Predicting progression of human prion disease

描述（由申请人提供）：人类朊病毒疾病，如jakb - creutzfeldt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，我们需要改进预测克雅氏病患者病程的方法。我们的CJD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，在过去的四年中约有750例RPD/CJD转诊。通过我们过去的R01，“人类朊病毒疾病的早期诊断”，我们获得了导致改进CJD诊断的数据。关于CJD，我们有几个重要的临床发现，包括：1)最广泛使用的sCJD诊断生物标志物CSF 14-3-3蛋白，尽管在几种诊断标准中，但其敏感性和特异性相对较低；2) DWI脑MRI显示灰质扩散受限，是sCJD的唯一最佳诊断测试，尽管脑脊液生物标志物，如总tau和神经元特异性烯醇化酶有时是有用的；3)在病程中，扩散在灰质中的限制不是不断增加，而是逐渐减少；因此，扩散在疾病的早期呈线性下降，但随后在后期向上移动（限制较少），从而形成U形甚至J形曲线：这使得在治疗试验中将受限扩散作为结果标记存在问题；4) sCJD的某些灰质区域在MRI上似乎优先参与，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疾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)虽然之前没有报道，但我们发现sCJD患者的白质弥漫性扩散受限，6)患者存在某些临床体征/症状，如小脑或视觉症状，预示着更短的生存期。这些发现大多是基于横断面评估。在目前的这个项目中，我们将纵向跟踪大约120名CJD患者，研究患者在连续访问期间，在

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