Mild Cognitive Impairment
Conditions
Keywords
Metformin, Mild Cognitive Impairment (MCI), Alzheimer's Disease (AD), Overweight, Insulin
Brief summary
Hyperinsulinemia and type 2 diabetes (T2D) are important potential risk factors for cognitive decline and Alzheimer's disease (AD). Two thirds of the US adult population are at risk for hyperinsulinemia and T2D, and half of the population 85 years and older have AD. Peripheral hyperinsulinemia can impair the clearance of amyloid beta in the brain, the main culprit in AD. Thus, the investigators hypothesize that lowering peripheral insulin in overweight persons with amnestic mild cognitive impairment (AMCI), a transition state between normal cognition and AD, can decrease the risk of cognitive decline and progression to AD. The investigators propose to conduct a phase II double blinded placebo controlled randomized clinical trial of metformin, a safe and effective medication that prevents hyperinsulinemia and diabetes, to test this hypothesis among 80 overweight persons aged 55 to 90 years with AMCI. The main outcome of the study will be changes in performance in a memory test (total recall of the Selective Reminding Test) and the Score a test of general cognitive function used in clinical trials (the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog)). Another aim is to compare brain function in an area affected by Alzheimer's disease between the metformin and placebo group mean changes from beginning to end among 40 participants using a PET scan.
Detailed description
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.
Interventions
DRUGMetformin
Metformin 1000 mg twice a day titrated from 500 mg once a day
DRUGPlacebo
Placebo identical to metformin 2 tablets twice a day titrated from one table once a day
Sponsors
Institute for the Study of Aging (ISOA)
National Institute on Aging (NIA)
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to 90 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total Recall Score in the Selective Reminding Test | 12 months | The Selective Reminding Test measures verbal learning and delayed recall through a multiple-trial list-learning paradigm. Patients are presented aurally with a list of 12 words for trial 1 and are asked to recall as many as possible. For trials 2-6, there is a selective presentation of only those words not recalled on the previous trial. Trial 7 is similar to the other trials but is assessed after an 11-minute delay. The score for the selective reminding test is the unweighted average of seven individual study results (min=0 and max=84) Higher scores indicate a better cognitive performance. The total recall score from the first visit was subtracted from that of the last visit to calculate the change in score (total words recalled). |
| Change in Score of the Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog) | 12 months | The ADAS-cog is an aggregate for several cognitive tests intended to provide a global cognitive score and consists of 11 tasks. The tasks (and corresponding score range)) are Word Recall (0-10), Naming (0-4), Commands (0-5), Constructional Praxis (0-5) Ideational Praxis (0-5), Orientation (0-8), Word Recognition (0-12), Language (0-5), Word Finding Difficulty (0-5), and Remembering Test Instructions (1-5). The range of aggregate scores (sum of scores) is 1 to 69, with higher scores meaning worse cognitive performance. The change was calculated subtracting the baseline score from the final visit score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Relative Glucose Uptake (rCMRg) in the Posterior Cingulate-precuneus. | 12 months | Change in relative glucose uptake (rCMRgl) in the posterior cingulate-precuneus measured with subscale (ADAS-Cog) from brain \[18\]F-labeled 2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET). The unit for rCMRgl is %. The results presented are absolute differences in rCMRgl, presented in % units; the change was calculated subtracting the baseline rCMRgl from the follow-up rCMRgl |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma Amyloid Beta-42 | 12 months | Change in plasma Amyloid beta-42 from baseline to 12 months |
Countries
United States
Participant flow
Recruitment details
Recruitment was completed in 32 months (2.5 subjects a month) \[38\]; 1426 subjects were screened by telephone and 331 were screened in person.
Pre-assignment details
1426 screened by telephone and 1095 excluded; 331 deemed eligible for in-person screen; 224 of those were excluded; 87 met eligibility criteria, 7 declined randomization, 80 were randomized
Participants by arm
| Arm | Count |
|---|---|
| Placebo placebo identical to metformin.
