Transcriptomic and Network Meta-Analysis of Frontotemporal Dementias

Abstract

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.