Mild Cognitive Impairment
Conditions
Keywords
Metabolic Syndrome, Mild Cognitive Impairment, Insulin Resistance, Endurance Exercise
Brief summary
The purpose of this study is to investigate novel treatments to delay progression to dementia in patients with mild cognitive impairment (MCI) and metabolic syndrome (MS). The hypothesis is that treatment with pioglitazone or endurance exercise training will improve, stabilize, or attenuate decline in cognitive function compared to controls. This study will also discover potential mechanisms for the improvements and determine the baseline prevalence of amnestic versus non-amnestic MCI.
Detailed description
The Metabolic Syndrome (MS) is a rapidly growing public health problem. This constellation of metabolic abnormalities increases the risk of diabetes, heart disease and death. Recently evidence has linked MS with cognitive impairment and dementia, including Alzheimer's Disease (AD). AD is preceded by a state called Mild Cognitive Impairment (MCI), characterized by subjective and objective memory impairment, but no functional impairment. Although not all persons with MCI will develop AD, the conversion rate from MCI to AD is about 15% per year, or 5-10 times that of cognitively normal individuals. There is great interest in finding treatments to prevent AD by intervening at an earlier stage, i.e. MCI. The mechanism(s) linking MS and cognitive impairment are not clear, although there is evidence that insulin resistance and inflammation play key roles. Thiazolidinediones (TZDs) are medications approved for the treatment of Type 2 Diabetes, which work by reducing insulin resistance. In addition, these drugs have anti-inflammatory properties. A recent pilot study showed improvements in some areas of cognition in patients with MCI or mild AD treated with the TZD rosiglitazone. Endurance exercise training (EET) is an established treatment for MS and insulin resistance. There is also evidence that EET may improve cognitive function as well. Adults aged 55 years or older with both MS and MCI at baseline will be randomized to a 6-month intervention with either (1) treatment with pioglitazone, (2) endurance exercise training, or (3) control (placebo and no exercise). The hypothesis is that treatment with the TZD pioglitazone or EET will improve cognitive function compared to controls, as evidenced by either improvement, stabilization, or lesser decline in performance on cognitive testing. Participants will undergo a physical exam including blood and urine tests, a complete neurologic exam, and a comprehensive battery of cognitive tests. They will also have a DEXA scan, exercise treadmill test, non-invasive tests of vascular function and a hyperglycemic-euglycemic clamp procedure to measure insulin resistance.
Interventions
BEHAVIORALEndurance Exercise Training
Individualized exercise prescription, 45-75 minutes (progressive increments) three times a week
DRUGPioglitazone
30 - 45mg tablet daily for 6 months
DRUGPlacebo
Matching tablet daily for 6 months
Sponsors
National Institute on Aging (NIA)
University of Colorado, Denver
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 No maximum
Healthy volunteers
Yes
Inclusion criteria
* Community-dwelling, over 55 years old, able to give full informed consent, willing to be randomized * Able to perform a telephone interview * Able to speak, read and understand English * Potential volunteers on a statin drug, angiotensin converting enzyme inhibitor (ACE-I), angiotensin II receptor blocker (ARB), non-steroidal anti-inflammatory drug (NSAID), or Vitamin E supplement, are eligible but must be on a stable dose for at least 2 months * Women must be post-menopausal, as defined by no menses for 12 months * Must meet 3 of the 5 requirements for Metabolic Syndrome: * Waist measurement: greater than 102 cm for men and 88 cm for women * Fasting hypertriglyceridemia: 150 mg/dl (1.7 mmol/L) or higher * Low HDL cholesterol: less than 40 mg/dl (1.0 mmol/L) for men and 50 mg/dl (1.3 mmol/L) for women * Hypertension: higher than 130 mmHg systolic or 85 mmHg diastolic (average of 2 seated measurements) or currently using an antihypertensive medication * Elevated (untreated) fasting glucose: 100 mg/dl (5.6 mmol/L) or higher * Meet the study's 4-step screening process for MCI (to rule out dementia)
Exclusion criteria
* Diagnosis of diabetes mellitus (DM), defined as: Fasting Blood Sugar 126 or higher, a history of known DM, or treatment with any glucose lowering medication * Current diagnosis of dementia (or MMSE less than 24) or a neurological co-morbidity other than MCI that might affect cognition including: large vessel stroke, brain tumor, severe brain injury, multiple sclerosis, or Parkinson's disease * Current diagnosis of depression assessed by a Centers for Epidemiologic Studies Depression Scale (CES-D) score of 36 or less * Major psychiatric conditions such as bipolar disorder, psychosis, schizophrenia, or alcoholism that could affect the ability to understand and/or cooperate fully with the protocol * Significant cerebral vascular disease * Modified Hachinski score greater than 4 * Pregnant, lactating or having child bearing potential * Concomitant medications with significant cholinergic or anticholinergic effects or adverse effects on cognition including: antipsychotics, tricyclic antidepressants, anticonvulsants, sedative/hypnotics, anxiolytics, glucocorticoids (chronic or frequent intermittent), gingko