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

摘要 我之前的培训、背景和经验与我在助学金中描述的具体计划非常相关。 我的整个职业发展目标是发展必要的技能，以追求独立的职业生涯 临床研究人员，能够进行研究，拓宽我们对这种关系的理解 衰老中的功能衰退和药物使用之间的关系。 我在5年获奖期间的具体研究培训目标是：1.增进我的知识 步态和认知功能障碍的神经关联。2.增进我对大脑肾素的了解 血管紧张素系统(RAS)和相互连接的通路，作为一条可能连接认知和 随着年龄的增长，汽车的销量会下降。3.学习神经成像模式和分析技术，以识别和量化 与认知和功能老化相关的结构性发现。4.提高我的知识水平 用于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 在此K23奖项结束时授予投资回报，以将这一系列研究扩展到更多的队列，从而实现 对CACE-I和相关药物用于防止步态下降的更详细调查 阿尔茨海默病和相关疾病风险较高的老年人的认知能力。 我的研究目的将增加我们对药物的临床和神经生物学后果的了解 通过关注对功能衰退负面影响较小的药物来治疗衰老 药物对应物。血管紧张素转换酶抑制剂(ACEI)被广泛用于许多 高血压以外的情况。根据他们的行为，他们可以被分类为集中或外围行为 穿越血脑屏障的能力。可获得的数据表明，集中作用的ACEI降低了 阿尔茨海默病及相关疾病患者的认知和功能衰退。我的特定 目标集中在没有阿尔茨海默病和相关疾病的老年人身上，目标是1)到 在老年人中量化CACE-I与PACE-I使用的运动后果(步态速度)，使用国家 代表性健康和退休研究(HRS)数据库。2)确定以下方面的认知后果 CACE-I与PACE-I在使用HRS的老年人中使用。3)考察CACE-I与PACE-I的关系 与阿尔茨海默病的痴呆症相关的神经退行性病变和血管病理一起使用 神经成像倡议(ADNI)数据库。 及早识别有认知障碍和体能衰退风险的老年人 性能，再加上更好地了解ACEI亚型如何影响与 痴呆症，作为确定靶向治疗以减缓痴呆的前奏是至关重要的 认知损害在衰老和阿尔茨海默病中的进展。有一个关于以下方面的知识差距 限制循证处方的不同类型血管紧张素转换酶抑制剂的临床后果。这项提议将 产生临床上相关的数据，这些数据将构成R01的基础，旨在将这一系列研究扩展到 更多的队列，以便更详细地调查CACE-I和相关药物在 预防患阿尔茨海默病及相关疾病的老年人步态和认知能力下降 精神错乱。

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.