Sleep, Circadian Rhythms and Dementing Illnesses

描述（由申请人提供）：睡眠障碍是一种由进行性痴呆疾病谱共享的破坏性症状，其存在通常会促使家庭决定为患者寻求机构护理。正常的睡眠-觉醒调节的特征在于振荡的、昼夜节律的、警觉过程和线性的、睡眠诱导过程，该睡眠诱导过程建立作为先前觉醒的持续时间的函数的睡眠需求。在我们以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，这与阿尔茨海默病、额颞叶变性和路易体病的睡眠-觉醒障碍的病因学有关。此外，我们发现男性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。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。我们建议在这段供资期间测试四个假设。1)AD患者的多导睡眠图显示，其核心体温昼夜节律有较大的相位延迟，睡眠效率降低，睡眠潜伏期延长。与AD患者相比，FTD患者的睡眠更加碎片化，觉醒次数增加。2)可能患有AD的女性患者与男性患者和正常对照相比，体温和活动的延迟相相似; 3）AD患者中观察到的夜间躁动和不安是由于视交叉上核的多巴胺能神经支配丧失所致，与FTD患者和对照相比，SCN中的RIA 5-羟色胺转运蛋白（5-HTT）较低，可检测到。此外，5-HTT较低的AD患者的夜间激越测量值较高;和4）与AD和对照组相比，FTD患者的下丘脑周围区、蓝斑、中线丘脑和/或中缝背核靶组织中的食欲素/下丘脑泌素水平较低。活动和温度的分离程度将与具有相同痴呆诊断的患者中的食欲素/下丘脑泌素的10 ss相关。为了实现这些目标，我们将研究患有进行性痴呆疾病的患者，每6个月收集一次核心体温、多导睡眠图和运动活动数据，然后进行尸检神经病理学研究以及基于诊断的神经病理学研究。

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.