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）是一种以不明原因和长期疲劳为特征的衰弱性多症状疾病，其诊断目前基于相对广泛的临床病例定义。因此，包括在疾病的临床研究中的CFS患者的池是非常异质性的-这一事实可能阻碍了迄今为止的研究进展。理解CFS的病理生理学的一个重要步骤是通过识别一个或多个具有不同病理生理学病因的患者亚组来减少这种异质性，然后选择其中一个亚组纳入研究。在过去的几年里，我们和其他人提供了大量的数据支持存在一个亚组的患者与神经生物学原因为他们的疾病，根据分层的样本根据共病轴I精神病理学（CFS-无精神或CFS-NP和CFS-精神或CFS-P，分别）。与CFS-P患者相比，CFS-NP患者有更多的认知功能障碍，更高的异常脑脊液（CSF）的结果，较低的局部脑血流量（rCBF），和较高的脑室CSF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脑相关变量，其在将CFS患者分成亚组方面的效用有限。目前探索性/发展性研究补助金（R21）提案的目的是严格评估和确认CFS- NP组的患者是否在几个不同的神经病理学变量中具有一致的异常-如果该组实际上确实具有不同的神经生物学基础，则预期会出现这种结果。具体而言，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）对通过腰椎穿刺获得的脊髓液样本进行生化分析;（c）分别使用磁共振成像和光谱法测量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中比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，以尝试将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组的成员资格比较所得到的亚组。这一目的将检验以下假设：聚类分析的结果将确定一组在所研究的多个基于大脑的变量中存在异常，并且该组将由比其他组显著更多的CFS-NP患者组成。 公共卫生相关性：慢性疲劳综合征（CFS）是一种医学上无法解释的使人衰弱的疾病，通过一组预定义的症状的存在来诊断。由于没有有效的诊断测试，了解其原因的进展一直很缓慢。从我们小组和其他人的一系列研究中，已经出现了强有力的初步证据，支持存在一个CFS患者亚组，其疾病似乎是由于大脑中特定的生物学异常。这项探索性/发展性补助金提案的目的是进行仔细对照的研究，以确认存在这样一个CFS患者亚组。如果成功完成，这项研究可以验证一种方法，在未来的研究中选择更同质的CFS患者人群，使他们能够更好地专注于了解CFS的确切原因并开发有效的治疗方法。

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. PUBLIC HEALTH RELEVANCE: Chronic fatigue syndrome (CFS) is a medically unexplained debilitating disease that is diagnosed by the presence of a set of predefined symptoms. Because there are no validated diagnostic tests for the illness, progress in understanding its causes has been slow. From a series of studies by our group and others there has emerged strong preliminary evidence that supports the existence of a subgroup of CFS patients whose illness appears to be due to specific biological abnormalities in the brain. The purpose of this Exploratory/Developmental grant proposal is to conduct carefully controlled studies that will seek to confirm the existence of such a subgroup of CFS patients. If successfully completed, this study could validate an approach for selecting more homogeneous CFS patient populations in future research studies to enable them to focus better on understanding the exact cause of CFS and developing effective treatments for the illness.