Penn Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States; Penn Image Computing and Science Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States.
Penn Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States.
Neuroimage Clin. 2018 May 15;19:497-506. doi: 10.1016/j.nicl.2018.05.017. eCollection 2018.
Mutations in the progranulin () gene are a major source of inherited frontotemporal degeneration (FTD) spectrum disorders associated with TDP-43 proteinopathy. We use structural MRI to identify regions of baseline differences and longitudinal changes in gray matter (GM) and white matter (WM) in presymptomatic mutation carriers (pGRN+) compared to young controls (yCTL).
Cognitively intact first-degree relatives of symptomatic GRN+ FTD patients with identified mutations (pGRN+; = 11, mean age = 41.4) and matched yCTL ( = 11, mean age = 53.6) were identified. They completed a MRI session with T1-weighted imaging to assess GM density (GMD) and diffusion-weighted imaging (DWI) to assess fractional anisotropy (FA). Participants completed a follow-up session with T1 and DWI imaging (pGRN+ mean interval 2.20 years; yCTL mean interval 3.27 years). Annualized changes of GMD and FA were also compared.
Relative to yCTL, pGRN+ individuals displayed reduced GMD at baseline in bilateral orbitofrontal, insular, and anterior temporal cortices. pGRN+ also showed greater annualized GMD changes than yCTL at follow-up in right orbitofrontal and left occipital cortices. We also observed reduced FA at baseline in bilateral superior longitudinal fasciculus, left corticospinal tract, and frontal corpus callosum in pGRN+ relative to yCTL, and pGRN+ displayed greater annualized longitudinal FA change in right superior longitudinal fasciculus and frontal corpus callosum.
Longitudinal MRI provides evidence of progressive GM and WM changes in pGRN+ participants relative to yCTL. Structural MRI illustrates the natural history of presymptomatic GRN carriers, and may provide an endpoint during disease-modifying treatment trials for pGRN+ individuals at risk for FTD.
颗粒体蛋白基因（）突变是与 TDP-43 蛋白病相关的额颞叶变性（FTD）谱系障碍的主要遗传来源。我们使用结构磁共振成像（MRI）来识别无症状突变携带者（pGRN+）与年轻对照组（yCTL）之间基线差异和纵向灰质（GM）和白质（WM）变化的区域。
我们确定了具有明确基因突变（pGRN+；=11，平均年龄=41.4）的症状性 GRN+FTD 患者的一级亲属中认知正常的认知正常的一级亲属（pGRN+；=11，平均年龄=53.6），并进行了 MRI 检查，包括 T1 加权成像以评估 GM 密度（GMD）和弥散加权成像（DWI）以评估各向异性分数（FA）。参与者完成了 T1 和 DWI 成像的随访检查（pGRN+的平均间隔为 2.20 年；yCTL 的平均间隔为 3.27 年）。还比较了 GMD 和 FA 的年变化率。
与 yCTL 相比，pGRN+个体在双侧眶额、岛叶和前颞叶皮质的基线 GM 密度降低。与 yCTL 相比，pGRN+在随访时右眶额和左枕叶皮质的 GM 密度年变化率更高。我们还观察到 pGRN+在双侧上纵束、左皮质脊髓束和额状胝体的基线 FA 降低，而 pGRN+的右上纵束和额状胝体的 FA 纵向变化率更高。
纵向 MRI 为 pGRN+参与者相对于 yCTL 的 GM 和 WM 进行性变化提供了证据。结构 MRI 说明了无症状 GRN 携带者的自然病史，并可能为处于 FTD 风险中的 pGRN+个体提供疾病修饰治疗试验的终点。
