Pioglitazone & Exercise Effects on Older Aldults with MCI and Metabolic Syndrome

吡格列酮

• 批准号: 7891161
• 负责人: Robert S Schwartz
• 金额: $ 49.61万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891161
• 关键词: 2,4-thiazolidinedione; Accounting; Affect; Age; Agonist; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid; Anti-Inflammatory Agents; Anti-inflammatory; Area; Attention; Biological; Biological Markers; Blood Vessels; Brain; Brain-Derived Neurotrophic Factor; Cardiovascular Diseases; Caregivers; Central obesity; Cerebral cortex; Clinical; Cognition; Cognitive; Collection; Control Groups; Data; Dementia; Development; Diabetes Mellitus; Disease; Dose; Double-Blind Method; Dyslipidemias; Educational Intervention; Effectiveness; Elderly; Environment; Euglycemic Clamping; Exercise; Future; Gene Expression; Glucose; Glucose Clamp; Glucose Transporter; Healthcare Systems; High Prevalence; Hispanics; Hyperinsulinism; Hypertension; Impaired cognition; Incidence; Individual; Inflammation; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; Intervention; Intervention Studies; Language; Life Style; Link; Measures; Mediating; Memory; Memory impairment; Metabolic; Metabolic Diseases; Metabolic syndrome; Mus; Neurofibrillary Tangles; Neuronal Plasticity; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; Nurses' Health Study; Obesity; Older Population; Pathologic; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Physical activity; Pilot Projects; Pioglitazone; Placebo Control; Placebos; Plasma; Play; Population; Prevalence; Production; Prospective Studies; Public Health; Publications; Randomized; Relative (related person); Research; Research Personnel; Risk Factors; Role; Sampling; Senile Plaques; Societies; Staging; Subgroup; Thiazolidinediones; Time; Training; Visuospatial; Work; aging population; cardiovascular risk factor; cognitive function; design; diabetic; executive function; functional disability; glucose disposal; glucose metabolism; glucose transport; high risk; improved; mild neurocognitive impairment; novel; older women; prevent; response; sedentary; theories

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD), and other forms of dementia, are devastating disorders with impressive untoward effects on patients, caregivers, our healthcare system and society as a whole. The incidence of AD increases with age and as our population ages, the prevalence will grow rapidly. New data suggest that there is a distinguishable prodromal state of AD, mild cognitive impairment (MCI). MCI is defined as subjective and objective memory impairment without functional impairment. While all patients with AD go through an MCI stage, not all MCI patients progress to AD. However, progression from MCI to AD is estimated to be ~15%/yr. Metabolic Syndrome (MS) is a collection of inter-related metabolic abnormalities with the cardinal feature being insulin resistance (IR). Because of its strong relation to inactivity and central obesity, the prevalence of MS is growing rapidly, and it is estimated to occur in ~50% of older adults. Recently, several large studies have linked MS to the development of cognitive impairment. Plausible theories to support this relationship include: 1) localized distribution of insulin receptors and neuronal production of insulin and glucose transport proteins in brain areas related to memory; 2) IR-related changes in insulin transport into the CNS; 3) effects of insulin on the amyloid cascade in the CNS; and 4) the pro-inflammatory state associated with MS. This pilot study proposes to investigate whether interventions to treat MS in older subjects with co-existing MCI can improve, stabilize or lessen the decline in cognitive function, when compared to control s. The planned interventions, Pioglitazone (Pio), a thiazolidinedione (TZD), and endurance exercise training (EET), have both been shown to ameliorate multiple components of MS, including IR, and both have also been demonstrated to have positive effects on cognition. TZDs may work by: 1) improving IR and enhancing glucose transporter- related glucose transport in specific brain areas; 2) improving vascular reactivity; or 3) reducing inflammation. EET may work by: 1) improving central adiposity and IR; 2) improving vascular reactivity; or 3) increased exercise-induced neuronal plasticity, through enhancing brain-derived neurotrophic factor (BNDF) We propose a double-blinded (drug), placebo-controlled, randomized pilot study, using a parallel design, to investigate the effect of Pio, EET or Control treatment on: 1) cognitive function in older adults with co-existing MCI and MS; 2) possible mechanisms of these effects on cognition (improved IR); 3) inflammatory biomarkers, and their possible relationships to improvements in IR and cognition. This pilot study will determine the feasibility of a larger study powered to more fully study these treatments and their interactions (Pio x EET). We also plan to over-sample Hispanics, a group with a high prevalence of both MS and cognitive impairment. Alzheimer 's disease (AD) is a devastating disorder with impressive untoward effects on patients, caregivers, the healthcare system and society as a whole. Mild cognitive impairment (MCI) is known to be a prodromal condition for AD in some patients. Metabolic syndrome (MS) is a common disorder that increases with age and predisposes to the development of diabetes mellitus. This study will assess novel metabolic treatments for patients with both MCI and MS, with the aim of delaying the progression of these patients to dementia.

