EFFCTS OF PIOGLITAZONE ON CGNTV FNCTION IN PTS W/MTBLC SYNDRM&MILD CGNTV IMPRMNT

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 阿尔茨海默病？S病(AD)是一种毁灭性的疾病，对患者、照顾者、医疗保健系统和整个社会都有令人印象深刻的影响。阿尔茨海默病的发病率随着年龄的增长而增加，随着人口老龄化，患病率将迅速增长。新的数据表明，AD有一种可区分的前驱状态，称为轻度认知障碍(MCI)。MCI被定义为无功能损害的主客观记忆损害。虽然所有AD患者都经历了MCI阶段，但并不是所有MCI患者都进展为AD。然而，据估计，从MCI到AD的进展每年约为15%。代谢综合征(MS)是一组相互关联的代谢异常的集合，其主要特征是胰岛素抵抗(IR)。由于它与缺乏运动和中心性肥胖密切相关，MS的患病率正在迅速增长，据估计，大约50%的老年人会发生MS。最近，几项大型研究将多发性硬化症与认知障碍的发展联系起来。支持这一关系的合理理论包括：1)胰岛素受体的局部分布以及与记忆相关的大脑区域胰岛素和葡萄糖运输蛋白的神经元产生；2)胰岛素进入中枢神经系统的IR相关变化；3)胰岛素对中枢神经系统淀粉样蛋白级联的影响；以及4)与MS相关的促炎状态。这项初步研究建议探讨与对照组相比，干预治疗MS合并MCI是否可以改善、稳定或减轻认知功能的下降。计划中的干预措施，吡格列酮(Pio)，是一种噻唑烷二酮(TZD)，已被证明可改善MS，包括IR，并已被证明对认知有积极影响。TZDS可能通过以下方式发挥作用：改善IR和增强特定脑区与葡萄糖转运体相关的葡萄糖运输；改善血管反应性；或减少炎症。我们提出了一项双盲、安慰剂对照、随机的初步研究，以调查(与对照组相比)Pio治疗对以下方面的影响：a)合并MCI和MS的老年人的认知功能；b)这些影响认知的可能机制(改善IR)；c)血浆淀粉样蛋白水平之间的关系。和炎性生物标志物，以及它们与IR和认知改善的可能关系。将招募50名患者并进行为期6个月的治疗。认知功能(CF)将通过标准化的计算机测试和专注的神经心理测试进行评估；IR的变化将通过HOMA评分来衡量。这项研究的结果将支持初级研究员S博士进行一项全面的NIH R01研究，该研究将包括：(1)根据IR反应量身定做不同剂量的吡格列酮，(2)在干预方案中增加运动，这对认知功能和IR都有好处，以及(3)纳入糖尿病患者。能够延缓或预防认知功能衰退的干预措施，通过降低与阿尔茨海默病、S病相关的高昂医疗费用，提高老年患者的生活质量，将具有重大的公共卫生意义。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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.