White Matter Tract Integrity biomarkers of neurodegeneration in aging and MCI

描述(由申请人提供)：预计到2050年阿尔茨海默病(AD)的患病率将增加两倍。为了解决这一迫在眉睫的公共卫生问题，NIA-AA于2011年公布了修订后的AD痴呆及其前驱阶段--轻度认知障碍(MCI)的诊断标准。这些标准允许提供者使用脑淀粉样变性(例如，通过淀粉样蛋白PET)和神经变性(例如，通过结构磁共振的海马区萎缩)的生物标记物来确定患者认知障碍是由AD引起的可能性。最近对这些标准的测试表明，有神经变性生物标志物证据的MCI患者很可能发展为痴呆症，而不考虑淀粉样变性。因此，鉴于神经退行性变对痴呆发病的必然影响，拟议的研究试图解决神经退行性变的补充生物标记物的需求，这些生物标记物可以提供MCI认知缺陷的特定地形图和神经生物学关联。申请人建议开发神经退行性变的白质束完整性(WMTI)生物标记物，该生物标记物源自扩散峰度成像(DKI)参数的生物物理模型。研究参与者将由80名临床诊断为MCI的患者组成，他们将接受临床评估、神经心理测试、磁共振成像，并进行为期两年的临床评估以确定诊断。这项研究旨在确定轴突密度和髓鞘完整性的WMTI指标在多大程度上检测到海马区萎缩以外的整个大脑的神经退行性变，与记忆、语言和执行功能的心理测量测试相关，并补充神经退行性变(如皮质萎缩、功能连通性)的其他研究MRI生物标记物。这项以患者为导向的导师职业发展奖(K23)的候选人贝尼特斯博士是一位临床神经心理学家，他的职业目标是改善对衰老和AD认知功能减退的诊断和预后。在她的机构KL2奖期间，拟议的K23将延长她之前在认知老化中脑白质损害的定量MRI方面的培训。具体地说，她建议教学和应用培训经验如下：1)精通多模式核磁共振研究，达到独立调查者的水平；2)获得老年/AD神经生物学的基础知识，作为解释MRI结果的基础；3)在MRI(Helpern博士)、老龄/AD神经生物学(Granholm博士)、以患者为导向的临床研究(Clark和Ovbiagele博士)以及生物统计学(Nietert博士)的杰出高级研究人员指导团队的支持下，培养负责任地进行老年/AD临床研究的基本技能。到颁奖结束时，贝尼特斯博士将有R01的初步数据，这将 将该项目扩展到包括淀粉样蛋白PET在内的纵向研究。R01将研究WMTI指标作为神经退行性变和淀粉样变性的临床生物标志物，因为最近的临床前研究结果表明，这可能是DKI的可能，但扩散张量成像不可能。这项工作将解决多个研究所为神经退行性疾病中认知功能下降的生物标记物提供资金的优先事项，这些疾病尚无有效的治疗方法。

DESCRIPTION (provided by applicant): The prevalence of Alzheimer's disease (AD) is projected to triple by 2050. To address this imminent public health concern, in 2011 the NIA-AA published revised diagnostic criteria for AD dementia and its anteceding stage, mild cognitive impairment (MCI). These criteria allow providers to determine the likelihood that a patient's cognitive impairment is due to AD using biomarkers of cerebral amyloidosis (e.g. via Amyloid PET) and neurodegeneration (e.g. hippocampal atrophy via structural MRI). Recent tests of these criteria indicate that MCI patients who have biomarker evidence of neurodegeneration are likely to develop dementia, irrespective of amyloidosis. Thus, given the consequential impact of neurodegeneration on dementia onset, the proposed study seeks to address the need for complementary biomarkers of neurodegeneration that can provide specific topographical and neurobiological correlates of cognitive deficits in MCI. The Applicant proposes to develop white matter tract integrity (WMTI) biomarkers of neurodegeneration derived from the biophysical modeling of diffusional kurtosis imaging (DKI) parameters. Study participants will be composed of 80 clinically diagnosed MCI patients who will undergo a clinical evaluation, neuropsychological testing, MRI, and a 2-year follow-up clinical evaluation for diagnostic confirmation. The study aims to determine the extent WMTI metrics of axonal density and myelin integrity detect neurodegeneration throughout the brain beyond hippocampal atrophy, correlate with psychometrically sophisticated tests of memory, language, and executive functions, and complement other investigational MRI biomarkers of neurodegeneration (i.e. cortical atrophy, functional connectivity). The candidate for this Mentored Patient-Oriented Career Development Award (K23), Dr. Benitez, is a clinical neuropsychologist whose career goal is to improve the diagnosis and prognosis of cognitive decline in aging and AD. The proposed K23 will extend her prior training in quantitative MRI of brain white matter compromise in cognitive aging during her institutional KL2 award. Specifically, she proposes didactic and applied training experiences to 1) become proficient in multi-modal MRI research to the level of an independent investigator, 2) acquire foundational knowledge on the neurobiology of aging/AD on which the interpretation of MRI findings is predicated, and 3) develop essential skills in the responsible conduct of clinical research in aging/AD, with the support of an outstanding mentoring team of senior researchers in MRI (Dr. Helpern), aging/AD neurobiology (Dr. Granholm), patient-oriented clinical research (Drs. Clark and Ovbiagele), and biostatistics (Dr. Nietert). By the end of the award, Dr. Benitez will have preliminary data for an R01 that will extend this project to a longitudinal study including Amyloid PET. This R01 will investigate WMTI metrics as clinical biomarkers of both neurodegeneration and amyloidosis, as recent preclinical findings suggest this may be possible with DKI but not diffusion tensor imaging. This work will address a multi-institute funding priority for biomarkers of cognitive decline across neurodegenerative diseases, for which no effective therapies exist.