Predicting progression of human prion disease

预测人类朊病毒病的进展

• 批准号: 8579837
• 负责人: MICHAEL D GESCHWIND
• 金额: $ 62.76万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579837
• 关键词: Algorithms; Alzheimer' s Disease; Area; Biological Markers; Brain; Brain Diseases; Brain region; Cessation of life; Clinical; Clinical Research; Cognitive; Creutzfeldt-Jakob Syndrome; Data; Dementia; Development; Diagnosis; Diagnostic; Diagnostic tests; Diffuse; Diffusion; Disease; Early Diagnosis; Family; Frontotemporal Dementia; Functional Magnetic Resonance Imaging; Goals; Grant; Health; Human; Image; Individual; Link; Longitudinal Studies; Magnetic Resonance Imaging; Maps; Measurement; Measures; Methods; Metric; Modeling; Motor; Myoclonus; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neuron-Specific Enolase; Neuropsychological Tests; Outcome; Parkinson Disease; Patients; Pattern; Phase; Play; Prion Diseases; Proteins; Reporting; Research; Role; Seeds; Sensitivity and Specificity; Shapes; Signs and Symptoms; Staging; Stratification; Survival Rate; Symptoms; Time; United States; Visit; Visual; Weight; base; brain volume; cerebral atrophy; functional decline; gray matter; improved; interest; prion-like; programs; tau Proteins; transmission process; treatment response; treatment trial; white matter

DESCRIPTION (provided by applicant): Human prion diseases, such as Jakob-Creutzfeldt disease (CJD) are devastating neurodegenerative diseases that currently are untreatable. As treatment trials are underway and planned, we need to have improved methods for predicting the course of progression of an individual with CJD. Our CJD and rapidly progressive dementia (RPD) clinical research program is a major referral center for prion diseases in the United States with about 750 RPD/CJD referrals over the past four years. Through our past R01, "Early diagnosis of human prion disease," we acquired data that led to improved diagnosis of CJD. We had several important clinical findings regarding CJD, including: 1) the most widely used biomarker for sCJD diagnosis, CSF 14-3-3 protein, has relatively low sensitivity and specificity, despite being in several diagnostic criteria; 2) DWI brain MRI, showing restricted diffusion in gray matter, is the single best diagnostic test for sCJD, although CSF biomarkers, such as total tau and neuron-specific enolase, sometimes are useful; 3) Diffusion does not continually become increasingly restricted in gray matter during the disease course, but eventually becomes less restricted; thus, diffusion is linearly downward in the earlier part of disease, but then moving upward (less restricted) in later stages, thus giving a U or even J shaped curve: this makes following restricted diffusion as an outcome marker problematic in treatment trials; 4) Certain areas of gray matter appear to be preferentially involved on MRI in sCJD, and they overlap with various functional connectivity networks identified by fMRI. It is not clear if prion disease spreads in the brain via functional and structural networks or through transmission to adjacent brain regions; 5) Although not previously reported, we found diffuse restricted diffusion in the white matter in sCJD and 6) the presence of certain clinical signs/symptoms in patients, such as cerebellar or visual symptoms, predict shorter survival. Most of these findings were based on cross-sectional assessment. For this current project, we will be following approximately 120 patients with CJD longitudinally, studying patients for at serial visits, between about 1-4 months after their initial visit. At each serial visit we will conduct a detailed assessment (neurological exam, neuropsychological testing, functional scores, various brain MRI metrics (discussed above), and CSF biomarkers). Through this prospectively acquired data of longitudinal assessment of CJD, we will develop an algorithm for disease staging (predicting the survival) and predicting progression of individual patients. This information will not only be helpful for prognosticating for patients and families, but also for development of treatment trials

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）是目前无法治疗的破坏性神经退行性疾病。随着治疗试验的进行和计划，我们需要有更好的方法来预测CJD患者的进展过程。我们的CJD和快速进展性痴呆（RPD）临床研究计划是美国朊病毒疾病的主要转诊中心，在过去四年中约有750例RPD/CJD转诊。通过我们过去的R 01，“人类朊病毒疾病的早期诊断”，我们获得的数据，导致改善诊断CJD。我们有几个重要的临床发现，包括：1）最广泛使用的sCJD诊断的生物标志物，CSF 14-3-3蛋白，尽管在几个诊断标准中，敏感性和特异性相对较低; 2）DWI脑MRI显示灰质中的扩散受限，是sCJD的唯一最佳诊断测试，尽管CSF生物标志物，如总tau蛋白和神经元特异性烯醇化酶，有时是有用的; 3）在疾病过程中，扩散在灰质中不会持续地变得越来越受限，而是最终变得不那么受限;因此，在疾病的早期，扩散是线性向下的，但随后向上移动。（较少限制）在后期，从而给出U形或甚至J形曲线：这使得以下限制扩散作为治疗试验中的结果标记物成问题; 4）sCJD患者的某些灰质区域似乎优先参与MRI，它们与fMRI识别的各种功能连接网络重叠。目前尚不清楚朊病毒疾病是通过功能和结构网络在脑内传播，还是通过传播到邻近的脑区; 5）虽然以前没有报道，但我们发现sCJD的白色物质中存在弥漫性限制扩散; 6）患者存在某些临床体征/症状，如小脑或视觉症状，预测生存期较短。这些发现大部分是基于横断面评估。在目前的项目中，我们将纵向跟踪大约120名CJD患者，研究患者的系列访视， 在初次就诊后1-4个月。在每次连续访视时，我们将进行详细评估（神经系统检查、神经心理学测试、功能评分、各种脑MRI指标（上文讨论）和CSF生物标志物）。通过这一前瞻性获得的CJD纵向评估数据，我们将开发一种疾病分期（预测生存率）和预测个体患者进展的算法。这些信息不仅有助于为患者和家属提供指导，而且有助于开展治疗试验