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Sleep and Orexin: Potential Markers of Progression from Preclinical to Mildly Symptomatic Alzheimer's Disease

睡眠和食欲素：从临床前到轻度症状阿尔茨海默病进展的潜在标志

基本信息

批准号：
10396450
负责人：
Brendan Patrick Lucey
金额：
$ 21.44万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-01-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396450
关键词：
Affect African American population Age Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer’s disease biomarker Amyloid Amyloid beta-Protein Animal Model Animals Apnea Biological Markers Brain Brain Injuries Cellular Phone Cerebrospinal Fluid Clinical Clinical Trials Clinical Trials Design Cognition Cognition Disorders Cognitive Cognitive deficits Cross-Sectional Studies Data Dementia Development Disease Progression Early Diagnosis Elderly Frequencies Future Goals Human Image Impaired cognition Individual Intercellular Fluid Magnetic Resonance Imaging Measurement Measures Mediating Monitor Mus Narcolepsy Neuronal Injury Neurons Neuropsychological Tests Neurotransmitters Not Hispanic or Latino Participant Pathogenesis Pathology Pharmaceutical Preparations Polysomnography Positron-Emission Tomography Prognosis Prognostic Marker REM Sleep Race Research Rodent Senile dementia Severities Signs and Symptoms Sleep Sleep Disorders Sleep Stages Sleep disturbances Spinal Puncture Stage II Sleep Symptoms Synapses System Tauopathies Testing Time Wakefulness Work abeta accumulation abeta deposition amyloid imaging apolipoprotein E-4 base cognitive performance cognitive testing cohort demented healthy aging human old age (65+)hypocretin imaging biomarker indexing individual response mild cognitive impairment minimally invasive molecular pathology neuroinflammation neuron loss non rapid eye movement novel novel therapeutics pre-clinical progression marker rapid eye movement rate of change sex sleep quality tau Proteins tau aggregation tau-1

项目摘要

Project 2 Project Summary Amyloid-β (Aβ) deposition in the brain is a key early step in the development of Alzheimer disease and is followed by tauopathy, neuronal and synaptic loss, and cognitive impairment. The presence of Alzheimer disease pathology in the brain without clinical symptoms is called “preclinical” Alzheimer disease and begins to develop at least 10-15 years prior to symptom onset. Once cognitive impairment begins, there is already marked neuronal loss. Therefore, a major goal of Alzheimer disease research is to identify the transition from Aβ deposition without evidence of neuronal injury to the early stages of tauopathy when neuronal loss and then cognitive deficts begin to develop. Reliably differentiating this transition in individuals with and without cognitive impairment is critical to: 1) predict prognosis; 2) screen and monitor response of individuals in Alzheimer disease clinical trials; and 3) guide Alzheimer disease clinical trial design. Current biomarkers of Alzheimer disease pathology are either invasive (lumbar puncture) and/or expensive (amyloid PET). Based on our data in both animals and humans, we propose that changes in sleep can serve as an informative biomarker of preclinical and symptomatic Alzheimer disease. Changes in sleep associated with Alzheimer disease pathology may provide a minimally invasive way to assess the transition from preclinical to symptomatic Alzheimer disease as well as be a functional marker that is responsive to new therapies. Work in both rodents and humans strongly suggests a bidirectional relationship between sleep and Alzheimer disease: the amount and quality of sleep may regulate Aβ deposition and/or changes in sleep parameters may indicate progression of Alzheimer disease pathology. Changes in sleep mediated by Alzheimer disease may also involve the orexinergic system. Orexin is a wake-promoting neurotransmitter and orexin deficiency results in narcolepsy. Recent cross-sectional studies associated higher CSF orexin levels with mild cognitive impairment as well as moderate and severe Alzheimer disease compared to controls. These findings suggest that orexin could be used for early detection of Alzheimer disease, however the relationship of orexin to different sleep parameters, CSF Alzheimer disease biomarkers, and neuropsychological testing is unknown. In this study, we hypothesize that longitudinally measuring sleep parameters and CSF orexin in cognitively normal and mildly demented individuals will serve to detect changes in global sleep markers and the orexinergic system as markers of brain injury at the very early progression from preclinical Alzheimer disease to mildly symptomatic Alzheimer disease.

项目二项目总结