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 (β = 6.9, 95% CI 2.4-11.0, p = 0.003) but a lower deterioration by year (β = -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.

中文翻译：

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GRN 额颞叶痴呆患者脑萎缩的初始侧与临床特征和疾病进展的关联。


背景和目的 GRN 基因的致病性变异导致额颞叶痴呆 （FTD-GRN） 伴有明显的脑不对称性。本研究旨在评估 FTD-GRN 的疾病进展是否取决于萎缩的初始侧。我们还研究了大脑不对称作为该疾病生物标志物的潜在用途。方法 回顾性检查来自前瞻性遗传额颞叶倡议 （GENFI） 队列研究的数据，该研究招募了携带或有可能携带导致 FTD 的致病性变异的个体。GENFI 参与者每年接受标准化的临床和神经心理学评估、MRI 和血样测试。我们为脑部 MRI 生成了不对称性指数，以表征患有 FTD-GRN 或有 FTD-GRN 风险的参与者的大脑不对称性。根据不对称的一侧，我们将有症状的 GRN 患者分为右 GRN 或左 GRN，并比较他们的临床特征和疾病进展。我们生成了广义加性模型来研究不对称指数在载流子和非载流子中如何演变，并将其模型与使用体积值和等离子体神经丝轻链创建的其他模型进行比较。结果 共纳入 399 名参与者 （平均年龄 49.7 岁，59% 为女性） （63 名有症状携带者、177 名症状前携带者和 159 名非携带者）。有症状携带者表现出更高的大脑不对称性 （11.6） 高于非携带者 （1.0，p < 0.001） 和症状前携带者 （1.0，p < 0.001），因此可以将他们中的大多数分类为右 GRN （n = 21） 或左 GRN （n = 36）。与左侧 GRN 患者相比，右侧 GRN 患者在基线时表现出更严重的疾病 （β = 6.9,95% CI 2.4-11.0，p = 0.003），但逐年恶化较低 （β = -1.5,95% CI -2.7 至 -0.31，p = 0.015）。 在症状出现前 10.4 年，GRN 携带者可发现大脑不对称 （标准差 0.85，CI 0.01-1.68）。讨论 FTD-GRN 不对称地影响大脑半球，并根据疾病发作的一侧导致 2 种解剖不对称模式。我们证明这 2 种解剖不对称模式呈现不同的症状、第一次就诊时的严重程度和不同的病程。我们的结果还表明，大脑不对称是 GRN 携带者转换的可能生物标志物。