Centres for SUDEP Research : the neuropathology of SUDEP

SUDEP 研究中心：SUDEP 的神经病理学

基本信息

批准号：
8934222
负责人：
Maura Boldrini
金额：
$ 39.58万
依托单位：
UNIVERSITY COLLEGE LONDON
依托单位国家：
美国
项目类别：
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/8934222
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 Health 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 Serotonergic System 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 purine raphe nuclei receptor receptor binding respiratory screening sex theories tool young adult

项目摘要

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（由适用提供）：提高我们对癫痫（SUDEP）突然意外死亡的理解的能力取决于对来自SUDEP病例的死后大脑的比较，以控制死于其他原因和没有癫痫病的患者的癫痫患者的大脑。我们寻求更好地定义证据，以支持或驳斥有关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。具体而言，我们假设与对照组相比，SUDEP中重要的自主神经脑干结构中的中间神经元，中间神经元，蠕虫能和血清素能系统的变化有所增加。 We will use advanced 9.4T MRI imaging completed by quantitative stereoological 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 nuclear) and the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大脑收集，前瞻性收集的冷冻和福尔马林固定大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/自主神经病理学分析将为SUDEP中改变的组织病理学和生化自主系统异常提供最完整的比较图。对人脑组织和详细表型数据的合并研究将为潜在的生物标志物与神经病理学患者的神经病理学研究之间的牢固，最直接的联系，从SUDEP病例患有神经病理学发现。我们的活着的患者可以将ICTAL和其他表型标记（例如MRI）与血清素能（5-HT1A和5-HT1C受体，5-HT转运蛋白）的活性联系起来，以及5-羟色胺合成的胰poph剂胰蛋白酶羟基酶的酶和葡萄球菌蛋白酶活性（腺苷酶活性的脑酶活性）。我们的SUDEP验尸研究将链接整个大脑的9.4T图像，以及皮质，皮层和脑干区域中的血清素能和蠕虫能活性。这些研究总之第一次将桥梁详细的表型数据，血清素能和嘌呤能活性的皮质和脑干研究。我们的研究还将与SUTRA 5：SUDEP的遗传学和表观遗传学一起研究非同义替代物在血清素能和嘌呤能基因中的潜在作用，以及这些与我们的定量定位和免疫组织化学发现和表型标记之间的关系。