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）已成为发展的风险因素， 神经退行性疾病如阿尔茨海默病（AD）和慢性创伤性脑病， 其特征在于神经细胞内tau蛋白的异常聚集。然而，机制 将mTBI与以后生活中的AD相关病理学联系起来仍然未知。 睡眠-觉醒周期（SWD）中断是mTBI后常见的慢性主诉， 伴随着AD的发展。最近的临床和转化研究表明， 实际上可能会促进老年痴呆症相关病理的发展。我们的初步数据显示睡眠 在患有AD的退伍军人中，疾病与CSF Aβ42水平降低（AD相关特征）显著相关。 mTBI >45岁。基于这些发现，我们提出，脑外伤后睡眠中断促进了脑损伤后睡眠的恢复。 mTBI后AD相关病理学的发展。这将在目标1中得到直接检验。 胶质淋巴系统是最近表征的血管周围空间的全脑网络，其支持 Aβ和tau的清除率。淋巴功能在睡眠期间最大，并因TBI而受损。我们 已发表的和初步的数据表明，MRI可见血管周围间隙负荷（MV-PVS），一个假定的标志物， 胶质淋巴损伤，是增加退伍军人与爆炸mTBI，这些变化是 与AD相关的CSF生物标志物谱相关。在目标2中，我们将使用新的基于MRI的方法来测试 胶质淋巴损伤是否预测原始细胞mTBI后AD相关病理学的发展。 睡眠-觉醒行为通过中枢去甲肾上腺素能（NA）神经传递调节， 蓝斑（LC）衍生的去甲肾上腺素（NE）促进清醒期间的唤醒。在我们的爆炸mTBI退伍军人， 与对照组相比，CSF NE升高，并与睡眠不良相关。然而，在这种情况下， 中枢NA信号传导在TBI后促进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张力测量值的变化是否可预测爆炸后AD相关病理的发展 mTBI。 Peskind博士的10年纵向退伍军人管理局队列将贡献70名以前和新登记的45岁以上退伍军人 有重复性冲击波mTBI病史的年龄<5岁，将接受以下评估：主观和客观 睡眠;多领域临床行为、神经学和神经认知评估;胶质淋巴功能 通过MRI测量，以及测量CSF/血浆AD/CTE相关生物标志物和NE。 目标1.定义睡眠中断在TBI后AD相关病理学发展中的作用。 目标2.确定胶质淋巴功能障碍在TBI后AD相关病理学发展中的作用。 目标3.定义中枢NA张力改变在TBI后AD相关发展中的作用。 TBI后的病理学