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: 10578663
• 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/10578663
• 关键词: Affect; Age; Alzheimer disease detection; 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 Glucose; Blood Vessels; Blood brain barrier dysfunction; California; Caring; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Chronic; Clinical; Cognition Disorders; Cognitive; Cognitive aging; Competence; Dementia; Detection; Diabetes Mellitus; Diagnosis; Disease; Disease Marker; Early identification; Endocrinologist; Event; Expenditure; Frequencies; 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; Persons; Pharmacologic Substance; Phase; Positron-Emission Tomography; Post-Traumatic Stress Disorders; Prevalence; Process; Radioactive Tracers; Rest; Risk; Risk Factors; Scientist; Spinal Puncture; Training; Training Programs; United States; Universities; Veterans; White Matter Hyperintensity; Work; arterial spin labeling; brain behavior; care costs; career; clinical care; clinical decision-making; clinical diagnosis; cognitive change; combat; comorbidity; cost; dementia risk; detection method; diabetic; diagnostic strategy; early detection biomarkers; functional decline; human old age (65+); 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; progression risk; 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，其中包括近四分之一的 老兵据估计，美国每年糖尿病的费用为2450亿美元， 糖尿病患者的支出是非糖尿病患者的2.3倍。在 除了与糖尿病相关的许多医学并发症和共存状况之外，糖尿病还 会增加患阿尔茨海默病和痴呆症的风险。AD发病机制被认为是 早在临床诊断之前开始许多年，因此一直有显著的重点放在使用生物 在轻度认知障碍中观察到的坦率认知障碍之前检测AD的方法 (MCI)和痴呆阶段。虽然PET神经成像与放射性示踪剂和腰椎穿刺（LP）， 获得AD标志物（Ab、p-tau、总tau）的脑脊液水平已经引起了显著的关注， 虽然这些方法对于我们理解AD的发病机制很重要，但它们并非没有局限性。 具体来说，这些方法是昂贵的，在理解方面仍处于实验阶段 "阳性"结果的含义，侵入性（需要注射放射性示踪剂或LP），并且通常 由于位置而不可访问（例如，农村环境）、费用或医疗禁忌症（例如，血液稀释剂）。 因此，非常需要开发和实施敏感的神经心理学标记物， 在与轻度认知障碍和痴呆相关的客观损害之前，捕捉微妙的临床前认知变化。 这项研究旨在研究神经心理学（NP）过程分数作为一种方法， 检测与糖尿病相关的最早认知变化，并使用这些评分来预测认知功能 功能衰退。NP过程分数来自标准NP测试，但提供以下信息 退伍军人如何获得总得分（例如，错误类型，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增值作用， 临床前AD的认知功能下降。这项研究将包括：1）对200名退伍军人（100 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（n = 46;[23例糖尿病患者]）的一个子集， 3）前瞻性招募66名新退伍军人（33名糖尿病患者）， 基线动脉自旋标记磁共振成像检查脑血流作为一种潜在的 糖尿病认知功能低下的标志;他们也将纵向跟踪[（总纵向 n = 112）]。本研究的创新之处在于首次将NP加工分数用于识别细微认知 变化和预测未来的糖尿病退伍军人，还没有神经认知障碍下降。 这个职业发展奖（CDA-2）的目标是为候选人发展必要的 技能，成为一个独立的科学家调查最早的认知变化和效率低下， 患有糖尿病的退伍军人。该CDA-2应用程序包括一个全面的培训计划， 申请人在NP评估/诊断、认知老化和纵向研究方面的背景和现有技能 分析。培训计划的重点是建立更多的能力，了解糖尿病 机制和标准的护理，脑灌注的神经成像，并发展进一步的专业知识， NP过程分数的应用。多学科指导小组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 过程分数。拟议的项目和特殊的培训机会，可在弗吉尼亚州圣地亚哥 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 长期的职业目标是过渡到一个独立的VA临床科学家进行以病人为导向的 神经心理学和糖尿病痴呆风险领域的研究。