Microbial Impact on NeuroDegeneration in Alzheimer's Dementia: MIND-AD

微生物对阿尔茨海默氏痴呆症神经退行性变的影响：MIND-AD

• 批准号: 10615227
• 负责人: Brion S Maher
• 金额: $ 91.33万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615227
• 关键词: 2019-nCoV; Acceleration; Affect; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid beta-Protein; Antibodies; Anxiety Disorders; Apolipoprotein E; Area; Attention; Baltimore; Biological; Biological Aging; Biological Assay; Biology of Aging; Blood; Blood specimen; Brain; CD8-Positive T-Lymphocytes; CDKN2A gene; COVID-19; Catchment Area; Cell Aging; Chronic; Cognitive; Cognitive aging; Communicable Diseases; Cyclin-Dependent Kinase Inhibitor; Cytomegalovirus; Data; Data Collection; Dementia; Depressive disorder; Development; Diagnosis; Diagnostic; Disease; Elderly; Epidemiology; Epigenetic Process; Etiology; Exhibits; Future; Genetic; Genetic Risk; Genotype; Growth; Health; Healthcare Systems; Herpesvirus 1; Human; Human Herpesvirus 2; Human Herpesvirus 4; Immune response; Impaired cognition; Individual; Infection; Inflammation; Interview; Length; Life; Life Style; Light; Link; Longitudinal cohort; Measures; Mental disorders; Methylation; Mind; Modification; Nerve Degeneration; Neuropsychology; Neurovirology; Older Population; Outcome; Participant; Pathway interactions; Performance; Persons; Phenotype; Physiological; Plasma; Prevalence; Prevention; Preventive; Public Health; Reporting; Research; Risk; Risk Factors; Role; SARS-CoV-2 infection; Sampling; Simplexvirus; Stress; Stressful Event; Structure; Subgroup; Symptoms; T cell differentiation; T cell response; Telomere Shortening; Testing; Therapeutic; Time; Toxoplasma gondii; Viral; Virus; Woman; Work; Wrist; abeta deposition; actigraphy; adjudication; blood-based biomarker; brain health; cognitive performance; cognitive testing; cohort; dementia risk; epidemiologic data; follow-up; functional decline; genome-wide; genomic data; hyperphosphorylated tau; interest; latent infection; microbial; mild cognitive impairment; modifiable risk; mouse model; neurofilament; neuroinflammation; novel; novel therapeutics; pathogen; poor sleep; reactivation from latency; risk variant; senescence; seropositive; sex; stressor; tau Proteins; telomere; traumatic event

Alzheimer’s disease is a major threat to public health. Because Alzheimer’s disease has no cure, it is critical to identify its modifiable risk factors that can be targeted to reduce its burden. Although initial evidence suggests its plausibility, relatively little attention has been paid to the role of common infections in Alzheimer’s disease etiology. We propose to investigate the association of infection with common pathogens—Herpes Simplex Virus Types 1 and 2, Cytomegalovirus, Epstein-Barr Virus, Toxoplasma gondii—measured four times over ~25 years, and SARS-CoV-2 (the virus that causes COVID-19), with: (a) cognitive decline, and adjudicated mild cognitive impairment (MCI) and dementia diagnoses; (b) plasma biomarkers of Alzheimer’s disease; and (c) markers of physiological aging (telomere shortening, cyclin-dependent kinase inhibitor p16INK4a, plasma-derived senescence-associated secretory phenotypes, and epigenetic clocks). We will also explore sex, Alzheimer’s disease risk genes, and stress-related exposures (mental disorders and their symptoms, stressful life events, and poor sleep) as moderators that amplify the risk of adverse infection-induced cognitive, brain health, and physiological aging outcomes. Inclusion of viral specific CD8 T-cell differentiation in combination with antibody levels measured serially in the same individuals will allow us to distinguish between long-term infections and reactivation and to evaluate the influence of the course of both infection and immune response to infection, on our outcomes. Senescence-associated secretory phenotypes will point to novel senescent pathways by which infections affect brain health. We will accomplish this using existing data and collecting new data from participants in the Baltimore Epidemiological Catchment Area (ECA) Study Follow-up, which has been assessed five times for >35 years (mean age = 70 years, range 58-100). Blood specimens have been collected three times over ~25 years in the ECA, and we will collect an additional blood draw to obtain infection status at four time points, providing a rare opportunity to quantify timing of exposure and reactivation of latent infections in relation to cognitive and functional decline and Alzheimer’s disease biomarkers and potential pathways. The MPIs of the proposed study are currently completing Wave 5 of data collection in the ECA, including measures of cognitive and functional decline, adjudicated MCI and dementia diagnoses, cellular aging and genome-wide genetic and epigenetics assays. Our preliminary data in the ECA link common pathogens of interest with lower cognitive performance and suggest effect modification by apolipoprotein E genotype. Our team consists of experts in cognitive aging and Alzheimer’s disease, neurovirology, neuropsychology, Alzheimer’s disease biomarkers, genetics and epigenetics, and the biology of aging. Results will clarify the extent to which common infections increase the risk for Alzheimer’s disease and related dementias, and because this work is performed in a longitudinal cohort, it will elucidate mechanisms, identify moderators and candidate pathways which precede decline, thus informing future preventive, and perhaps therapeutic, efforts.

