Insulin Resistance in Late-Life Depression

晚年抑郁症中的胰岛素抵抗

• 批准号: 8651543
• 负责人: Christopher Marano
• 金额: $ 18.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8651543
• 关键词: Acute; Adrenal Gland Hyperfunction; Age; Alzheimer' s Disease; Amyloid beta-Protein; Antidepressive Agents; Blood Vessels; Body mass index; Brain; Clinical; Clinical Research; Cognition; Cognitive aging; Comorbidity; Control Groups; Dementia; Depressed mood; Development; Development Plans; Diabetes Mellitus; Disease; Disease remission; Dyslipidemias; Education; Elderly; Endocrinology; Epidemiology; Executive Dysfunction; Functional disorder; Future; Geriatric Psychiatry; Geriatrics; Goals; Hypertension; Impaired cognition; Individual; Inflammation; Institution; Insulin Resistance; Intervention; Intervention Studies; Investigation; K-Series Research Career Programs; Lead; Link; Long-Term Effects; Magnetic Resonance Imaging; Measurable; Measures; Medical; Mental Depression; Mentored Patient-Oriented Research Career Development Award; Mentors; Meta-Analysis; Modeling; Mood Disorders; Moods; Neurobiology; Neuropsychological Tests; Neuropsychology; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Pathology; Patients; Prevention; Prevention strategy; Psychiatrist; Public Health; Recruitment Activity; Refractory; Research; Research Infrastructure; Research Methodology; Research Personnel; Research Training; Risk; Risk Factors; Role; Sampling; Symptoms; Testing; Training; Universities; Vascular Dementia; Vascular Diseases; White Matter Hyperintensity; Work; accomplished suicide; base; career; career development; clinical infrastructure; cohort; disability; executive function; geriatric depression; geriatric neuropsychiatry; glucose metabolism; imaging modality; improved; interest; medical schools; meetings; mind control; molecular imaging; mortality; neuroimaging; neuropsychiatry; non-diabetic; prevent; programs; sex; single episode major depressive disorder; suicide mortality; tau Proteins; therapy development; vascular depression

DESCRIPTION (provided by applicant): My career goal is to be an independent investigator in the neurobiology and treatment of late life depression (LLD) with a focus on understanding the relationship between depression and cognitive impairment (CI) to inform the development of treatments aimed at prevention of cognitive decline in LLD. Thus, this Mentored Patient-Oriented Research Career Development Award (K23) builds upon my background in glucose metabolism in affective disorders and my training as a geriatric psychiatrist to integrate my interest in the mechanisms underlying CI in LLD as well as the role of medical co-morbidity by focusing on the relationship between insulin resistance (IR), brain vascular disease and CI. The overarching hypothesis is that IR represents an early, measurable and modifiable mechanism that links LLD to CI and that the link between IR and CI will be stronger in LLD than in non-depressed individuals. In accordance with my career goals, the career development plan will focus on training in: 1) clinical research methodology including testing longitudinal models, and 2) the neurobiology of LLD with an emphasis on endocrinology and metabolism and the relationship to brain vascular disease and CI. The host institution, the Johns Hopkins University School of Medicine is an ideal setting to meet these objectives. There are strong clinical and academic programs in geriatric psychiatry and neuropsychiatry, geriatric medicine, endocrinology and metabolism, neuropsychology, and neuroimaging. The primary mentor, Dr. Constantine Lyketsos (Clinical Research Methodology) is a geriatric neuropsychiatrist who has made major scientific contributions to epidemiological and treatment studies of neuropsychiatric symptoms in late life and the relationship to cognitive decline. The co-mentor, Dr Gwenn Smith (Neurobiology of LLD) is a neuropsychologist who has focused on the development and applications of molecular imaging methods in late life neuropsychiatric disorders, including LLD. I have developed a productive working relationship with my mentors and together, we have developed the clinical and research infrastructure for LLD. The research plan will focus on measuring IR in LLD and evaluating the relationship to CI and brain vascular disease. The specific aims of the research plan are: 1) To compare IR in the LLD group to a demographically matched control group, and 2) To evaluate the association between IR, brain vascular disease, and CI in the LLD versus controls. The hypotheses to be tested are: 1) the LLD group will have higher mean IR versus the control group; and 2) IR will be correlated with CI in LLD, and that this correlation will be stronger in LLD than in the control group after controlling for brain vascular disease (via white matter hyperintensities (WMH) on brain magnetic resonance imaging), and known cognitive (age, education, and APOE4 status) as well as vascular risk factors (hypertension, dyslipidemia) for CI. We will recruit 40 non-diabetic individuals with a current major depressive episode (onset of current episode after age 60) and 40 non-diabetic, non-depressed, demographically matched controls to undergo an oral glucose tolerance test (to measure IR), neuropsychological testing and a structural brain magnetic resonance imaging scan (to measure WMHs). At the conclusion of the K award, I will have assembled a well-characterized cohort of individuals with LLD (as well as the ability to expand the cohort) who could be followed longitudinally to evaluate the role of IR and brain vascular disease for the development of cognitive decline. The understanding obtained in the proposed study will inform the development of an intervention study to evaluate whether treating IR will lead to acute improvements in cognition as well as lessen the progression of brain vascular disease and CI in LLD.

