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.
Highlights
Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder presenting with distinct changes in behaviour, language and motor function
Whilst executive function deficits seem common across the different genetic groups, specific patterns of cognitive decline have been identified at a presymptomatic stage in microtubule-associated protein tau (MAPT), genes: progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72) carriers [32]
In the other FTD clinical phenotypes, where the risk is lower of a genetic cause, we offer testing on an individual basis, mainly in those with a strong family history, but the identification of a PPA syndrome not fitting criteria for one of the three described subtypes is a red flag for consideration of testing [26, 76]
Summary
Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder presenting with distinct changes in behaviour, language and motor function. Whilst executive function deficits seem common across the different genetic groups, specific patterns of cognitive decline have been identified at a presymptomatic stage in MAPT, GRN and C9orf carriers [32]. C9orf mutation carriers appear to have earlier grey matter volume loss than the other two groups, before the age of 40 [39], and potentially more than 25 years prior to symptom onset [32]. A number of studies have shown that white matter hyperintensities (which are generally an unusual finding in FTD) are characteristic of GRN mutations [44, 45] This is mainly in symptomatic mutation carriers ( for unclear reasons only a subset of patients), but there is an association in presymptomatic mutation carriers with time from expected symptom onset [45]. Small molecule therapies and tau monoclonal antibodies are being developed for tauopathies (with a potential for use in MAPT mutations) [86], and other options for GRN mutations include modification of proteins such as sortilin and HDAC that lead to increased GRN levels [87, 88]
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