Cognitive impairment associated with androgen deprivation therapy for prostate cancer

前列腺癌雄激素剥夺疗法相关的认知障碍

基本信息

批准号：
10310426
负责人：
David A Morilak
金额：
$ 33.83万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10310426
关键词：
Address Age Age-associated memory impairment Androgens Antidepressive Agents Anxiety Attention Attenuated Behavior Behavioral Breast CREB1 gene Cancer Patient Candidate Disease Gene Castration Chronic Cognition Cognitive Continuance of life Data Diet Future Gene Expression Gene Proteins Genetic Transcription Glutamates Gonadotropin Releasing Hormone Inhibitor Hippocampus (Brain)Impaired cognition Impairment Intervention Location Major Depressive Disorder Malignant Neoplasms Malignant neoplasm of prostate Measures Medial Mediating Mental Depression Methods Microarray Analysis Modeling Morphology Neuronal Plasticity Neurons Output Pathway interactions Pharmacology Phosphorylation Pilot Projects Prefrontal Cortex Process Prostate Cancer therapy Pyramidal Cells Quality of life Rattus Resistance Rest Safety Selective Serotonin Reuptake Inhibitor Signal Pathway Signaling Molecule Synapses Testing Thalamic structure Treatment Efficacy Vascular Endothelial Growth Factors Vertebral column Western Blotting androgen deprivation therapy behavioral study calmodulin-dependent protein kinase II cancer complication chemotherapy cognitive function cognitive process density depressive symptoms deprivation docetaxel efficacy testing flexibility follow-up forced swim test functional plasticity improved mRNA Expression male middle age multimodality neurobiological mechanism neuroimaging neuromechanism novel predicting response prevent prostate cancer model prostate cancer survivors protein expression relating to nervous system response serotonin receptor serotonin transporter spatial memory standard of care young adult

项目摘要

Cognitive impairment has a serious detrimental impact on the quality of life for prostate cancer survivors treated by androgen deprivation therapy (ADT). Neuroimaging studies have shown structural and functional deficits in the medial prefrontal cortex (mPFC) and hippocampus (Hipp), which mediate higher order cognitive processes, including cognitive flexibility and spatial cognition, that are impaired after ADT. In this project, we will investigate mechanisms that underly the cognitive impairments we have now shown to be induced by androgen deprivation in rats. Also, as there is currently no satisfactory treatment for cognitive impairment after ADT, we will test the efficacy of vortioxetine, a novel multi-modal antidepressant drug that has been shown to have specific and unique positive effects on cognitive impairment in depression, in potentially reversing cognitive impairment after ADT. Similar to SSRIs, vortioxetine blocks the serotonin transporter, but it also has direct actions on several pre- and post-synaptic serotonin receptors that give it additional efficacy against symptoms of depression that are often resistant to treatment, including cognitive impairment. To assess mPFC-mediated cognitive function in rats, we will use the Attentional Set-shifting Test (AST). And to assess spatial cognition mediated in the hippocampus (Hipp), we will use the Novel Object Location (NOL) test. We have already shown that ADT induces an impairment in cognitive set-shifting. Thus in aim 1A, we will complete the pilot study in which we have preliminary data showing a spatial cognition deficit in the NOL test as well. In addition, there are many factors to consider in the full context of treating prostate cancer. Thus, in the rest of aim 1, together with ADT and vortioxetine, we will investigate the interacting influences of factors including age-related cognitive decline; an alternate method of inducing ADT with the GnRH antagonist degarelix; and chemotherapy with docetaxel. Indeed, because of recent changes to standard of care, we will also include docetaxel in all subsequent aims. In aim 2, we will then study neural processes related to functional plasticity that may underly the cognitive effects of ADT and vortioxetine, measuring changes in electrical response evoked in mPFC by stimulating afferents from the mediodorsal thalamus (MDT) and ventral Hipp, an indication of synaptic efficacy and functional integrity of cortical circuits. In aim 3, we will study processes related to structural plasticity, measuring changes in dendritic complexity and synaptic spine density and morphology on pyramidal cells that drive the behavioral output of the mPFC and Hipp. Effects of androgens are mediated by gene transcription and protein expression. Thus, in aim 4, we will assess changes in gene expression in the mPFC and Hipp by microarray analysis, then use a “candidate factor” approach to investigate changes in mRNA and protein expression and phosphorylation of specific plasticity-related signaling molecules. The results of this project may identify new targets for treating cognitive impairment after ADT, and they may reveal new mechanisms underlying the efficacy of vortioxetine.

认知障碍对前列腺癌幸存者的生活质量产生严重不利影响通过雄激素剥夺疗法（ADT）进行治疗，神经影像学研究表明其结构和功能。内侧前额叶皮层 (mPFC) 和海马体 (Hipp) 的缺陷，它们介导高阶认知 ADT 后受损的过程，包括认知灵活性和空间认知。研究我们现在发现的由雄激素引起的认知障碍的机制此外，由于目前 ADT 后认知障碍尚无令人满意的治疗方法，我们将测试沃替西汀的功效，沃替西汀是一种新型多模式抗抑郁药物，已被证明具有特异性对抑郁症认知障碍和潜在逆转障碍具有独特的积极作用 ADT 后，与 SSRI 类似，沃替西汀会阻断血清素转运蛋白，但它也对多种药物有直接作用。突触前和突触后血清素受体，使其对抑郁症状具有额外功效通常对治疗有抵抗力，包括认知障碍评估 mPFC 介导的认知功能。在大鼠中，我们将使用注意力转移测试（AST）来评估介导的空间认知。海马体（Hipp），我们将使用新物体定位（NOL）测试我们已经证明了ADT。因此，在目标 1A 中，我们将完成试点研究。 NOL测试中也有初步数据显示空间认知缺陷，此外还有很多。因此，在目标 1 的其余部分中，应与 ADT 一起考虑。和沃替西汀，我们将研究包括年龄相关认知能力下降在内的因素的相互作用影响；另一种方法是使用 GnRH 拮抗剂地加瑞克诱导 ADT 并使用多西他赛进行化疗。事实上，由于最近护理标准的变化，我们还将在所有后续目标中纳入多西紫杉醇。在目标 2 中，我们将研究与功能可塑性相关的神经过程，这可能是认知效应的基础 ADT 和沃替西汀，测量通过刺激传入神经引起的 mPFC 电反应的变化来自内侧丘脑 (MDT) 和腹侧希普，突触功效和功能完整性的指标在目标 3 中，我们将研究与结构可塑性相关的过程，测量皮质回路的变化。驱动行为的锥体细胞上的树突复杂性和突触棘密度和形态 mPFC 和 Hipp 的输出由基因转录和蛋白质表达介导。因此，在目标 4 中，我们将通过微阵列分析评估 mPFC 和 Hipp 中基因表达的变化，然后使用“候选因子”方法来研究 mRNA 和蛋白质表达以及磷酸化的变化该项目的结果可能会确定新的治疗靶点。 ADT 后的认知障碍，它们可能揭示沃替西汀功效的新机制。