描述（由申请人提供）：我的职业目标是成为神经生物学和治疗后期抑郁症（LLD）的独立研究者，重点是理解抑郁症与认知障碍（CI）之间的关系，以告知旨在预防LLD认知能力下降的治疗方法的发展。因此，这项受过指导的注重患者研究职业发展奖（K23）以我在情感障碍中的葡萄糖代谢背景为基础，以及我作为老年医生精神病医生的培训，以使我对LLD中CI基础机制的兴趣融入我的兴趣。总体假设是，IR代表了将LLD与CI联系起来的早期，可测量和可修改的机制，并且IR和CI之间的联系在LLD中将比在非抑郁的个体中更强。根据我的职业目标，职业发展计划将重点介绍：1）包括测试纵向模型在内的临床研究方法论，以及2）LLD的神经生物学，重点是内分泌学和代谢以及与脑血管疾病和CI的关系。约翰·霍普金斯大学医学院的东道机构是实现这些目标的理想场所。老年精神病学和神经精神病学，老年医学，内分泌学和代谢，神经心理学和神经影像学都有强大的临床和学术课程。主要的导师君士坦丁·莱克托斯（Constantine Lyketsos）（临床研究方法论）是一位老年神经精神科医生，他对晚期神经精神症状的流行病学和治疗研究做出了重大科学贡献，并且与认知能力下降的关系。联合学者Gwenn Smith博士（LLD的神经生物学）是一名神经心理学家，他专注于分子成像方法在包括LLD在内的晚期神经精神疾病中的发展和应用。我与导师建立了富有成效的工作关系，我们共同开发了LLD的临床和研究基础设施。该研究计划将着重于测量LLD中的IR，并评估与CI和脑血管疾病的关系。研究计划的具体目的是：1）将LLD组的IR与人口统计匹配的对照组进行比较，以及2）评估IR，脑血管疾病和LLD与对照中的IR之间的关联。要测试的假设是：1）LLD组与对照组的平均值较高； 2）IR将与LLD中的CI相关，并且在控制脑血管疾病（通过白质超强度（WMH）上，与对照组相比，LLD中的相关性将比对照组更强，并且在脑电磁谐振成像上），以及已知的认知（年龄，教育和APOE4状态），以及血管造成风险因素（以及血管含量因素）（高度ci）。我们将招募40个非糖尿病患者，目前具有重大抑郁发作（60岁以后的当前发作发作）和40个非糖尿病性，非抑郁，人口统计学匹配的控件，以经过口服葡萄糖耐受性测试（测量IR），神经心理学测试和结构性的脑电磁共振扫描（以测量WMHS）。在K奖的结束时，我将组建一个可以纵向遵循的LLD（以及扩展同类群）的人（以及扩展同类群）的人群，以评估IR和脑血管疾病在认知下降的发展中的作用。拟议的研究中获得的理解将为一项干预研究的发展提供信息，以评估治疗IR是否会导致认知的急剧改善，并减少LLD中脑血管疾病和CI的进展。