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.

阿尔茨海默病是对公众健康的主要威胁，因为阿尔茨海默病无法治愈，因此对其进行治疗至关重要。尽管初步证据表明，可以确定可改变的风险因素，以减轻其负担。尽管其合理性，但人们对常见感染在阿尔茨海默病中的作用的关注相对较少我们建议调查感染与常见病原体——单纯疱疹的关联。 1 型和 2 型病毒、巨细胞病毒、EB 病毒、弓形虫 — 在约 25 小时内测量四次年，以及 SARS-CoV-2（导致 COVID-19 的病毒），具有：(a) 认知能力下降，并且被判定为轻度认知障碍 (MCI) 和痴呆症诊断；(b) 阿尔茨海默病的血浆生物标志物；以及 (c) 生理衰老标志物（端粒缩短、细胞周期蛋白依赖性激酶抑制剂 p16INK4a、血浆源性衰老相关的分泌表型和表观遗传时钟）我们还将探索性、阿尔茨海默病。疾病风险基因和与压力相关的暴露（精神障碍及其症状、压力生活事件、和睡眠不佳）作为调节因素，放大了感染引起的认知、大脑健康和健康不良的风险包括病毒特异性 CD8 T 细胞分化与抗体的结合。在同一个体中连续测量的水平将使我们能够区分长期感染和再激活并评估感染过程和对感染的免疫反应的影响，我们的结果将指出衰老相关的分泌表型。我们将利用现有数据并收集新数据来实现这一目标。巴尔的摩流行病学集水区 (ECA) 研究随访的参与者，该研究已评估五次，持续时间 > 35 岁（平均年龄 = 70 岁，范围 58-100）。在 ECA 的约 25 年内进行了 3 次，我们将在以下时间进行额外的抽血以获得感染状态：四个时间点，为量化潜在感染的暴露时间和重新激活提供了难得的机会与认知和功能下降以及阿尔茨海默病生物标志物和潜在途径相关。拟议研究的 MPI 目前正在 ECA 中完成第 5 波数据收集，包括措施认知和功能下降、MCI 和痴呆诊断、细胞衰老和全基因组我们在 ECA 中的初步数据将常见的感兴趣病原体与较低的病原体联系起来。认知表现并建议通过载脂蛋白 E 基因型进行影响修改我们的团队由以下人员组成。认知衰老和阿尔茨海默病、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的结果将阐明衰老的程度。常见感染会增加患阿尔茨海默病和相关痴呆症的风险，并且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先于衰退，从而为未来的预防甚至治疗努力提供信息。