Cerebral blood flow in presymptomatic MAPT and GRN mutation carriers: A longitudinal arterial spin labeling study
Cerebral blood flow in presymptomatic MAPT and GRN mutation carriers: A longitudinal arterial spin labeling study
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DOI：
10.1016/j.nicl.2016.08.001
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发表时间：
2016-01-01
影响因子：
4.2
通讯作者：
van Swieten, John C.
中科院分区：
文献类型：
--
作者：
Dopper, Elise G. P.;Chalos, Vicky;van Swieten, John C.
目的：额颞叶痴呆（Frontotemporal dementia，FTD）是一种以行为障碍和语言障碍为特征的痴呆。家族性形式可由微管相关蛋白tau（MAPT）、颗粒蛋白前体（GRN）和C9orf72的遗传缺陷引起。鉴于即将进行的潜在疾病调节剂临床试验，开发敏感的生物标志物以在FTD的最早阶段评价此类药物至关重要。在目前的纵向研究中，我们使用动脉自旋标记MRI（ASL）在先兆携带者的MAPT和GRN突变，以调查脑血流（CBF）的早期变化。方法：健康的一级亲属的MAPT或GRN突变患者进行ASL在基线和随访两年后。我们调查了突变携带者（n = 34）和对照组之间CBF的横截面和纵向差异，而没有突变（n = 31）。结果：GRN突变携带者在随访时与对照组相比，显示出显着的额顶叶低灌注，而我们没有发现总研究组或MAPT亚组的横截面组差异。纵向分析显示，在突变携带者总组和GRN亚组中，额叶、颞叶、顶叶和皮质下区域的CBF显著降低，其中在随访期间转换为临床FTD的两个突变携带者的CBF降低最明显。解释：我们证明了症状前FTD的CBF纵向变化与灰质萎缩无关，其中在随访期间出现症状的个体下降幅度最大。因此，ASL有可能在未来的临床试验中作为FTD症状前期疾病进展的敏感生物标志物。(C)2016作者爱思唯尔公司出版
Objective: Frontotemporal dementia (FTD) is characterized by behavioral disturbances and language problems. Familial forms can be caused by genetic defects in microtubule-associated protein tau (MAPT), progranulin (GRN), and C9orf72. In light of upcoming clinical trials with potential disease-modifying agents, the development of sensitive biomarkers to evaluate such agents in the earliest stage of FTD is crucial. In the current longitudinal study we used arterial spin labeling MRI (ASL) in presymptomatic carriers of MAPT and GRN mutations to investigate early changes in cerebral blood flow (CBF).Methods: Healthy first-degree relatives of patients with a MAPT or GRN mutation underwent ASL at baseline and follow-up after two years. We investigated cross-sectional and longitudinal differences in CBF between mutation carriers (n = 34) and controls without a mutation (n = 31).Results: GRN mutation carriers showed significant frontoparietal hypoperfusion compared with controls at follow-up, whereas we found no cross-sectional group differences in the total study group or the MAPT subgroup. Longitudinal analyses revealed a significantly stronger decrease in CBF in frontal, temporal, parietal, and subcortical areas in the total group of mutation carriers and the GRN subgroup, with the strongest decrease in two mutation carriers who converted to clinical FTD during follow-up.Interpretation: We demonstrated longitudinal alterations in CBF in presymptomatic FTD independent of grey matter atrophy, with the strongest decrease in individuals that developed symptoms during follow-up. Therefore, ASL could have the potential to serve as a sensitive biomarker of disease progression in the presymptomatic stage of FTD in future clinical trials. (C) 2016 The Authors. Published by Elsevier Inc.