基底副交感神经系统活动减弱是额颞叶痴呆的特征,与左额脑岛功能障碍和移情障碍有关。在9号染色体开放阅读框72(C9orf72)中具有六核苷酸重复致病性扩展的个体,额颞叶痴呆和肌萎缩侧索硬化症最常见的遗传原因,提供了一个独特的机会,以检查副交感神经活动是否在额颞叶痴呆的遗传形式中被破坏,并研究副交感神经缺陷何时在病理生理级联中表现出来。我们测量了基线呼吸性窦性心律失常,心率变异性的副交感神经测量,在102名参与者的样本中,包括19名无症状的扩张携带者(C9+非对称),14名患有轻度认知障碍(C9+MCI)的扩张携带者,16例额颞叶痴呆症状扩张携带者(C9+FTD),53名扩增阴性健康对照(C9-HC)也接受了结构磁共振成像。在后续分析中,我们比较了C9+FTD组的基线呼吸性窦性心律失常与独立年龄,sex-,和临床严重程度匹配的26名散发性行为变异性额颞叶痴呆患者组。额颞叶变性改良临床痴呆评分-箱和评分用于量化行为症状严重程度,人际反应指数的线人评级提供了参与者当前情绪(移情关注)和认知(透视)移情的衡量标准。结果表明,C9+FTD组的基线呼吸性窦性心律失常低于C9+MCI,C9+不对称,和C9-HC组,与散发性行为变异额颞叶痴呆相当的缺陷。线性回归分析表明,较低的基线呼吸性窦性心律失常与行为症状严重程度较差,在C9orf72扩展携带者临床范围内,移情关注和观点较低相关。C9orf72致病性扩张参与者的基于全脑体素的形态计量学分析发现,较低的基线呼吸窦性心律失常与左额脑岛和双侧丘脑较小的灰质体积相关,支持副交感神经功能的关键结构,在双侧顶叶,枕叶,还有小脑,在C9orf72扩张的个体中也很脆弱的地区。这项研究提供了新的证据,表明由于C9orf72扩张,FTD的基底副交感神经功能减弱,并表明基线呼吸性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敏感。
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.