Diagnostic Values of Plasma Hypocretin Measures for Sleep Disorders

描述(由申请人提供)：这项修订提案的主要目标是建立一种用于人类发作性睡病诊断测试的血液下丘脑泌素测定方法。嗜睡症是一种令人衰弱的睡眠障碍，每2000名美国公民中就有一人受到影响。虽然这种疾病的发病大多发生在青春期，但诊断往往会推迟长达10年的时间。这主要是因为目前还没有具体的发作性睡病诊断工具。我们发现，大多数发作性睡病-猝倒患者的脑脊液(CSF)中的下丘脑分泌素水平低得难以察觉。考虑到下丘脑分泌素配体和受体的遗传消融导致动物发作性睡病的事实，下丘脑分泌素神经传递缺陷可能是大多数人类发作性睡病的主要病理生理机制。在各种睡眠和神经疾病中，无法检测到的低水平的脑脊液下分泌素水平是发作性睡病的非常特异的指标，现在，脑脊液下分泌素测定被列入国际睡眠障碍分类(ICSD)第二版中，作为发作性睡病-猝倒的阳性诊断。尽管许多患者可能会从这种新的诊断测试中受益，但开发侵入性更小的方法，如血液测试将是理想的，特别是在门诊睡眠诊所。我们的初步结果表明，在健康受试者的血浆中可以检测到降克素，但在发作性睡病的受试者中可能没有。因此，我们将评估血浆测量是否可以作为发作性睡病的替代诊断工具。我们将专注于血浆检测的验证以及更灵敏的血浆检测方法的开发。如果成功实现了这一点，就可以在睡眠诊所通过常规血液测试来检测中枢性降克素缺乏症。与公共卫生相关：嗜睡症是一种使人衰弱的疾病，每2000名美国公民中就有一人受到影响。我们的初步结果表明，在健康受试者的血浆中可以检测到降克素，但在发作性睡病的受试者中可能没有。因此，我们将评估血浆测量是否可以作为治疗发作性睡病的替代诊断工具。

DESCRIPTION (provided by applicant): The principal goal of this revised proposal is to establish a blood hypocretin measure for a diagnostic test for human narcolepsy. Narcolepsy is a debilitating sleep disorder that affects 1 in 2000 U.S. citizens. Although the onset of the disease most typically occurs in adolescence, the diagnosis is often delayed by up to 10 years from the disease onset. This is mainly due to the fact that no specific diagnostic tool of narcolepsy is currently available. We have discovered that hypocretin levels are undetectably low in the cerebrospinal fluid (CSF) of most patients with narcolepsy-cataplexy. Considering the fact that genetic ablations of the hypocretin ligand and receptors induce narcolepsy in animals, deficits in hypocretin neurotransmission is likely to be the major pathophysiology of most human narcolepsy. Undetectably low CSF hypocretin levels are very specific for narcolepsy among various sleep and neurological disorders, and CSF hypocretin measures are now included as a positive diagnosis of narcolepsy-cataplexy in the 2nd revision of International Classification of Sleep Disorders (ICSD). Although many patients will likely receive benefits from this new diagnostic test, development of less invasive-methods, such as blood testing would be ideal, especially at outpatient sleep clinics. Our preliminary results suggest that hypocretin can be detected in the plasma of healthy subjects, but may be absent in narcoleptic subjects. We therefore will evaluate whether plasma measurement can be used as an alternative diagnostic tool for narcolepsy. We will focus on the validation of the plasma assay as well as the development of more sensitive assays for plasma measurement. If this is successfully achieved, central hypocretin deficiency can be tested for at sleep clinics by a routine blood test. PUBLIC HEALTH RELEVANCE: Narcolepsy is a debilitating disorder that affects 1 in 2000 U.S. citizens. Our preliminary results suggest that hypocretin can be detected in the plasma of healthy subjects, but may be absent in narcoleptic subjects. We will therefore evaluate whether a plasma measurement can be used as an alternative diagnostic tool for the treatment of narcolepsy.