Supplementary funding for U01NS104326 Clinical Trial Readiness for SCA1 and SCA3 (“READISCA”)

U01NS104326 SCA1 和 SCA3 临床试验准备的补充资金 (–READISCA–)

基本信息

批准号：
10623060
负责人：
TETSUO ASHIZAWA
金额：
$ 16.38万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2023-12-31
项目状态：
已结题

项目摘要

Project Summary/Abstract To enhance the clinical trial readiness of the ongoing READISCA project, this Administrative Supplement application requests approval and funding for two longitudinal biomarker studies: 1) determination of the plasma level of neurofilament light chain (NfL), and 2) additional analyses of the volumetric and diffusion MRI data obtained from subjects who carry a mutation of SCA1 or SCA3. 1) Plasma samples obtained at baseline visits showed that the NfL level can distinguish pre-ataxia samples from control and early-ataxia samples. NfL levels in the follow-up samples are expected to provide the evolution of the NfL level from the pre-ataxia range to the early ataxia range, the resoponsiveness of the plasma NfL level with indices such as the standardized response mean (SRM), and the utility of plasma NfL level in predicting the age at onset in pre-ataxia subjects. All samples to be analyzed are currently stored at the BioSEND repository as a part of Aim1. The SIMOA analysis of the plasma samples will determine the NfL level. The plasma NfL level will be correlated with clinical outcome assessment (COA) data. 2) To augment the value of standard region-of-interest (ROI) based volumetric analyses of the structural MR data and the simple diffusion tensor imaging (DTI) analyses in Aim 2 of READISCA, we will perform add voxel-based analyses for structural MR data and use higher-order models and fixel-based analysis. Our hypothesis is that there are critical thresholds for the evolving plasma NfL level and MR parameters at which the phenoconversion (i.e., ataxia disease onset) occurs in pre-ataxia subjects who carry the SCA1 or SCA3 mutation. We further postulate that plasma and imaging biomarkers together provide the prediction of the conversion and the age at onset stronger than individual biomarkers. We will use the SARA total score ≥3 as the phenoconversion indicator. For statistics, we plan to use survival models to identify predictors of conversion. Joint models that combine survival models and linear mixed models will be used to look for the influence of time varying covariates. The best model will be selected using C statics criteria.

项目摘要/摘要为了增强正在进行的Readisca项目的临床试验阅读，此行政补充申请请求对两个纵向生物标志物研究的批准和资金：1）确定神经丝光链（NFL）的血浆水平和2）对体积和扩散MRI的其他分析从携带SCA1或SCA3突变的受试者获得的数据。 1）在基线访问时获得的血浆样品表明，NFL水平可以区分出去时来自对照和早期 - 大大样本的样品。后续样品中的NFL水平有望提供NFL水平从前域范围到早期共济失调范围的演变，等离子NFL水平的重量性具有指数，例如标准化响应均值（SRM），以及血浆NFL水平的实用性在预测大大最佳受试者发作时的年龄。所有样品目前，对AIM1的一部分进行了分析，目前存储在生物端存储库中。 SIMOA分析血浆样品将确定NFL水平。血浆NFL水平将与临床相关结果评估（COA）数据。 2）增强基于标准利益区域（ROI）的体积分析的价值 MR数据和简单的扩散张量成像（DTI）分析在Readisca的AIM 2中，我们将执行为结构MR数据添加基于体素的分析，并使用高阶模型和基于固定的分析。我们的假设是，不断发展的血浆NFL水平和MR参数有关键阈值在携带SCA1或 SCA3突变。我们进一步假设血浆和成像生物标志物共同提供了预测比单个生物标志物更强的转化率和年龄。我们将使用Sara总分≥3 作为表现指标。对于统计，我们计划使用生存模型来识别转换。结合生存模型和线性混合模型的联合模型将用于寻找时间变化的协变量的影响。最佳模型将使用C静态标准选择。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Temporal Dynamics of the Scale for the Assessment and Rating of Ataxia in Spinocerebellar Ataxias.

DOI：
10.1002/mds.29255
发表时间：
2023-01
期刊：
Movement disorders : official journal of the Movement Disorder Society
影响因子：
0
作者：
通讯作者：

MR Imaging in Ataxias: Consensus Recommendations by the Ataxia Global Initiative Working Group on MRI Biomarkers.

共济失调中的 MR 成像：共济失调全球倡议 MRI 生物标志物工作组的共识建议。

DOI：
10.1007/s12311-023-01572-y
发表时间：
2023
期刊：
Cerebellum (London, England)
影响因子：
0
作者：
Öz,Gülin;Cocozza,Sirio;Henry,Pierre-Gilles;Lenglet,Christophe;Deistung,Andreas;Faber,Jennifer;Schwarz,AdamJ;Timmann,Dagmar;VanDijk,KoeneRA;Harding,IanH;AGIWorkingGrouponMRIBiomarkers
通讯作者：
AGIWorkingGrouponMRIBiomarkers

Pharmacological perturbation reveals deficits in D2 receptor responses in Thap1 null mice.