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

描述（由申请人提供）：本提案旨在促进我的科学发展，以便成为一名独立的临床研究者。寻求的支持是培训作为临床翻译科学家，在新的脑成像技术的具体专业知识，作为职业生涯的基础，在皮质病变（CL）和认知障碍（CI）的研究在多发性硬化症（MS）。直到最近很少有人注意到MS的认知方面。然而，CI在高达60%的MS患者中发展，并且是影响工作效率和长期残疾的主要因素。由于缺乏现成和负担得起的诊断工具，无法进行早期检测和适当管理，这可能会延长患者的经济和社会独立性。CI在神经生物学水平上知之甚少。最近的研究表明CL在MS相关CI中发挥作用;以前CL的准确MRI检测是次优的。2005年，我获得了美国国立卫生研究院的少数民族补助金，由Ponnada Narayana博士资助。这笔资金使我能够完成初步但重要的研究，以检测皮质灰质病变。我们的研究显著改善了CL的检测和分类，表明CI与CL的存在相关，并支持MS引起的整体MRI定义的损伤也起作用。虽然已经取得了进展，但目前对于CI检测的最可靠MRI测量没有达成共识。该项目的目标是通过使用多模态MRI和神经心理学（NP）评估客观地将CI与脑病理学联系起来，找到准确，可重复，易于获得的诊断工具来检测CI。这将通过确定由新型MRI技术检测到的CL与功能性MRI（fMRI）和扩散张量成像（DTI）结果之间的相关性来完成。具体目标是：1）通过fMRI上的血氧水平依赖（BOLD）激活来评估CL对局部皮层活动的影响：2）通过fMRI来确定CL对认知任务表现的影响; 3）评价功能磁共振成像（fMRI）上BOLD激活异常与DTI检测到的白色相关通路完整性之间的关系，（4）建立功能磁共振成像模式相对于标准NP测试检测CI的准确性。该奖项的培训方面将侧重于增加我对fMRI生理学原理，激活，实验设计，图像处理，数据分析和解释的知识，并将涉及临床/翻译试验设计的结构化培训。MRI研究部门和德克萨斯大学休斯顿健康科学中心（UTHSC-H）的临床和转化科学中心（CCTS）将为我提供完成该项目的理想环境。通过与导师Ponnada Narayana博士，Jerry Wolinsky MD和Joel Steinberg MD的互动，以及经验丰富的研究人员的广泛网络，我将进一步发展独立的学术生涯。通过多模式MRI方法评估CI将增加我们对CI潜在病理生理学的理解，并可能提供与CI的存在和严重程度密切相关的客观、可重复的测量。这将显着提高检测准确性，并转化为早期诊断/干预措施，可以改善MS患者的预后，并为MS和临床神经科学的其他潜在领域的未来临床试验提供基础。 公共卫生相关性：认知障碍（CI）是多发性硬化症（MS）残疾的重要原因。诊断是通过神经心理学测试进行的，这种测试的可用性有限，价格昂贵，而且通常不在保险范围内。这使得许多患者无法得到诊断和治疗。皮质病变（CL）在CI中发挥作用。我们的团队已经开发出可以检测这些病变的成像技术。这是第一项使用功能性MRI评估CL对认知功能影响的研究。我们希望更好地了解CL和CI之间的关系，找到更好，更容易获得的CI诊断工具，并希望改善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.