Depression and Cognitive Impairment in Transverse Myelitis

PI的长期职业兴趣是帮助阐明潜在的生物机制 情绪调节和认知功能障碍。这一职业发展奖的目标是让具有基础科学背景的首席调查员(PI)成为研究自身免疫性中枢神经系统疾病中免疫介导性抑郁和认知障碍的神经精神病学转化研究的临床研究员。为了实现他的目标，PI将接受神经免疫学、神经成像和临床调查方法方面的额外培训。约翰斯·霍普金斯医学院将在所有这些培训领域为PI提供专家指导。为了研究情绪和认知的生物学基础，我们将调查多发性硬化症(MS)和横断性脊髓炎(TM)患者的抑郁和认知障碍。多发性硬化症(MS)是所有慢性病中抑郁发生率最高的，认知障碍的患病率为50%。横贯性脊髓炎(TM)是一种与MS类似的自身免疫性疾病，但脱髓鞘病变仅存在于脊髓。我们发现，患有多发性硬化症的受试者严重抑郁的发生率高于多发性硬化症患者 TM受试者的控制性和选择性认知障碍与多发性硬化症患者相当。 细胞因子是免疫细胞用来协调其反应的化学信使。最近的研究表明，细胞因子除了在调节免疫系统功能方面发挥作用外，还影响中枢神经系统和HPA轴。在人类和动物研究中，越来越多的证据支持促炎细胞因子在调节抑郁和认知障碍中的作用。我们认为MS和TM提供了一种细胞因子介导的抑郁和认知损害的模型。我们计划对MS、TM和对照受试者进行神经精神病学评估、细胞因子分析和磁共振波谱(MRS)，以阐明与抑郁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跟踪以确定 如果细胞因子水平和大脑代谢物的变化与情绪、认知和神经学结果的变化同步。TM和MS受试者抑郁的神经内分泌相关性将通过检查他们的HPA轴的功能来确定。我们预计，这项研究的结果将对MS、TM和其他中枢神经系统自身免疫性疾病的神经精神共病有直接的影响。这些发现可以显著扩展我们诊断、预测和治疗不同类型精神分裂症患者的神经精神后遗症的能力。 自身免疫性疾病。此外，这些研究有可能阐明特发性抑郁症的免疫机制，从而产生新的治疗策略。

The PI's long-term career interests are to help elucidate the biological mechanisms underlying disorders of mood regulation and cognitive function. The goal of this career development award is to allow the Principle Investigator (PI), who has a basic science background, to become a clinical investigator in neuropsychiatric translational research studying immune-mediated depression and cognitive impairment in autoimmune CNS diseases. To accomplish his goals the PI will obtain additional training in neuroimmunology, neuroimaging, and methods of clinical investigation. The Johns Hopkins School of Medicine will provide the PI with expert mentorship in all of these areas of training. In order to study the biological basis of mood and cognition, depression and cognitive impairment will be investigated in patients with Multiple Sclerosis (MS) and Transverse Myelitis (TM). Multiple Sclerosis (MS) has the highest rate of depression of any chronic disease, and a 50% prevalence of cognitive impairment. 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. Cytokines are chemical messengers that immune cells use to coordinate their responses. In addition to their role in modulating immune system function, recent studies have shown that cytokines also influence the CNS and the HPA axis. There is a growing body of evidence in human and animal investigations supporting a role for proinflammatory cytokines in mediating depression and cognitive impairment. We propose that MS and TM provide a model of cytokine-mediated depression and cognitive impairment. We plan to employ neuropsychiatric evaluations, cytokine profiling, and Magnetic Resonance Spectroscopy (MRS) of MS, 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 MS, TM and other CNS autoimmune diseases. These findings could significantly expand our ability to diagnose, prognosticate, and treat neuropsychiatric sequelae in patients with diverse types of autoimmune disorders. Furthermore, these studies have the potential to illuminate immune mechanisms in idiopathic Major Depression that could result in novel therapeutic strategies.