Dementia Research Centre, UCL Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK.
Neuroimage. 2010 Nov 15;53(3):1070-6. doi: 10.1016/j.neuroimage.2009.12.088. Epub 2010 Jan 4.
Neural network breakdown is a key issue in neurodegenerative disease, but the mechanisms are poorly understood. Here we investigated patterns of brain atrophy produced by defined molecular lesions in the two common forms of genetically mediated frontotemporal lobar degeneration (FTLD). Nine patients with progranulin (GRN) mutations and eleven patients with microtubule-associated protein tau (MAPT) mutations had T1 MR brain imaging. Brain volumetry and grey and white matter voxel-based morphometry (VBM) were used to assess patterns of cross-sectional atrophy in the two groups. In a subset of patients with longitudinal MRI rates of whole-brain atrophy were derived using the brain-boundary-shift integral and a VBM-like analysis of voxel-wise longitudinal volume change was performed. The GRN mutation group showed asymmetrical atrophy whereas the MAPT group showed symmetrical atrophy. Brain volumes were smaller in the GRN group with a faster rate of whole-brain atrophy. VBM delineated a common anterior cingulate-prefrontal-insular pattern of atrophy in both disease groups. Additional disease-specific profiles of grey and white matter loss were identified on both cross-sectional and longitudinal imaging: GRN mutations were associated with asymmetrical inferior frontal, temporal and inferior parietal lobe grey matter atrophy and involvement of long intrahemispheric association white matter tracts, whereas MAPT mutations were associated with symmetrical anteromedial temporal lobe and orbitofrontal grey matter atrophy and fornix involvement. The findings suggest that the effects of GRN and MAPT mutations are expressed in partly overlapping but distinct anatomical networks that link specific molecular dysfunction with clinical phenotype.
神经网络崩溃是神经退行性疾病的一个关键问题，但机制尚不清楚。在这里，我们研究了两种常见的遗传性额颞叶变性（FTLD）中明确的分子病变引起的脑萎缩模式。9 名颗粒蛋白前体（GRN）突变患者和 11 名微管相关蛋白 tau（MAPT）突变患者进行了 T1MR 脑部成像。脑容积和灰质及白质体素形态计量学（VBM）用于评估两组的横断面萎缩模式。在一组具有纵向 MRI 的患者中，使用脑边界移位积分得出全脑萎缩的纵向速率，并对体素水平的纵向体积变化进行了类似 VBM 的分析。GRN 突变组表现为不对称性萎缩，而 MAPT 组表现为对称性萎缩。GRN 组的脑体积较小，全脑萎缩的速度较快。VBM 描绘了两组疾病中共同的前扣带回-额-岛叶萎缩模式。在横断面和纵向成像上还确定了额外的疾病特异性灰质和白质丢失的特征性模式：GRN 突变与不对称性下额、颞叶和下顶叶灰质萎缩以及长内半球联系白质束的参与有关，而 MAPT 突变与对称的前内侧颞叶和眶额皮质灰质萎缩以及穹窿的参与有关。研究结果表明，GRN 和 MAPT 突变的影响在部分重叠但又不同的解剖网络中表达，这些网络将特定的分子功能障碍与临床表型联系起来。
