An update on genetic frontotemporal dementia

Abstract

Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, with around 30% of patients having a strong family history. The majority of that heritability is accounted for by autosomal dominant mutations in the chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT) genes, with mutations more rarely seen in a number of other genes. This review will discuss the recent updates in the field of genetic FTD. Age at symptom onset in genetic FTD is variable with recently identified genetic modifiers including TMEM106B (in GRN carriers particularly) and a polymorphism at a locus containing two overlapping genes LOC101929163 and C6orf10 (in C9orf72 carriers). Behavioural variant FTD (bvFTD) is the most common diagnosis in each of the genetic groups, although in C9orf72 carriers amyotrophic lateral sclerosis either alone, or with bvFTD, is also common. An atypical neuropsychiatric presentation is also seen in C9orf72 carriers and family members of carriers are at greater risk of psychiatric disorders including schizophrenia and autistic spectrum disorders. Large natural history studies of presymptomatic genetic FTD are now underway both in Europe/Canada (GENFI-the Genetic FTD Initiative) and in the US (ARTFL/LEFFTDS study), collaborating together under the banner of the FTD Prevention Initiative (FPI). These studies are taking forward the validation of cognitive, imaging and fluid biomarkers that aim to robustly measure disease onset, staging and progression in genetic FTD. Grey matter changes on MRI and hypometabolism on FDG-PET are seen at least 10 years before symptom onset with white matter abnormalities seen earlier, but the pattern and exact timing of changes differ between different genetic groups. In contrast, tau PET has yet to show promise in genetic FTD. Three key fluid biomarkers have been identified so far that are likely to be helpful in clinical trials-CSF or blood neurofilament light chain levels (in all groups), CSF or blood progranulin levels (in GRN carriers) and CSF poly(GP) dipeptide repeat protein levels (in C9orf72 carriers). Increased knowledge about genetic FTD has led to more clinical presymptomatic genetic testing but this has not yet been mirrored in the development of either an accepted FTD-specific testing protocol or provision of appropriate psychological support mechanisms for those living through the at-risk phase. This will become even more relevant as disease-modifying therapy trials start in each of the genetic groups over the next few years.

Keywords: Biomarkers; C9orf72; Frontotemporal dementia; Neurogenetics; Progranulin; Tau.

Fig. 1

The landscape of the frontotemporal dementia spectrum disorders. About 70% is sporadic with approximately equal numbers of TDP-43 proteinopathies and tauopathies (including corticobasal degeneration, CBD progressive supranuclear palsy, PSP Pick’s disease, GGT globular glial tauopathy), and a smaller number of FUSopathies (including atypical frontotemporal lobar degeneration with ubiquitin inclusions, aFTLDU). About 30% is genetic with TDP-43 proteinopathies being the commonest cause (mutations in C9orf72 (usually TDP-43 types A or B), GRN (type A), TBK1 (types A or B), VCP (type D), SQSTM1, and TARDBP) then tauopathies (mutations in MAPT), FUSopathies (mutations in FUS) and other proteinopathies (mutations in CHMP2B)

Fig. 2

Schematic of fluid, imaging and cognitive biomarker profiles across the lifespan of C9orf72, MAPT and GRN mutation carriers. NfL neurofilament light chain, DTI diffusion tensor imaging, WM white matter, WMH white matter hyperintensities, GM grey matter, EF executive function, VF verbal fluency, M memory; N naming

Fig. 3

Genetic testing, counselling and support through the timecourse of genetic FTD. There is commonly a period in proximity to symptom onset of FTD where subtle symptoms may be present but diagnostic criteria have not yet been met—this requires careful assessment and discussion