BACKGROUND AND OBJECTIVES Sleep dysfunction is common in patients with neurodegenerative disorders; however, its neural underpinnings remain poorly characterized in genetic frontotemporal dementia (FTD). Hypothalamic nuclei important for sleep regulation may be related to this dysfunction. Thus, we examined changes in hypothalamic structure across the lifespan in patients with genetic FTD and whether these changes related to sleep dysfunction. METHODS Data from the observational multisite Genetic Frontotemporal Dementia Initiative (GENFI) study were used. GENFI participants were adult members of a family with known pathogenic variants in the microtubule-associated protein tau (MAPT) or progranulin (GRN) genes or an expansion in the chromosome 9 open reading frame 72 (C9orf72) gene. Family members without a pathogenic variant served as controls. GENFI participants were followed annually, with up to 7 visits, and underwent clinical characterization, neuropsychological testing, biological sampling, and brain MRI. For our analyses, participants were included if they had at least 1 T1-weighted structural MRI scan available. Linear mixed-effect models were used to examine changes in sleep dysfunction, measured using the Cambridge Behavioural Inventory-Revised sleep subscale, volumetric changes in hypothalamic regions, and the associations between cortical and hypothalamic atrophy and sleep dysfunction. RESULTS Participants included 491 adults with pathogenic genetic variants of FTD (27.9% symptomatic; median age: 49.4 years, 56.4%F) and 321 controls (median age: 44.2 years, 57.3%F). Pathogenic variant carriers showed greater sleep dysfunction across the adult lifespan (β = [0.25-0.34], q < 0.005) with MAPT carriers alone showing presymptomatic sleep changes (β = 0.34, q = 0.005). Cortical thinning in frontal and parietal regions was associated with greater sleep disturbances in C9orf72 and GRN carriers (q < 0.05). MAPT carriers showed consistently significant volume loss over time across all sleep-relevant hypothalamic subunits (β = [-0.56 to -0.39], q < 0.005), and reduced volumes in these subunits were related to increased sleep dysfunction (β = [-0.20 to -0.16], q < 0.05). DISCUSSION These findings suggest that sleep dysfunction in patients with genetic FTD may be attributable to atrophy in sleep-relevant hypothalamic subunits, with the most severe and consistent deficits observed in MAPT carriers. While biologically plausible, our statistical approach cannot confirm a causal link between atrophy and sleep disturbances.

中文翻译：

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遗传性额颞叶痴呆患者大脑和下丘脑结构变化与睡眠功能障碍的关联。


背景和目的 睡眠功能障碍在神经退行性疾病患者中很常见;然而，其神经基础在遗传性额颞叶痴呆 （FTD） 中仍然难以表征。对睡眠调节很重要的下丘脑核可能与这种功能障碍有关。因此，我们检查了遗传性 FTD 患者在整个生命周期中下丘脑结构的变化，以及这些变化是否与睡眠功能障碍有关。方法 使用来自观察性多中心遗传额颞叶痴呆倡议 （GENFI） 研究的数据。GENFI 参与者是微管相关蛋白 tau （MAPT） 或颗粒蛋白前体 （GRN） 基因中已知致病性变异或 9 号染色体开放阅读框 72 （C9orf72） 基因扩增的家族的成年成员。没有致病性变异的家庭成员作为对照。每年对 GENFI 参与者进行随访，最多 7 次就诊，并接受临床特征描述、神经心理学测试、生物采样和脑部 MRI。在我们的分析中，如果参与者至少有 1 次 T1 加权结构 MRI 扫描可用，则他们被纳入。线性混合效应模型用于检查睡眠功能障碍的变化，使用剑桥行为量表-修订的睡眠分量表测量，下丘脑区域的体积变化，以及皮质和下丘脑萎缩与睡眠功能障碍之间的关联。结果 参与者包括 491 名患有 FTD 致病性遗传变异的成年人 （27.9% 有症状;中位年龄： 49.4 岁，56.4%F） 和 321 名对照 （中位年龄： 44.2 岁，57.3%F）。致病性变异携带者在成人一生中表现出更大的睡眠功能障碍 （β = [0.25-0.34]，q < 0.005），单独使用 MAPT 携带者表现出症状前睡眠变化 （β = 0.34，q = 0。额叶和顶叶区域的皮质变薄与 C9orf72 和 GRN 携带者更大的睡眠障碍有关 （q < 0.05）。MAPT 携带者在所有与睡眠相关的下丘脑亚基中显示出随着时间的推移持续显着的体积损失 （β = [-0.56 至 -0.39]，q < 0.005），并且这些亚基的体积减少与睡眠功能障碍增加有关（β = [-0.20 至 -0.16]，q < 0.05）。讨论这些发现表明，遗传性 FTD 患者的睡眠功能障碍可能归因于睡眠相关下丘脑亚单位的萎缩，在 MAPT 携带者中观察到最严重和一致的缺陷。虽然在生物学上是合理的，但我们的统计方法无法证实萎缩和睡眠障碍之间的因果关系。