Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: a GENFI study.
Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: a GENFI study.
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DOI：
10.1093/brain/awx103
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发表时间：
2017-06-01
期刊：
影响因子：
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通讯作者：
Genetic FTD Initiative (GENFI)
中科院分区：
文献类型：
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作者：
Premi E;Grassi M;van Swieten J;Galimberti D;Graff C;Masellis M;Tartaglia C;Tagliavini F;Rowe JB;Laforce R Jr;Finger E;Frisoni GB;de Mendonça A;Sorbi S;Gazzina S;Cosseddu M;Archetti S;Gasparotti R;Manes M;Alberici A;Cardoso MJ;Bocchetta M;Cash DM;Ourselin S;Padovani A;Rohrer JD;Borroni B;Genetic FTD Initiative (GENFI)
额颞叶痴呆（FTD）表现出显著的表型变异性。在一项多中心研究中，Premi et al.探索了认知储备和TMEM106 B基因型在调节症状前FTD灰质体积中的作用。环境和遗传因素影响脑萎缩的发生率，这提示了一种延缓疾病发作的可能策略。额颞叶痴呆是一种异质性神经退行性疾病，约三分之一的病例具有常染色体显性遗传。即使在受影响的家庭中，表型也有很大的差异，这就提出了关于疾病进展和发病年龄的决定因素的问题。最近的研究表明，认知储备（以正规教育年限衡量）可以抵消正在进行的病理过程。TMEM106B基因型也被发现是TDP-43病理学的额颞叶痴呆患者发病年龄的调节剂。因此，本研究的目的是阐明环境（即认知储备测量的教育程度）和遗传背景（即TMEM106 B多态性，rs1990622 T/C）对灰质体积在一个大型队列的症状前患者额颞叶痴呆相关的致病性突变的调节作用。GENFI研究的231名参与者包括：108名症状前MAPT、GRN和C9orf72突变携带者和123名非携带者。对于每一个主题，皮质和皮质下灰质体积产生使用体积T1加权磁共振成像脑扫描的parcellation。进行TMEM106B基因分型，并记录受教育年限。首先，我们得到了一个综合措施的灰质体积的图形-拉普拉斯主成分分析，然后拟合一个线性混合效应相互作用模型，考虑的作用（i）遗传状态;（ii）教育程度;（iii）TMEM106B基因型对灰质体积。突变的存在与较低的灰质体积（P = 0.002），即使在前驱受试者。教育直接影响所有样本的灰质体积（P = 0.02）与较低的教育程度与较低的体积。TMEM106B基因型本身并不直接影响灰质体积，但在突变携带者中，它调制了教育与灰质体积之间相关性的斜率（P = 0.007）。总之，这些结果表明，常见额颞叶痴呆突变的症状前携带者的脑萎缩受到遗传和环境因素的影响，使得TMEM106 B增强了认知储备对脑结构的益处。这些发现应该在未来的疾病修饰试验中评估结果时加以考虑，并支持在有痴呆风险的人群中寻找可能促进新治疗策略的保护机制。
Frontotemporal dementia (FTD) shows substantial phenotypic variability. In a multicentre study, Premi et al. explore the effect of cognitive reserve and TMEM106B genotype in modulating grey matter volume in presymptomatic FTD. Environmental as well as genetic factors affect rates of brain atrophy, suggesting a possible strategy for delaying disease onset. Frontotemporal dementia is a heterogeneous neurodegenerative disorder with around a third of cases having autosomal dominant inheritance. There is wide variability in phenotype even within affected families, raising questions about the determinants of the progression of disease and age at onset. It has been recently demonstrated that cognitive reserve, as measured by years of formal schooling, can counteract the ongoing pathological process. The TMEM106B genotype has also been found to be a modifier of the age at disease onset in frontotemporal dementia patients with TDP-43 pathology. This study therefore aimed to elucidate the modulating effect of environment (i.e. cognitive reserve as measured by educational attainment) and genetic background (i.e. TMEM106B polymorphism, rs1990622 T/C) on grey matter volume in a large cohort of presymptomatic subjects bearing frontotemporal dementia-related pathogenic mutations. Two hundred and thirty-one participants from the GENFI study were included: 108 presymptomatic MAPT, GRN, and C9orf72 mutation carriers and 123 non-carriers. For each subject, cortical and subcortical grey matter volumes were generated using a parcellation of the volumetric T1-weighted magnetic resonance imaging brain scan. TMEM106B genotyping was carried out, and years of education recorded. First, we obtained a composite measure of grey matter volume by graph-Laplacian principal component analysis, and then fitted a linear mixed-effect interaction model, considering the role of (i) genetic status; (ii) educational attainment; and (iii) TMEM106B genotype on grey matter volume. The presence of a mutation was associated with a lower grey matter volume (P = 0.002), even in presymptomatic subjects. Education directly affected grey matter volume in all the samples (P = 0.02) with lower education attainment being associated with lower volumes. TMEM106B genotype did not influence grey matter volume directly on its own but in mutation carriers it modulated the slope of the correlation between education and grey matter volume (P = 0.007). Together, these results indicate that brain atrophy in presymptomatic carriers of common frontotemporal dementia mutations is affected by both genetic and environmental factors such that TMEM106B enhances the benefit of cognitive reserve on brain structure. These findings should be considered in evaluating outcomes in future disease-modifying trials, and support the search for protective mechanisms in people at risk of dementia that might facilitate new therapeutic strategies.