Association of Initial Side of Brain Atrophy with Clinical Features and Disease Progression in Patients with GRN Frontotemporal Dementia

Sergi Borrego-Ecija,Jordi Junca-Parella，Jonathan Daniel Rohrer,Raquel Sanchez-Valle

NEUROLOGY（2024）

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Abstract

Background and Objectives Pathogenic variants in the GRN gene cause frontotemporal dementia (FTD-GRN) with marked brain asymmetry. This study aims to assess whether the disease progression of FTD-GRN depends on the initial side of the atrophy. We also investigated the potential use of brain asymmetry as a biomarker of the disease. Methods Retrospective examination of data from the prospective Genetic Frontotemporal Initiative (GENFI) cohort study that recruits individuals who carry or were at risk of carrying a pathogenic variant causing FTD. GENFI participants underwent a standardized clinical and neuropsychological assessment, MRI, and a blood sample test yearly. We generated an asymmetry index for brain MRI to characterize brain asymmetry in participants with or at risk of FTD-GRN. Depending on the side of the asymmetry, we classified symptomatic GRN patients as right-GRN or left-GRN and compared their clinical features and disease progression. We generated generalized additive models to study how the asymmetry index evolves in carriers and noncarriers and compare its models with others created with volumetric values and plasma neurofilament light chain. Results A total of 399 participants (mean age 49.7 years, 59% female) were included (63 symptomatic carriers, 177 presymptomatic carriers, and 159 noncarriers). Symptomatic carriers showed higher brain asymmetry (11.6) than noncarriers (1.0, p < 0.001) and presymptomatic carriers (1.0, p < 0.001), making it possible to classify most of them as right-GRN (n = 21) or left-GRN (n = 36). Patients with right-GRN showed more disease severity at baseline (beta = 6.9, 95% CI 2.4-11.0, p = 0.003) but a lower deterioration by year (beta = -1.5, 95% CI -2.7 to -0.31, p = 0.015) than patients with left-GRN. Brain asymmetry could be found in GRN carriers 10.4 years before the onset of the symptoms (standard difference 0.85, CI 0.01-1.68). Discussion FTD-GRN affects the brain hemispheres asymmetrically and causes 2 anatomical asymmetry patterns depending on the side of the disease onset. We demonstrated that these 2 anatomical asymmetry patterns present different symptoms, severity at the time of the first visit, and different disease courses. Our results also suggest brain asymmetry as a possible biomarker of conversion in GRN carriers.

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【要点】：研究探讨了初始脑萎缩侧别与GRN基因突变导致的额颞叶痴呆（FTD-GRN）的临床特征和疾病进展的关系，并提出脑不对称性作为疾病生物标志物的潜在应用。

【方法】：通过回顾性分析遗传性额颞叶痴呆前瞻性队列研究（GENFI）的数据，对参与者进行标准化临床和神经心理学评估、MRI扫描和年度血液检测，计算脑MRI的不对称性指数以量化脑不对称性。

【实验】：共纳入399名参与者（平均年龄49.7岁，59%为女性），包括63名症状性携带者、177名无症状携带者和159名非携带者。结果显示，症状性携带者脑不对称性指数显著高于非携带者和无症状携带者，根据不对称性侧别将症状性携带者分类为右侧GRN（n=21）和左侧GRN（n=36）。右侧GRN患者在基线时疾病严重程度更高，但年进展速度较左侧GRN患者慢。脑不对称性可以在症状出现前10.4年检测到。