Clinic, neuropathology and molecular genetics of frontotemporal dementia: a mini-review

Xiao-dong Pan, Xiao-chun Chen

Frontotemporal lobar degeneration (FTLD) represents a group of clinically, neuropathologically and genetically heterogeneous disorders with plenty of overlaps between the neurodegenerative mechanism and the clinical phenotype. FTLD is pathologically characterized by the frontal and temporal lobar atrophy. Frontotemporal dementia (FTD) clinically presents with abnormalities of behavior and personality and language impairments variants. The clinical spectrum of FTD encompasses distinct canonical syndromes: behavioural variant of FTD (bvFTD) and primary progressive aphasia. The later includes nonfluent/agrammatic variant PPA (nfvPPA or PNFA), semantic variant PPA (svPPA or SD) and logopenic variant PPA (lvPPA). In addition, there is also overlap of FTD with motor neuron disease (FTD-MND or FTD-ALS), as well as the parkinsonian syndromes, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). The FTLD spectrum disorders are based upon the predominant neuropathological proteins (containing inclusions of hyperphosphorylated tau or ubiquitin protein, e.g transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) and fusedin-sarcoma protein in neurons and glial cells) into three main categories: (1) microtubule-associated protein tau (FTLD-Tau); (2) TAR DNA-binding protein-43 (FTLD-TDP); and (3) fused in sarcoma protein (FTLD-FUS). There are five main genes mutations leading clinical and pathological variants in FTLD that identified by molecular genetic studies, which are chromosome 9 open reading frame 72 (C9ORF72) gene, granulin (GRN) gene, microtubule associated protein tau gene (MAPT), the gene encoding valosin-containing protein (VCP) and the charged multivesicular body protein 2B (CHMP2B). In this review, recent advances on the different clinic variants, neuroimaging, genetics, pathological subtypes and clinicopathological associations of FTD will be discussed.