Multimodal Biological Assessment of Gulf War Illness

海湾战争疾病的多模式生物学评估

• 批准号: 9278098
• 负责人: ELAINE R. PESKIND
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9278098
• 关键词: Address; Alleles; Apolipoprotein E; Arylesterase; Attention; Biological; Biological Markers; Blast Cell; Brain; Brain Diseases; Brain region; Brain-Derived Neurotrophic Factor; Catechols; Cerebrospinal Fluid; Cerebrum; Circadian Rhythms; Cognition; Cognitive; Congenital neurologic anomalies; CpG Islands; DNA Methylation; Diffusion Magnetic Resonance Imaging; Dorsal; Environmental Exposure; Epigenetic Process; Exposure to; F2-Isoprostanes; Fatigue; Freedom; Frequencies; Genes; Genetic; Geography; Goals; Gulf War; Haplotypes; Hormones; Immune System Diseases; Immune System and Related Disorders; Immunologic Factors; Impaired cognition; Impairment; MAPT gene; Magnetic Resonance Imaging; Medial; Metabolism; Methylation; Microtubule Stabilization; Mild Concussions; Nerve Degeneration; Nervous System Physiology; Nervous system structure; Neuraxis; Neurobiology; Neurocognition; Neurocognitive; Neuroendocrinology; Neurons; Neuropeptides; Neurotransmitters; Organophosphates; Pain; Perception; Peripheral; Persian Gulf; Physiology; Post-Traumatic Stress Disorders; Proteins; Protons; Quality of life; Readability; Recording of previous events; Resistance; Risk Factors; Scientist; Sensory; Signal Transduction; Single Nucleotide Polymorphism; Sleep; Stress; Structure; Symptoms; System; Temporal Lobe; Testing; Thalamic structure; Transferase; Traumatic Brain Injury; Variant; Veterans; apolipoprotein E-4; biomarker development; blood oxygen level dependent; brain metabolism; chronic pain; disability; endogenous opioids; fluorodeoxyglucose positron emission tomography; genetic variant; glucose metabolism; improved functioning; interdisciplinary approach; mild traumatic brain injury; mu opioid receptors; multidisciplinary; multimodality; multitask; neuroimaging; neuroimaging marker; neurotrophic factor; neurotropin; new technology; novel; operation; oxidative damage; processing speed; prospective memory; public health relevance; response; symptomatology; tau Proteins; tau-1; therapy development

DESCRIPTION (provided by applicant): Gulf War Veterans' illness (GWVI) continues to cause suffering and disability for many Veterans decades after returning from their deployment. Although the major GWVI symptoms clearly point to persistent biologic nervous system abnormalities, the limited neurobiological studies to date of nervous system function and structure in GWVI have not yet clearly demonstrated pathobiologies that can guide treatment development. This application incorporates neuroscientific advances in neuroimaging, genetics, pain and sleep physiology, neuroendocrinology and neurodegeneration biomarker development in a multidisciplinary approach to defining neurobiologic abnormalities underlying GWVI symptomatology. Rationale for this effort is strengthened by our neuroimaging evidence of reduced brain metabolism and cerebrospinal fluid (CSF) biomarker evidence of neuronal damage in Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND)-deployed Veterans who had no lifetime history of traumatic brain injury or posttraumatic stress disorder. A multidisciplinary group of neuroscientists will address the following Specific Aims: Specific Aim 1. To identify in GWVI abnormalities in brain structural and functional integrity. Hypothesis 1a - GWVI is characterized by decreased cerebral glucose metabolism in brain regions relevant to cognition (e.g., medial temporal lobes) using fluorodeoxyglucose-positron emission tomography; decreased structural and compositional structural integrity using magnetic resonance imaging diffusion tensor imaging and macromolecular proton fraction mapping; and decreased brain regional connectivity among nodes of the ventral and dorsal attention networks on blood oxygen level dependent functional connectivity MRI. Hypothesis Ib - GWVI is characterized by changes in CSF biomarkers associated with neurodegeneration (decreased Ab42, increased CSF total tau and phosphorylated tau (ptau181) and oxidative damage (increased F2-isoprostanes), and decreases in the neurotrophin, brain derived neurotrophic factor, Hypothesis Ic - GWVI is characterized by deficits on challenging neurocognitive tasks that assess prospective memory, cognitive processing speed, and multitasking. Specific Aim 2. To identify in GWVI abnormalities in central and peripheral systems regulating pain perception, fatigue, and sleep. Hypothesis 2a: GWVI is characterized by increased pain sensitivity by Quantitative Sensitivity Testing and impaired activation of endogenous opioids in response to Conditioned Pain Modulation. Hypothesis 2b: GWVI is characterized by abnormalities in neuropeptides, neurotransmitters, hormones, and immune factors associated with pain and fatigue perception and sleep. Hypothesis 2c: GWVI is characterized by decreased cerebral glucose metabolism in brain regions modulating sensory pain (e.g., thalamus). Specific Aim 3. To identify in GWVI genetic variants and/or epigenetic alterations associated with neurodegeneration, impaired pain processing, and metabolism of organophosphates. Hypothesis 3a: GWVI is characterized by increased frequency of the apolipoprotein E (APOE)-e4 - allele, the microtubule associated protein tau (MAPT) H1 haplotype, the Met allele of the brain derived neurotrophic factor Val66Met variant, the Val allele of the catechol-O-methyl transferase Val158Met variant, the G allele of the mu opioid receptor 1 A118G single nucleotide polymorphism (i.e., rs1799971), the Arg allele of the paraoxonase 1 (PON1) Gln192Arg variant, and decreased functional activity of PON1. Hypothesis 3b: GWVI is characterized by altered DNA methylation levels in CpG Islands in the PON1, APOE, MAPT, and BDNF genes.

