Sleep, Circadian Rhythms and Dementing Illnesses

睡眠、昼夜节律和痴呆症

• 批准号: 7110114
• 负责人: DAVID G HARPER
• 金额: $ 33.34万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7110114
• 关键词: Alzheimer' s disease; Lewy body; actigraphy; anxiety; body temperature; body temperature regulation; circadian rhythms; clinical research; dementia; histopathology; human subject; neural degeneration; orexin; patient oriented research; polysomnography; serotonin; serotonin transporter; sleep disorders; suprachiasmatic nucleus

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.

描述（由申请人提供）：睡眠障碍是一系列进行性痴呆疾病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-觉醒调节的特点是一个振荡的、昼夜节律的警报过程和一个线性的、睡眠诱导的过程，需要睡眠作为先前清醒持续时间的函数。在我们之前对这一人群的研究中，我们发现了男性诊断特异性昼夜节律异常，这暗示了阿尔茨海默病、额颞叶变性和路易体病中睡眠觉醒障碍的中枢昼夜节律功能障碍。此外，我们还发现男性SCN细胞群的异常与阿尔茨海默病中特定的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。我们建议在此资助期内测试四个假设。1)阿尔茨海默病患者的多导睡眠图睡眠在其昼夜核心-体温节律相延迟较大的患者中会受到更大的干扰，其特征是睡眠效率降低，睡眠潜伏期延长。与觉醒次数增加的AD患者相比，FTD患者的睡眠更加碎片化。2)可能患有AD的女性患者与男性患者和正常对照者有相似的体温和活动延迟期；3) AD患者的夜间躁动和躁动是由于视交叉上核血清素能神经支配的丧失，与FTD患者和对照组相比，SCN患者的RIA血清素转运蛋白（5-HTT）较低。此外，5-HTT较低的AD患者夜间躁动的测量值更高；4)与AD和对照组相比，FTD患者下丘脑阴囊周围区、蓝斑、丘脑中线和/或中缝背核的靶组织中食欲素/下丘脑分泌素水平降低。在患有相同痴呆诊断的患者中，活性和温度的分离程度将与食欲素/下丘脑泌素的10ss有关。为了实现这些目标，我们将对进行性痴呆患者进行研究，每6个月收集一次核心体温、多导睡眠图和运动活动数据，然后进行死后神经病理学研究，以及基于诊断的神经病理学研究。