placebo: placebo identical to metformin 2 tablets twice a day titrated from one table once a day. Participants remained on the maximum number of tolerated tablets (0,1,2,3,4). | 40 |
| Metformin metformin 1000 mg twice a day
metformin: metformin 1000 mg twice a day titrated from 500 mg once a day.Participants remained on the maximum number of tolerated tablets (0,1,2,3,4). | 40 |
| Total | 80 |
Baseline characteristics
| Characteristic | Placebo | Metformin | Total |
|---|---|---|---|
| Age, Continuous | 64.1 Years STANDARD_DEVIATION 7.9 | 65.3 Years STANDARD_DEVIATION 7 | 64.5 Years STANDARD_DEVIATION 7.6 |
| APOE Epsilon 4 ApoE epsilon 4 negative | 29 participants | 30 participants | 59 participants |
| APOE Epsilon 4 ApoE Epsilon 4 positive | 11 participants | 10 participants | 21 participants |
| Body Mass Index | 31.3 kg/m⌃2 STANDARD_DEVIATION 4.7 | 30.9 kg/m⌃2 STANDARD_DEVIATION 4.1 | 31.1 kg/m⌃2 STANDARD_DEVIATION 4.4 |
| Education in Years | 13.1 Years STANDARD_DEVIATION 4.5 | 13.8 Years STANDARD_DEVIATION 3.4 | 13.4 Years STANDARD_DEVIATION 4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 17 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 23 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Fasting insulin | 13.4 IU/dl STANDARD_DEVIATION 7.6 | 16.3 IU/dl STANDARD_DEVIATION 9.5 | 14.7 IU/dl STANDARD_DEVIATION 8.6 |
| Hemoglobin A1c | 6.1 percent HbA1c STANDARD_DEVIATION 0.5 | 6.1 percent HbA1c STANDARD_DEVIATION 0.8 | 6.1 percent HbA1c STANDARD_DEVIATION 0.6 |
| High Density lipoprotein | 58.3 mg/dl STANDARD_DEVIATION 17.7 | 51.5 mg/dl STANDARD_DEVIATION 14.1 | 54.8 mg/dl STANDARD_DEVIATION 16.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 11 Participants | 26 Participants |
| Race (NIH/OMB) More than one race | 13 Participants | 17 Participants | 30 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 12 Participants | 24 Participants |
| Region of Enrollment United States | 40 participants | 40 participants | 80 participants |
| Score of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) | 14.6 score STANDARD_DEVIATION 6.1 | 12.0 score STANDARD_DEVIATION 4 | 13.3 score STANDARD_DEVIATION 5.3 |
| Selective Reminding Test Total Recall score | 36.1 score STANDARD_DEVIATION 9.5 | 34.2 score STANDARD_DEVIATION 7.9 | 35.2 score STANDARD_DEVIATION 8.7 |
| Sex: Female, Male Female | 24 Participants | 18 Participants | 42 Participants |
| Sex: Female, Male Male | 16 Participants | 22 Participants | 38 Participants |
| Systolic blood pressure | 132.1 mmHg STANDARD_DEVIATION 12.4 | 130.8 mmHg STANDARD_DEVIATION 10.9 | 131.4 mmHg STANDARD_DEVIATION 11.6 |
| Total Cholesterol | 208.2 mg/dl STANDARD_DEVIATION 46.7 | 204.2 mg/dl STANDARD_DEVIATION 43.6 | 206.2 mg/dl STANDARD_DEVIATION 44.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 40 | 3 / 40 |
| serious Total, serious adverse events | 0 / 40 | 0 / 40 |
Outcome results
Primary
Change in Score of the Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog)
The ADAS-cog is an aggregate for several cognitive tests intended to provide a global cognitive score and consists of 11 tasks. The tasks (and corresponding score range)) are Word Recall (0-10), Naming (0-4), Commands (0-5), Constructional Praxis (0-5) Ideational Praxis (0-5), Orientation (0-8), Word Recognition (0-12), Language (0-5), Word Finding Difficulty (0-5), and Remembering Test Instructions (1-5). The range of aggregate scores (sum of scores) is 1 to 69, with higher scores meaning worse cognitive performance. The change was calculated subtracting the baseline score from the final visit score.
Time frame: 12 months
Population: Analyses used an intent to treat approach with last observation carried forward
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Score of the Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog) | -1.98 score | Standard Deviation 5.5 |
| Metformin | Change in Score of the Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog) | 0.0 score | Standard Deviation 3.3 |
p-value: 0.06t-test, 2 sided
p-value: 0.34ANCOVA
Primary
Change in Total Recall Score in the Selective Reminding Test
The Selective Reminding Test measures verbal learning and delayed recall through a multiple-trial list-learning paradigm. Patients are presented aurally with a list of 12 words for trial 1 and are asked to recall as many as possible. For trials 2-6, there is a selective presentation of only those words not recalled on the previous trial. Trial 7 is similar to the other trials but is assessed after an 11-minute delay. The score for the selective reminding test is the unweighted average of seven individual study results (min=0 and max=84) Higher scores indicate a better cognitive performance. The total recall score from the first visit was subtracted from that of the last visit to calculate the change in score (total words recalled).
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Total Recall Score in the Selective Reminding Test | 5.7 score on a scale | Standard Deviation 8.7 |
| Metformin | Change in Total Recall Score in the Selective Reminding Test | 9.4 score on a scale | Standard Deviation 8.5 |
p-value: 0.05t-test, 2 sided
p-value: 0.05ANCOVA
Secondary
Change in Relative Glucose Uptake (rCMRg) in the Posterior Cingulate-precuneus.
Change in relative glucose uptake (rCMRgl) in the posterior cingulate-precuneus measured with subscale (ADAS-Cog) from brain \[18\]F-labeled 2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET). The unit for rCMRgl is %. The results presented are absolute differences in rCMRgl, presented in % units; the change was calculated subtracting the baseline rCMRgl from the follow-up rCMRgl
Time frame: 12 months
Population: Out of 40 persons recruited in the imaging sub study, 33 underwent a 12 month scan (18 in the placebo group, 15 in the metformin group).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Relative Glucose Uptake (rCMRg) in the Posterior Cingulate-precuneus. | 0.0 percentage of rCMRgl | Standard Deviation 6 |
| Metformin | Change in Relative Glucose Uptake (rCMRg) in the Posterior Cingulate-precuneus. | 2.0 percentage of rCMRgl | Standard Deviation 6.3 |
p-value: 0.36t-test, 2 sided
Other Pre-specified
Change in Plasma Amyloid Beta-42
Change in plasma Amyloid beta-42 from baseline to 12 months
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Plasma Amyloid Beta-42 | -4.40 pg/ml | Standard Deviation 23.51 |
| Metformin | Change in Plasma Amyloid Beta-42 | 0.69 pg/ml | Standard Deviation 18.5 |
p-value: 0.34t-test, 2 sided