Impact of Diabetes on Cognitive and Perfusion Inefficiencies in Preclinical AD

糖尿病对临床前 AD 认知和灌注低效的影响

• 批准号: 10041705
• 负责人: Kelsey R Thomas
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10041705
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid beta-Protein; Anticoagulants; Attention; Behavior; Behavioral; Biological; Biological Markers; Blood - brain barrier anatomy; Blood Glucose; Blood Vessels; California; Caring; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Chronic; Clinical; Cognition Disorders; Cognitive; Cognitive aging; Competence; Dementia; Detection; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Disease Marker; Early identification; Endocrinologist; Event; Expenditure; Frequencies; Functional disorder; Future; Glycosylated hemoglobin A; Goals; Health; Healthcare Systems; Herbicides; Hypoglycemia; Imaging Techniques; Impaired cognition; Impairment; Injections; Intervention; K-Series Research Career Programs; Lead; Learning; Life Style; Location; Long-Term Care; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Medical; Mentors; Methods; Modeling; Neuropsychological Tests; Neuropsychology; Outcome; Pathogenesis; Pathologic; Pathology; Performance; Perfusion; Pharmacologic Substance; Phase; Positron-Emission Tomography; Post-Traumatic Stress Disorders; Prevalence; Process; Radioactive Tracers; Rest; Risk; Risk Factors; Scientist; Spin Labels; Spinal Puncture; Structure; Time; Training; Training Programs; United States; Universities; Veterans; White Matter Hyperintensity; Work; base; brain behavior; care costs; career; clinical Diagnosis; clinical care; clinical decision-making; cognitive change; combat; comorbidity; cost; dementia risk; diabetic; early detection biomarkers; functional decline; hypoperfusion; improved; innovation; longitudinal analysis; medical complication; medication compliance; memory recall; mild cognitive impairment; multidisciplinary; neurocognitive disorder; neuroimaging; patient oriented research; potential biomarker; pre-clinical; prevent; prospective; recruit; response; rural setting; skills; tau Proteins; tau-1; training opportunity; vascular risk factor

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.

糖尿病影响着超过 3000 万 18 岁以上的美国人，其中近四分之一 美国退伍军人每年因糖尿病造成的费用估计为 2450 亿美元，而且医疗费用也高达 2450 亿美元。 糖尿病患者的支出是没有糖尿病患者的 2.3 倍。 除了与糖尿病相关的许多医疗并发症和共存病症外，糖尿病还 增加患阿尔茨海默病 (AD) 的风险，而 AD 的发病机制被认为与此相关。 在临床诊断之前很多年就开始了，因此人们非常关注生物诊断的使用 在轻度认知障碍中观察到的明显认知障碍之前检测 AD 的方法 (MCI) 和痴呆阶段，同时使用放射性示踪剂和腰椎穿刺 (LP) 进行 PET 神经影像检查。 获取 AD 标志物（Ab、p-tau、总 tau）脑脊液水平已引起广泛关注， 这些方法对于我们了解 AD 的发病机制很重要，但并非没有局限性。 具体来说，这些方法成本高昂，在理解方面仍处于实验阶段 “阳性”结果的影响、侵入性（需要注射放射性示踪剂或LP），并且经常 由于地点（例如农村环境）、成本或医疗禁忌症（例如血液稀释剂）而无法获得。 因此，非常需要开发和实施敏感的神经心理学标记物 在与 MCI 和痴呆相关的客观损害之前捕捉微妙的临床前认知变化。 拟议的研究旨在检查神经心理学（NP）过程分数，作为一种方法 检测与糖尿病相关的最早的认知变化并使用这些分数来预测认知 NP 过程分数来自标准 NP 测试，但提供有关的信息。 退伍军人如何获得总体总分（例如，所犯错误的类型、学习斜率）。 分数已被证明可以增加预测未来认知能力下降的价值，并可用于识别微妙的 临床前 AD 中的认知能力下降 本研究将涉及 1) 对 200 名退伍军人 (100 名) 进行回顾性记录审查。 患有糖尿病），没有神经认知障碍，之前完成了神经心理学评估 作为 VA 临床护理的一部分，2) 招募这 200 名退伍军人中的一部分（n=46；[23 名患有糖尿病]） 纵向跟踪，以及 3) 前瞻性招募 66 名新退伍军人（其中 33 名患有糖尿病），他们将 基线动脉自旋标记磁共振成像检查脑血流量作为潜在的 糖尿病认知效率低下的标志；它们也将被纵向跟踪[（总纵向 n=112)] 这项研究具有高度创新性，因为它是第一个使用 NP 过程分数来识别微妙认知的研究。 变化并预测尚未患有神经认知障碍的糖尿病退伍军人的未来下降。 该职业发展奖 (CDA-2) 的目标是让候选人发展必要的能力 成为独立科学家的技能，研究最早的认知变化和低效率 患有糖尿病的退伍军人。此 CDA-2 应用程序包括一个基于该计划的综合培训计划。 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 培训计划的重点是培养了解糖尿病的额外能力。 护理机制和标准、脑灌注的神经影像学以及进一步发展专业知识 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，在血管危险因素和 拟议的项目以及 VA 圣地亚哥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协助申请人完成她的任务 长期职业目标是成为一名独立的 VA 临床科学家，进行以患者为导向的工作 神经心理学和糖尿病痴呆风险领域的研究。