepsy; Etiology; Excision; Formalin; Foundations; Freezing; Functional disorder; Funding; Genes; Genetic; High Pressure Liquid Chromatography; Hippocampus (Brain); Human; Image; Immunofluorescence Microscopy; Immunohistochemistry; In Situ Hybridization; Inflammation; Injury; Insula of Reil; Interneurons; Investigation; Joints; Life; Link; Literature; Magnetic Resonance Imaging; Maps; Measures; Mediating; Messenger RNA; Metabolic Activation; Mutation; National Institute of Neurological Disorders and Stroke; Neocortex; Neuromodulator; Neuronal Injury; Neurons; Neurotransmitters; Operative Surgical Procedures; Pathology; Patients; Pharmaceutical Preparations; Phase; Physiological; Pilot Projects; Pontine structure; Population; Prevention; Prevention strategy; Preventive Intervention; Pulvinar structure; Purinergic P1 Receptors; Purines; Research; Resources; Respiratory physiology; Risk; Role; Sampling; Secure; Seizures; Serotonin; Serotonin Receptor 5-HT1A; Structure; Sudden Death; System; Techniques; Time; Tissue Banking; Tissue Banks; Tissue Sample; Tissues; Tonic - clonic seizures; Tryptophan 5-monooxygenase; Western Blotting; Work; brain tissue; case control; cell type; cingulate cortex; clinical phenotype; comparative; density; high risk; human FRAP1 protein; mind control; mortality; neurochemistry; neuron loss; neuropathology; prevent; prospective; public health relevance; purine; raphe nuclei; receptor; receptor binding; respiratory; screening; sex; theories; tool; young adult

 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.

 描述（由申请人提供）：能否加深我们对癫痫猝死（SUDEP）的理解，关键取决于对 SUDEP 病例的死后大脑与因其他原因死亡的癫痫患者和非癫痫患者的对照大脑进行比较我们寻求更好地定义证据来支持或反驳有关 SUDEP 原因的主要理论：脑干功能障碍的作用以及血清素和血清素的作用。腺苷。我们致力于与对照组相比，SUDEP 中重要自主脑干结构中的中间神经元、嘌呤能和血清素能系统的改变有所增加。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来研究神经元、神经元间和星形细胞。中枢自主网络结构（如岛叶、前扣带皮层和杏仁核）的密度重点关注关键脑干区域（例如心肺核和中缝核）以及神经递质血清素和腺苷我们将利用世界上最大的福尔马林固定 SUDEP 大脑收藏、冷冻和福尔马林固定大脑的前瞻性收集以及癫痫手术病例的组织。研究我们的假设。我们的系统脑干/自主神经病理学分析将提供组织病理学和生化自主系统的最完整的比较图。对人类脑组织和详细表型数据的综合研究将在活体患者的潜在生物标志物和神经病理学研究之间提供最强和最直接的联系，并通过 SUDEP 病例的神经病理学发现将发作和其他疾病联系起来。血清素能（5-HT1A 和 5-HT1C 受体、5-HT 转运蛋白）活性和酶的表型标记（例如 MRI）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血清素能和嘌呤能活性。这些研究将首次将详细的表型数据、皮质和脑干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，研究非同义替换在血清素能和嘌呤能基因中的潜在作用，以及它们与我们的定量体视学和免疫组织化学发现和表型标记的关系。