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.

抽象的 轻度创伤性脑损伤（MTBI，咨询）已成为发展的危险因素 神经退行性疾病，例如阿尔茨海默氏病（AD）和慢性创伤性脑病， 其特征是神经细胞内tau的异常聚集。但是，机制 将MTBI与AD相关的病理联系起来，这是未知的。 睡眠觉醒周期（SWD）的破坏是MTBI之后的慢性投诉，也是 涉及广告的发展。最近的临床和翻译研究表明SWD 实际上可能会促进阿尔茨海默氏症相关病理的发展。我们的初步数据表明睡眠 干扰与较低的CSFAβ42水平（与AD相关的特征）显着相关 MTBI> 45岁。根据这些发现，我们建议TBI睡眠中断促进 MTBI之后的广告相关病理的发展。这将在AIM 1中直接测试。 糖基系统是最近表征的脑血管周空间网络，支持 Aβ和tau的清除率。睡眠期间的肾小球功能最大，受TBI损害。我们的 已发布和初步数据表明，MRI-Visible周围空间太空伯恩（MV-PVS），一种推定的标记 果糖损伤的损害，爆炸MTBI的退伍军人增加了，这些变化是 与AD相关的CSF生物标志物谱相关。在AIM 2中，我们将使用基于MRI的新方法进行测试 糖性损害是否预测了爆炸MTBI后与AD相关的病理的发展。 睡眠效果行为通过中央甲肾上腺素能（NA）神经传递调节 在唤醒过程中促进唤醒的核（LC）衍生的去甲肾上腺素（NE）。在我们的爆炸MTBI退伍军人中， 与对照组相比，CSF NE升高，与睡眠不良有关。但是，改变的作用 TBI后促进与广告相关的病理学中的中央NA信号发挥尚不清楚。在AIM 3中，我们将测试 中央NA音调测量的变化是否预测了爆炸后与AD相关病理的发展 mtbi。 Peskind博士的10年纵向VA队列将贡献70名以前的和新入选的退伍军人> 45 年龄具有重复性爆炸史mTBI的历史，他们将接受评估：主观和客观 睡觉;多域临床行为，神经系统和神经认知评估；乙二醇功能 通过MRI测量以及与CSF/等离子体AD/CTE相关的生物标志物和NE的测量。 目标1。定义睡眠破坏在与TBI广告后病理学发展中的作用。 AIM 2。定义糖性功能障碍在与TBI后AD相关病理学发展中的作用。 目的3。定义改变中央NA音调在TBI AD相关后开发中的作用 TBI之后的病理。