Pioglitazone Or Exercise to Treat Mild Cognitive Impairment (MCI)

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.

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