Early Diagnosis of Human Prion Disease

描述（由申请人提供）：人类朊病毒疾病，如雅各布-克罗伊茨费尔特病（CJD），很难诊断，由于传播风险，日益引起公众健康关注。我们的痴呆症项目是美国朊病毒疾病的主要转诊中心，在过去六年中有952例潜在的CJD转诊。我们还在进行美国第一个由NIH赞助的散发性CJD（sCJD）治疗试验。不幸的是，许多sCJD病例被误诊或在治疗过程中被诊断得太晚，以至于未来任何潜在的治疗都无法有效。我们和其他人已经表明，脑部MRI对sCJD诊断具有非常高的敏感性和特异性。不幸的是，sCJD最广泛使用的诊断标准，1998年修订的WHO标准，由于以下几个原因而存在问题：1.他们需要的症状往往不会出现，直到后期的疾病过程; 2.他们不使用MRI; 3.他们使用脊髓液中的替代生物标志物14-3-3蛋白，我们发现其缺乏敏感性和特异性;以及4.他们依赖于某些敏感性低的脑电图（EEG）结果，特别是在疾病早期。我们将前瞻性评估100例sCJD患者，20例有症状的gCJD患者，40例无症状（症状前gCJD）患者和80例其他形式的快速进展性痴呆（RPD）患者。我们将进行全面的评估，包括临床、行为、脊髓液替代标记物、EEG和MRI分析。我们将在接近其预测发病年龄的年龄评估我们的gCJD，这将有助于我们识别朊病毒疾病的最早迹象。一个主要的重点将是确定特定的区域和模式的异常FLAIR和DTI MRI，可以区分sCJD从其他RPD。通过这些前瞻性获得的数据，我们将设计一个最先进的诊断方案，使用当代统计分类技术和逻辑回归，用于sCJD的早期诊断。公共卫生相关性：朊病毒疾病是一致致命的、可传播的神经退行性疾病。至少有一种形式可以通过输血传播，现在已经在神经系统以外的其他几种组织中发现了朊病毒，包括肌肉，淋巴网状组织和嗅觉上皮。透过及早诊断，病人可省却不必要和费时的诊断程序，并有更大机会对可能的治疗作出反应，而传播的风险亦可大大减低。

DESCRIPTION (provided by applicant): Human prion diseases, such as Jakob-Creutzfeldt disease (CJD), are difficult to diagnose and are of increasing public health concern due to the risk of transmission. Our dementia program is a major referral center for prion diseases in the United States with 952 potential CJD referrals over the past six years. We also are conducting the first ever US sporadic CJD (sCJD) treatment trial, sponsored by the NIH. Unfortunately, many cases of sCJD are misdiagnosed or are diagnosed too late in the course for any future potential treatment to be effective. We, and others, have shown that brain MRI has very high sensitivity and specificity for sCJD diagnosis. Unfortunately, the most widely used diagnostic criteria for sCJD, Revised 1998 WHO Criteria, are problematic for several reasons: 1. they require symptoms that often do not occur until late in the disease course; 2. they do not use MRI; 3. they use a surrogate biomarker in the spinal fluid, the 14-3-3 protein, which we have found lacks sensitivity and specificity; and 4. they rely on certain electroencephalography (EEG) findings that have low sensitivity, particularly earlier in the disease. We will prospectively evaluate 100 patients with sCJD, 20 patients with symptomatic gCJD, and 40 patients with asymptomatic (presymptomatic gCJD) and 80 with other forms of rapidly progressive dementia (RPDs) over five years. We will conduct comprehensive assessments, including clinical, behavioral, spinal fluid surrogate marker, EEG, and MRI analyses. We will evaluate our gCJD at an age close to their predicted age of onset which will help us to identify the earliest signs of prion disease. A major focus will be to identify specific regions and patterns of abnormality on FLAIR and DTI MRI that can differentiate sCJD from other RPDs. Through this prospectively acquired data, we will devise a state of the art diagnostic scheme, using contemporary statistical classification techniques and logistic regression, for early diagnosis of sCJD. PUBLIC HEALTH RELEVANCE: Prion diseases are uniformly fatal, transmissible neurodegenerative diseases. At least one form can be transmitted by blood transfusion, and prions have now been found in several other tissues outside of the nervous system, including muscle, lymphoreticular tissues, and olfactory epithelia. Through earlier diagnosis, patients may be spared unnecessary and time-consuming diagnostic procedures and have better chance of responding to potential treatments, and the risk of transmission can be greatly reduced.