Neuropathologic Abnormalities Define A Subgroup of Patients with CFS

描述（由申请人提供）：慢性疲劳综合征（CFS）是一种使人衰弱的多症状疾病，其特征是无法解释的和长期的疲劳，其诊断目前基于相对广泛的临床病例定义。因此，临床研究中纳入的慢性疲劳综合症患者群体存在很大的异质性——这一事实可能阻碍了迄今为止的研究进展。了解慢性疲劳综合症病理生理学的一个重要步骤是通过确定一个或多个具有不同病理生理病因的患者亚组，然后选择其中一个亚组纳入研究，从而减少这种异质性。在过去的几年中，我们和其他人提供了大量数据，支持存在一个具有神经生物学原因的患者亚组，该亚组是根据有无共病轴I精神病理（分别为CFS-no psych或CFS-NP和CFS-psych或CFS-P）对样本进行分层的。与CFS-P患者相比，CFS-NP患者有更多的认知功能障碍、更高的脑脊液（CSF）异常发生率、更低的局部脑血流量（rCBF）和更高的脑脊液乳酸值。这些研究的另一个复杂性和局限性是，每项研究都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效用有限。目前探索性/发展研究基金（R21）提案的目的是严格评估和确认CFS- NP组患者是否在几个不同的神经病理变量中存在一致的异常-如果该组实际上确实具有独特的神经生物学基础，则可以预期结果。具体来说，在相同的受试者中，我们将(a)使用客观神经心理学测试评估认知功能；(b)对腰椎穿刺所得的脊髓液样本进行生化分析；(c)分别使用磁共振成像和波谱法测量CFS-P和CFS-NP患者的rCBF和心室乳酸。这将使我们能够检验CFS-NP患者在这些结果变量上比CFS-P患者有更多异常的假设。我们的第二个目标将在聚类分析中使用第一个目标的结果，尝试将CFS受试者客观地、数据驱动地分类为亚型，然后根据CFS- np或CFS- p组的隶属关系比较结果子组。这一目的将检验这样一个假设，即聚类分析的结果将识别出一个在研究的多个基于大脑的变量中存在异常的群体，并且该群体将由比其他群体多得多的CFS-NP患者组成。

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.