biloba, NMDA receptor antagonists, cholinesterase inhibitors, strongly lipid soluble beta blockers (e.g., propranolol) * Hormone replacement therapy (male or female) * Visual/hearing impairment that would significantly impact the ability to undergo psychometric testing * Significant medical illness or organ failure including hepatic or renal failure, unstable cardiac disease, or life expectancy less than 18 months * Exercise-limiting conditions including: neuromuscular, joint/bone, cardiovascular, peripheral vascular, cerebrovascular or pulmonary disease; recent MI, pulmonary embolus, significant aortic stenosis; or exercise limiting obesity * Untreated B12 deficiency or hypothyroidism (stable treatment for at least 3 months is allowable) * Uncontrolled hypertension: over 160 mmHg systolic or 100 mmHg diastolic (stable treatment is allowable) * Endurance exercise training more than twice a week for 20 minutes (at a level that produces sweating) consistently during the last 6 months * Unstable weight in the last 6 months * Increased risk for Pio toxicity including: a) baseline liver dysfunction (over 2.5xULN for AST, ALT); b) hematocrit less than 33% men or 30% women; c) problematic edema; or d) congestive heart failure NYHA class II or greater * Stage 5 renal impairment (GFR less than 15 or dialysis) * Already taking a TZD or other drug that would modify insulin resistance (e.g. metformin), or has taken a TZD in the past and experienced a significant adverse effect or allergy * Currently taking any of following medications that may interact with Pio metabolism: atorvastatin at 80mg/day (lower doses are allowed), and medications with major CYP 3A4 inhibiting effects, such as nefazodone or systemic antifungal agents * Participating in another clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cognitive Performance | Baseline to 6 months | Participants were administered a neuropsychological testing battery consisting of assessments in four cognitive domains: memory (Visual Reproduction II, Logical Memory II, Rey Auditory Verbal Learning Test), language (Boston Naming Test , Category Fluency), visuospatial (Block Design, Picture Completion), and executive function (Trail Making Test B, Digit Symbol Test). Raw test scores for these primary cognitive domain measures were transformed into age-adjusted scaled scores with a mean of 10 and a standard deviation (SD) of 3, with higher numbers indicating better cognitive performance, using the Mayo's Older American Normative Studies data. Cognitive domain scores were calculated as the arithmetic mean of the normatively derived scaled scores for all of the tests in that domain. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Insulin Resistance | Baseline to 6 months | Change in whole body glucose disposal rate (mg/kg/min) calculated during a single-stage (40 mU/m2/min), 3-hour hyperinsulinemic, euglycemic clamp |
| Change in Peak Oxygen Uptake (VO2 Peak) | Baseline to 6 months | Peak oxygen consumption (VO2 peak, ml/kg/min) was determined by open circuit spirometry during a standard treadmill stress test (modified Balke protocol). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone Pioglitazone: 45mg oral tablet daily for 6 months | 24 |
| Endurance Exercise Training Endurance Exercise Training: Supervised, thrice-weekly, 45-75 minute sessions of treadmill walking, initially moderate intensity (50-60% of maximum heart rate), with progressive increases in intensity to the best of the subject's ability, up to 85% of maximal heart rate. | 17 |
| Placebo Placebo: Matching oral tablet daily for 6 months | 25 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 9 | 2 |
Baseline characteristics
| Characteristic | Total | Placebo | Endurance Exercise Training | Pioglitazone |
|---|---|---|---|---|
| Age, Continuous | 65 years STANDARD_DEVIATION 7 | 68 years STANDARD_DEVIATION 7 | 64 years STANDARD_DEVIATION 7 | 65 years STANDARD_DEVIATION 6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 0 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 61 Participants | 24 Participants | 17 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 58 Participants | 23 Participants | 15 Participants | 20 Participants |
| Region of Enrollment United States | 66 participants | 25 participants | 17 participants | 24 participants |
| Sex: Female, Male Female | 35 Participants | 15 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 31 Participants | 10 Participants | 10 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 25 | 19 / 26 | 23 / 27 |
| serious Total, serious adverse events | 3 / 25 | 1 / 26 | 3 / 27 |
Outcome results
Primary
Change in Cognitive Performance
Participants were administered a neuropsychological testing battery consisting of assessments in four cognitive domains: memory (Visual Reproduction II, Logical Memory II, Rey Auditory Verbal Learning Test), language (Boston Naming Test , Category Fluency), visuospatial (Block Design, Picture Completion), and executive function (Trail Making Test B, Digit Symbol Test). Raw test scores for these primary cognitive domain measures were transformed into age-adjusted scaled scores with a mean of 10 and a standard deviation (SD) of 3, with higher numbers indicating better cognitive performance, using the Mayo's Older American Normative Studies data. Cognitive domain scores were calculated as the arithmetic mean of the normatively derived scaled scores for all of the tests in that domain.
