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.

抽象的 我之前的培训、背景和经验与拨款中描述的具体计划非常相关。 我的总体职业发展目标是培养独立从事职业所需的技能 临床研究人员，能够进行调查以扩大我们对这种关系的理解 衰老导致的功能衰退和药物使用之间的关系。 我在五年奖励期内的具体研究培训目标是： 1. 增强我的知识 步态和认知功能障碍的神经相关性。 2. 增进我对大脑肾素的了解 血管紧张素系统（RAS）和连接的通路作为可能将认知和认知联系起来的生物通路 衰老时运动能力下降。 3. 学习神经影像学模式和分析技术来识别和量化 与衰老过程中认知和功能下降相关的结构发现。 4. 提高我的知识 用于观察研究和纵向分析的流行病学方法和生物统计学。 5. 申请 K23 奖项结束时提供 ROI 补助金，将这一研究范围扩展到其他群体，从而允许 关于使用 CACE-I 和相关药物预防步态下降的更详细研究 和有阿尔茨海默病及相关疾病风险的老年人的认知能力。 我的研究目标将增加我们对药物临床和神经生物学后果的了解 通过专注于对功能衰退的负面影响小于类似药物的药物来治疗衰老 药物同行。血管紧张素转换酶抑制剂（ACEI）广泛用于许多领域 高血压以外的疾病。根据作用的不同，它们可以分为中枢性作用或外围性作用。 穿过血脑屏障的能力。现有数据表明，中枢作用的 ACEI 可降低 阿尔茨海默病及相关疾病患者的认知和功能下降。我的具体 目标重点关注没有阿尔茨海默病和相关疾病的老年人，并且是 1) 使用全国范围内的数据来量化老年人使用 CACE-I 与 PACE-I 的运动后果（步态速度） 代表性健康与退休研究 (HRS) 数据库。 2）确定认知后果 CACE-I 与 PACE-I 在使用 HRS 的老年人中的使用情况。 3）考察CACE-I和PACE-I的关系 用于与阿尔茨海默病相关的神经退行性和血管病变 神经影像倡议 (ADNI) 数据库。 及早识别有认知障碍和体力下降风险的老年人 性能，再加上更好地了解 ACEI 亚型如何影响与相关的皮质区域 痴呆症，作为确定靶向治疗以减缓痴呆症的前奏至关重要 衰老和阿尔茨海默氏病认知障碍的进展。存在知识差距 不同类别 ACEI 的临床后果限制了基于证据的处方。该提案将 产生临床相关数据，这些数据将构成 R01 的基础，旨在将这一研究范围扩展到 额外的队列，以便对 CACE-I 和相关药物的使用进行更详细的调查 防止有阿尔茨海默病及相关疾病风险的老年人的步态和认知能力下降 失调。