Detection of MS Related Cognitive Impairment: In Search of MRI Surrogate Markers

描述(申请人提供)：这项建议是为了促进我的科学发展，以便成为一名独立的临床研究员。寻求的支持是作为一名在新型脑成像技术方面拥有特定专业知识的临床翻译科学家的培训，以作为多发性硬化症(MS)皮质损伤(CL)和认知障碍(CI)研究的领先者的职业生涯的基础。直到最近，对MS的认知方面的关注还很少，然而，CI在高达60%的MS患者中发展，是影响工作效率和长期残疾的主要因素。缺乏现成和负担得起的诊断工具阻碍了早期发现和适当的治疗，这可能会延长患者的经济和社会独立性。在神经生物学水平上，人们对CI知之甚少。最近的研究表明CL在MS相关性CI中发挥了作用；以前对CL的准确MRI检测一直是次优的。2005年，在Ponnada Narayana博士的父母资助下，我获得了NIH少数民族补助金。这笔资金使我能够完成检测皮质灰质损伤的初步但重要的研究。我们的研究显著改善了CL的发现和分类，表明CI与CL的存在相关，并支持MS引起的MRI定义的整体损害也起到了一定作用。虽然已经取得了进展，但目前对于检测CI最可靠的MRI方法还没有达成共识。该项目的目标是通过使用多模式磁共振成像和神经心理学(NP)评估客观地将CI与脑病理联系起来，寻找准确、可重复性、易获得的诊断工具来检测CI。这将通过确定新的MRI技术检测到的CL与功能MRI(FMRI)和弥散张量成像(DTI)所见之间的相关性来完成。其具体目的是：1)评估CL对局部皮质活动的影响，由fMRI上的血氧水平依赖项(BOLD)激活确定；2)确定CL对fMRI所揭示的认知任务操作的影响；3)评估fMRI BOLD激活异常与DTI所检测到的脑白质相关通路完整性之间的关系；以及4)建立相对于标准NP测试的fMRI范式检测CI的准确性。该奖项的培训方面将侧重于增加我在功能磁共振生理原理、激活、实验设计、图像处理以及数据分析和解释方面的知识，并将涉及临床/转化性试验设计的结构化培训。位于休斯顿的德克萨斯大学健康科学中心(UTHSC-H)的MRI研究部和临床与转化科学中心(CCTS)将为我提供完成这一项目的理想环境。通过与导师波纳达·纳拉亚纳博士、曾傑瑞·沃林斯基博士和乔尔·斯坦伯格博士的互动，以及由经验丰富的研究人员组成的广泛网络，我将进一步发展独立的学术事业。通过多模式MRI方法评估CI将增加我们对CI潜在病理生理机制的了解，并可能提供与CI的存在和严重程度密切相关的客观、可重复性的测量方法。这将显著提高检测的准确性，并转化为早期诊断/干预，从而改善多发性硬化症患者的预后，并为未来多发性硬化症的临床试验以及临床神经科学的其他潜在领域提供基础。 公共卫生相关性：认知障碍(CI)是多发性硬化症(MS)致残的重要原因。诊断是通过神经心理测试进行的，这种测试可获得性有限，费用昂贵，而且通常不在保险范围内。这使许多患者无法得到诊断和治疗。皮质损害(CL)在脑梗塞中起一定作用。我们小组已经开发出可以检测这些损伤的成像技术。这是第一个使用功能磁共振来评估CL对认知功能影响的研究。我们希望更好地了解CL与CI的关系，寻找更好、更方便的CI诊断工具，并有望改善MS患者的预后。

DESCRIPTION (provided by applicant): This proposal is to foster my scientific development in order to become an independent clinical investigator. The support sought is for training as a clinical translational scientist with specific expertise in novel brain imaging techniques to serve as the foundation for a career as a leader in the study of cortical lesions (CL) and cognitive impairment (CI) in multiple sclerosis (MS). Until recently little attention was paid to the cognitive aspects of MS. Yet, CI develops in up to 60% of MS patients and is a main factor influencing job productivity and long term disability. The lack of readily available and affordable diagnostic tools prevents early detection and appropriate management that could potentially prolong a patient's financial and social independence. CI is poorly understood at the neurobiological level. Recent studies indicate that CL play a role in MS related CI; previously accurate MRI detection of CL had been suboptimal. In 2005 I was awarded an NIH minority supplement under the parent grant of Ponnada Narayana, PhD. That funding allowed me to complete preliminary but important studies in detection of cortical gray matter lesions. Our studies significantly improved detection and classification of CL, showed that CI correlates with the presence of CL, and supported that the overall MRI-defined damage caused by MS also plays a role. While progress has been made, currently there is no consensus on the most reliable MRI measure for CI detection. The goal of this project is to find accurate, reproducible, easily accessible diagnostic tools for detection of CI by objectively relating CI to brain pathology using multi-modal MRI and neuropsychological (NP) assessments. This will be done by determining correlations between CL detected by novel MRI techniques and findings on functional MRI (fMRI) and diffusion tensor imaging (DTI). The specific aims are: 1) To assess the impact of CL on regional cortical activity as determined by blood oxygen level dependant (BOLD) activation on fMRI; 2) To determine the impact of CL on performance of cognition tasks as revealed by fMRI; 3) To evaluate the association between abnormalities in BOLD activation on fMRI and integrity of white matter associated pathways as detected by DTI, and 4) To establish the accuracy of CI detection by fMRI paradigms relative to the standard NP testing. The award's training aspects will focus on increasing my knowledge on fMRI physiological principles, activation, experiment design, image processing, and data analysis and interpretation, and will involve structured training in clinical/translational trial design. The MRI Research Division and the Center for Clinical and Translational Sciences (CCTS) at The University of Texas Health Science Center at Houston (UTHSC-H) will provide me with the ideal setting to accomplish this project. Through interaction with mentors Drs. Ponnada Narayana PhD, Jerry Wolinsky MD and Joel Steinberg MD, and an extensive network of experienced researchers, I will further the development of an independent academic career. Assessment of CI by a multimodal MRI approach will increase our understanding of the underlying pathophysiology of CI and may provide an objective, reproducible measure that strongly correlates with the presence and severity of CI. This will significantly improve detection accuracy and translate into early diagnosis/interventions that could improve prognosis for MS patients and provide a foundation for future clinical trials in MS and potentially other fields in the clinical neurosciences. PUBLIC HEALTH RELEVANCE: Cognitive impairment (CI) is an important cause for disability in multiple sclerosis (MS). Diagnosis is made by neuropsychological testing which is limited in availability, expensive and not often covered by insurance. This prevents many patients from being diagnosed and treated. Cortical lesions (CL) play a role in CI. Our group has developed imaging techniques that can detect these lesions. This is the first study that evaluates the effect of CL on cognitive function using functional MRI. We hope to better understand the relationship between CL and CI, find better, more accessible diagnostic tools for CI and hopefully improve prognosis for MS patients.