Network degeneration and dysfunction in presymptomatic C9ORF72 expansion carriers.
Network degeneration and dysfunction in presymptomatic C9ORF72 expansion carriers.
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DOI：
10.1016/j.nicl.2016.12.006
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Seeley WW
中科院分区：
文献类型：
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作者：
Lee SE;Sias AC;Mandelli ML;Brown JA;Brown AB;Khazenzon AM;Vidovszky AA;Zanto TP;Karydas AM;Pribadi M;Dokuru D;Coppola G;Geschwind DH;Rademakers R;Gorno-Tempini ML;Rosen HJ;Miller BL;Seeley WW
C9ORF72中的六核苷酸重复扩增是家族性和散发性额颞叶痴呆和肌萎缩侧索硬化症的最常见的已知遗传原因。先前的研究表明，由于C9ORF72导致的行为变异型额颞叶痴呆患者表现出与散发性行为变异型额颞叶痴呆患者相当的显著性和感觉运动网络中断，但仍然不清楚这些和其他大脑结构和功能变化在生命早期出现的时间。为了深入了解这个问题，我们比较了15名前驱症状携带者（年龄43.7 ± 10.2岁，9名女性）和匹配的健康对照。我们使用基于体素的形态测量来评估灰质，使用扩散张量成像来询问白色物质束，使用无任务功能性MRI来探测显着性、感觉运动、默认模式和内侧丘脑枕种子网络。我们进一步使用回顾性病历来确定携带者及其非携带者家庭成员的精神病史。携带者表现出正常的认知和行为，尽管早在40岁时就出现了灰质体积和大脑连接缺陷。灰质体积缺陷的地形相似，但不太严重的行为变异型额颞叶痴呆患者由于C9ORF72，扣带回，丘脑，纹状体的主要病灶。胼胝体、扣带束、皮质脊髓束、钩束和下纵束中的白色物质完整性降低。内在的连接缺陷检测在所有四个网络，但最突出的显着性和内侧枕丘脑种子网络。携带者和对照组的影像学指标和年龄之间的关系具有可比性，这表明赤字出现在成年早期。携带者和非携带者的家庭成员有类似的精神症状的终身史。综上所述，研究结果表明，症状前C9ORF72扩增载体表现出功能性代偿的脑容量和连接缺陷，这些缺陷与症状期报告的相似，但不太严重。成年早期出现这些缺陷表明，它们代表了发育过程中的异常网络模式，早期神经退行性疾病前驱症状，或两者兼而有之。症状前C9ORF72扩增携带者具有脑连接缺陷。这些缺陷可能是一种发育性病变，而不是早期神经退行性变。非携带者和症状前携带者共享精神病学。
Hexanucleotide repeat expansions in C9ORF72 are the most common known genetic cause of familial and sporadic frontotemporal dementia and amyotrophic lateral sclerosis. Previous work has shown that patients with behavioral variant frontotemporal dementia due to C9ORF72 show salience and sensorimotor network disruptions comparable to those seen in sporadic behavioral variant frontotemporal dementia, but it remains unknown how early in the lifespan these and other changes in brain structure and function arise. To gain insights into this question, we compared 15 presymptomatic carriers (age 43.7 ± 10.2 years, nine females) to matched healthy controls. We used voxel-based morphometry to assess gray matter, diffusion tensor imaging to interrogate white matter tracts, and task-free functional MRI to probe the salience, sensorimotor, default mode, and medial pulvinar thalamus-seeded networks. We further used a retrospective chart review to ascertain psychiatric histories in carriers and their non-carrier family members. Carriers showed normal cognition and behavior despite gray matter volume and brain connectivity deficits that were apparent as early as the fourth decade of life. Gray matter volume deficits were topographically similar though less severe than those in patients with behavioral variant frontotemporal dementia due to C9ORF72, with major foci in cingulate, insula, thalamus, and striatum. Reduced white matter integrity was found in the corpus callosum, cingulum bundles, corticospinal tracts, uncinate fasciculi and inferior longitudinal fasciculi. Intrinsic connectivity deficits were detected in all four networks but most prominent in salience and medial pulvinar thalamus-seeded networks. Carrier and control groups showed comparable relationships between imaging metrics and age, suggesting that deficits emerge during early adulthood. Carriers and non-carrier family members had comparable lifetime histories of psychiatric symptoms. Taken together, the findings suggest that presymptomatic C9ORF72 expansion carriers exhibit functionally compensated brain volume and connectivity deficits that are similar, though less severe, to those reported during the symptomatic phase. The early adulthood emergence of these deficits suggests that they represent aberrant network patterning during development, an early neurodegeneration prodrome, or both. Presymptomatic C9ORF72 expansion carriers have brain connectivity deficits. These deficits may be a developmental lesion rather than early neurodegeneration. Non-carriers and presymptomatic carriers share psychiatric symptomatology.