Role of Liver Fibrosis in Cognitive Impairment and Dementia

肝纤维化在认知障碍和痴呆中的作用

基本信息

批准号：
10456884
负责人：
Neal S Parikh
金额：
$ 19.49万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2021-08-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10456884
关键词：
Abeta clearance Address Adult Affect Age-Years Age-associated memory impairment Alcohol consumption Alcohols Alzheimer&apos s disease related dementia American Analysis of Covariance Ancillary Study Area Atherosclerosis Risk in Communities Biological Markers Blood Vessels Brain Brain imaging Cardiovascular Diseases Cerebrovascular Trauma Characteristics Clinic Clinical Cognition Cognitive Data Dementia Enrollment Epidemiology Etiology Extracellular Matrix Familiarity Fibrosis Future General Population Goals Gold Health Hepatic Encephalopathy Hepatology Hippocampus (Brain)Human Image Impaired cognition Internal Medicine Iron K-Series Research Career Programs Laboratories Linear Regressions Link Liver Liver Dysfunction Liver Fibrosis Liver diseases Logistic Regressions Magnetic Resonance Imaging Measures Memory Disorders Memory impairment Mentors Mentorship Metabolic syndrome Methods Modeling National Institute of Neurological Disorders and Stroke Neurologic Neurologist Neurology Neuropsychological Tests Outcome Participant Pathologic Pathway interactions Patients Peripheral Persons Pharmaceutical Preparations Population Positioning Attribute Prevalence Preventive Prospective cohort study Proteins Public Health Research Research Design Research Personnel Risk Factors Role Sampling Studies Standardization Statistical Methods Systemic disease Testing Therapeutic Training United Kingdom United States National Institutes of Health Virus Diseases White Matter Hyperintensity Work abeta deposition adjudicate apolipoprotein E-4 base biobank brain health brain volume career chronic liver disease chronic liver injury cognitive performance cohort dementia risk elastography hazard imaging biomarker innovation insight liver metabolism mild cognitive impairment multidisciplinary nervous system disorder neuroimaging neuroimaging marker non-demented novel novel therapeutic intervention patient oriented research prospective public health relevance recruit response screening secondary analysis skills symposium tomography tool uptake β-amyloid burden

项目摘要

PROJECT SUMMARY/ABSTRACT This is a K23 career development award application for Dr. Neal Parikh, a neurologist and junior investigator pursuing patient-oriented research on the contribution of liver fibrosis to cognitive impairment and dementia. Dr. Parikh seeks to develop expertise in two key content areas: 1) cognitive impairment and Alzheimer’s disease and related dementias (ADRD), with a focus on neuroimaging correlates of ADRD and mechanisms of cognitive impairment, and 2) chronic liver disease hepatology with a focus on liver fibrosis and biomarkers. He also seeks to develop advanced skills in study design and statistical methods specific to the study of ADRD. Dr. Parikh has assembled a mentoring team led by Dr. Costantino Iadecola, a neurologist with expertise in the links between systemic factors and cognition, in addition to three co-mentors: Dr. David E. Cohen, a hepatologist with expertise in chronic liver disease and liver metabolism, Dr. Mony de Leon, an investigator with expertise in ADRD neuroimaging, and Dr. Rebecca Gottesman, a neurologist with expertise in ADRD epidemiology. Based on emerging evidence and his preliminary data, Dr. Parikh’s central hypothesis is that liver fibrosis is independently associated with cognitive impairment, dementia, and related neuroimaging markers. Dr. Parikh will test this hypothesis in three specific aims. Specific Aim 1 will test the hypothesis that liver fibrosis is associated with cognitive impairment, incident dementia risk, and related imaging markers at the population level among 500,000 participants in the United Kingdom Biobank prospective cohort study. Specific Aim 2 will test the hypothesis that liver fibrosis is associated with cortical β-amyloid deposition on florbetapir position emission tomography (PET) imaging in a diverse, multi-center cohort of 346 nondemented participants in an Atherosclerosis Risk in Communities-PET ancillary study. Specific Aim 3 will characterize the prevalence, causes, and impact of subclinical liver fibrosis in a prospectively enrolled cohort of 120 patients with cognitive impairment and dementia. The proposed aims will use multiple liver fibrosis markers and complementary cognitive endpoints, spanning neuropsychological testing, adjudicated incident dementia outcomes, and neuroimaging markers including white matter hyperintensity volume and cortical β-amyloid burden. The proposed research is significant because it seeks to establish a novel risk factor for cognitive impairment and dementia, thus raising the possibility of new liver-targeted preventive and therapeutic strategies in ADRD and cognitive impairment broadly. The proposed research is innovative because it seeks to expand the paradigm of multi-etiology cognitive impairment and dementia by establishing a role for liver fibrosis in cognition beyond hepatic encephalopathy. Further, this work will bridge hepatology and neurology to address the burden of neurological disease by adapting contemporary and nascent hepatology tools to neurological research.

项目概要/摘要这是 Neal Parikh 博士的 K23 职业发展奖申请，他是一名神经科医生和大三学生研究人员致力于以患者为中心的研究，探讨肝纤维化对认知障碍和认知功能障碍的影响 Parikh 博士致力于发展两个关键领域的专业知识：1) 认知障碍和阿尔茨海默氏病和相关痴呆症 (ADRD)，重点关注 ADRD 和相关痴呆症的神经影像学相关性认知障碍的机制，2) 慢性肝病肝病学，重点关注肝纤维化和他还寻求发展针对特定研究设计和统计方法的高级技能。 Parikh 博士组建了一个由神经科医生 Costantino Iadecola 博士领导的指导团队。除了三位共同导师之外，他们还拥有系统因素与认知之间联系的专业知识：David E. Cohen 是一位肝病专家，在慢性肝病和肝脏代谢方面拥有丰富的专业知识；Mony de Leon 博士是一位具有 ADRD 神经影像学专业知识的研究员，以及具有 ADRD 神经影像学专业知识的神经科医生 Rebecca Gottesman 博士 ADRD 流行病学基于新出现的证据和他的初步数据，Parikh 博士的中心假设是肝纤维化与认知障碍、痴呆和相关神经影像学独立相关 Parikh 博士将在三个特定目标中检验这一假设。具体目标 1 将检验以下假设。肝纤维化与认知障碍、痴呆风险和相关影像学标志物相关英国生物银行前瞻性队列研究中 500,000 名参与者的人口水平。目标 2 将检验肝纤维化与氟贝丕皮质 β-淀粉样蛋白沉积相关的假设对 346 名非痴呆参与者进行的多样化、多中心队列的位置发射断层扫描 (PET) 成像在社区动脉粥样硬化风险 - PET 辅助研究中，具体目标 3 将描述患病率，前瞻性纳入 120 名认知障碍患者的队列中亚临床肝纤维化的原因和影响拟议的目标将使用多种肝纤维化标志物和补充。认知终点，涵盖神经心理学测试、判定的痴呆事件结果，以及神经影像标记物包括白质高信号体积和皮质 β-淀粉样蛋白负荷。拟议的研究意义重大，因为它试图建立一种新的减值风险因素，痴呆症，从而提高了 ADRD 和 ADRD 中新的针对肝脏的预防和治疗策略的可能性所提出的研究具有创新性，因为它试图扩展认知障碍的范式。通过建立肝纤维化在认知之外的作用来治疗多病因认知障碍和痴呆此外，这项工作将连接肝病学和神经病学，以解决肝性脑病的负担。通过将当代和新兴的肝病学工具应用于神经学研究来研究神经系统疾病。