Background

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.

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

中文翻译：

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额颞叶痴呆谱系自动萎缩测量的比较：对试验的影响

背景

额颞叶痴呆 (FTD) 是年轻发病痴呆症的常见原因，虽然目前没有治疗方法，但有几个有希望的候选药物处于开发和早期试验阶段。缺乏对整个 FTD 疾病进展的神经影像学标志物的综合调查，迫切需要促进这些试验。

客观的

研究用于量化 FTD 的临床、遗传和病理亚组的纵向全脑萎缩的多个自动分割和注册管道的比较性能，以便为即将进行的试验提供有关合适的基于神经影像学的终点的信息。

方法

在 226 名接受纵向结构 3D T1 加权成像的参与者的队列中应用并直接比较了 17 种用于提取全脑萎缩测量的全自动技术。临床诊断为行为变异 FTD (n = 56) 和原发性进行性失语症 (PPA, n = 104)，包括语义变异 PPA (n = 38)、非流利变异 PPA (n = 42)、对数开放变异 PPA (n = 18）和PPA-未另行指定（n = 6）。这些患者中有 49 名具有已知的致病突变或死后证实其潜在病理学。包括 66 名健康对照进行比较。样本量估计可以检测到萎缩减少 30%（80% 功效；0.

结果

多种自动化技术显示出巨大的希望，检测到全脑萎缩率显着增加（p <0.001），并且每个治疗组需要的样本量大大少于 100 名患者。在不同的 FTD 子组中，无论初始分割质量如何，体积变化的直接测量始终优于其间接测量。在技​​术和患者亚组之间发现了显着的性能差异，突出了基于感兴趣的患者群体选择知情生物标志物的重要性。

结论

这项工作扩展了当前的知识，并建立在 FTD 目前可用的有限纵向研究的基础上，并提供有关全自动神经影像生物标志物在散发性和遗传性 FTD 试验中的潜力的有价值信息。