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)在许多退伍军人从部署返回数十年后继续造成痛苦和残疾。虽然GWVI的主要症状清楚地表明持续的生物神经系统异常，但迄今为止关于GWVI神经系统功能和结构的有限神经生物学研究尚未明确表明可以指导治疗进展的病理生物学。这项应用结合了神经成像、遗传学、疼痛和睡眠生理学、神经内分泌学和神经退行性生物标记物开发方面的神经科学进展，以多学科方法定义GWVI症状的神经生物异常。在持久自由行动/伊拉克自由行动/新黎明行动(OEF/OIF/OND)部署的没有创伤性脑损伤或创伤后应激障碍病史的退伍军人中，脑脊液(CSF)生物标记物证据表明神经元受损，这一努力的理由得到了我们的神经成像证据的支持。一个由神经学家组成的多学科小组将致力于以下具体目标：具体目标1.确定GWVI中大脑结构和功能完整性的异常。假设1a- GWVI的特点是：使用氟脱氧葡萄糖正电子发射断层扫描，与认知相关的大脑区域(如内侧颞叶)的大脑葡萄糖代谢降低；使用磁共振成像、扩散张量成像和大分子质子分数图，结构和成分结构完整性降低；以及通过血氧水平依赖的功能连通性MRI，腹侧和背侧注意网络的节点之间的大脑区域连通性降低。假说Ib-GWVI的特点是脑脊液中与神经退变相关的生物标志物的变化(AB42降低，脑脊液总tau和磷酸化tau(Ptau181)增加)和氧化损伤(F2-异前列腺素增加)，以及神经营养因子和脑源性神经营养因子的减少，假说IC-GWVI的特点是在评估前瞻性记忆、认知处理速度和多任务的挑战性神经认知任务方面存在缺陷。具体目标2.确定GWVI中调节痛觉、疲劳和睡眠的中枢和外周系统的异常。假设2a：GWVI的特征是通过定量敏感性测试增加疼痛敏感性，以及内源性阿片类药物对条件性疼痛调制的反应减弱。假设2b：GWVI的特征是与疼痛、疲劳感觉和睡眠相关的神经肽、神经递质、激素和免疫因素的异常。假设2c：GWVI的特点是调节感觉疼痛的大脑区域(如丘脑)的大脑葡萄糖代谢降低。具体目标3.确定GWVI中与神经退行性变、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的特点是载脂蛋白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Val66Met变体的Met等位基因、儿茶酚-O-甲基转移酶Val158Met变体的Val等位基因、u阿片受体1A118G单核苷酸多态的G等位基因(即rs1799971)、对氧磷酶1(PON1)Gln192Arg变体的Arg等位基因，以及PON1的功能活性降低。假设3b：GWVI的特点是CpG岛的PON1、APOE、MAPT和BDNF基因的DNA甲基化水平发生了变化。

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.