White Matter Tract Integrity biomarkers of neurodegeneration in aging and MCI

描述（由申请人提供）：阿尔茨海默病（AD）的患病率预计到2050年将增加两倍。为了解决这一迫在眉睫的公共卫生问题，2011年，NIA-AA发布了修订后的AD痴呆及其前期阶段轻度认知障碍（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PET）和神经变性（例如，通过结构MRI的海马萎缩）的生物标志物来确定患者的认知障碍是由于AD引起的可能性。最近对这些标准的测试表明，具有神经变性生物标志物证据的MCI患者可能发展为痴呆，而与淀粉样变性无关。因此，考虑到神经变性对痴呆发作的影响，拟议的研究旨在解决对神经变性的互补生物标志物的需求，这些生物标志物可以提供MCI中认知缺陷的特定地形和神经生物学相关性。申请人提出开发源自扩散峰度成像（DKI）参数的生物物理建模的神经变性的白色物质束完整性（WMTI）生物标志物。研究参与者将由80名临床诊断的MCI患者组成，他们将接受临床评价、神经心理学测试、MRI和2年随访临床评价以进行诊断确认。该研究旨在确定轴突密度和髓鞘完整性的WMTI指标检测海马萎缩以外的整个大脑神经变性的程度，与记忆，语言和执行功能的心理测量学复杂测试相关，并补充其他神经变性的研究MRI生物标志物（即皮质萎缩，功能连接）。Benitez博士是一位临床神经心理学家，其职业目标是改善衰老和AD认知衰退的诊断和预后。拟议的K23将延长她以前的培训，在定量MRI的大脑白色物质妥协认知老化期间，她的机构KL 2奖。具体而言，她提出了教学和应用培训经验，以1）精通多模态MRI研究，达到独立研究者的水平，2）获得有关衰老/AD神经生物学的基础知识，并预测MRI结果的解释，以及3）发展负责任地进行衰老/AD临床研究的基本技能，在MRI（Helpern博士），衰老/AD神经生物学（Granholm博士），以患者为导向的临床研究（Clark博士和Ovbiagele博士）和生物统计学（Nietert博士）的高级研究人员的优秀指导团队的支持下。在颁奖结束时，贝尼特斯博士将获得R 01的初步数据， 将该项目扩展到包括淀粉样蛋白PET的纵向研究。该R 01将研究WMTI指标作为神经变性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，DKI可能有此可能，但扩散张量成像则无此可能。这项工作将解决多个研究所资助的神经退行性疾病认知下降生物标志物的优先事项，这些疾病没有有效的治疗方法。

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.