Sleep, Circadian Rhythms and Dementing Illnesses

睡眠、昼夜节律和痴呆症

• 批准号: 6937842
• 负责人: DAVID G HARPER
• 金额: $ 34.14万
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6937842
• 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）：睡眠障碍是由渐进性痴呆疾病的范围共享的破坏性症状，其存在通常会导致家庭决定为患者寻求机构护理。正常的睡眠效果调节的特征是振荡，昼夜节律，警报过程和线性，诱导睡眠过程的构建需要睡眠，这是先前清醒的持续时间。在我们先前在该人群中的研究中，我们发现男性诊断特异性的昼夜节律异常，这意味着中心的昼夜节律功能障碍在阿尔茨海默氏病，额颞变性和路易疾病的睡眠效果障碍病因中。此外，我们发现与特定昼夜节律和阿尔茨海默氏病的行为变化有关的男性SCN细胞种群异常。现在，我们希望以这些初步发现为基础，并将我们的研究扩展到超级SCN昼夜节律系统以及SCN本身。我们建议在此资金期间检验四个假设。 1）AD中的多症计算睡眠对昼夜节律核心体温度节奏的大阶段延期的患者将更加干扰，其特征是睡眠效率降低增加了更长的睡眠潜伏期。与觉醒数量增加相比，FTD患者的睡眠将更加分散。 2）可能AD的女性患者将具有类似的延迟温度和活性阶段，作为男性患者和正常对照； 3）与FTD患者相比，SCN中SCN中较低的RIA 5-羟色胺转运蛋白（5-HTT），在AD中看到的Noctumal Distitation和Discation和躁动不安。此外，在较低的5-HTT的AD患者中，夜间躁动的测量将更高。 4）与AD和对照相比，FTD枯萎病的患者在下丘脑，小核基因座，中线丘脑和/或背侧raphe核的靶向区域中降低了Orexin/dypocretin的水平。在接受相同痴呆症诊断的患者中，活性和温度解离的程度将与Orexin/pocretin的10SS有关。为了实现这些目标，我们将研究每6个月收集核心体温度，多摄影学和运动活性数据的患者，除了基于诊断的神经病理学研究外，还进行了每6个月的疾病。