Longitudinal Magnetic Resonance Imaging in Asymptomatic C9orf72 Mutation Carriers Distinguishes Phenoconverters to Amyotrophic Lateral Sclerosis or Amyotrophic Lateral Sclerosis With Frontotemporal Dementia.

IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Annals of Neurology Pub Date : 2024-11-02 DOI:10.1002/ana.27116
Kevin van Veenhuijzen, Harold H G Tan, Abram D Nitert, Michael A van Es, Jan H Veldink, Leonard H van den Berg, Henk-Jan Westeneng
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Abstract

Objective: We prospectively studied asymptomatic C9orf72 mutation carriers, identifying those developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD).

Methods: We enrolled 56 asymptomatic family members (AFM) with a C9orf72 mutation (AFM C9+), 132 non-carriers (AFM C9-), and 359 population-based controls. Using 3 T magnetic resonance imaging, we measured cortical thickness, gyrification, and subcortical volumes longitudinally. Linear mixed-effects models on non-converting AFM C9+ scans (n = 107) created a reference for these measurements, establishing individual atrophy patterns. Atrophy patterns from presymptomatic phenoconverters (n = 10 scans) served as a template for group comparisons and similarity assessments. Similarity with phenoconverters was quantified using Dice similarity coefficient (DSC) for cortical and Kullback-Leibler similarity (KLS) for subcortical measures. Using longitudinal similarity assessments, we predicted when participants would reach the average similarity level of phenoconverters at their first post-onset scan.

Results: Five AFM C9+ converted to ALS or ALS-FTD. Up to 6 years before symptoms, these phenoconverters exhibited significant atrophy in frontal, temporal, parietal, and cingulate cortex, along with smaller thalamus, hippocampus, and amygdala compared to other AFM C9+. Some non-converted AFM C9+ had high DSC and KLS, approaching values of phenoconverters, whereas others, along with AFM C9- and controls, had lower values. At age 80, we predicted 27.9% (95% confidence interval, 13.2-40.1%) of AFM C9+ and no AFM C9- would reach the same DSC as phenoconverters.

Interpretation: Distinctive atrophy patterns are visible years before symptom onset on presymptomatic scans of phenoconverters. Combining baseline and follow-up similarity measures may serve as a promising imaging biomarker for identifying those at risk of ALS or ALS-FTD. ANN NEUROL 2024.

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无症状 C9orf72 基因突变携带者的纵向磁共振成像可区分肌萎缩侧索硬化症或伴有额颞叶痴呆的肌萎缩侧索硬化症的表观转化者。
目的:我们对无症状的C9orf72基因突变携带者进行了前瞻性研究,以确定那些患肌萎缩侧索硬化症(ALS)或额颞叶痴呆症(FTD)的患者:我们招募了56名C9orf72突变无症状家庭成员(AFM)(AFM C9+)、132名非携带者(AFM C9-)和359名人群对照。我们使用 3 T 磁共振成像技术纵向测量了皮质厚度、回旋和皮质下体积。非转换 AFM C9+ 扫描(n = 107)的线性混合效应模型为这些测量结果提供了参考,从而确定了个体萎缩模式。无症状表型转换者的萎缩模式(n = 10 次扫描)可作为群体比较和相似性评估的模板。与表型转换者的相似性通过皮质的戴斯相似系数(DSC)和皮质下的库尔贝克-莱布勒相似性(KLS)进行量化。通过纵向相似性评估,我们预测了参与者在发病后第一次扫描时达到表型转换者平均相似性水平的时间:结果:5 名 AFM C9+ 患者转为 ALS 或 ALS-FTD。与其他 AFM C9+ 相比,这些表型转换者在症状出现前 6 年表现出额叶、颞叶、顶叶和扣带回皮层明显萎缩,丘脑、海马和杏仁核也较小。一些未转化的 AFM C9+ 具有较高的 DSC 和 KLS,接近表型转化者的数值,而其他 AFM C9+ 和对照组的数值则较低。我们预测,在 80 岁时,27.9%(95% 置信区间,13.2-40.1%)的 AFM C9+ 和 AFM C9- 将达到与表型转换者相同的 DSC 值:解释:在表型转换者的症状前扫描中,可看到症状发作前数年的独特萎缩模式。结合基线和随访相似性测量可作为一种有前途的成像生物标志物,用于识别 ALS 或 ALS-FTD 的高危人群。ann neurol 2024.
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来源期刊
Annals of Neurology
Annals of Neurology 医学-临床神经学
CiteScore
18.00
自引率
1.80%
发文量
270
审稿时长
3-8 weeks
期刊介绍: Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.
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