[18F]FE-PE2I PET: a novel biomarker for Parkinson’s disease

目前特发性帕金森病（PD）的治疗方案主要是对症治疗，但不能阻止进行性神经变性。为了评估新的疾病修饰疗法，例如靶向α -突触核蛋白的单克隆抗体，迫切需要能够在细胞水平上检测细微神经保护作用的足够的生物标志物。[18F]FE-PE2I是一种新型的正电子发射断层扫描（PET）诊断剂，它与多巴胺转运体（DAT）结合。最近的研究表明，它能够精确地评估产生多巴胺的神经元的神经变性。除了纹状体神经末梢的完整性外，它还能显示整个黑质纹状体通路，包括黑质内的细胞体，以及起源于黑质的束和轴突，从而揭示神经元细胞丢失的顺序。本项目旨在评估[18F]FE-PE2I与DAT结合的两个结果指标：(i)不可置换结合电位（BPND），这需要高分辨率PET系统和超过93分钟的动态脑扫描；（ii）特定结合比（SBR），这是一种简化的量化方法，在标准临床PET扫描仪上仅需26分钟即可获得。BPND将通过小波辅助参数成像进行信噪降噪和Logan图形分析；SBR将基于模拟临床PET系统分辨率的静态图像计算。对这两项措施的评估将涉及三个方面。(i)在10例PD患者队列中[18F]FE-PE2I PET测量的重测信度。（ii）纵向效度描述了15例PD患者的[18F]FE-PE2I结合随着PD进展而下降（平均随访2年）。（iii）比较40例健康对照和40例PD患者（新发、早期和晚期）[18F]FE-PE2I结合值，以及BPND与SBR、人口统计学和临床参数（如年龄、病程、运动（亚）评分和非运动症状）的相关性。[18F]FE-PE2I PET在单个受试者、横断面和随访数据中的可重复性尚未得到检验。该项目将证明[18F]FE-PE2I结合作为疾病进展的替代生物标志物的适用性，为更广泛地应用于临床和研究环境铺平道路。

Current therapeutic options for idiopathic Parkinson’s disease (PD) offer a predominantly symptomatic treatment but cannot halt the progressive neurodegeneration. For the evaluation of new disease-modifying therapies, such as monoclonal antibodies targeting alpha-synuclein, adequate biomarkers that can detect subtle neuroprotective effects on a cellular level are urgently needed. [18F]FE-PE2I is a novel diagnostic agent for positron emission tomography (PET), which binds to the dopamine transporter (DAT). Recent studies showed its ability to precisely evaluate the neurodegeneration of dopamine-producing neurons. Beside the integrity of striatal nerve terminals, it also visualizes the whole nigro-striatal pathway including the cell bodies in, and the tracts and axons originating from the substantia nigra and thus, reveals information about the sequence of neuronal cell loss.This project aims to assess two outcome measures of [18F]FE-PE2I binding to the DAT: (i) the non-displaceable binding potential (BPND), which requires a high-resolution PET system and a dynamic brain scan over 93 min, and (ii) the specific binding ratio (SBR), which is a simplified quantification method and can be obtained with an acquisition time of just 26 min on a standard clinical PET scanner. BPND will be estimated via wavelet-aided parametric imaging for signal-to-noise reduction and Logan graphical analysis; the SBR will be calculated based on static images with a simulated resolution of a clinical PET system. The assessment of both measures will involve three aspects. (i) Test-retest reliability of [18F]FE-PE2I PET measures in a cohort of 10 PD patients. (ii) Longitudinal validity describing the decline of [18F]FE-PE2I binding along with PD progression in a subset of 15 PD patients (mean follow-up of 2 years). (iii) Comparison of [18F]FE-PE2I binding values in 40 healthy controls and 40 PD patients (de novo, early and advanced disease stage) and correlation of BPND with SBR, demographic and clinical parameters (e.g. age, disease duration, motor (sub-)scores, and non-motor symptoms). The reproducibility in a single subject, cross-sectional and follow-up data have not yet been examined for [18F]FE-PE2I PET. This project will show the suitability of [18F]FE-PE2I binding as a surrogate biomarker for disease progression, paving the way for more extensive use in clinical and research settings.