This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Alzheimer ??s Disease (AD) is a devastating disorder with impressive effects on patients, caregivers, the healthcare system and society as a whole. The incidence of AD increases with age and as the population ages, the prevalence will grow rapidly. New data suggests that there is a distinguishable prodromal state of AD, called mild cognitive impairment (MCI). MCI is defined as subjective and objective memory impairment without functional impairment. While all patients with AD go through a stage of MCI, not all MCI patients progress to AD. However, progression from MCI to AD is estimated to be ~15% per year. 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 intervention to treat MS in older patients with co-existing MCI can improve, stabilize or lessen the decline in cognitive function compared to controls. The planned intervention, Pioglitazone (Pio), which is a thiazolidinedione (TZD),has been shown to improve MS, including IR, and also has been demonstrated to have positive effects on cognition. TZDs may work by: improving IR and enhancing glucose transporter-related glucose transport in specific brain areas; improving vascular reactivity; or reducing inflammation. We propose a double-blinded, placebo-controlled, randomized pilot study to investigate (compared to controls) the effect of Pio treatment on: a) cognitive function in older adults with co-existing MCI and MS; b) possible mechanisms of these effects on cognition (improved IR); c) associations between plasma levels of Amyloid ?? ? and inflammatory biomarkers, and their possible relationships to improvements in IR and cognition. Fifty patients will be recruited and followed for 6-months of treatment. Cognitive funtion (CF) will be assessed by standardized computer testing and focused neuropsychologic testing; changes in IR will be measured by the HOMA score. The findings from this study will support Dr. Heyn ??s Junior Investigator carreer towards the development of a full-scale NIH R01 study that will include: (1) variable doses of pioglitazone tailored to the IR response, (2) addition of exercise to the intervention protocol, which is known to be beneficial for both cognitive function and IR, and (3) inclusion of patients with diabetes. An intervention that can delay or prevent cognitive decline will be of great public health significance through decreasing the high health care costs related to Alzheimer ??s disease and in improving the quality of life of elderly patients.
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