Sleep, Circadian Rhythms and Dementing Illnesses

睡眠、昼夜节律和痴呆症

• 批准号: 7470299
• 负责人: DAVID G HARPER
• 金额: $ 35.64万
• 依托单位: BEDFORD VA RESEARCH CORPORATION, INC.
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470299
• 关键词: Affect; Age; Agitation; Alzheimer' s Disease; Area; Behavioral; Body Temperature; Carrier Proteins; Cessation of life; Characteristics; Circadian Rhythms; Data; Dementia; Deterioration; Diagnosis; Disease; Disruption; Dissociation; Elderly; Etiology; Family; Female; Functional disorder; Funding; Hour; Human; Hypothalamic structure; Illness impact; Immunohistochemistry; Indium; Institutionalization; Laboratories; Lewy Body Disease; Link; Measurement; Measures; Motor Activity; Nature; Numbers; Patient Care; Patients; Pattern; Periodicity; Phase; Physiological; Pick Disease of the Brain; Play; Polysomnography; Population; Principal Investigator; Process; REM Sleep; Radioimmunoassay; Regulation; Reporting; Role; Sleep; Sleep disturbances; Symptoms; System; Temperature; Testing; Thalamic structure; Thinking; Time; Tissues; Wakefulness; Work; base; behavior measurement; cost; disorder control; dorsal raphe nucleus; hypocretin; improved; locus ceruleus structure; male; men; nerve supply; phase change; programs; serotonin transporter; suprachiasmatic nucleus

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.

睡眠障碍是一系列进行性痴呆症共有的一种破坏性症状， 它的存在常常促使家庭决定为患者寻求机构护理。正常睡眠-觉醒 调节的特点是振荡、昼夜节律、警报过程和线性、睡眠诱导过程 建筑需要睡眠作为先前清醒持续时间的函数。在我们之前的研究中 我们在男性中发现了诊断特异性的昼夜节律异常，这涉及中枢、 阿尔茨海默病睡眠觉醒障碍病因中的昼夜节律功能障碍，额颞叶 变性和路易体病。此外，我们还发现了 SCN 细胞群的异常 与阿尔茨海默病的特定昼夜节律和行为变化有关的男性。我们现在希望建立 根据这些初步发现，并将我们的研究扩展到视交叉上核外昼夜节律系统以及视交叉上核 本身。我们建议在本资助期内测试四个假设。 1) AD 中的多导睡眠 昼夜核心体温节律相位延迟较大的患者更容易受到干扰 其特点是睡眠效率降低，睡眠潜伏期延长。睡眠会更加碎片化 FTD患者与AD患者相比觉醒次数增多。 2) 女性患者 疑似 AD 患者的体温和活动阶段与男性患者和正常人相似 控制； 3) AD 中出现的夜间躁动和不安，是由于大脑的血清素能神经支配丧失所致。 视交叉上核，可在 SCN 中检测到较低的 RIA 血清素转运蛋白 (5-HTT) 与 FTD 患者和对照组相比。此外，AD 患者夜间躁动的测量值会更高 5-HTT较低的患者； 4) FTD 患者的食欲素/下丘脑分泌素水平降低 下丘脑、蓝斑、中线丘脑和/或中缝背核的周围区域组织 与 AD 和对照相比。活性解离的程度与温度有关 具有相同痴呆诊断的患者的食欲素/下丘脑分泌素为 10ss。为了实现这些目标 我们将研究患有进行性痴呆症的患者，收集核心体温， 每 6 个月收集一次多导睡眠图和运动活动数据，然后进行尸检 除了基于诊断的神经病理学研究之外的神经病理学研究。