Pioglitazone & Exercise Effects on Older Aldults with MCI and Metabolic Syndrome
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DESCRIPTION (provided by applicant): Alzheimer's Disease (AD), and other forms of dementia, are devastating disorders with impressive untoward effects on patients, caregivers, our healthcare system and society as a whole. The incidence of AD increases with age and as our population ages, the prevalence will grow rapidly. New data suggest that there is a distinguishable prodromal state of AD, mild cognitive impairment (MCI). MCI is defined as subjective and objective memory impairment without functional impairment. While all patients with AD go through an MCI stage, not all MCI patients progress to AD. However, progression from MCI to AD is estimated to be ~15%/yr. Metabolic Syndrome (MS) is a collection of inter-related metabolic abnormalities with the cardinal feature being insulin resistance (IR). Because of its strong relation to inactivity and central obesity, the prevalence of MS is growing rapidly, and it is estimated to occur in ~50% of older adults. Recently, several large studies have linked MS to the development of cognitive impairment. Plausible theories to support this relationship include: 1) localized distribution of insulin receptors and neuronal production of insulin and glucose transport proteins in brain areas related to memory; 2) IR-related changes in insulin transport into the CNS; 3) effects of insulin on the amyloid cascade in the CNS; and 4) the pro-inflammatory state associated with MS. This pilot study proposes to investigate whether interventions to treat MS in older subjects with co-existing MCI can improve, stabilize or lessen the decline in cognitive function, when compared to control s. The planned interventions, Pioglitazone (Pio), a thiazolidinedione (TZD), and endurance exercise training (EET), have both been shown to ameliorate multiple components of MS, including IR, and both have also been demonstrated to have positive effects on cognition. TZDs may work by: 1) improving IR and enhancing glucose transporter- related glucose transport in specific brain areas; 2) improving vascular reactivity; or 3) reducing inflammation. EET may work by: 1) improving central adiposity and IR; 2) improving vascular reactivity; or 3) increased exercise-induced neuronal plasticity, through enhancing brain-derived neurotrophic factor (BNDF) We propose a double-blinded (drug), placebo-controlled, randomized pilot study, using a parallel design, to investigate the effect of Pio, EET or Control treatment on: 1) cognitive function in older adults with co-existing MCI and MS; 2) possible mechanisms of these effects on cognition (improved IR); 3) inflammatory biomarkers, and their possible relationships to improvements in IR and cognition. This pilot study will determine the feasibility of a larger study powered to more fully study these treatments and their interactions (Pio x EET). We also plan to over-sample Hispanics, a group with a high prevalence of both MS and cognitive impairment.
Alzheimer 's disease (AD) is a devastating disorder with impressive untoward effects on patients, caregivers, the healthcare system and society as a whole. Mild cognitive impairment (MCI) is known to be a prodromal condition for AD in some patients. Metabolic syndrome (MS) is a common disorder that increases with age and predisposes to the development of diabetes mellitus. This study will assess novel metabolic treatments for patients with both MCI and MS, with the aim of delaying the progression of these patients to dementia.
