Impact of Diabetes on Cognitive and Perfusion Inefficiencies in Preclinical AD

糖尿病影响着3000多万18岁以上的美国人，其中包括近四分之一的 退伍军人。据估计，美国每年治疗糖尿病的成本为2450亿美元，而医疗保健 糖尿病患者的支出是没有糖尿病的人的2.3倍。在……里面 除了与糖尿病相关的许多医学并发症和并存疾病外，糖尿病还 会增加患阿尔茨海默病(AD)和痴呆症的风险。AD的发病机制被认为是 早在临床诊断之前多年就开始了，因此一直以来都非常重视生物学的使用 方法在轻度认知损害中观察到明显的认知损害之前检测AD (MCI)和痴呆症阶段。而使用放射性示踪剂和腰椎穿刺术(LP)进行PET神经成像 获取脑脊液中AD标志物(抗体、p-tau、总tau)的水平已引起人们的极大关注 这些方法对于我们理解AD的发病机制很重要，但也有其局限性。 具体地说，这些方法是昂贵的，在理解方面仍处于实验阶段 “阳性”发现的含义，侵入性的(需要注射放射性示踪剂或LP)，而且通常 由于地理位置(例如，农村环境)、费用或医疗禁忌(例如，血液稀释剂)而无法访问。 因此，有必要开发和实施敏感的神经心理学标记物 捕捉微小的临床前认知变化，在与MCI和痴呆症相关的客观损害之前。 这项拟议的研究旨在检查神经心理学(NP)过程评分，作为一种方法 检测与糖尿病相关的最早认知变化，并使用这些分数来预测认知 和功能衰退。NP过程分数来自标准的NP测试，但提供了以下信息 退伍军人如何获得总分(例如，所犯错误的类型、学习斜率)。过程 分数已被证明在预测未来认知能力下降方面具有附加值，并可用来识别细微之处 临床前阿尔茨海默病的认知功能下降。这项研究将包括1)对200名退伍军人(100名)的回顾记录 患有糖尿病)，没有神经认知障碍，之前完成了神经心理评估 作为退伍军人管理局临床护理的一部分，2)招募这200名退伍军人中的一部分(46名；[23名糖尿病患者])，以 进行纵向跟踪，以及3)预期招募66名新退伍军人(33名患有糖尿病)，他们将拥有 基线动脉自旋标记磁共振成像检查脑血流的潜力 糖尿病患者认知效率低下的标志；他们也将被纵向追踪[(总纵向 N=112)]。这项研究具有很高的创新性，因为它是第一次使用NP加工分数来识别细微认知 改变和预测尚未有神经认知障碍的糖尿病退伍军人的未来下降。 这一职业发展奖(CDA-2)的目标是让候选人发展必要的 成为一名独立科学家的技能，研究最早的认知变化和低效 患有糖尿病的退伍军人。此CDA-2应用程序包括一个全面的培训计划，该计划建立在 申请人在NP评估/诊断、认知老化和纵向方面的背景和现有技能 分析。培训计划的重点是培养更多了解糖尿病的能力 护理的机制和标准，脑灌注的神经成像，以及进一步的专业知识 NP过程分数的应用。多学科指导团队包括一名内分泌学家，一名 磁共振物理学家和神经心理学家，他们的专业知识涵盖了血管风险因素和 处理分数。拟议的项目和退伍军人事务部圣地亚哥分校提供的特殊培训机会 医疗保健系统和加州大学圣地亚哥分校将帮助申请者完成她的 转变为独立的退伍军人临床科学家，指导以患者为中心的长期职业目标 神经心理学领域的研究与糖尿病痴呆风险。

Diabetes affects more than 30 million Americans over the age of 18, including nearly one quarter of Veterans. The estimated yearly cost of diabetes in the United States is $245 billion, and the medical expenditures of people with diabetes is 2.3 times higher than they would be in the absence of diabetes. In addition to the many medical complications and co-existing conditions associated with diabetes, diabetes also confers a greater risk for developing Alzheimer’s disease (AD) and dementia. AD pathogenesis is thought to begin many years prior to the clinical diagnosis, so there has been significant focus on the use of biological methods to detect AD prior to the frank cognitive impairment that is observed in the mild cognitive impairment (MCI) and dementia phases. While PET neuroimaging with radioactive tracers and lumbar puncture (LP) to obtain cerebrospinal fluid levels of AD markers (Ab, p-tau, total tau) have drawn significant attention and are important for our understanding of the pathogenesis of AD, these methods are not without limitations. Specifically, these approaches are expensive, still in experimental phases in regard to understanding implications of “positive” findings, invasive (require injection of radioactive tracers or LP), and often inaccessible due to location (e.g., rural setting), cost, or medical contraindications (e.g., on blood thinners). Therefore, there is a significant need to develop and implement sensitive neuropsychological markers that capture subtle, preclinical cognitive changes, before objective impairment associated with MCI and dementia. The proposed study aims to examine neuropsychological (NP) process scores as a method for detecting the earliest cognitive changes associated with diabetes and to use these scores to predict cognitive and functional decline. NP process scores are derived from standard NP tests, but provide information about how the Veteran obtained an overall total score (e.g., types of errors that were made, learning slope). Process scores have been shown to add value in predicting future cognitive decline and can be used to identify subtle cognitive decline in preclinical AD. This study will involve 1) a retrospective record review of 200 Veterans (100 with diabetes) without a neurocognitive disorder who previously completed a neuropsychological assessment as part of their VA clinical care, 2) recruitment of a subset of these 200 Veterans (n=46; [23 with diabetes]) to be followed longitudinally, and 3) prospective recruitment of 66 new Veterans (33 with diabetes) who will have baseline arterial spin labeling magnetic resonance imaging to examine cerebral blood flow as a potential marker of cognitive inefficiency in diabetes; they will also be followed longitudinally [(total longitudinal n=112)]. This study is highly innovative in that it is the first to use NP process scores to identify subtle cognitive changes and predict future decline in diabetic Veterans that do not yet have a neurocognitive disorder. The goal of this Career Development Award (CDA-2) is for the candidate to develop the necessary skills to become an independent scientist investigating the earliest cognitive changes and inefficiencies in Veterans with diabetes. This CDA-2 application includes a comprehensive training program that builds upon the applicant’s background and existing skills in NP assessment/diagnosis, cognitive aging, and longitudinal analyses. The training plan is focused on building additional competencies in understanding diabetes mechanisms and standards of care, neuroimaging of cerebral perfusion, and developing further expertise in application of NP process scores. The multidisciplinary mentoring team includes an endocrinologist, a magnetic resonance physicist, and neuropsychologists with expertise spanning both vascular risk factors and process scores. The proposed project and the exceptional training opportunities available at the VA San Diego Healthcare System and the University of California, San Diego will assist the applicant in accomplishing her long-term career objective of transitioning into an independent VA clinical scientist conducting patient-oriented research in the field of neuropsychology and dementia risk in diabetes.