Early Diagnosis of Human Prion Disease

人类朊病毒病的早期诊断

• 批准号: 8113956
• 负责人: MICHAEL D GESCHWIND
• 金额: $ 47.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113956
• 关键词: Age; Age of Onset; Alzheimer' s Disease; Autopsy; Behavioral; Biological Markers; Biopsy; Blood Transfusion; Brain; California; Cerebrospinal Fluid; Cessation of life; Classification; Clinical; Clinical Data; Cognitive; Creutzfeldt-Jakob Syndrome; Data; Degenerative Disorder; Dementia; Diagnosis; Diagnostic; Diagnostic Procedure; Diffusion; Disease; Doctor of Philosophy; Early Diagnosis; Electroencephalogram; Electroencephalography; Future; Goals; Gold; Health; Health Personnel; Hospitals; Human; Image; Laboratories; Lead; Logistic Regressions; Magnetic Resonance Imaging; Medical Records; Methods; Movement; Muscle; Nervous system structure; Neurodegenerative Disorders; Neurologist; Olfactory Epithelium; Pathology; Patients; Pattern; Phase; Primary Care Physician; Principal Investigator; Prion Diseases; Prions; Procedures; Proteins; Public Health; Recruitment Activity; Regression Analysis; Research; Risk; San Francisco; Scheme; Sensitivity and Specificity; Serological; Signs and Symptoms; Specialist; Specificity; Staging; Structure; Surrogate Markers; Symptoms; Techniques; Time; Tissues; Trees; United States; United States National Institutes of Health; Universities; Visual; base; cohort; evidence base; experience; forest; improved; meetings; mild neurocognitive impairment; neuroimaging; programs; tertiary care; transmission process; treatment program; treatment trial

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.

描述（由申请人提供）：人类朊病毒病，例如雅各布-克罗伊茨菲尔德病（CJD），很难诊断，并且由于传播风险而日益引起公众健康关注。我们的痴呆项目是美国主要的朊病毒病转诊中心，在过去六年中转诊了 952 名潜在的克雅氏病患者。我们还正在进行由 NIH 赞助的美国首个散发性克雅氏病 (sCJD) 治疗试验。不幸的是，许多 sCJD 病例被误诊或诊断得太晚，以至于未来任何潜在的治疗都无法有效。我们和其他人已经证明，脑 MRI 对 sCJD 诊断具有非常高的敏感性和特异性。不幸的是，最广泛使用的 sCJD 诊断标准（1998 年修订的 WHO 标准）存在以下几个原因： 1. 它们要求的症状通常要到病程晚期才出现； 2.他们不使用MRI； 3.他们使用了脊髓液中的替代生物标志物，即14-3-3蛋白，我们发现它缺乏敏感性和特异性； 4. 他们依赖于某些敏感性较低的脑电图 (EEG) 结果，尤其是在疾病早期。我们将在五年内对 100 名 sCJD 患者、20 名有症状 gCJD 患者、40 名无症状（症状前 gCJD）患者和 80 名其他形式的快速进展性痴呆 (RPD) 患者进行前瞻性评估。我们将进行全面的评估，包括临床、行为、脊髓液替代标记物、脑电图和核磁共振分析。我们将在接近预测发病年龄的年龄评估 gCJD，这将有助于我们识别朊病毒病的最早迹象。主要重点是确定 FLAIR 和 DTI MRI 异常的特定区域和模式，以区分 sCJD 和其他 RPD。通过这些前瞻性获得的数据，我们将利用当代统计分类技术和逻辑回归设计出最先进的诊断方案，用于 sCJD 的早期诊断。公共卫生相关性：朊病毒病都是致命的、传染性的神经退行性疾病。至少一种形式可以通过输血传播，并且现已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。通过早期诊断，患者可以避免不必要且耗时的诊断程序，并有更好的机会对潜在的治疗做出反应，并且可以大大降低传播风险。