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Impact of sleep apnea and its treatment on memory and tau accumulation in the brain

睡眠呼吸暂停及其治疗对记忆和大脑中 tau 蛋白积累的影响

基本信息

批准号：
10380657
负责人：
Ricardo S Osorio
金额：
$ 66.04万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10380657
关键词：
Acute Address Adherence Affect Aftercare Age Alzheimer&apos s Disease Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid Amyloid beta-42 Anatomy Apnea Arousal Blood Brain Brain Stem Brain imaging Cerebrospinal Fluid Chronic Clinical Cognitive Communities Consensus Data Deterioration Disease Disorientation Drowsiness Education Elderly Genotype Heart Diseases Home Hour Hypoxia Impaired cognition Individual Long-Term Effects Lung diseases Measures Medial Medicare Memory Memory Loss Metabolism Monitor Neurobehavioral Manifestations Neurodegenerative Disorders Neurofibrillary Tangles Neuropsychological Tests Obstructive Sleep Apnea Oxygen Pathologic Processes Patient Self-Report Patients Performance Persons Plasma Polysomnography Positron-Emission Tomography Prevalence Process Regulation Resolution Risk Risk Factors Role Senile Plaques Severities Sleep Sleep Apnea Syndromes Sleep Disorders Sleep Fragmentations Sleep disturbances Spinal Puncture Symptoms Temporal Lobe Testing Time Withdrawal actigraphy aged apolipoprotein E-4 behavior measurement brain magnetic resonance imaging cohort effective therapy expectation follow-up interest memory process modifiable risk neuropsychiatric disorder positive airway pressure sex spatial memory tau Proteins tau aggregation tau-1 uptake vigilance way finding

项目摘要

Project Summary Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by the accumulation of tau tangles and amyloid plaques. Current consensus is that the AD pathological process begins decades before overt clinical symptoms occur. Emerging evidence suggests that sleep disruption may be an important factor in both early cognitive deterioration leading to AD and in the metabolism of amyloid and tau. Obstructive sleep apnea (OSA) is the most common sleep disorder in the US with an estimated prevalence of 40-50% in the cognitively normal elderly. We have previously shown that OSA severity is associated with longitudinal increase in brain amyloid load, but less is known about the long-term effects of OSA on tau and its hyperphosphorylation, a crucial step in the formation of tangles, as well as the effects of OSA on spatial navigational memory, perhaps the earliest form of memory affected in AD. Our preliminary cross-sectional data suggest that higher OSA severity is associated with higher levels of total tau (T-tau) and phosphorylated tau (P-tau) in the cerebrospinal fluid (CSF) and poorer overnight processing of spatial navigational memory in cognitively normal elderly. Further, self-reported presence of OSA is associated with greater longitudinal increase in CSF T-tau and P-tau over 3 years. Although these observations implicate OSA in aberrant memory processing and regulation of tau in the brain, a causal role for OSA in these processes would be strengthened by additional analyses. By measuring behavioral readouts of both the encoding and processing of spatial navigation memory, and quantifying brain tau burden with precise anatomical resolution by adding tau PET brain imaging at baseline and 2.5 years later in 60 asymptomatic, cognitively normal older individuals with a wide range of OSA severity who are already being followed with polysomnography (PSG), actigraphy, and structural brain MRI as part of R01AG056031, we can test the expectations that overnight processing of spatial memory declines longitudinally (Aim 1) and that brain tau burden increases longitudinally (Aim 2) in a way that is dependent on measured OSA severity. A role for OSA in the metabolism of tau also would be strengthened by treating OSA with positive airway pressure (PAP). Whereas CSF Aβ42 levels can change in a matter of hours depending on sleep condition, CSF tau levels are thought to change over several weeks. Therefore, we aim to examine T-tau and P-tau in CSF and T-tau in plasma prior to treatment and 8 weeks later in 80 cognitively normal older individuals with OSA and subjective sleepiness prescribed PAP treatment for the first time at the Mount Sinai Integrative Sleep Center (MSISC). Satisfactory PAP adherence occurs in typically 50% of patients at the MSISC, and we will monitor adherence through downloads from users' machines. Measuring CSF and plasma tau as a function of PAP adherence serves as the basis for Aim 3.

项目总结