阿尔茨海默病是对公众健康的一大威胁。由于阿尔茨海默病无法治愈，因此至关重要的是 确定其可修改的风险因素，以便有针对性地减轻其负担。尽管初步证据表明 它的合理性，相对较少关注常见感染在阿尔茨海默病中的作用 病因学。我们建议调查感染与常见病原体--单纯疱疹病毒的关系 1型和2型病毒、巨细胞病毒、爱泼斯坦-巴尔病毒、弓形虫--测量结果是~25的四倍 年，和SARS-CoV-2(导致新冠肺炎的病毒)，有：(A)认知能力下降，并被判定为轻度 认知障碍(MCI)和痴呆症的诊断；(B)阿尔茨海默病的血浆生物标记物；和(C) 生理性衰老的标记物(端粒缩短，细胞周期蛋白依赖性激酶抑制物p16INK4a，血浆来源 衰老相关的分泌表型和表观遗传时钟)。我们还将探索性，阿尔茨海默氏症 疾病风险基因和与压力相关的暴露(精神障碍及其症状，应激性生活事件， 和睡眠不佳)作为调节因素，放大了不良感染导致的认知、大脑健康和 生理性衰老的结果。病毒特异性CD8 T细胞分化与抗体结合的研究 在相同个体中连续测量的水平将使我们能够区分长期感染和 重新激活，并评估感染过程和对感染的免疫反应对 我们的结果。衰老相关的分泌表型将指向新的衰老途径，通过 感染会影响大脑健康。我们将使用现有数据并从以下位置收集新数据来完成此任务 巴尔的摩流行病学集水区(ECA)研究后续行动的参与者 评估5次，年龄为35岁(平均年龄=70岁，范围58-100岁)。已经采集了血液样本 在~25年内三次，我们将收集额外的血液样本，以获得感染状态 四个时间点，提供了一个难得的机会来量化潜在感染的暴露和重新激活的时间 与认知和功能衰退以及阿尔茨海默病的生物标志物和潜在途径有关。这个 拟议研究的主计长目前正在完成非洲经委会第五波数据收集工作，包括各项措施 认知和功能衰退，MCI和痴呆症的诊断，细胞老化和全基因组 遗传和表观遗传学分析。我们在ECA中的初步数据将常见感兴趣的病原体与较低的 载脂蛋白E基因型对认知表现和提示效应的影响。我们的团队由以下人员组成 认知老化与阿尔茨海默病、神经病毒学、神经心理学、阿尔茨海默病专家 生物标志物、遗传学和表观遗传学，以及衰老生物学。结果将澄清在多大程度上 常见的感染增加了阿尔茨海默病和相关痴呆症的风险，因为这项工作是 在纵向队列中进行，它将阐明机制，确定调节因素和候选途径 它们先于下降，从而预示着未来的预防，甚至可能是治疗。