Early Diagnosis of Human Prion Disease

描述(由申请人提供)：雅各布-克雅茨费尔特病(CJD)等人类普恩病毒疾病很难诊断，由于传播的风险，越来越受到公共卫生的关注。我们的痴呆症计划是美国一个主要的普恩病毒疾病转诊中心，在过去六年中有952名潜在的CJD转诊患者。我们还在进行由美国国立卫生研究院赞助的首次美国散发性CJD(SCJD)治疗试验。不幸的是，许多sCJD病例被误诊或在病程中被诊断得太晚，以至于未来的任何潜在治疗都无法奏效。我们和其他人已经证明，脑MRI对sCJD的诊断具有非常高的敏感性和特异性。不幸的是，1998年修订的WHO标准中使用最广泛的sCJD诊断标准有几个原因：1.它们需要通常直到病程晚期才出现的症状；2.它们不使用MRI；3.它们使用脊髓液中的替代生物标记物--14-3-3蛋白，我们发现它缺乏敏感性和特异性；4.它们依赖于某些灵敏度较低的脑电(EEG)结果，特别是在疾病的早期。我们将在五年内前瞻性评估100名sCJD患者、20名有症状的gCJD患者、40名无症状(无症状的gCJD)患者和80名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。我们将在接近预测发病年龄的年龄评估我们的gCJD，这将有助于我们识别Pron病的最早迹象。主要的焦点将是确定FLAIR和DTI MRI上特定的异常区域和模式，以区分sCJD和其他RPD。通过这些前瞻性获得的数据，我们将设计一种最先进的诊断方案，使用现代统计分类技术和Logistic回归，用于sCJD的早期诊断。公共卫生相关性：普恩病毒疾病通常是致命的、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几个组织中发现了普恩病毒，包括肌肉、淋巴网状组织和嗅觉上皮细胞。通过早期诊断，患者可以避免不必要和耗时的诊断程序，对潜在的治疗有更好的反应机会，传播的风险可以大大降低。

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.