THE USE OF MRS AND CYTOKINE MEASUREMENTS TO INVESTIGATE DEPRESSION IN PATIENTS W

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。抑郁症的调查一直受到其原因和表现的异质性的阻碍。为了克服这些障碍，抑郁症的病变模型将大大提高我们对这种疾病的理解。多发性硬化症（MS）是所有慢性疾病中抑郁症发病率最高的。MS有50%的认知障碍患病率。证据支持脱髓鞘脑病变和细胞因子效应是MS患者抑郁和认知功能障碍的原因。横肌萎缩症（TM）是一种自身免疫性疾病，如MS，但脱髓鞘病变只存在于脊髓。我们发现TM受试者的严重抑郁症发生率高于MS对照组，TM受试者的选择性认知障碍与MS受试者相当。在人类和动物中，细胞因子诱导抑郁症（或其行为等价物）和认知障碍。在特发性抑郁症患者中发现促炎细胞因子水平升高，这是一种相对高皮质醇血症的状态。在一个稳态调节周期中，促炎细胞因子刺激HPA轴释放皮质醇，这反过来又减弱了免疫反应。因此，在自身免疫性疾病中，免疫系统激活与细胞因子产生和情感大脑状态和认知的变化之间存在合理的联系。我们建议TM提供了一个模型的麻黄碱介导的抑郁症和认知障碍。我们将调查这些神经精神现象的流行病学TM科目相比，MS和非自身免疫性脊髓病的控制。然后，我们的研究将采用TM和对照受试者的神经精神评估、细胞因子分析和磁共振波谱（MRS）来阐明与抑郁症和认知功能障碍相关的细胞因子升高和脑神经化学变化。将对受试者进行纵向随访，以确定细胞因子水平和脑代谢物的变化是否与情绪、认知和神经学结局的变化平行。TM和MS受试者中抑郁的神经内分泌相关性将通过检查其HPA轴的功能来确定。我们预计，这项研究的结果将有直接的影响，TM和MS的神经精神共病。这些研究结果可以显着扩大我们的能力，诊断，诊断和治疗神经精神后遗症患者的各种类型的自身免疫性疾病。这些研究也有可能阐明特发性抑郁症的免疫机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Investigation of depression has been hampered by the heterogeneity of its causes and presentations. To overcome these impediments, a lesion model of depression would significantly enhance our understanding of this illness. Multiple Sclerosis (MS) has the highest rate of depression of any chronic disease. MS has a 50% prevalence of cognitive impairment. Evidence supports both demyelinated brain lesions and cytokine effects as causes of depression and cognitive dysfunction in MS patients. Transverse Myelitis (TM) is an autoimmune disorder like MS but with demyelinating lesions present only in the spinal cord. We found rates of severe depression in subjects with TM to be higher than those of MS controls and selective cognitive impairments in TM subjects comparable to their MS counterparts. In humans and animals, cytokines induce depression (or its behavioral equivalent) and cognitive impairment. Elevated pro-inflammatory cytokine levels are found in patients with idiopathic depression, which is a state of relative hypercortisolemia. In a homeostatic regulatory cycle, pro-inflammatory cytokines stimulate the HPA axis to release cortisol, which in turn attenuates the immune response. Thus, there is a plausible link in autoimmune disorders between immune system activation with cytokine production and changes in emotional brain states and cognition. We propose that TM provides a model of cytokine-mediated depression and cognitive impairment. We will investigate the epidemiology of these neuropsychiatric phenomena in TM subjects compared to MS and non-autoimmune myelopathy controls. Our study will then employ neuropsychiatric evaluations, cytokine profiling, and Magnetic Resonance Spectroscopy (MRS) of TM and control subjects to elucidate cytokine elevations and brain neurochemical changes that correlate with depression and cognitive dysfunction. Subjects will be followed longitudinally to determine if changes in cytokine levels and brain metabolites parallel changes in mood, cognition and neurologic outcomes. Neuroendocrine correlates of depression in TM and MS subjects will be ascertained through examination of the function of their HPA axis. We anticipate that the results of this study will have direct implications for the neuropsychiatric comorbidities of TM and MS. These findings could significantly expand our ability to diagnose, prognosticate, and treat neuropsychiatric sequelae in patients with diverse types of autoimmune disorders. These studies also have the potential to illuminate immune mechanisms in idiopathic Major Depression.