Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands.
Neurology. 2013 Feb 26;80(9):814-23. doi: 10.1212/WNL.0b013e31828407bc. Epub 2013 Feb 6.
We aimed to investigate whether cognitive deficits and structural and functional connectivity changes can be detected before symptom onset in a large cohort of carriers of microtubule-associated protein tau and progranulin mutations.
In this case-control study, 75 healthy individuals (aged 20-70 years) with 50% risk for frontotemporal dementia (FTD) underwent DNA screening, neuropsychological assessment, and structural and functional MRI. We used voxel-based morphometry and tract-based spatial statistics for voxelwise analyses of gray matter volume and diffusion tensor imaging measures. Using resting-state fMRI scans, we assessed whole-brain functional connectivity to frontoinsula, anterior midcingulate cortex (aMCC), and posterior cingulate cortex.
Although carriers (n = 37) and noncarriers (n = 38) had similar neuropsychological performance, worse performance on Stroop III, Ekman faces, and Happé cartoons correlated with higher age in carriers, but not controls. Reduced fractional anisotropy and increased radial diffusivity throughout frontotemporal white matter tracts were found in carriers and correlated with higher age. Reductions in functional aMCC connectivity were found in carriers compared with controls, and connectivity between frontoinsula and aMCC seeds and several brain regions significantly decreased with higher age in carriers but not controls. We found no significant differences or age correlations in posterior cingulate cortex connectivity. No differences in regional gray matter volume were found.
This study convincingly demonstrates that alterations in structural and functional connectivity develop before the first symptoms of FTD arise. These findings suggest that diffusion tensor imaging and resting-state fMRI may have the potential to become sensitive biomarkers for early FTD in future clinical trials.
我们旨在研究在大量携带微管相关蛋白 tau 和颗粒蛋白前体突变的个体中，是否可以在症状出现之前发现认知缺陷以及结构和功能连接的改变。
在这项病例对照研究中，75 名健康个体（年龄在 20-70 岁之间）具有 50%患额颞叶痴呆（FTD）的风险，接受了 DNA 筛查、神经心理学评估以及结构和功能磁共振成像检查。我们使用基于体素的形态计量学和基于束的空间统计学来进行灰质体积和扩散张量成像测量的体素分析。使用静息状态 fMRI 扫描，我们评估了整个大脑与额眶回、前扣带皮层（aMCC）和后扣带皮层的功能连接。
尽管携带者（n = 37）和非携带者（n = 38）的神经心理学表现相似，但在 Stroop III、Ekman 面孔和 Happé 漫画测试中的表现较差与携带者的较高年龄相关，但与对照组无关。在前额皮质白质束中发现了各向异性分数降低和径向弥散度增加，这在携带者中与较高年龄相关。与对照组相比，携带者的 aMCC 功能连接减少，并且在与额眶回种子的连接以及几个大脑区域的连接在携带者中随年龄的增加而显著减少，但在对照组中则没有。我们在后扣带皮层连接中没有发现显著差异或年龄相关性。在区域灰质体积方面没有发现差异。
这项研究令人信服地表明，结构和功能连接的改变在 FTD 首次出现之前就已经发生了。这些发现表明，扩散张量成像和静息状态 fMRI 可能具有成为未来临床试验中早期 FTD 的敏感生物标志物的潜力。
