C9orf72六核苷酸重复扩增携带者的基础副交感神经缺陷与前半岛和丘脑体积较小及移情能力较低有关

IF 3.4 2区 医学 Q2 NEUROIMAGING
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引用次数: 0

摘要

基底副交感神经系统活动减弱是额颞叶痴呆症的一个特征,与左前庭功能障碍和移情障碍有关。9号染色体开放阅读框72(C9orf72)中六核苷酸重复的致病性扩增是额颞叶痴呆症和肌萎缩侧索硬化症最常见的遗传病因,它为研究遗传性额颞叶痴呆症患者的副交感神经活动是否受到干扰以及副交感神经功能障碍何时在病理生理级联中表现出来提供了一个独特的机会。我们测量了102名参与者两分钟内的基线呼吸窦性心律失常,这是副交感神经对心率变异性的一种测量。这些参与者包括19名无症状扩增携带者(C9+ asymp)、14名轻度认知障碍扩增携带者(C9+ MCI)、16名有症状的额颞叶痴呆扩增携带者(C9+ FTD)和53名扩增阴性健康对照组(C9- HC),他们也接受了结构性磁共振成像检查。在后续分析中,我们将 C9+ FTD 组的基线呼吸窦性心律失常与年龄、性别和临床严重程度相匹配的 26 名散发性行为变异型额颞叶痴呆患者进行了比较。前额颞叶痴呆改良临床痴呆分级-盒子总分用于量化行为症状的严重程度,人际反应指数的线人评分则用于衡量参与者当前的情感(移情关注)和认知(透视)移情能力。结果表明,C9+ FTD 组的基线呼吸窦性心律失常低于 C9+ MCI、C9+ asymp 和 C9- HC 组,其缺失程度与散发性行为变异型额颞叶痴呆相当。线性回归分析表明,较低的基线呼吸窦性心律失常与较差的行为症状严重程度以及较低的移情关注和透视能力有关,且与整个 C9orf72 扩大携带者临床谱系有关。对C9orf72致病性扩增参与者进行的基于体素的全脑形态计量分析发现,基线呼吸窦性心律失常与左侧前半岛和双侧丘脑(支持副交感神经功能的关键结构)以及双侧顶叶、枕叶和小脑(C9orf72扩增个体中也很脆弱的区域)的灰质体积较小相关。这项研究提供了新的证据,证明由于C9orf72扩增,FTD患者的基础副交感神经功能减弱,并提示基线呼吸窦性心律失常可能是一种潜在的非侵入性生物标志物,对疾病早期的行为症状非常敏感。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Basal parasympathetic deficits in C9orf72 hexanucleotide repeat expansion carriers relate to smaller frontoinsula and thalamus volume and lower empathy

Diminished basal parasympathetic nervous system activity is a feature of frontotemporal dementia that relates to left frontoinsula dysfunction and empathy impairment. Individuals with a pathogenic expansion of the hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis, provide a unique opportunity to examine whether parasympathetic activity is disrupted in genetic forms of frontotemporal dementia and to investigate when parasympathetic deficits manifest in the pathophysiological cascade. We measured baseline respiratory sinus arrhythmia, a parasympathetic measure of heart rate variability, over two minutes in a sample of 102 participants that included 19 asymptomatic expansion carriers (C9+ asymp), 14 expansion carriers with mild cognitive impairment (C9+ MCI), 16 symptomatic expansion carriers with frontotemporal dementia (C9+ FTD), and 53 expansion-negative healthy controls (C9- HC) who also underwent structural magnetic resonance imaging. In follow-up analyses, we compared baseline respiratory sinus arrhythmia in the C9+ FTD group with an independent age-, sex-, and clinical severity-matched group of 26 people with sporadic behavioral variant frontotemporal dementia. The Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating-Sum of Boxes score was used to quantify behavioral symptom severity, and informant ratings on the Interpersonal Reactivity Index provided measures of participants’ current emotional (empathic concern) and cognitive (perspective-taking) empathy. Results indicated that the C9+ FTD group had lower baseline respiratory sinus arrhythmia than the C9+ MCI, C9+ asymp, and C9- HC groups, a deficit that was comparable to that of sporadic behavioral variant frontotemporal dementia. Linear regression analyses indicated that lower baseline respiratory sinus arrhythmia was associated with worse behavioral symptom severity and lower empathic concern and perspective-taking across the C9orf72 expansion carrier clinical spectrum. Whole-brain voxel-based morphometry analyses in participants with C9orf72 pathogenic expansions found that lower baseline respiratory sinus arrhythmia correlated with smaller gray matter volume in the left frontoinsula and bilateral thalamus, key structures that support parasympathetic function, and in the bilateral parietal lobes, occipital lobes, and cerebellum, regions that are also vulnerable in individuals with C9orf72 expansions. This study provides novel evidence that basal parasympathetic functioning is diminished in FTD due to C9orf72 expansions and suggests that baseline respiratory sinus arrhythmia may be a potential non-invasive biomarker that is sensitive to behavioral symptoms in the early stages of disease.

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来源期刊
Neuroimage-Clinical
Neuroimage-Clinical NEUROIMAGING-
CiteScore
7.50
自引率
4.80%
发文量
368
审稿时长
52 days
期刊介绍: NeuroImage: Clinical, a journal of diseases, disorders and syndromes involving the Nervous System, provides a vehicle for communicating important advances in the study of abnormal structure-function relationships of the human nervous system based on imaging. The focus of NeuroImage: Clinical is on defining changes to the brain associated with primary neurologic and psychiatric diseases and disorders of the nervous system as well as behavioral syndromes and developmental conditions. The main criterion for judging papers is the extent of scientific advancement in the understanding of the pathophysiologic mechanisms of diseases and disorders, in identification of functional models that link clinical signs and symptoms with brain function and in the creation of image based tools applicable to a broad range of clinical needs including diagnosis, monitoring and tracking of illness, predicting therapeutic response and development of new treatments. Papers dealing with structure and function in animal models will also be considered if they reveal mechanisms that can be readily translated to human conditions.
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