Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
Neuroimage Clin. 2021;32:102842. doi: 10.1016/j.nicl.2021.102842. Epub 2021 Oct 5.
Frontotemporal dementia (FTD) is a common cause of young onset dementia, and whilst there are currently no treatments, there are several promising candidates in development and early phase trials. Comprehensive investigations of neuroimaging markers of disease progression across the full spectrum of FTD disorders are lacking and urgently needed to facilitate these trials.
To investigate the comparative performance of multiple automated segmentation and registration pipelines used to quantify longitudinal whole-brain atrophy across the clinical, genetic and pathological subgroups of FTD, in order to inform upcoming trials about suitable neuroimaging-based endpoints.
Seventeen fully automated techniques for extracting whole-brain atrophy measures were applied and directly compared in a cohort of 226 participants who had undergone longitudinal structural 3D T1-weighted imaging. Clinical diagnoses were behavioural variant FTD (n = 56) and primary progressive aphasia (PPA, n = 104), comprising semantic variant PPA (n = 38), non-fluent variant PPA (n = 42), logopenic variant PPA (n = 18), and PPA-not otherwise specified (n = 6). 49 of these patients had either a known pathogenic mutation or postmortem confirmation of their underlying pathology. 66 healthy controls were included for comparison. Sample size estimates to detect a 30% reduction in atrophy (80% power; 0.05 significance) were computed to explore the relative feasibility of these brain measures as surrogate markers of disease progression and their ability to detect putative disease-modifying treatment effects.
Multiple automated techniques showed great promise, detecting significantly increased rates of whole-brain atrophy (p<0.001) and requiring sample sizes of substantially less than 100 patients per treatment arm. Across the different FTD subgroups, direct measures of volume change consistently outperformed their indirect counterparts, irrespective of the initial segmentation quality. Significant differences in performance were found between both techniques and patient subgroups, highlighting the importance of informed biomarker choice based on the patient population of interest.
This work expands current knowledge and builds on the limited longitudinal investigations currently available in FTD, as well as providing valuable information about the potential of fully automated neuroimaging biomarkers for sporadic and genetic FTD trials.
额颞叶痴呆（FTD）是一种常见的早发性痴呆症病因，尽管目前尚无治疗方法，但有几种有前途的候选药物正在开发和进行早期临床试验。全面研究 FTD 疾病谱中疾病进展的神经影像学标志物尚缺乏，迫切需要这些试验。
研究多个自动分割和配准管道在 FTD 的临床、遗传和病理亚组中的纵向全脑萎缩的比较性能，以便为即将到来的试验提供合适的基于神经影像学的终点。
在一个 226 名接受纵向结构 3D T1 加权成像的参与者队列中，应用了 17 种全自动技术来提取全脑萎缩测量值，并直接进行了比较。临床诊断为行为变异型额颞叶痴呆（n=56）和原发性进行性失语症（PPA，n=104），包括语义变异型 PPA（n=38）、非流利型 PPA（n=42）、失读型 PPA（n=18）和 PPA 未特指（n=6）。其中 49 名患者有已知的致病性突变或死后证实其潜在病理。66 名健康对照者用于比较。为了探索这些脑测量值作为疾病进展替代标志物的相对可行性及其检测潜在疾病修饰治疗效果的能力，计算了检测 30%萎缩减少的样本量估计值（80%功率；0.05 显著性）。
多种自动技术显示出巨大的潜力，检测到全脑萎缩率显著增加（p<0.001），每个治疗组所需的样本量大大少于 100 名患者。在不同的 FTD 亚组中，体积变化的直接测量值始终优于间接测量值，而与初始分割质量无关。在技术和患者亚组之间都发现了性能的显著差异，强调了基于感兴趣的患者人群选择有针对性的生物标志物的重要性。
这项工作扩展了当前的知识，并建立在 FTD 中目前有限的纵向研究的基础上，为散发性和遗传性 FTD 试验提供了有价值的全自动神经影像学生物标志物的潜力信息。
