Table_2_Transcriptomic and Network Meta-Analysis of Frontotemporal Dementias.xlsx

Frontotemporal lobar degeneration (FTLD), also known as frontotemporal dementia (FTD), results in a progressive decline in executive function, leading to behavioral changes, speech problems, and movement disorders. FTD is the second most common cause of young-onset dementia affecting approximately 50–60,000 Americans. FTD exists in familial and sporadic forms, with GRN progranulin and C9orf72 mutations being the most common causes. In this study, we compared the sporadic and familial transcriptome within the cerebellum, frontal cortex, hippocampus, and Brodmann’s area 8 of patients with FTD to determine genes and pathways involved in the disease process. Most dysregulated genes expression occurred in the frontal cortex and Brodmann’s area 8 for genetic and sporadic forms of FTD, respectively. A meta-analysis revealed 50 genes and 95 genes are dysregulated in at least three brain regions in patients with familial mutations and sporadic FTD patients, respectively. Familial FTD genes centered on the Wnt signaling pathway, whereas genes associated with the sporadic form of FTD centered on MAPK signaling. The results reveal the similarities and differences between sporadic and familial FTD. In addition, valproic acid and additional therapeutic agents may be beneficial in treating patients with FTD.

额颞叶变性（Frontotemporal lobar degeneration, FTLD）又称额颞痴呆（frontotemporal dementia, FTD），可引发执行功能进行性衰退，进而导致行为改变、言语障碍及运动障碍。FTD是早发性痴呆的第二大常见病因，在美国约影响50000至60000名患者。FTD可分为家族性与散发性两种亚型，其中颗粒蛋白前体（progranulin, GRN）及C9orf72基因突变是最为常见的致病诱因。本研究针对FTD患者的小脑、额叶皮层、海马体及布罗德曼8区，对比分析了家族性与散发性FTD的转录组特征，旨在明确参与疾病进程的基因与信号通路。研究发现，家族性与散发性FTD的异常表达基因分别主要富集于额叶皮层与布罗德曼8区。荟萃分析结果显示，家族性突变型FTD患者与散发性FTD患者中，分别有50个和95个基因在至少3个脑区内存在异常表达。家族性FTD的异常表达基因以Wnt信号通路（Wnt signaling pathway）为核心，而散发性FTD的异常表达基因则集中于丝裂原活化蛋白激酶信号通路（Mitogen-Activated Protein Kinase signaling pathway, MAPK）。本研究结果揭示了家族性与散发性FTD之间的异同点。此外，丙戊酸及其他治疗药物或可用于FTD患者的临床治疗。