Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, Canada.
PET Center, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
Brain. 2019 Apr 1;142(4):1108-1120. doi: 10.1093/brain/awz039.
Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.
遗传性额颞叶痴呆最常见的原因是三个基因的突变，即 C9orf72、GRN 或 MAPT，有症状前携带者来自有患病风险的家族。虽然脑血流在额颞叶痴呆和其他形式的痴呆之间存在差异，但在额颞叶痴呆的有症状前阶段，其应用的证据有限。本研究旨在使用基于体素的方法描绘有症状前遗传性额颞叶痴呆的脑血流特征。在多中心 GENetic Frontotemporal dementia Initiative (GENFI) 研究中，我们使用一般线性混合效应模型和基于体素的分析方法，研究了有症状前 C9orf72、GRN 或 MAPT 基因突变携带者（n = 107）和非携带者（n = 113）之间动脉自旋标记 MRI 脑血流的横断面差异。然后，从该模型中得出的感兴趣区域内的脑血流被用来识别个体基因携带者组之间的差异，并估计这些差异的表达时间框架。基于体素的分析显示，脑血流与携带者的预期发病年龄呈显著负相关，但与非携带者无关。包括双侧岛叶/眶额皮质、前扣带回/旁扣带回回和下顶叶皮质，以及左侧颞中回。对于所有双侧区域，右侧的关联更大。在感兴趣区域分析中对部分体积效应进行校正后，结果主要归因于 C9orf72 遗传亚组。这些脑血流差异最早出现在基于个体确定的预期发病年龄前约 12.5 年。在关键的额颞叶痴呆特征区域，有症状前突变携带者的脑血流在接近和超过预期发病年龄时更低。这些结果表明，动脉自旋标记 MRI 可能是遗传性额颞叶痴呆有症状前阶段有前途的非侵入性成像生物标志物。
