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

描述（由申请人提供）：这个提议是为了促进我的科学发展，成为一名独立的临床研究者。所寻求的支持是培训临床转化科学家，在新的脑成像技术方面具有特定的专业知识，为成为多发性硬化症（MS）皮质病变（CL）和认知障碍（CI）研究的领导者奠定基础。直到最近，人们很少关注MS的认知方面。然而，高达60%的MS患者存在CI，并且CI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妨碍了早期发现和适当的管理，这可能会延长患者的经济和社会独立。在神经生物学水平上，CI的理解很差。最近的研究表明，CL在MS相关CI中起作用；以前对CL的准确MRI检测并不理想。2005年，在Ponnada Narayana博士的父母资助下，我获得了NIH的少数族裔补助。这笔资金使我能够完成检测皮质灰质病变的初步但重要的研究。我们的研究显著提高了CL的检测和分类，表明CI与CL的存在相关，并支持mri定义的MS引起的整体损伤也起作用。虽然取得了进展，但目前对于最可靠的脑梗死MRI检测方法还没有达成共识。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、易于获取的CI检测诊断工具。这将通过确定新型MRI技术检测到的CL与功能性MRI （fMRI）和弥散张量成像（DTI）结果之间的相关性来完成。具体目的是：1)通过fMRI上的血氧水平依赖（BOLD）激活来评估CL对区域皮层活动的影响；2)研究功能性磁共振成像（fMRI）对认知任务表现的影响；3)评估fMRI上BOLD激活异常与DTI检测到的白质相关通路完整性之间的关系；4)相对于标准NP测试，建立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fMRI生理原理、激活、实验设计、图像处理、数据分析和解释方面的知识，并将涉及临床/转化试验设计方面的结构化培训。德克萨斯大学休斯顿健康科学中心（UTHSC-H）的MRI研究部和临床与转化科学中心（CCTS）将为我完成这个项目提供理想的环境。通过与导师的互动。Ponnada Narayana博士，Jerry Wolinsky医学博士和Joel Steinberg医学博士，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。通过多模态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存在和严重程度密切相关的客观、可重复的测量。这将显著提高检测准确性，并转化为早期诊断/干预，从而改善MS患者的预后，并为MS的未来临床试验和潜在的其他临床神经科学领域提供基础。

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.