The Role of Impaired Neurobehavioral Alertness in Cognitive Decline and Alzheimer’s Disease Pathology

神经行为警觉性受损在认知能力下降和阿尔茨海默病病理学中的作用

• 批准号: 10662040
• 负责人: David T Plante
• 金额: $ 76.52万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662040
• 关键词: Acceleration; Address; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Area; Biological; Blood; Blood specimen; Cognition; Cognitive; Cohort Studies; Collection; Data; Data Set; Dementia; Disease; Disease Progression; Drowsiness; Early identification; Elderly; Epidemic; Excessive Daytime Sleepiness; Future; Genetic; Health; Hypoxia; Impaired cognition; Impairment; Individual; Investigation; Light; Link; Longitudinal Studies; Longitudinal cohort; Measures; Meta-Analysis; National Institute on Alcohol Abuse and Alcoholism; Natural History; Nature; Nerve Degeneration; Neurocognitive; Neuropsychology; Obstructive Sleep Apnea; Outcome; Participant; Pathologic; Persons; Phosphorylation; Populations at Risk; Positioning Attribute; Prevention strategy; Public Health; Recording of previous events; Research; Risk; Role; Sampling; Severities; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Statistical Models; Structural defect; Testing; Therapeutic; Time; Wisconsin; aging population; alertness; apolipoprotein E-4; clinical phenotype; cognitive function; cohort; design; disorder prevention; experience; human old age (65+); improved; inter-individual variation; middle age; modifiable risk; nervous system disorder; neurobehavioral; neurofilament; novel strategies; progression risk; prospective; sleep abnormalities; social; targeted treatment; tau Proteins; tau-1; treatment strategy; vigilance

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is a debilitating neurological disorder, and soon will reach epidemic proportions in the context of an aging population. There is a clear need to identify persons at risk for AD pathology, so that preventative strategies can be developed and implemented. Multiple emerging lines of research demonstrate that sleep disturbance, and particularly excessive daytime sleepiness and obstructive sleep apnea (OSA), both increase the risk for AD pathology and dementia. Excessive daytime sleepiness is an important clinical phenotype of OSA, with individuals with impaired alertness – a function (and salient manifestation) of excessive sleepiness – experiencing more severe sequelae. Preliminary studies from our investigative team demonstrate that diminished daytime alertness measured by the psychomotor vigilance task (PVT) is specifically related to AD pathology and cognition, and that OSA moderates relationships between impaired alertness, AD pathology, and neurocognitive function. This project will advance this vital research area by leveraging emerging Alzheimer's disease biomarkers that can be detected in blood with the wealth of unique sleep data available in the Wisconsin Sleep Cohort (WSC) Study. The WSC has followed participants since the late 1980s, and is the only longitudinal cohort with stored biospecimens, sleep, PVT, and neurocognitive data spanning decades to elucidate the relationships of daytime alertness and OSA with AD pathology and cognitive decline. This investigation will prospectively collect additional blood specimens, PVT, and neurocognitive data in a targeted sample of 450 WSC participants who are now older aged, to address three Specific Aims with testable hypotheses supported by preliminary data. First, it will determine if impaired neurobehavioral alertness is associated with higher levels of pathological phosphorylated tau. Second, it will determine whether impaired neurobehavioral alertness is associated with more severe markers of neurodegeneration. Third, it will determine if impaired neurobehavioral alertness is associated with longitudinal cognitive trajectory. For all Aims, it is hypothesized that OSA moderates relationships between daytime alertness and AD pathology and cognitive decline. Detailed sleep and health history data available in the WSC importantly allows for many key covariates to be included in statistical models used for hypothesis testing. Addressing the Specific Aims of this application will have a sizeable impact on AD and sleep research, by linking a readily obtained objective measure of neurobehavioral alertness to longitudinal risk of AD pathology and cognitive decline. In so doing, this project will ultimately lead to improved preventative and therapeutic strategies that target sleep and alertness as modifiable risk factors for Alzheimer's disease.

项目摘要/摘要 阿尔茨海默病(AD)是一种使人衰弱的神经疾病，很快就会在 人口老龄化的背景。显然有必要确定AD病理的高危人群，以便 可以制定和实施预防性战略。多个新兴研究领域展示了 睡眠障碍，特别是白天过度嗜睡和阻塞性睡眠呼吸暂停(OSA)，两者都 增加AD病理和痴呆症的风险。白天过度嗜睡是一种重要的临床症状。 OSA的表型，伴有警觉性受损的个人--OSA的功能(和显著表现) 嗜睡过度--后遗症更加严重。我们调查小组的初步研究 证明通过精神运动警戒任务(PVT)测量的白天警觉性减弱是 特别与AD的病理和认知有关，OSA调节受损的人之间的关系 警觉性、AD病理和神经认知功能。该项目将通过以下方式推进这一重要研究领域 利用新出现的阿尔茨海默病生物标记物，可以在血液中检测到独特的 威斯康星州睡眠队列(WSC)研究提供了睡眠数据。WSC自2010年以来一直跟踪参与者 20世纪80年代末，是唯一存储了生物样本、睡眠、PVT和神经认知数据的纵向队列 数十年来阐明日间警觉性和OSA与AD病理和 认知能力下降。这项调查将前瞻性地收集更多的血液样本，PVT，和 对450名现在年龄较大的WSC参与者进行了定向样本的神经认知数据，以解决三个问题 具有初步数据支持的可检验假设的特定目标。首先，它将确定是否受损 神经行为的警觉性与较高水平的病理磷酸化tau相关。其次，它将 确定神经行为警觉性受损是否与更严重的 神经退行性变。第三，它将确定神经行为警觉性受损是否与纵向 认知轨迹。对于所有目标，假设OSA调节白天之间的关系 警觉性与阿尔茨海默病病理和认知功能下降。WSC提供详细的睡眠和健康历史数据 重要的是，允许在用于假设检验的统计模型中包括许多关键协变量。 解决此应用程序的特定目标将对AD和睡眠研究产生相当大的影响， 将容易获得的神经行为警觉性的客观测量与AD病理的纵向风险联系起来 和认知能力下降。通过这样做，该项目最终将导致改善预防和治疗 将睡眠和警觉作为阿尔茨海默病的可改变风险因素的策略。