Neural Mechanisms of Chemotherapy-Induced Cognitive Disorder

描述(由申请人提供)：系统性癌症化疗与认知和记忆障碍有关，可能是长期的(Ahles，Saykin等人，2002年)。关于认知变化的前瞻性研究很少，其潜在的病理生理机制也没有得到系统的研究。脑成像可以帮助识别这些机制，但目前还没有前瞻性的、控制良好的研究。我们将通过使用磁共振成像(MRI)和分析技术的集合来解决这一知识差距，以确定与化疗相关的大脑结构和功能的特定变化。这项成像研究将建立在我们团队在NCI赞助的化疗认知研究(CA87845)经验的基础上。我们的具体目标是：(I)确定接受化疗的患者大脑结构和组织成分的短期和长期变化的频率、数量和特征，(Ii)使用功能磁共振成像检测和表征记忆处理过程中大脑激活的变化，以评估与任务相关的电路和(Iii)。系统地检查关键治疗、疾病和个体差异因素(例如，化疗方案、遗传风险、年龄、教育、基线功能)作为认知缺陷和康复的预测因素，以促进未来的模型建立。参与者将包括接受化疗或仅接受局部治疗的乳腺癌患者(n=50)和30名健康对照组。这些措施将在化疗前、化疗后1个月和12个月(或同等间隔)获得。综合MRI检查将检测和测量：局灶性炎症/脱髓鞘(FLAIR)和分布的灰质和白质变化(基于体素的形态计量学)，记忆关键结构的完整性(海马3D体积和形状分析)和白质完整性和连通性(扩散张量成像，DTI)，以及工作和情景记忆处理过程中的脑激活模式(功能MRI，fMRI)。预期结果：这项研究将确定哪些成像方法对化疗最敏感、最有信息量和最特异。认知改变机制的识别和新措施的引入将有助于推动神经副作用评估和风险/效益分析的进展，并将为神经保护剂、神经药物治疗和康复方法的设计和评估提供基础。

DESCRIPTION (provided by applicant): Systemic cancer chemotherapy has been associated with cognitive and memory deficits that may be long-lasting (Ahles, Saykin et al, 2002). There are very few prospective studies of cognitive changes and the underlying pathophysiological mechanisms have not been systematically examined. Brain imaging could help to identify these mechanisms, yet there are no prospective, well-controlled studies. We will address this knowledge gap by employing an ensemble of magnetic resonance imaging (MRI) and analysis techniques to identify specific changes in brain structure and function associated with chemotherapy. The imaging study will build on our team's experience with NCI-sponsored cognitive studies of chemotherapy (CA87845). Our specific aims are to: (i) Determine the frequency, quantity and characteristics of short and long term changes in brain structure and tissue composition in patients undergoing chemotherapy, (ii) Detect and characterize alterations in brain activation during memory processing using fMRI to assess task-relevant circuits and (iii). Systematically examine key treatment, disease and individual difference factors (e.g., chemotherapy regimen, genetic risk, age, education, baseline functioning) as predictors of cognitive deficits and recovery, to facilitate future model building. Participants will include breast cancer patients undergoing chemotherapy (n=50) or local therapy only (n=50), and 30 healthy controls. Measures will be obtained before and 1 and 12 months after chemotherapy (or equivalent intervals). An integrated MRI exam will detect and measure: focal inflammation/demyelination (FLAIR) and distributed gray and white matter changes (voxel-based morphometry), the integrity of memory critical structures (hippocampal 3D volume and shape analysis) and white matter integrity and connectivity (diffusion tensor imaging, DTI), and brain activation patterns during working and episodic memory processing (functional MRI, fMRI). Expected outcomes: The study will determine which imaging measures are most sensitive, informative and specific to chemotherapy. Identification of the mechanisms of cognitive changes and introduction of new measures will help to drive advances in assessment of neurological side effects and risk/benefit analyses, and it will provide a foundation for design and evaluation of neuroprotective agents, neuropharmacologic treatment and rehabilitative approaches.