描述（由申请人提供）： 海湾退伍军人的病（GWVI）在部署后几十年继续造成许多退伍军人的苦难和残疾。尽管主要的GWVI症状显然表明持续存在的生物神经系统异常，但GWVI神经系统功能和结构的神经生物学研究有限，尚未清楚地证明可以指导治疗发展的病原体。该应用结合了神经影像学，遗传学，疼痛和睡眠生理学，神经内分泌学和神经变性生物标志物发育的神经科学进展，以定义GWVI症状学为基础的神经生物学异常来定义神经生物学异常。通过我们的神经影像学证据证明，脑海中的神经元损害的证据持续/伊拉克自由/操作，新黎明（OEF/OIF/OND）没有生命的退伍军人，他们没有生命的重点或Post Post post traa traaumaumaum beraumaumaumaumby new dawn（OEF/OIF/OND），这项工作的基本原理得到了加强。多学科的神经科学家将解决以下特定目的：特定目的1。确定脑结构和功能完整性中GWVI异常。 假设1a- GWVI的特征在于使用氟脱氧葡萄糖 - 固醇发射断层扫描与认知相关的大脑区域脑葡萄糖代谢降低；使用磁共振成像扩散张量成像和大分子质子分数映射减少结构和组成结构完整性；并降低了腹侧和背注意网络的大脑区域连通性在血氧水平依赖性功能连通性MRI上降低。 假说IB -GVI的特征是与神经变性相关的CSF生物标志物的变化（AB42降低，CSF总TAU和磷酸化的TAU（PTAU181）（PTAU181）（PTAU181）和氧化损伤（F2-异质）以及降低了神经素的神经素的降低，并降低了神经素的特征。在评估前瞻性记忆，认知处理速度和多任务的挑战性任务上，要确定中央和周围系统中的GWVI异常，调节疼痛感，疲劳和睡眠的疼痛敏感性，使疼痛的敏感性提高了敏感性，从而调节疼痛感。调制。假设2b：GWVI的特征是神经肽，神经递质，激素和疼痛和疲劳感知和睡眠的免疫因子的异常。 具体目的3。确定与神经变性，疼痛处理受损和有机磷酸盐代谢相关的GWVI遗传变异和/或表观遗传学改变。 Hypothesis 3a: GWVI is characterized by increased frequency of the apolipoprotein E (APOE)-e4 - allele, the microtubule associated protein tau (MAPT) H1 haplotype, the Met allele of the brain derived neurotrophic factor Val66Met variant, the Val allele of the catechol-O-methyl transferase Val158Met variant, the G allele of the mu opioid receptor 1 A118G单核苷酸多态性（即rs1799971），二氧氧酶1（PON1）GLN192ARG变体的ARG等位基因，PON1的功能活性降低。 假设3b：GWVI的特征是PON1，APOE，MAPT和BDNF基因的CpG岛中DNA甲基化水平改变。