Defining the Role of Post-TBI Sleep Disruption in the Development of CTE and Alzheimer's Disease-Related Neuropathology

确定 TBI 后睡眠中断在 CTE 发展和阿尔茨海默病相关神经病理学中的作用

• 批准号: 10523939
• 负责人: ELAINE R. PESKIND
• 金额: $ 385.99万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523939
• 关键词: Acute; Afghanistan; Age; Age-Years; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-42; Amyloid beta-Protein; Arousal; Behavior; Behavioral; Biological Markers; Brain; Brain Concussion; Cerebrospinal Fluid; Chronic; Clinical; Clinical Research; Data; Dementia; Development; Diffuse; Disease; Dose; Drowsiness; Enrollment; Epinephrine; Exhibits; Explosion; Exposure to; Human; Impaired cognition; Impairment; Individual; Iraq; Life; Link; Longitudinal cohort; Magnetic Resonance Imaging; Measurement; Measures; Metabolism; Military Personnel; Nerve Degeneration; Neurocognitive; Neurodegenerative Disorders; Neurologic; Neurons; Norepinephrine; Outcome; Pathologic; Pathology; Pathway interactions; Physiological; Plasma; Play; Poison; Population; Positron-Emission Tomography; Prevention; Process; Proteins; Publishing; Recording of previous events; Reporting; Risk Factors; Rodent Model; Role; Senile Plaques; Signal Transduction; Sleep; Sleep Deprivation; Sleep Wake Cycle; Sleep disturbances; System; Testing; Translational Research; Traumatic Brain Injury; Veterans; Visit; Waste Products; base; brain dysfunction; chronic traumatic encephalopathy; cognitive function; cognitive performance; cohort; combat veteran; dementia risk; epidemiology study; experience; follow-up; glymphatic dysfunction; glymphatic function; glymphatic system; imaging approach; interstitial; locus ceruleus structure; member; mild traumatic brain injury; multimodality; neuropathology; neurotransmission; noradrenergic; novel; poor sleep; prevent; primary outcome; receptor expression; response; sleep quality; tau Proteins; tau aggregation; tau-1; β-amyloid burden

ABSTRACT Mild traumatic brain injury (mTBI, concussion) has emerged as a risk factor for the development of neurodegenerative disorders such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy, which are characterized by the aberrant aggregation of tau within neural cells. However, the mechanisms linking mTBI to AD-related pathology later in life remain unknown. Disruption of the sleep-wake cycle (SWD) is a frequent chronic complaint after mTBI and also accompanies the development of AD. More recent clinical and translational research suggests that SWD may actually promote the development of Alzheimer’s-related pathology. Our preliminary data show that sleep disturbance is significantly associated with lower CSF Aβ42 levels (an AD-associated profile) in Veterans with mTBI >45 years of age. Based on these findings, we propose that post-TBI sleep disruption promotes the development of AD-related pathology following mTBI. This will be directly tested in Aim 1. The glymphatic system is a recently characterized brain-wide network of perivascular spaces that supports the clearance of both Aβ and tau. Glymphatic function is greatest during sleep and is impaired by TBI. Our published and preliminary data show that MRI-visible perivascular space burden (MV-PVS), a putative marker of glymphatic impairment, is increased among Veterans with blast mTBI and that these changes are associated with AD-related CSF biomarker profiles. In Aim 2, we will use novel MRI-based approaches to test whether glymphatic impairment predicts the development of AD-related pathology after blast mTBI. Sleep-wake behavior is regulated through central noradrenergic (NA) neurotransmission, with locus coeruleus (LC)-derived norepinephrine (NE) promoting arousal during waking. In our blast mTBI Veterans, CSF NE was elevated compared to controls and associated with poor sleep. However, the role that changes in central NA signaling play in promoting AD-related pathology following TBI is unknown. In Aim 3 we will test whether changes in measures of central NA tone predict the development of AD-related pathology after blast mTBI. Dr. Peskind’s 10-year longitudinal VA cohort will contribute 70 previously- and newly-enrolled Veterans >45 years of age with a history of repetitive blast mTBIs who will undergo assessment of: subjective and objective sleep; multi-domain clinical behavioral, neurological, and neurocognitive assessment; glymphatic function measured by MRI, and measurement of CSF/plasma AD/CTE-related biomarkers and NE. Aim 1. Define the role of sleep disruption in the development of post-TBI AD-related pathology. Aim 2. Define the role of glymphatic dysfunction in the development of post-TBI AD-related pathology. Aim 3. Define the role of alterations in central NA tone in the development of post-TBI AD-related pathology after TBI.

摘要 轻度创伤性脑损伤(mTBI，脑震荡)已成为发展为 神经退行性疾病，如阿尔茨海默病(AD)和慢性创伤性脑病， 以tau在神经细胞内的异常聚集为特征。然而，这些机制 在以后的生活中，mTBI与AD相关的病理联系仍不清楚。 睡眠-觉醒周期(SWD)的中断是mTBI后常见的慢性主诉，也 伴随着AD的发展。最近的临床和翻译研究表明，社会保障署 实际上可能会促进阿尔茨海默氏症相关病理的发展。我们的初步数据显示，睡眠 精神障碍与退伍军人脑脊液Aβ42水平降低(AD相关特征)显著相关 MTBI&GT；45岁。基于这些发现，我们认为，脑外伤后的睡眠中断促进了 颅脑损伤后AD相关病理的发展。这将直接在目标1中进行测试。 淋巴系统是最近表征的一个全脑范围的血管周围空间网络，支持 Aβ和Tau的清关。睡眠时淋巴功能最强，受脑外伤的影响最大。我们的 已发表的初步数据显示，MRI可见的血管周围空间负荷(MV-PVS)是一种可能的标志物 在患有冲击性mTBI的退伍军人中，淋巴功能障碍的发生率增加，这些变化是 与AD相关的脑脊液生物标记物相关。在目标2中，我们将使用基于MRI的新方法来测试 淋巴功能损害是否能预测冲击性mTBI后AD相关病理的发展。 睡眠-觉醒行为是通过中枢去甲肾上腺素(NA)神经传递调节的，基因座 蓝斑(LC)衍生的去甲肾上腺素(NE)在清醒时促进觉醒。在我们的mTBI老兵爆炸中， 脑脊液NE较对照组升高，且与睡眠不佳有关。然而，变化中的角色 中枢NA信号在促进脑外伤后AD相关病理中的作用尚不清楚。在目标3中，我们将测试 中枢NA音调的变化是否可预测BLAST后AD相关病理的发展 MTBI。 佩斯金德博士为期10年的纵向退伍军人队列将贡献70名以前和新加入的退伍军人 有重复爆炸史的年龄将接受以下评估的MTBI：主观和客观 睡眠；多领域临床行为、神经和神经认知评估；淋巴功能 测定脑脊液/血浆AD/CTE相关生物标志物和去甲肾上腺素。 目的1.明确睡眠障碍在颅脑损伤后AD相关病理发展中的作用。 目的2.明确淋巴功能障碍在脑外伤后AD相关病理发展中的作用。 目的3.明确中枢NA音调改变在脑外伤后AD相关发展中的作用 颅脑损伤后的病理改变。