Predicting progression of human prion disease

预测人类朊病毒病的进展

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：人类朊病毒病，例如雅各布-克罗伊茨菲尔德病（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，我们需要改进的方法来预测克雅氏病患者的进展过程。我们的克雅氏病和快速进展性痴呆 (RPD) 临床研究项目是美国朊病毒疾病的主要转诊中心，在过去四年中转诊了约 750 例 RPD/克雅氏病。通过过去的 R01“人类朊病毒病的早期诊断”，我们获得了改进克雅氏病诊断的数据。我们获得了有关克雅氏病的几项重要临床发现，包括：1）用于诊断 sCJD 的最广泛使用的生物标志物 CSF 14-3-3 蛋白，尽管符合多种诊断标准，但敏感性和特异性相对较低； 2) DWI 脑部 MRI 显示灰质弥散受限，是诊断 sCJD 的最佳单一测试，尽管 CSF 生物标志物（例如总 tau 蛋白和神经元特异性烯醇化酶）有时很有用； 3) 在病程中，灰质中的扩散不会持续受到越来越多的限制，但最终会变得越来越不受限制；因此，在疾病的早期阶段，扩散呈线性向下，但在后期则向上移动（限制较少），从而给出 U 形甚至 J 形曲线：这使得以下限制性扩散作为结果标记在治疗试验中出现问题； 4) sCJD 的 MRI 似乎优先涉及灰质的某些区域，并且它们与 fMRI 识别的各种功能连接网络重叠。目前尚不清楚朊病毒病是通过功能和结构网络在大脑中传播还是通过传播到邻近的大脑区域； 5) 尽管之前没有报道过，但我们发现 sCJD 的白质存在弥漫性受限扩散，6) 患者出现某些临床体征/症状，如小脑或视觉症状，预示生存期较短。这些发现大部分都是基于横断面评估。对于当前的项目，我们将纵向跟踪大约 120 名克雅氏病患者，在连续访视期间研究患者初次访问后约 1-4 个月。每次连续访视时，我们都会进行详细的评估（神经学检查、神经心理学测试、功能评分、各种脑 MRI 指标（如上所述）和脑脊液生物标志物）。通过前瞻性获得的克雅氏病纵向评估数据，我们将开发一种用于疾病分期（预测生存）和预测个体患者进展的算法。这些信息不仅有助于患者和家庭的预测，而且有助于治疗试验的开展