Sleep, Circadian Rhythms and Dementing Illnesses

描述(申请人提供)：睡眠障碍是进行性痴呆疾病谱系共有的一种破坏性症状，它的存在往往促使家庭决定为患者寻求机构护理。正常的睡眠-觉醒调节的特征是一个振荡的、昼夜节律的、警觉的过程，以及一个线性的、诱导睡眠的过程，根据先前觉醒的持续时间来构建睡眠需要。在我们之前对这一人群的研究中，我们在男性中发现了诊断特异性的昼夜节律异常，这些异常涉及阿尔茨海默病、额颞部退行性变和路易体病的睡眠-觉醒障碍的病因中的中枢昼夜节律障碍。此外，我们还发现男性SCN细胞群体的异常与阿尔茨海默病的特定昼夜节律和行为变化有关。我们现在希望在这些初步发现的基础上，将我们的研究扩展到SCN外的昼夜节律系统以及SCN本身。我们建议在这一资金期内检验四个假设。1)以睡眠效率降低和睡眠潜伏期延长为特征的昼夜核心体温节律延迟较大的AD患者多导睡眠图睡眠将受到更多的干扰。与觉醒次数增加的AD患者相比，FTD患者的睡眠更分散。2)女性疑似AD患者的体温和活动期与男性患者和正常对照组相似：3)AD患者的夜间躁动和躁动是由于视交叉上核5-羟色胺能神经支配的丧失所致，与FTD患者和对照组相比，SCN中可检测到较低的RIA 5-羟色胺转运蛋白(5-HTT)。此外，5-HTT降低的AD患者夜间兴奋程度更高；4)FTD萎缩症患者下丘脑穹隆周区、蓝斑、中线丘脑和/或中缝背侧核靶组织中增食欲素/下丘脑肌酸水平低于AD和对照组。在同样患有痴呆症的患者中，活动和体温的分离程度将与食欲素/下丘脑分泌素的10ss有关。为了实现这些目标，我们将每6个月收集核心体温、多导睡眠图和运动活动数据，并在基于诊断的神经病理学研究之外，对进行性痴呆症患者进行死后神经病理学研究。

DESCRIPTION (provided by applicant): Sleep disturbance is a disruptive symptom shared by the spectrum of progressive dementing illnesses, and its presence often precipitates decisions by families to seek institutional care for patients. Normal sleep-wake regulation is characterized by an oscillatory, circadian, alerting process and a linear, sleep-inducing process building need to sleep as a function of the duration of prior wakefulness. In our previous studies in this population, we have found diagnosis-specific circadian abnormalities in men, which implicate central, circadian dysfunction in the etiology of sleep-wake disturbance in Alzheimer's disease, frontotemporal degeneration, and Lewy body disease. In addition, we have found abnormalities in SCN cellular populations in men linked with specific circadian and behavioral changes in Alzheimer's disease. We now wish to build upon these initial findings and expand our studies to the extra-SCN circadian system as well as the SCN itself. We propose for this funding period to test four hypotheses. 1) Polysomnographic sleep in AD will be more disturbed in patients with large phase-delays of their circadian core-body temperature rhythm characterized by reduced sleep efficiency add longer sleep latency. Sleep will be more fragmented in patients with FTD compared to AD patients with an increased number of awakenings. 2) Female patients with probable AD will have similady delayed phase of temperature and activity as male patients and normal controls; 3) Noctumal agitation and restlessness, seen in AD, results from loss of serotonergic innervation of the suprachiasmatic nuclei and will be detectable as lower RIA serotonin transporter protein (5-HTT) in SCN compared to FTD patients and controls. In addition, measurements of nocturnal agitation will be higher in AD patients with lower 5-HTT; and 4) Patients with FTD wilt have lowered levels of orexin/hypocretin in target tissue of perifonical area of the hypothalamus, locus coeruleus, midline thalamus and/or dorsal raphe nuclei compared to AD and controls. The extent of dissociation of activity and temperature will be related to the 10ss of orexin/hypocretin in patients carrying the same dementia diagnoses. To accomplish these objectives we will study patients with progressive dementing illnesses collecting core-body temperature, polysomnographic and locomotor activity data every 6 months and followed by post-mortem neuropathological studies in addition to diagnosis-based neuropathological studies.