PROSPAX: an integrated multimodal progression chart in spastic ataxias

痉挛性共济失调（SPAX）是一种以小脑和皮质脊髓束（CST）联合损害为主的罕见神经退行性疾病。虽然快速的遗传分层促进了目前分子治疗的发展，但由于缺乏有效的结果测量和自然历史研究，SPAX的有效试验计划受到阻碍。联合欧洲所有主要的共济失调和痉挛性截瘫网络，并以我们之前的网络和试点数据集为基础，PROSPAX将建立一个典型的irdirc指导的SPAX疾病进展和机制进化的综合试验准备模型，这将允许跟踪和理解小脑和CST的选择性和重叠功能障碍。在一项为期2年的跨大西洋自然历史研究中，我们将纵向验证临床医生和患者报告的数字和分子结果。此外，PROSPAX将改进现有的和开发新的结果参数，显示出对变化的优越敏感性。其中包括一种新的临床SPAX综合评分，一种智能手机移动健康工具箱，将可穿戴传感器对日常生活的远程评估与基于应用程序的患者输入结果（SPAX）相结合。app)和多模态MRI放射组学，采用创新的机器学习方法进行多位点MRI分析，特别是幕下空间。靶向液体生物标志物候选物的纵向验证将通过小鼠单细胞多组学研究进行补充，这将允许识别小脑和皮质脊髓神经元之间的共享通路和脆弱性，并将揭示新的分子生物标志物。通过专注于两种最常见的隐性SPAX (SPG7， ARSACS)， PROSPAX将创建一个典型的试验准备途径，用于绘制疾病进展和多模式结果测量，这将适用于许多bbbb100 SPAX疾病。

Spastic ataxias (SPAX) present an expanding group of >100 rare neurodegenerative diseases with joined damage of cerebellum and corticospinal tract (CST). While rapid genetic stratification facilitates current development of molecular therapies, effective trial-planning for SPAX is hampered by a lack of valid outcome measures and natural history studies. Uniting all major European ataxia and spastic paraplegia networks, and building on our prior networks and pilot data-sets, PROSPAX will establish a paradigmatic IRDiRC-guided integrated trial-ready model of disease progression and mechanistic evolution in SPAX, which will allow to track and understand selective as well as overlapping dysfunction of the cerebellum and CST. In a 2-year transatlantic natural history study we will longitudinally validate clinician- and patient-reported, digital and molecular outcomes. In addition, PROSPAX will improve on existing and develop new outcome parameters that show superior sensitivity to change. These include a novel clinical SPAX composite score, a smartphone mHealth toolbox combining remote assessment of daily living by wearable sensors with app-based patient-entered outcomes (SPAX.app), and multimodal MRI radiomics with an innovative machine learning approach for multisite MRI analysis, including in particular the infratentorial space. Longitudinal validation of targeted fluid biomarker candidates will be complemented by single-cell multi-omic studies in mouse which will allow to identify shared pathways and vulnerabilities between cerebellar and corticospinal neurons and will unravel new molecular biomarkers. By focusing on the two most prevalent recessive SPAX (SPG7, ARSACS), PROSPAX will create a paradigmatic trial-readiness pathway for charting disease progression and multimodal outcome measures that will be applicable to many of the >100 SPAX diseases alike.