Metformin in Amnestic Mild Cognitive Impairment
关键词
抽象
描述
The prevalence of Alzheimer's disease (AD) is expected to quadruple by the year 2047. There are no known curative or preventive measures for AD. Current treatment options for AD only address symptoms, and no treatments are available that focus on delaying the actual disease process. One of the currently accepted hypothesis of the pathogenesis of AD is that the main culprit is the accumulation of Aβ in the brain, and this process has become a target for treatments and preventive measures. Amnestic mild cognitive impairment (MCI) has been used to describe a transitional state between normal cognitive function and AD, and has thus been targeted for interventions. Persons with MCI progress to AD at the rate of nearly 10% to 15% per year. The criteria most commonly used for the definition of AD dementia from MCI. The investigators propose to use these criteria with slight modification to recruit persons for a pilot trail of AD prevention in persons with amnestic MCI.
Peripheral hyperinsulinemia (high insulin levels) potentially impair Aβ clearance, and in this study we are proposing to use metformin, an insulin lowering agent, to prevent AD by improving Aβ clearance in the brain. The insulin resistance syndrome and hyperinsulinemia are common in individuals with and without diabetes, and are related to increased risk of cardiovascular and cerebrovascular outcomes. Hyperinsulinemia predicts the development of diabetes; therefore, diabetes can be considered a consequence and a marker of past hyperinsulinemia. According to NHANES III data, more than 40% of the population over the age of 60 years has problems of glucose intolerance or diabetes, all related to insulin resistance and hyperinsulinemia. The investigators have found that the risk of AD in individuals without diabetes increases with increasing levels of fasting insulin, and that high insulin levels are related to a faster decline in memory scores. The high prevalence of hyperinsulinemia and diabetes (49% of the elderly in Northern Manhattan) and its biological plausibility as a risk factor for cognitive decline and AD has attracted increasing attention. In this application we are targeting hyperinsulinemia, the most important risk factor for AD identified in the elderly population of Northern Manhattan. The risk of AD attributable to hyperinsulinemia or diabetes in Northern Manhattan was 39%, and is higher in Hispanics and African-Americans, who have a higher prevalence of diabetes and insulin resistance, and will comprise the majority of our sample.
日期
| 最后验证: | 08/31/2020 |
| 首次提交: | 02/06/2008 |
| 提交的预估入学人数: | 02/18/2008 |
| 首次发布: | 02/20/2008 |
| 上次提交的更新: | 09/29/2020 |
| 最近更新发布: | 10/22/2020 |
| 首次提交结果的日期: | 06/07/2015 |
| 首次提交质量检查结果的日期: | 09/29/2020 |
| 首次发布结果的日期: | 10/22/2020 |
| 实际学习开始日期: | 05/31/2008 |
| 预计主要完成日期: | 01/31/2012 |
| 预计完成日期: | 01/31/2012 |
状况或疾病
干预/治疗
Drug: Metformin
Drug: Matching Placebo
相
手臂组
| 臂 | 干预/治疗 |
|---|---|
| Placebo Comparator: Matching Placebo Placebo identical to metformin | Drug: Matching Placebo Placebo identical to metformin 2 tablets twice a day titrated from one table once a day |
| Experimental: Metformin Metformin 1000 mg twice a day | Drug: Metformin Metformin 1000 mg twice a day titrated from 500 mg once a day |
资格标准
| 有资格学习的年龄 | 55 Years 至 55 Years |
| 有资格学习的性别 | All |
| 接受健康志愿者 | 是 |
| 标准 | Inclusion criteria: - Age range: 55 years to 90 years. The main rationale for this inclusion criteria is to follow the standard set by the Alzheimer's Disease Cooperative Study (ADCS). - Memory complaint expressed by the participant and recognized by the informant. The memory complaint must represent a change from previous functioning based on information provided by both subject and informant. - Fluent in English or Spanish. - Mini-Mental State Examination (MMSE) equal or more than 20. - Subjects must fulfill criteria for amnestic mild cognitive impairment (MCI). Guidelines for the diagnosis of MCI: Subjects must score below a predetermined cut-off score on the logical memory II delayed paragraph recall sub-test of the Wechsler Memory Scale Revised (WMS-R) or the selective reminding test (SRT). - Global Clinical Dementia Rating (CDR) score must be 0.5 at screening. - Subjects without a known history of diabetes or diabetes that has never been treated with medications. If diabetes is diagnosed during screening or they have a history of diabetes not treated in the last 12 months they will be excluded if their Hemoglobin A1c (HbA1c) is > 6.5. In addition, a diagnosis of diabetes can be made if the HbA1c is 6.5% or more. - Overweight or obese by National Heart, Lung, and Blood Institute (NHLBI) criteria (Body Mass Index (BMI) of more or equal of 25 kg/ m2). - No contraindications to metformin treatment. - Hachinski score less or equal to 4. - Hamilton score less or equal to 12 on the 17 item scale. - General cognition and functional performance such that a diagnosis of dementia cannot be made at the time of screening based on DSM-IV criteria. - Vision and hearing must be sufficient for compliance with testing procedures. Exclusion criteria: - Individuals with dementia - MMSE < 20 - Subjects with neurologic diseases associated to neurologic deficits. - Subjects with current psychiatric diagnoses such as depression, bipolar disorder or schizophrenia. - Subjects with uncontrolled hypertension (systolic blood pressure more than 160 mmHg or diastolic blood pressure more than 95 mmHg. - Subjects with a history of active cancer or cancer within last five years, with the exception of squamous or basal cell carcinoma of the skin. - Subjects who for any reason may not complete the study as judged by the study physician. - Subjects with a known history of diabetes treated with medications. - Subjects with a new or old diagnosis of diabetes, never treated, with a HbA1c of more than 6.5 . - Contraindications to metformin: Contraindications to metformin use include a creatinine of > 1.5, liver disease by history or by elevated transaminases, congestive heart failure, and alcohol abuse. - Use of cholinesterase inhibitors. Exclusion criteria for brain imaging study: - Presence of diabetes, even if the HbA1c is less or equal to 6.5. - Inability to lie down for any reason. - Presence of any metallic implant. - Claustrophobia. - Any contraindication to magnetic resonance imaging (MRI) or fluorodeoxyglucose (FDG) positron emission tomography (PET). |
结果
主要结果指标
1. Change in Total Recall Score in the Selective Reminding Test [12 months]
2. Change in Score of the Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog) [12 months]
次要成果指标
1. Change in Relative Glucose Uptake (rCMRg) in the Posterior Cingulate-precuneus. [12 months]
其他成果措施
1. Change in Plasma Amyloid Beta-42 [12 months]
