Pioglitazone Or Exercise to Treat Mild Cognitive Impairment (MCI)
Condition: Mild Cognitive Impairment
MeSH terms: Cognitive Dysfunction
Intervention: Pioglitazone; Placebo; Endurance Exercise Training
Intervention description: 30 - 45mg tablet daily for 6 months; Matching tablet daily for 6 months; Individualized exercise prescription, 45-75 minutes (progressive increments) three times a week
Intervention MeSH terms: Pioglitazone
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 78.0
Sex: All
Minimum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Metabolic Syndrome; Mild Cognitive Impairment; Insulin Resistance; Endurance Exercise

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.
    

Eligibility criteria:

        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