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

基本信息

批准号：
10491877
负责人：
Brion S Maher
金额：
$ 87.13万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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/10491877
关键词：
2019-nCoV Affect Age Aging Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos 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 Development Diagnosis Diagnostic Disease Elderly Epidemiology Epigenetic Process Etiology Exhibits Follow-Up Studies Future Genetic Genetic Risk Genotype Growth Health Healthcare Systems Herpes Simplex Infections Herpesviridae 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 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 adjudicate anxiety symptoms base blood-based biomarker brain health cognitive performance cognitive testing cohort dementia risk depressive symptoms epidemiologic data functional decline genome-wide genomic data 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

项目摘要

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.

阿尔茨海默氏病是对公共卫生的主要威胁。由于阿尔茨海默氏病无法治愈，因此至关重要确定其可修改的危险因素，这些风险因素可以针对以减轻其负担。尽管最初的证据表明它的合理性，对普通感染在阿尔茨海默氏病中的作用的相对关注很少病因。我们建议研究感染与常见病原体的关联 - 单纯疱疹病毒类型1和2，巨细胞病毒，爱泼斯坦 - 巴尔病毒，弓形虫弓形病毒 - 在〜25次以上四次测量年和SARS-COV-2（导致COVID-19的病毒），（a）认知能力下降，并调整了中期认知障碍（MCI）和痴呆诊断；（b）阿尔茨海默氏病的血浆生物标志物；（c）物理衰老的标记（端粒缩短，依赖细胞周期蛋白依赖性激酶抑制剂p16ink4a，等离子体衍生感官相关的秘书表型和表观遗传钟）。我们还将探索性行为，阿尔茨海默氏症疾病风险基因以及与压力有关的暴露（精神障碍及其症状，压力性生活事件，睡眠不佳）作为主持人，可以扩大不良感染引起的认知，脑健康和生理老化结果。将病毒特异性CD8 T细胞分化与抗体结合在一起在同一个人中串行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和免疫反应感染的影响，对感染的影响我们的结果。衰老相关的秘书表型将指向新的感觉途径感染会影响大脑健康。我们将使用现有数据并从中收集新数据来完成此操作巴尔的摩流行病学集水区（ECA）研究后续活动的参与者一直是评估五次> 35岁（平均年龄= 70岁，范围58-100）。已经收集了血液标本在ECA中约25年以上三次，我们将收集一次额外的抽血，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时间和重新激活与认知和功能下降以及阿尔茨海默氏病生物标志物和潜在途径有关。拟议研究的MPI目前正在完成ECA中数据收集的第5波，包括措施认知和功能下降，调整后的MCI和痴呆诊断，细胞衰老和全基因组遗传和表观遗传学测定法。我们在ECA中的初步数据链接较低感兴趣的常见病原体认知性能并暗示载脂蛋白E基因型的作用修饰。我们的团队包括认知衰老和阿尔茨海默氏病，神经病毒学，神经心理学，阿尔茨海默氏病的专家生物标志物，遗传学和表观遗传学以及衰老的生物学。结果将阐明在多大程度上常见感染增加了阿尔茨海默氏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，识别主持人和候选途径这是在下降之前的，从而为未来的预防和治疗努力提供了信息。