Neuropathologic Abnormalities Define A Subgroup of Patients with CFS

描述(申请人提供)：慢性疲劳综合征(CFS)是一种以原因不明和长期疲劳为特征的多症状衰弱疾病，目前其诊断基于相对宽泛的临床病例定义。因此，纳入这种疾病的临床研究的CFS患者池是非常不同的--这一事实可能阻碍了迄今为止的研究进展。在理解CFS的病理生理学方面向前迈出的重要一步将涉及通过识别一个或多个具有不同疾病病理生理学原因的患者亚组，然后选择其中一个亚组纳入研究，从而减少这种异质性。在过去的几年里，我们和其他人已经提供了大量的数据，支持存在一组有神经生物学原因的患者，根据是否存在共病的Axis I精神病理学对样本进行分层(分别为CFS-无心理或CFS-NP和CFS-心理或CFS-P)。与CFS-P患者相比，CFS-NP患者的认知功能障碍更严重，脑脊液(CSF)异常率更高，局部脑血流量(RCBF)更低，脑室脑脊液乳酸水平更高。这些研究的另一个复杂性和局限性是，每个研究只研究了一个与大脑相关的变量，其在将CFS患者划分为亚组方面的作用有限。目前的探索性/发展性研究补助金(R21)提案的目的是严格评估和确认CFS-NP组的患者在几个不同的神经病理变量上是否有一致的异常-如果这组患者确实有明显的神经生物学基础，这一结果是可以预期的。具体地说，在同一受试者中，我们将(A)使用客观神经心理测试评估认知功能；(B)对腰椎穿刺术获得的脊液样本进行生化分析；以及(C)使用磁共振成像和光谱分析分别测量CFS-P和CFS-NP患者的rCBF和脑室乳酸。这将使我们能够检验CFS-NP患者在这些结局变量上比CFS-P患者有更多异常的假设。我们的第二个目标将使用聚类分析中第一个目标的结果来尝试将CFS受试者客观地、数据驱动地分类为亚型，然后根据成员资格将得到的子组比较为CFS-NP组或CFS-P组。这一目标将检验这样一种假设，即聚类分析的结果将识别出一组在所研究的多个基于大脑的变量中存在异常的组，并且这一组将比其他组组成明显更多的CFS-NP患者。

DESCRIPTION (provided by applicant): Chronic fatigue syndrome (CFS) is a debilitating multi-symptom disorder characterized by unexplained and prolonged fatigue, whose diagnosis is currently based on a relatively broad clinical case definition. Consequently, the pool of CFS patients included in clinical studies of the illness is greatly heterogeneous - a fact that might have impeded research progress to date. A major step forward in understanding the pathophysiology of CFS would involve reducing this heterogeneity by identifying one or more subgroups of patients with different pathophysiological causes of their illness, and then selecting one of these subgroups for inclusion into research studies. Over the past few years, we and others have provided substantial data supporting the existence of a subgroup of patients with a neurobiological cause for their illness, based on stratifying the sample according to the absence or presence of comorbid Axis I psychopathology (CFS-no psych or CFS-NP and CFS-psych or CFS-P, respectively). Compared to CFS-P patients, the CFS-NP patients had more cognitive dysfunction, a higher rate of abnormal cerebrospinal fluid (CSF) findings, lower regional cerebral blood flow (rCBF), and higher ventricular CSF lactate values. A further complication and limitation of these studies is that each had investigated only one brain-related variable, whose utility in separating CFS patients into subgroups was limited. The purpose of the present Exploratory/Developmental Research Grant (R21) proposal is to rigorously assess and confirm whether patients in the CFS- NP group have consistent abnormalities across several different neuropathological variables - an outcome that would be expected if this group, in fact, does have distinct neurobiological underpinnings. Specifically, in the same subjects, we will (a) assess cognitive function using objective neuropsychological testing; (b) conduct biochemical analysis of spinal fluid samples obtained by lumbar puncture; and (c) measure rCBF and ventricular lactate using magnetic resonance imaging and spectroscopy, respectively, in CFS-P and CFS-NP patients. This will allow us to test the hypothesis that CFS-NP patients have more abnormalities in these outcome variables than CFS-P patients. Our second Aim will use the results from the first Aim in a cluster analysis to attempt objective, data-driven classification of the CFS subjects into subtypes, and then compare the resulting subgroups based on membership into CFS-NP or CFS-P groups. This aim will test the hypothesis that the results of the cluster analysis will identify a group with abnormalities across the multiple brain-based variables studied, and this group will be constituted of significantly more CFS-NP patients than in other groups.