White Matter Tract Integrity biomarkers of neurodegeneration in aging and MCI

衰老和 MCI 中神经退行性变的白质束完整性生物标志物

• 批准号: 9059561
• 负责人: Andreana Benitez
• 金额: $ 16.29万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9059561
• 关键词: APP-PS1; Address; Age; Aging; Alzheimer' s Disease; Amyloid; Amyloidosis; Atrophic; Award; Biological Markers; Biometry; Blood; Brain; Clinical; Clinical Research; Cognitive; Cognitive aging; Cognitive deficits; Complement; Data; Dementia; Detection; Development; Diagnosis; Diagnostic; Diffusion Magnetic Resonance Imaging; Elderly; Etiology; Evolution; Fasting; Funding; Future; Goals; Health; Image; Impaired cognition; Institutes; K-Series Research Career Programs; Knowledge; Language; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Medial; Memory; Mentors; Mentorship; Myelin; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neuropsychological Tests; Outcome; Participant; Pathology; Patients; Performance; Positron-Emission Tomography; Prevalence; Procedures; Provider; Public Health; Publications; Publishing; Recruitment Activity; Research; Research Personnel; Risk; Science; Staging; Techniques; Temporal Lobe; Testing; Training; Work; amyloid imaging; axonal degeneration; biophysical model; candidate marker; career; cerebral amyloidosis; cerebral atrophy; clinical biomarkers; cognitive function; computerized; density; effective therapy; executive function; experience; follow-up; hippocampal atrophy; improved; indexing; meetings; mild cognitive impairment; mouse model; neuroimaging; outcome forecast; patient oriented; pre-clinical; prognostic; public health priorities; research clinical testing; skills; therapy development; white matter

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.

描述（由申请人提供）：到2050年，阿尔茨海默病（AD）的患病率预计将增加两倍。为了解决这一迫在眉睫的公共卫生问题，2011年NIA-AA发布了AD痴呆及其前阶段轻度认知障碍（MCI）的修订诊断标准。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进行海马萎缩）的生物标志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，无论淀粉样变性如何，具有神经变性生物标志物证据的MCI患者都可能发展为痴呆。因此，鉴于神经退行性变对痴呆发病的影响，本研究旨在解决对神经退行性变的补充生物标志物的需求，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。申请人建议开发来自弥漫性峰度成像（DKI）参数的生物物理建模的神经退行性变的白质束完整性（WMTI）生物标志物。研究参与者将由80名临床诊断为轻度认知损伤的患者组成，他们将接受临床评估、神经心理测试、MRI和2年的随访临床评估以确诊。该研究旨在确定WMTI轴突密度和髓磷脂完整性指标在海马萎缩之外的整个大脑中检测神经退行性变的程度，与记忆、语言和执行功能的心理测量学复杂测试相关，并补充其他研究性MRI神经退行性变生物标志物（即皮质萎缩、功能连接）。本次指导患者导向职业发展奖（K23）的候选人Benitez博士是一名临床神经心理学家，其职业目标是改善衰老和AD认知能力下降的诊断和预后。拟议的K23将在她获得机构KL2奖期间扩展她之前在认知衰老中脑白质妥协的定量MRI方面的培训。具体而言，她提出了教学和应用培训经验，以使1)熟练掌握多模态MRI研究，达到独立研究者的水平；2)获得衰老/AD神经生物学的基础知识，并以此为基础解释MRI结果；3)在MRI高级研究人员（Dr. Helpern）的杰出指导团队的支持下，培养负责任地进行衰老/AD临床研究的基本技能。衰老/AD神经生物学（Granholm博士），以患者为导向的临床研究（Granholm博士）。Clark和Ovbiagele)和生物统计学（Nietert博士）。到奖项结束时，贝尼特斯博士将获得R01的初步数据