Multimodal Biological Assessment of Gulf War Illness

描述（由申请人提供）： 海湾战争退伍军人疾病（GWVI）继续造成许多退伍军人的痛苦和残疾几十年后，从他们的部署返回。虽然主要的GWVI症状明确指出持续的生物神经系统异常，有限的神经生物学研究，迄今为止的神经系统功能和结构的GWVI尚未明确证明病理生物学，可以指导治疗的发展。该申请将神经科学在神经影像学、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开发方面的进展纳入多学科方法中，以定义GWVI神经病学的神经生物学异常。我们的神经影像学证据表明，在持久自由行动/伊拉克自由行动/新黎明行动（OEF/OIF/OND）部署的退伍军人中，脑代谢降低，脑脊液（CSF）生物标志物证据表明神经元损伤，这些退伍军人没有创伤性脑损伤或创伤后应激障碍的终身病史，这加强了这项工作的依据。一个多学科的神经科学家小组将解决以下具体目标：具体目标1。识别GWVI中大脑结构和功能完整性的异常。 假设1a - GWVI的特征在于与认知相关的脑区域（例如，内侧颞叶）;使用磁共振成像扩散张量成像和大分子质子分数映射降低的结构和组成结构完整性;以及在血氧水平依赖性功能连接MRI上腹侧和背侧注意网络的节点之间降低的脑区域连接。 假设Ib - GWVI的特征在于与神经变性相关的CSF生物标志物的变化（Ab 42减少，CSF总tau和磷酸化tau（ptau 181）增加，氧化损伤假设Ic-GWVI的特征在于在评估前瞻性记忆，认知处理速度，和多任务处理 具体目标2。确定GWVI中调节疼痛感知、疲劳和睡眠的中枢和外周系统异常。 假设2a：GWVI的特征在于通过定量敏感性测试增加的疼痛敏感性和响应于条件性疼痛调节的内源性阿片样物质的活化受损。 假设2b：GWVI的特征在于与疼痛和疲劳感知和睡眠相关的神经肽、神经递质、激素和免疫因子的异常。 假设2c：GWVI的特征在于调节感觉疼痛的脑区域中的脑葡萄糖代谢降低（例如，丘脑）。 具体目标3。确定GWVI中与神经变性、疼痛处理受损和有机磷代谢相关的遗传变异和/或表观遗传改变。 假设3a：GWVI的特征在于载脂蛋白E（APOE）-e4 -等位基因、微管相关蛋白tau（MAPT）H1单倍型、脑源性神经营养因子Val 66 Met变体的Met等位基因、儿茶酚-O-甲基转移酶Val 158 Met变体的瓦尔等位基因、μ阿片受体1 A118 G单核苷酸多态性（即，rs 1799971）、对氧磷酶1（PON 1）Gln 192 Arg变体的Arg等位基因，并降低PON 1的功能活性。 假设3b：GWVI的特征是PON 1、APOE、MAPT和BDNF基因中CpG岛的DNA甲基化水平改变。

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.