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: 10408178
• 负责人: Claudene George
• 金额: $ 15.48万
• 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/10408178
• 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; 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 我先前的培训，背景和经验与赠款中所述的具体计划非常相关。 我的整体职业发展目标是发展从事独立职业所需的技能 临床研究人员，能够进行调查，以扩大我们对关系的理解 在衰老的功能下降和用药使用之间。 我在5年奖励期间的具体研究培训目标是：1。提高我的知识 步态和认知功能障碍的神经相关性。 2。提高我对大脑肾素的了解 血管紧张素系统（RAS）和连接的途径是一种可能联系认知和 汽车衰老的下降。 3。学习神经影像学方法和分析技术以识别和量化 结构性发现与衰老的认知和功能下降有关。 4。提高我对 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 ROI Grant在该K23奖项结束时，将此研究范围扩展到其他同类群体中 对CACE-I和相关代理在防止步态下降中使用的更详细调查 以及老年人有阿尔茨海默氏病和相关疾病风险的认知。 我的研究目的将增加我们对药物临床和神经生物学后果的了解 通过专注于对功能下降的负面影响的药物而不是类似的药物，用于衰老 药物对应物。血管紧张素转化酶抑制剂（ACEI）被广泛用于多个 超出高血压的情况。它们可以根据他们的中心或外围表现归类为 能够越过血脑屏障的能力。可用数据表明，集中作用ACEI降低了 患有阿尔茨海默氏病和相关疾病的人的认知和功能下降。我的具体 目的是专注于没有阿尔茨海默氏病和相关疾病的老年人，为1） 使用全国的成年人量化CACE-I与PACE-I使用的摩托车后果（步态速度） 代表性健康和退休研究（HRS）数据库。 2）确定认知后果 CACE-I与使用HRS的老年人使用PACE-I。 3）检查CACE-I和PACE-I的关系 与使用阿尔茨海默氏病有关的神经退行性和血管病理与痴呆有关 神经影像计划（ADNI）数据库。 早期鉴定有认知障碍和身体下降的老年人有风险 性能，加上对ACEI亚型如何影响与相关的皮质区域的更好理解 痴呆症是识别靶向疗法以减慢目标的序言至关重要的 衰老和阿尔茨海默氏病认知障碍的进展。关于知识差距 不同类别的ACEI的临床后果限制了基于证据的处方。该提议将 产生与临床相关的数据，该数据将构成R01的基础，旨在将此研究扩展到 其他队列，以便对CACE-I和相关代理的使用进行更详细的研究 防止患有阿尔茨海默氏病风险及相关的老年人的GET和认知下降 疾病。