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White Matter Tract Integrity Biomarkers of Neurodegeneration in Aging and MCI Administrative Supplement

衰老过程中神经退行性变的白质束完整性生物标志物和 MCI 行政补充剂

基本信息

批准号：
10087215
负责人：
Andreana Benitez
金额：
$ 5.31万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10087215
关键词：
Address Administrative Supplement Aging Alzheimer&apos s Disease Alzheimer’s disease biomarker Amyloid Amyloidosis Award Axon Biological Assay Biological Markers Biometry Brain Clinical Clinical Research Cognitive aging Cognitive deficits Complement Consequentialism Data Dementia Detection Diagnosis Diagnostic Diffusion Foundations Funding Goals Image Impaired cognition Institutes Investigation K-Series Research Career Programs Knowledge Language Light Longitudinal Studies Magnetic Resonance Imaging Memory Mentored Patient-Oriented Research Career Development Award Mentors Myelin Nerve Degeneration Neurobiology Neurodegenerative Disorders Neuropsychological Tests Participant Patients Plasma Positron-Emission Tomography Prevalence Provider Psychometrics Public Health Publishing Research Research Personnel Structure Testing Training Work biophysical model career cerebral amyloidosis cerebral atrophy clinical Diagnosis clinical biomarkers density effective therapy executive function experience follow-up hippocampal atrophy improved magnetic resonance imaging biomarker mild cognitive impairment multimodality neurofilament neuroimaging marker outcome forecast patient oriented pre-clinical public health priorities research clinical testing skills tau Proteins therapy development white matter

项目摘要

PROJECT SUMMARY/ABSTRACT The following section was taken directly from the awarded K23 application. 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. The requested funds for this administrative supplement will be dedicated to the efficient processing of the MRI data and to assaying collected plasma for AD biomarkers (i.e. AB40, AB42, tau, neurofilament light) to complement the proposed aims and to enhance the preliminary data for the subsequent R01.

项目概要/摘要以下部分直接取自已获批的 K23 申请。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众问题出于对健康的关注，NIA-AA 于 2011 年发布了修订后的 AD 痴呆及其前因后果的诊断标准阶段，轻度认知障碍（MCI）。这些标准使提供商能够确定使用脑淀粉样变性生物标志物（例如通过淀粉样蛋白 PET），患者的认知障碍是由于 AD 造成的和神经退行性变（例如通过结构 MRI 发现海马萎缩）。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 患者可能会患上痴呆症，与淀粉样变性无关。因此，考虑到神经退行性变对痴呆症发病的影响，拟议的研究旨在解决神经退行性疾病补充生物标志物的需求，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。申请人提议开发源自神经退行性变的白质束完整性（WMTI）生物标志物扩散峰度成像 (DKI) 参数的生物物理建模。研究参与者将包括 80 名临床诊断的 MCI 患者将接受临床评估、神经心理学测试、MRI、以及为期 2 年的后续临床评估以确认诊断。该研究旨在确定程度轴突密度和髓磷脂完整性的 WMTI 指标可检测整个大脑的神经退行性变海马萎缩，与记忆、语言和执行能力的心理测量复杂测试相关功能，并补充神经退行性变的其他研究性 MRI 生物标志物（即皮质萎缩、功能连接）。以患者为导向的职业发展奖（K23）的候选人， Benitez 博士是一位临床神经心理学家，其职业目标是改善以下疾病的诊断和预后衰老和 AD 导致的认知能力下降。拟议的 K23 将扩展她之前在脑部定量 MRI 方面的培训在她获得机构 KL2 奖期间，白质对认知衰老的影响有所妥协。具体来说，她建议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，2) 获得衰老/AD 神经生物学的基础知识， MRI 结果的解释是有前提的，并且 3）培养负责任地进行临床的基本技能在 MRI 高级研究人员的杰出指导团队（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）。颁奖结束时，贝尼特斯博士将获得 R01 的初步数据：将将该项目扩展到包括淀粉样蛋白 PET 在内的纵向研究。此 R01 将调查 WMTI 指标：神经变性和淀粉样变性的临床生物标志物，最近的临床前研究结果表明这可能可以使用 DKI，但不能使用扩散张量成像。这项工作将解决多机构资助优先事项神经退行性疾病中认知能力下降的生物标志物，目前尚无有效的治疗方法。该行政补充申请的资金将专门用于 MRI 的有效处理数据并分析收集的血浆中的 AD 生物标志物（即 AB40、AB42、tau、神经丝光），以补充拟议的目标并增强后续 R01 的初步数据。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Women's leadership in neuropsychology: historical perspectives, present trends, and future directions.

女性在神经心理学领域的领导地位：历史观点、当前趋势和未来方向。

DOI：
10.1080/13854046.2017.1420234
发表时间：
2018
期刊：
The Clinical neuropsychologist
影响因子：
0
作者：
Sachs,BonnieC;Benitez,Andreana;Buelow,MelissaT;Gooding,Amanda;Schaefer,LynnA;Sim,AnitaH;Tussey,ChriscelynM;Shear,PaulaK
通讯作者：
Shear,PaulaK

Validity of Normative Volumetric Estimates from Open Access Software in Amnestic Mild Cognitive Impairment.