Insulin Resistance in Late-Life Depression

晚年抑郁症中的胰岛素抵抗

• 批准号: 8495420
• 负责人: Christopher Marano
• 金额: $ 18.47万
• 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/8495420
• 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; 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; 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; white matter

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晚年抑郁症（LLD）的神经生物学和治疗方面的独立研究者，重点是了解抑郁症与认知障碍（CI）之间的关系，为预防老年抑郁症认知能力下降的治疗方法的发展提供信息。因此，这个以患者为导向的指导研究职业发展奖（K23）建立在我在情感性疾病中葡萄糖代谢的背景和我作为老年精神病学家的培训基础上，通过关注胰岛素抵抗（IR）、脑血管疾病和CI之间的关系，将我对LLD中CI的潜在机制以及医学合并症的作用的兴趣结合起来。最重要的假设是，IR代表了一种早期的、可测量的和可修改的机制，将LLD与CI联系起来，并且LLD中IR和CI之间的联系将比非抑郁个体更强。根据我的职业发展目标，职业发展规划将重点培训：1)临床研究方法，包括纵向模型测试；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。主办机构约翰霍普金斯大学医学院是实现这些目标的理想场所。在老年精神病学和神经精神病学、老年医学、内分泌学和代谢学、神经心理学和神经影像学方面有很强的临床和学术项目。主要导师Constantine Lyketsos博士（临床研究方法学）是一位老年神经精神病学家，他对老年神经精神症状的流行病学和治疗研究以及与认知能力下降的关系做出了重大的科学贡献。共同导师Gwenn Smith博士（LLD神经生物学）是一名神经心理学家，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。我和我的导师建立了富有成效的工作关系，我们一起为LLD开发了临床和研究基础设施。研究计划将侧重于测量LLD中的IR并评估其与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与人口统计学匹配的对照组进行比较，2)评估LLD组与对照组的IR、脑血管疾病和CI之间的关系。有待检验的假设是：1)LLD组的平均IR高于对照组；2) LLD患者IR与CI相关，且在控制了脑血管疾病（通过脑磁共振成像白质高信号（WMH））、已知认知（年龄、教育程度和APOE4状态）以及血管危险因素（高血压、血脂异常）后，LLD患者IR与CI的相关性强于对照组。我们将招募40名目前有重度抑郁发作的非糖尿病个体（60岁后发病）和40名非糖尿病、非抑郁、人口统计学匹配的对照组，接受口服葡萄糖耐量试验（测量IR）、神经心理测试和结构脑磁共振成像扫描（测量WMHs）。在K奖结束时，我将组建一个具有良好特征的LLD个体队列（以及扩大队列的能力），可以纵向随访，以评估IR和脑血管疾病在认知衰退发展中的作用。在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性改善，并减轻LLD中脑血管疾病和CI的进展。