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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.