Multimodal MRI Biomarker of Mild Cognitive Impairment in Breast Cancer

描述（由申请人提供）：患有乳腺癌的女性，特别是那些年龄较大和接受辅助化疗的女性，患轻度认知障碍（MCI）的风险显著增加。我们以前的研究表明，在癌症治疗结束后很长一段时间内，MCI仍在持续和进行。这种认知障碍往往涉及记忆和执行功能（即多任务处理，解决问题）的困难，干扰日常生活技能并降低生活质量。默认模式网络（DMN）是一种对正常认知功能非常重要的脑回路。随着年龄的增长，DMN大脑区域之间的连接往往会自然减弱。 DMN功能连接已被证明是非癌症人群中MCI的非常有前途的神经影像学生物标志物。DMN功能连接的破坏与向痴呆的转化密切相关，甚至已被证明先于其他神经退行性疾病的生物标志物。以前的研究，包括我们自己的研究，显示乳腺癌化疗后DMN区域萎缩，连接这些区域的白色通路受损。我们认为，化疗治疗加速DMN下降，导致乳腺癌后MCI的频率增加。然而，到目前为止，还没有研究直接评估DMN或其与乳腺癌MCI的关系。因此，拟议研究的具体目的是1）确定接受化疗的老年乳腺癌受试者中MCI的频率，2）确定接受化疗的老年乳腺癌受试者中的DMN神经影像学生物标志物，3）开发预测该人群中MCI易感性的模型。我们将通过整合认知功能，情绪和行为的纵向多维神经心理学评估与先进的，非侵入性的多模态磁共振成像技术和APOE基因分型来实现这些目标。我们将评估55名女性原发性乳腺癌化疗前，化疗后一个月和化疗后六个月。我们将化疗治疗组与55名未接受化疗的乳腺癌女性和55名健康女性进行比较，所有女性都在重要的人口统计学和临床因素上匹配。将在相同的时间间隔对所有组进行评估。我们将强调记忆和执行功能以及DMN功能连接的评估。我们将把临床、人口统计学、精神病学（如抑郁、疲劳）和遗传（如APOE）因素与DMN连接纳入MCI的预测模型。识别化疗相关MCI的神经影像学生物标志物将改善对神经退行性变风险最高的个体的识别，并有助于开发这些损伤的治疗方法。鉴于社会老龄化以及乳腺癌和MCI的发病率和脆弱性增加，这一点至关重要。 公共卫生相关性：接受化疗的乳腺癌女性患轻度认知障碍（MCI）的风险显著增加，这降低了生活质量并延长了疾病相关的残疾。这项研究旨在确定这些女性MCI的神经影像学生物标志物，并开发方法来帮助预测哪些女性最脆弱。这项研究与乳腺癌高度相关，乳腺癌是最常见的公共卫生问题之一，影响八分之一的妇女。

DESCRIPTION (provided by applicant): Women with breast cancer, particularly those who are older and who receive adjuvant chemotherapy, are at significantly increased risk for mild cognitive impairment (MCI). Our previous research shows persistent and progressive MCI long after cancer treatment has ended. This cognitive impairment tends to involve difficulties with memory and executive function (i.e. multi-tasking, problem solving) that interfere with daily livin skills and reduce quality of life. The default mode network (DMN) is a brain circuit important for normal cognitive function. The connections between the DMN brain regions tend to naturally decrease in strength as we age. DMN functional connectivity has been demonstrated to be a highly promising neuroimaging biomarker of MCI in non-cancer populations. Disruption of DMN functional connectivity is strongly associated with conversion to dementia and has even been show to precede other biomarkers of neurodegeneration. Previous studies, including our own, show atrophy of DMN regions and damage to the white matter pathways that connect these regions following breast cancer chemotherapy. We believe that chemotherapy treatment accelerates DMN decline resulting in increased frequency of MCI following breast cancer. However, no studies to date have directly assessed the DMN or its relationship to MCI in breast cancer. The specific aims of the proposed study are therefore to 1) determine the frequency of MCI in older breast cancer subjects who receive chemotherapy, 2) identify DMN neuroimaging biomarkers in older breast cancer subjects treated with chemotherapy, and 3) develop models that predict vulnerability to MCI in this population. We will accomplish these aims by integrating longitudinal multidimensional neuropsychological assessments of cognitive function, mood and behavior with advanced, non-invasive multimodal magnetic resonance imaging techniques and APOE genotyping. We will evaluate 55 women with primary breast cancer prior to chemotherapy, one month following chemotherapy and six months following chemotherapy. We will compare the chemotherapy-treated group to 55 women with breast cancer who do not receive chemotherapy and 55 healthy females, all matched on important demographic and clinical factors. All groups will be assessed at the same time intervals. We will emphasize the assessment of memory and executive function as well as DMN functional connectivity. We will incorporate clinical, demographic, psychiatric (e.g. depression, fatigue) and genetic (e.g. APOE) factors with DMN connectivity into our predictive models of MCI. Identifying neuroimaging biomarkers underlying chemotherapy-related MCI will improve identification of individuals at highest risk for neurodegeneration and aid the development of treatments for these impairments. This is of critical importance given an aging society and the increased incidence of and vulnerability to both breast cancer and MCI. PUBLIC HEALTH RELEVANCE: Women with breast cancer who receive chemotherapy are at significantly increased risk for mild cognitive impairment (MCI) which reduces quality of life and extends disease-related disability. The proposed study aims to identify neuroimaging biomarkers of MCI in these women and develop methods to help predict which women are most vulnerable. This research is highly relevant to breast cancer, one of the most common public health problems, affecting 1 in 8 women.