Utility of Centrally Acting Angiotensin Converting Enzyme Inhibitors to slow the progression of Dementia

中枢作用血管紧张素转换酶抑制剂减缓痴呆进展的效用

• 批准号: 10259832
• 负责人: Claudene George
• 金额: $ 16万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10259832
• 关键词: Acetylcholine; Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Attention; Award; Biological; Biometry; Blood - brain barrier anatomy; Blood Pressure; Blood Vessels; Brain; Cerebrovascular Circulation; Clinical; Clinical Markers; Cognition; Cognitive; Consumption; Coupled; Data; Databases; Dementia; Detection; Development; Diabetes Mellitus; Disease; Drug Prescriptions; Early identification; Elderly; Epidemiologic Methods; Gait; Goals; Grant; Harm Reduction; Health and Retirement Study; Heart failure; Hypertension; Impaired cognition; Incidence; Individual; Inflammatory; Investigation; Kidney; Kidney Diseases; Knowledge; Lacunar Infarctions; Learning; Link; Memory; Memory impairment; Mentored Patient-Oriented Research Career Development Award; Microvascular Dysfunction; Modality; Motor; Nerve Degeneration; Neurobiology; Neurons; Neuropsychological Tests; Observational Study; Outcome; Participant; Pathologic; Pathology; Pathway interactions; Peripheral; Pharmaceutical Preparations; Physical Performance; Physicians; Population; Prevalence; Prevention; Registries; Renin-Angiotensin System; Research; Research Personnel; Research Training; Risk; Role; Structure; System; Techniques; Testing; Time; Training; White Matter Disease; Work; base; career; career development; clinically relevant; cognitive development; cohort; cytokine; dementia risk; design; evidence base; executive function; experience; falls; functional decline; hippocampal atrophy; improved; longitudinal analysis; memory consolidation; memory retrieval; mild cognitive impairment; neural correlate; neuroimaging; neuropathology; rate of change; skills; targeted treatment

Abstract My prior training, background, and experiences are very relevant to my specific plans as described in the grant. My overall career development goal is to develop the skills necessary to pursue a career as an independent clinical researcher, able to conduct investigations that will broaden our understanding of the relationship between functional decline in aging and medication use. My specific research training objectives during the 5-year award period are: 1. To enhance my knowledge of neural correlates of gait and cognitive dysfunction. 2. Advance my knowledge of the brain Renin Angiotensin System (RAS) and connected pathways as a biological pathway that may link cognitive and motoric declines in aging. 3. Learn neuroimaging modalities and analytic techniques to identify and quantify structural findings related to cognitive and functional decline in aging. 4. Improve my knowledge of epidemiological methods and biostatistics for observational studies and longitudinal analysis. 5. Apply for an ROI grant at the end of this K23 award to extend this line of research into additional cohorts that will allow for more detailed investigations into the use of CACE-I and related agents in protecting against declines in gait and cognition in older adults at risk for Alzheimer’s disease and related disorders. My research aims will add to our knowledge of the clinical and neurobiological consequences of medication use in aging by focusing on medications with less of a negative impact on functional decline than similar medication counterparts. Angiotensin Converting Enzyme Inhibitors (ACEI) are widely used for a number of conditions beyond hypertension. They can be categorized as centrally or peripherally acting based upon their ability to cross the blood brain barrier. Available data suggests that centrally acting ACEI decrease the rate of cognitive and functional decline among those with Alzheimer’s Disease and related disorders. My specific aims focus on older individuals without Alzheimer’s disease and related disorders and are to 1) To quantify motoric consequences (gait velocity) of CACE-I versus PACE-I use in older adults using the nationally representative Health and Retirement Study (HRS) database. 2) To determine cognitive consequences of CACE-I versus PACE-I use in older adults using the HRS. 3) To examine the relation of CACE-I and PACE-I use with neurodegenerative and vascular pathologies linked to dementia using the Alzheimer’s disease Neuroimaging Initiative (ADNI) database. Early identification of older adults at risk for the development of cognitive impairment and decline in physical performance, coupled with a better understanding of how ACEI subtypes affect cortical regions associated with dementia, is of paramount importance as a prelude to identification of targeted therapies to slow the progression of cognitive impairment in aging and Alzheimer’s Disease. There is a knowledge gap regarding clinical consequences of different classes of ACEI that limits evidence based prescribing. This proposal will produce clinically relevant data that will form the basis of an R01 designed to extend this line of research into additional cohorts, to allow for more detailed investigations into the use of CACE-I and related agents in protecting against declines in gait and cognition in older adults at risk for Alzheimer’s disease and related disorders.

摘要 我之前的培训，背景和经验与我在资助中描述的具体计划非常相关。 我的总体职业发展目标是发展必要的技能，以追求作为一个独立的职业生涯 临床研究人员，能够进行调查，这将扩大我们对关系的理解 与药物使用之间的联系 我在5年获奖期间的具体研究培训目标是：1。为了增进我的知识 步态和认知功能障碍的神经相关性。2.增进我对大脑的了解 血管紧张素系统（RAS）和相关通路作为一种生物学通路，可能将认知和 运动能力下降3.学习神经成像模式和分析技术，以识别和量化 结构发现与认知和功能衰退的老龄化。4.提高我的知识 观察性研究和纵向分析的流行病学方法和生物统计学。5.申请 在K23奖结束时的ROI赠款，将这一系列研究扩展到其他队列， 对CACE-I和相关药物在防止步态下降中的应用进行了更详细的研究 和认知能力的研究。 我的研究目标将增加我们对药物治疗的临床和神经生物学后果的认识 通过专注于对功能衰退的负面影响小于类似药物的药物， 药物对应。血管紧张素转化酶抑制剂（ACEI）广泛用于许多治疗。 高血压以外的疾病它们可以被分类为中心或外围作用的基础上，其 穿越血脑屏障的能力。现有的数据表明，中枢作用的ACEI降低了 认知和功能下降与阿尔茨海默病和相关疾病。我的具体 目标集中在老年人没有阿尔茨海默病和相关疾病，并1） 使用全国范围内的标准，量化CACE-I与PACE-I在老年人中使用的运动后果（步态速度） 健康与退休研究（HRS）数据库。2)为了确定认知后果 CACE-I与PACE-I在使用HRS的老年人中的使用。3)检查CACE-I和PACE-I的关系 用于与阿尔茨海默病痴呆相关的神经变性和血管病变 神经影像学倡议（ADNI）数据库。 早期识别有认知障碍和身体机能下降风险的老年人 性能，再加上更好地了解ACEI亚型如何影响与 痴呆症，是至关重要的，作为一个前奏，以确定有针对性的治疗，以减缓 老年认知障碍和阿尔茨海默病的进展。在以下方面存在知识差距： 不同类别ACEI的临床后果限制了循证处方。这项建议会 产生临床相关数据，这些数据将构成R 01的基础，R 01旨在将这一研究领域扩展到 额外的队列，以便更详细地研究CACE-I和相关药物的使用， 防止有阿尔茨海默病及相关疾病风险的老年人步态和认知能力下降 紊乱