Frontotemporal dementia: clinical, genetic and pathological heterogeneity

Dr. Harro Seelaar, Erasmus MC – University Medical Center, Rotterdam The Netherlands

Frontotemporal dementia (FTD) is, after Alzheimer’s disease, the most common early-onset dementia. FTD is a clinically, genetically and pathologically heterogeneous disorder. It is clinically characterized by progressive behavioural changes and frontal executive deficits and/or selective language difficulties. FTD encompasses distinct canonical syndromes: the behavioural variant of FTD (bvFTD), and two language variants, semantic dementia (SD), and progressive non-fluent aphasia (PNFA). FTD is accompanied by motor neuron disease (MND) in 5 – 15 percent of the cases.

The estimated prevalence of FTD is 9.4 per 100.000 inhabitants aged 60-69 years. The average age at onset is around 50 – 60 years, although approximately 10 percent have an age at onset of over 70 years, and even up to 89 years. There is a wide range in duration of illness (2-20 years) with a mean of 8 years. Patients with FTD-MND have the shortest survival wit a mean of 3 years.

A positive family history for dementia, parkinsonism or motor neuron disease (MND) is found in 30 – percent of the patients. Genetic heterogeneity of FTD is reflected by the identification of mutations in the microtubule associated protein tau (MAPT), progranulin (GRN) genes and very recently hexanucleotide repeat expansions in C9orf72 gene. C9orf72 repeat expansions were predominantly found in families with FTD and MND.

FTD is part of a clinicopathological spectrum named frontotemporal lobar degeneration (FTLD). FTLD can be divided in two major subtypes: FTLD with tau-positive inclusions (FTLD-tau) and FTLD with ubiquitin- and TDP-43-positive inclusions (FTLD-TDP). There is a clear correlation between the genetic defect and neuropathological findings. All patients with MAPT mutations have FTLD- tau pathology, whereas patients with GRN gene mutations and C9orf72 hexanucleotide repeat expansions have FTLD-TDP pathology. There is also one minor subgroup with FUS-positive cases (FTLD-FUS). These cases are characterized by a young age at onset (< 40 years), bvFTD, negative family history and typical neuroimaging findings.

There is a strong relation between the genetics and neuropathological finding in FTD. However, over 50 percent of the FTD cases are sporadic. In particular patients with bvFTD can have tau, TDP-43 or FUS as underlying pathology. To predict the underling pathology during life will be important in the near future, as therapeutic interventions will be protein specific. Development of biomarkers such as neuroimaging, plasma and cerebrospinal fluid will play an important role in the future diagnostic work-up of FTD and also the prediction of the underlying pathology.

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