Relationships between local and global mechanisms of sleep apnea, Alzheimer's disease biomarkers, and memory impairment in cognitively asymptomatic older adults

无认知症状老年人睡眠呼吸暂停、阿尔茨海默病生物标志物和记忆障碍的局部和整体机制之间的关系

• 批准号: 10625981
• 负责人: BRYCE A. MANDER
• 金额: $ 12.73万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625981
• 关键词: Acoustic Stimulation; Address; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Apnea; Atrophic; Biological Markers; Brain; Breathing; Cephalic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cognitive; Dementia; Development; Differential Diagnosis; Disease Progression; Elderly; Electroencephalography; Epidemiology; Episodic memory; Functional disorder; Funding; Future; Geriatric Psychiatry; Goals; Hippocampus; Human; Hypoxemia; Impaired cognition; Intervention; Intervention Studies; Knowledge; Link; Magnetic Resonance Imaging; Magnetism; Measures; Medial; Memory; Memory Loss; Memory impairment; Mentors; Methodology; Methods; Molecular; Monitor; Motor Skills; Nerve Degeneration; Neurodegenerative Disorders; Obstructive Sleep Apnea; Onset of illness; Parietal; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Perforant Pathway; Physiological; Play; Population; Positron-Emission Tomography; Prevalence; Preventive treatment; Process; Research; Research Activity; Research Personnel; Research Proposals; Resolution; Resources; Risk; Risk Reduction; Role; Severities; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Structure; Temporal Lobe; Training; Treatment Efficacy; Work; age related; candidate identification; career; certificate program; clinically relevant; density; entorhinal cortex; epidemiology study; indexing; memory consolidation; memory encoding; neuroimaging; novel; pharmacologic; positive airway pressure; pre-clinical; procedural memory; programs; sleep spindle; standard of care; symptomatology; tau Proteins; ultra high resolution; β-amyloid burden

Project Summary/Abstract Epidemiologic evidence has established obstructive sleep apnea (OSA) as a risk factor for Alzheimer’s disease (AD). However, the mechanisms of this increase in AD risk remain unclear. Three potentially AD-relevant clinical features of OSA include severity of hypoxemia, global sleep fragmentation, and local deficits in memory-relevant sleep oscillations, i.e. slow waves and sleep spindles. These clinical features of OSA have been independently linked to amyloid and tau burden and accumulation, medial temporal lobe (MTL) degeneration, and MTL- dependent memory impairment—all hallmark biomarkers of AD. However, it remains unclear how each of these features relate to AD pathophysiology or MTL-dependent memory decline in patients with OSA. The overarching research objective of this proposal is to address these unknowns. The proposed specific aims are to determine whether distinct global and local OSA features are associated with 1) cortical amyloid burden, 2) MTL tau burden, and 3) degeneration of specific MTL brain circuits supporting multiple forms of memory known to depend on sleep and be vulnerable to AD pathophysiology. The proposed aims will be supported by leveraging existing resources, and collecting high density electroencephalography (hdEEG, 256 channels) sleep recordings in cognitively normal older adults (60-85 years) undergoing positron emission tomography (PET) to assess amyloid and tau burden, as well as ultrahigh resolution magnetic resonance imaging (uhr-MRI) of MTL structure. The proposed study will therefore capitalize on an opportunity to examine how OSA relates to AD pathological burden, MTL structure and function, and memory in an unprecedented level of detail and breadth. This is congruent with both my short and long-term career goals. Specifically, I plan to generate research proposals seeking funding to uncover the impact of distinct forms of sleep disturbance on circuit and molecular mechanisms of AD pathogenesis in humans. This will support my efforts to establish a clinical research program evaluating i) the contribution of sleep disturbance to the onset and progression of various forms of neurodegenerative disease across clinical stages, ii) the utility of sleep-based biomarkers to predict dementia onset and aid differential diagnosis between dementias, and iii) the utility of targeted sleep-based interventions to arrest cognitive decline associated with AD and related dementias. This research proposal and my long-term career goals are supported by my training plan overseen by my mentoring team which includes experts in hdEEG, uhr-MRI, MTL-dependent memory circuit function, PET methods in the context of aging and AD—including amyloid and tau PET, clinical aspects of sleep disorders, geriatric psychiatry, and neurodegenerative disease, and clinical trial design and implementation in the context of sleep disorders and AD. The proposed training plan includes structured mentoring on each of these topics and participation in a clinical research certificate program, as well as a course focused on clinical trials in AD. By establishing this research program, I hope to develop sleep-based approaches to reduce risk, delay onset, and slow progression of dementia and age-related cognitive decline.

项目总结/文摘

项目成果

Local Sleep and Alzheimer's Disease Pathophysiology.

• DOI: 10.3389/fnins.2020.525970
• 发表时间: 2020
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Mander BA

Older adults at greater risk for Alzheimer's disease show stronger associations between sleep apnea severity and verbal memory.

患有阿尔茨海默病风险较高的老年人表现出睡眠呼吸暂停严重程度与言语记忆之间更强的关联。

• DOI: 10.21203/rs.3.rs-3683218/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Lui,Kitty;Dave,Abhishek;Sprecher,Kate;Chappel-Farley,Miranda;Riedner,Brady;Heston,Margo;Taylor,Chase;Carlsson,Cynthia;Okonkwo,Ozioma;Asthana,Sanjay;Johnson,Sterling;Bendlin,Barbara;Mander,Bryce;Benca,Ruth
• 通讯作者: Benca,Ruth

Sleep Disturbance Forecasts β-Amyloid Accumulation across Subsequent Years.

• DOI: 10.1016/j.cub.2020.08.017
• 发表时间: 2020-11-02
• 期刊: Current biology : CB
• 作者: Winer JR;Mander BA;Kumar S;Reed M;Baker SL;Jagust WJ;Walker MP
• 通讯作者: Walker MP

The Effects of Daytime Psilocybin Administration on Sleep: Implications for Antidepressant Action.

白天psilocybin给药对睡眠的影响：对抗抑郁作用的影响。

• DOI: 10.3389/fphar.2020.602590
• 发表时间: 2020
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Dudysová D;Janků K;Šmotek M;Saifutdinova E;Kopřivová J;Bušková J;Mander BA;Brunovský M;Zach P;Korčák J;Andrashko V;Viktorinová M;Tylš F;Bravermanová A;Froese T;Páleníček T;Horáček J
• 通讯作者: Horáček J

Self-reported sleep in relation to risk of dementia a quarter of a century later at age 90+: The 90+ Study.

四分之一世纪后 90 岁时自我报告的睡眠与痴呆风险的关系：90 年研究。

• DOI: 10.1080/15402002.2022.2148668
• 发表时间: 2023
• 期刊: Behavioral sleep medicine
• 影响因子: 3.1
• 作者: Melikyan,ZaruiA;Kawas,ClaudiaH;Paganini-Hill,Annlia;Jiang,Luohua;Mander,BryceA;Corrada,MaríaM
• 通讯作者: Corrada,MaríaM