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）：预计到2050年，阿尔茨海默氏病（AD）的患病率预计将三倍。为了解决这一即将公共的健康问题，2011年，NIA-AA发布了AD痴呆症及其前的痴呆阶段诊断标准及其对抗性阶段，轻度认知障碍（MCI）。这些标准允许提供者确定患者的认知障碍的可能性是由于使用脑淀粉样变性的生物标志物（例如，通过淀粉样蛋白PET）和神经变性（例如，通过结构MRI通过海马萎缩）。这些标准的最新测试表明，具有神经退行性的生物标志物证据的MCI患者可能会发展为痴呆症，而与淀粉样变性无关。因此，鉴于神经变性对痴呆发作的结果影响，拟议的研究旨在满足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认知缺陷的特定地形和神经生物学相关性。申请人提议开发从扩散峰度成像（DKI）参数的生物物理模型得出的神经变性的白质完整性（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，他们将接受临床评估，神经心理学测试，MRI和2年的随访临床评估，以进行诊断确认。 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).这项受过指导的患者职业发展奖（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将扩大她在机构KL2奖期间先前在认知衰老中对脑白质妥协的定量MRI进行培训。 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),衰老/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）和生物统计学（Nietert博士）。在奖励结束时，贝尼特斯博士将获得R01的初步数据 将该项目扩展到包括淀粉样蛋白宠物在内的纵向研究。该R01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，因为最近的临床前发现表明，DKI可能是可能的，但不是扩散张量张量成像。这项工作将介绍神经退行性疾病认知下降的生物标志物的多元化资金优先级，而这些疾病不存在有效的疗法。