Vandebergh Marijne, Ramos Eliana Marisa, Corriveau-Lecavalier Nick, Ramanan Vijay K, Kornak John, Mester Carly, Kolander Tyler, Brushaber Danielle, Staffaroni Adam M, Geschwind Daniel, Wolf Amy, Kantarci Kejal, Gendron Tania F, Petrucelli Leonard, Van den Broeck Marleen, Wynants Sarah, Baker Matthew C, Borrego-Écija Sergi, Appleby Brian, Barmada Sami, Bozoki Andrea, Clark David, Darby R Ryan, Dickerson Bradford C, Domoto-Reilly Kimiko, Fields Julie A, Galasko Douglas R, Ghoshal Nupur, Graff-Radford Neill, Grant Ian M, Honig Lawrence S, Hsiung Ging-Yuek Robin, Huey Edward D, Irwin David, Knopman David S, Kwan Justin Y, Léger Gabriel C, Litvan Irene, Masdeu Joseph C, Mendez Mario F, Onyike Chiadi, Pascual Belen, Pressman Peter, Ritter Aaron, Roberson Erik D, Snyder Allison, Sullivan Anna Campbell, Tartaglia M Carmela, Wint Dylan, Heuer Hilary W, Forsberg Leah K, Boxer Adam L, Rosen Howard J, Boeve Bradley F, Rademakers Rosa
VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
medRxiv. 2024 Apr 5:2024.04.05.24305253. doi: 10.1101/2024.04.05.24305253.
has been proposed as a modifier of disease risk in FTLD-TDP, particularly in mutation carriers. Furthermore, has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients.
Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in , symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR+NACC-FTLD sum of boxes. Subsequently, associations between and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by predictor interactions were fitted.
The minor allele of rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic mutation carriers only. The minor allele of rs1990622 also associated with greater cognitive scores among all mutation carriers and in presymptomatic mutation carriers, under the recessive dosage model.
We identified associations of with gray matter volume and cognition in the presence of and mutations. This further supports as modifier of TDP-43 pathology. The association of with outcomes of interest in presymptomatic and mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.
已被提出作为额颞叶变性伴TAR DNA结合蛋白43（FTLD-TDP）疾病风险的修饰因子，尤其是在[具体基因]突变携带者中。此外，在健康衰老背景下以及多种神经退行性疾病中，[该因素]已被作为疾病修饰因子进行研究。本研究的目的是评估和比较[该因素]对各常见遗传性额颞叶痴呆（FTD）组以及散发性FTD患者灰质体积和认知功能的影响。
通过ARTFL/LEFFTDS额颞叶变性纵向研究（ALLFTD）招募参与者，该研究包括有[具体基因]致病突变的有症状和无症状个体、有症状的非突变携带者以及非携带者家族对照。所有参与者均进行了[具体基因]rs1990622单核苷酸多态性（SNP）基因分型。横断面研究中，拟合线性混合效应模型以评估[该因素]与基因分组交互作用与各结局指标（灰质体积和用于认知功能的UDS3-执行功能）之间的关联，并对教育程度、年龄、性别和临床痴呆评定量表（CDR）+国家阿尔茨海默病协调中心-额颞叶变性（NACC-FTLD）框总和进行校正。随后，在基因分组内研究[该因素]与各结局指标之间的关联。对于纵向建模，拟合具有时间与[该因素]预测变量交互作用的线性混合效应模型。
与FTD风险降低相关的[具体基因]rs1990622次要等位基因，在隐性剂量模型下，与[具体基因]突变携带者更大的灰质体积相关。这在左半球丘脑最为明显，仅考虑无症状[具体基因]突变携带者时仍存在关联。在隐性剂量模型下，[具体基因]rs1990622次要等位基因在所有[具体基因]突变携带者以及无症状[具体基因]突变携带者中也与更高的认知得分相关。
我们在存在[具体基因1]和[具体基因2]突变的情况下，确定了[该因素]与灰质体积和认知功能之间的关联。这进一步支持[该因素]作为TDP-43病理学的修饰因子。[该因素]与无症状[具体基因1]和[具体基因2]突变携带者感兴趣的结局之间的关联，还可能反映跨膜蛋白106B（TMEM106B）在临床症状出现之前对不同病理生理变化的影响。