Time frame: Baseline to 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pioglitazone | Change in Cognitive Performance | Memory domain | 0.8 units on a scale |
| Pioglitazone | Change in Cognitive Performance | Language domain | 0.4 units on a scale |
| Pioglitazone | Change in Cognitive Performance | Visuospatial domain | 0.3 units on a scale |
| Pioglitazone | Change in Cognitive Performance | Executive function domain | 1.0 units on a scale |
| Endurance Exercise Training | Change in Cognitive Performance | Executive function domain | 0.7 units on a scale |
| Endurance Exercise Training | Change in Cognitive Performance | Memory domain | 0.7 units on a scale |
| Endurance Exercise Training | Change in Cognitive Performance | Visuospatial domain | 1.1 units on a scale |
| Endurance Exercise Training | Change in Cognitive Performance | Language domain | 0.6 units on a scale |
| Placebo | Change in Cognitive Performance | Executive function domain | 0.9 units on a scale |
| Placebo | Change in Cognitive Performance | Language domain | 0.4 units on a scale |
| Placebo | Change in Cognitive Performance | Visuospatial domain | 0.8 units on a scale |
| Placebo | Change in Cognitive Performance | Memory domain | 1.2 units on a scale |
Comparison: The mean change in domain score with PIO was compared with the mean change in domain score with Placebo in a linear regression conditioned on the stratification categories (MCI subtype and number of APOE ε4 alleles) and the baseline domain score.p-value: <0.0125Regression, Linear
Comparison: The mean change in domain score with EET was compared with the mean change in domain score with Placebo in a linear regression conditioned on the stratification categories (MCI subtype and number of APOE ε4 alleles) and the baseline domain score.p-value: <0.0125Regression, Linear
Secondary
Change in Insulin Resistance
Change in whole body glucose disposal rate (mg/kg/min) calculated during a single-stage (40 mU/m2/min), 3-hour hyperinsulinemic, euglycemic clamp
Time frame: Baseline to 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | Change in Insulin Resistance | 1.7 mg/kg/min |
| Endurance Exercise Training | Change in Insulin Resistance | 0.7 mg/kg/min |
| Placebo | Change in Insulin Resistance | 0.1 mg/kg/min |
Comparison: The mean change with PIO was compared with the mean change with Placebo in a linear regression conditioned on the stratification categories (MCI subtype and number of APOE ε4 alleles) and the baseline level of the outcome variable.p-value: <0.05Regression, Linear
Comparison: The mean change with EET was compared with the mean change with Placebo in a linear regression conditioned on the stratification categories (MCI subtype and number of APOE ε4 alleles) and the baseline level of the outcome variable.p-value: <0.05Regression, Linear
Secondary
Change in Peak Oxygen Uptake (VO2 Peak)
Peak oxygen consumption (VO2 peak, ml/kg/min) was determined by open circuit spirometry during a standard treadmill stress test (modified Balke protocol).
Time frame: Baseline to 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | Change in Peak Oxygen Uptake (VO2 Peak) | 0.9 ml/kg/min |
| Endurance Exercise Training | Change in Peak Oxygen Uptake (VO2 Peak) | 3.2 ml/kg/min |
| Placebo | Change in Peak Oxygen Uptake (VO2 Peak) | 1.3 ml/kg/min |
Comparison: The mean change with PIO was compared with the mean change with Placebo in a linear regression conditioned on the stratification categories (MCI subtype and number of APOE ε4 alleles) and the baseline level of the outcome variable.p-value: <0.05Regression, Linear
Comparison: The mean change with EET was compared with the mean change with Placebo in a linear regression conditioned on the stratification categories (MCI subtype and number of APOE ε4 alleles) and the baseline level of the outcome variable.p-value: <0.05Regression, Linear