Vita-Salute San Raffaele University, Milan, Italy.
Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Neurol Sci. 2019 Mar;40(3):515-521. doi: 10.1007/s10072-018-3685-7. Epub 2018 Dec 15.
The hexanucleotide repeat expansion in C9orf72 is an associated genetic cause in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In the "ALS/FTD" spectrum prevails clinical heterogeneity and an in vivo knowledge of the underling brain dysfunction in patients carrying C9orf72 mutation remain limited and only described at group level. The study aimed to assess the brain metabolic alterations characterizing patients with C9orf72 mutation using FDG-PET in single individuals.
We applied a validated statistical parametric mapping (SPM) voxel-based procedure for FDG-PET data to obtain maps of brain relative hypometabolism and hypermetabolism at single-subject level in six FTD/ALS patients carrying the C9orf72 mutation.
Clinical diagnoses classified the patients as right semantic variant of frontotemporal dementia (one case, C9svFTD), behavioral variant of frontotemporal dementia (two cases, C9bvFTD), and bulbar amyotrophic lateral sclerosis (three cases, C9bALS). The FDG-PET SPM revealed a prevalent frontal hypometabolism in C9bvFTD cases, and right temporal polar and lateral involvement in C9svFTD, consistent with the clinical diagnosis. There was a quite comparable occipital and cerebellar hypermetabolism in these cases. The three C9bALS patients showed variable patterns of hypo- and hypermetabolism.
The present work is the first in vivo FDG-PET study showing the heterogeneous patterns of brain regional hypo- and hypermetabolism in single patients sharing C9orf72 mutation. Brain hypometabolism was consistent with the clinical phenotypes, supporting the diagnostic importance of neuroimaging functional biomarkers to capture at single-subject level specific brain dysfunction.
C9orf72 六核苷酸重复扩增是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的相关遗传原因。在“ALS/FTD”谱系中，临床异质性占主导地位，而携带 C9orf72 突变的患者的潜在脑功能障碍的体内知识仍然有限，并且仅在组水平上进行了描述。本研究旨在使用 FDG-PET 在个体患者中评估表征 C9orf72 突变患者的脑代谢改变。
我们应用了经过验证的统计参数映射（SPM）基于体素的 FDG-PET 数据处理程序，以在 6 名携带 C9orf72 突变的 FTD/ALS 患者中单个体获得脑相对低代谢和高代谢的图谱。
临床诊断将患者分为右语义变异额颞叶痴呆（1 例，C9svFTD）、行为变异额颞叶痴呆（2 例，C9bvFTD）和球部肌萎缩侧索硬化症（3 例，C9bALS）。FDG-PET SPM 显示 C9bvFTD 病例中普遍存在额叶低代谢，C9svFTD 病例中存在右侧颞极和外侧受累，与临床诊断一致。这些病例中存在相当可比的枕叶和小脑高代谢。3 名 C9bALS 患者表现出不同的低代谢和高代谢模式。
本研究是首例在体内 FDG-PET 研究中显示共享 C9orf72 突变的单个患者的脑区域低代谢和高代谢的异质性模式。脑代谢降低与临床表型一致，支持神经影像学功能生物标志物的诊断重要性，以在单个体水平上捕获特定的脑功能障碍。