描述（由申请人提供）：阿尔茨海默氏病（AD）和其他形式的痴呆症是毁灭性疾病，对患者，看护人，我们的医疗保健系统和整个社会具有令人印象深刻的不良影响。 AD的发病率随着年龄的增长而增加，随着我们人口的年龄增长，患病率将迅速增长。新数据表明，AD，轻度认知障碍（MCI）存在可区分的前驱状态。 MCI被定义为没有功能障碍的主观和客观记忆障碍。当所有AD患者都经历了MCI阶段，但并非所有MCI患者都会发展为AD。但是，从MCI到AD的发展估计为约15％/年。代谢综合征（MS）是相互相关的代谢异常的集合，基本特征是胰岛素抵抗（IR）。由于它与无活动性和中央肥胖症的密切关系，MS的患病率正在迅速增长，据估计发生在约50％的老年人中。最近，一些大型研究将MS与认知障碍的发展联系起来。支持这种关系的合理理论包括：1）胰岛素受体的局部分布以及与记忆有关的大脑区域中胰岛素和葡萄糖转运蛋白的神经元产生； 2）与IR相关的胰岛素转运转移到中枢神经系统中； 3）胰岛素对中枢神经系统淀粉样蛋白级联反应的影响； 4）与MS相关的促炎状态。这项试验研究建议与对照s相比，研究MCI的老年受试者的干预措施是否可以改善，稳定或减少认知功能的下降。计划中的干预措施，吡格列酮（PIO），噻唑烷二酮（TZD）和耐力运动训练（EET），都证明既可以改善包括IR在内的MS的多个组成部分，并且都证明都证明对认知有积极影响。 TZD可以通过：1）改善IR并增强特定大脑区域中葡萄糖转运蛋白相关的葡萄糖转运； 2）提高血管反应性；或3）减少炎症。 EET可以通过：1）提高中央肥胖和IR； 2）提高血管反应性；或3）通过增强脑衍生的神经营养因子（BNDF）来增加运动诱导的神经元可塑性，我们提出了一种双盲（药物），安慰剂对照的，随机的飞行员研究，使用平行设计，以研究PIO，EET或对照治疗的效果：Eet或对照治疗的效果：1）在：1）与Co-Excim McI和MSS的老年人在成人中的认知功能； 2）这些对认知作用的可能机制（改善了IR）； 3）炎症生物标志物及其与IR和认知改善的可能关系。这项试验研究将确定一项更大的研究的可行性，该研究能够更全面地研究这些处理及其相互作用（Pio X Eet）。我们还计划过度样本的西班牙裔，这是MS和认知障碍较高的群体。 阿尔茨海默氏病（AD）是一种毁灭性疾病，对患者，护理人员，医疗保健系统和整个社会产生了令人印象深刻的影响。众所周知，轻度认知障碍（MCI）在某些患者中是AD的前驱状况。代谢综合征（MS）是一种常见的疾病，随着年龄的增长而增加，糖尿病的发展。这项研究将评估MCI和MS患者的新代谢治疗，目的是延迟这些患者对痴呆症的进展。