Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review

Abstract

Frontotemporal dementia (FTD) is the second most common young-onset dementia and is clinically characterised by progressive behavioural change, executive dysfunction and language difficulties. Three clinical syndromes, behavioural variant FTD, semantic dementia and progressive non-fluent aphasia, form part of a clinicopathological spectrum named frontotemporal lobar degeneration (FTLD). The classical neuropsychological phenotype of FTD has been enriched by tests exploring Theory of Mind, social cognition and emotional processing. Imaging studies have detailed the patterns of atrophy associated with different clinical and pathological subtypes. These patterns offer some diagnostic utility, while measures of progression of atrophy may be of use in future trials. 30e50% of FTD is familial, and mutations in two genes, microtubule associated protein tau and Progranulin (GRN), account for about half of these cases. Rare defects in VCP, CHMP2B, TARDP and FUS genes have been found in a small number of families. Linkage to chromosome 9p13.2e21.3 has been established in familial FTD with motor neuron disease, although the causative gene is yet to be identified. Recent developments in the immunohistochemistry of FTLD, and also in amyotrophic lateral sclerosis (ALS), have led to a new pathological nomenclature. The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin-positive and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusions (FTLD-TDP). Recently, a new protein involved in familial ALS, fused in sarcoma (FUS), has been found in FTLD patients with ubiquitin-positive and TDP-43-negative inclusions. In this review, the authors discuss recent clinical, neuropsychological, imaging, genetic and pathological developments that have changed our understanding of FTD, its classification and criteria. The potential to establish an early diagnosis, predict underlying pathology during life and quantify disease progression will all be required for diseasespecific therapeutic trials in the future.

White Matter Integrity Disruptions Associated With Cognitive Impairments in Type 2 Diabetic Patients

“…Correspondingly, executive dysfunctions are closely related to WM abnormalities in T2DM. At the same time, many investigations have found that FTD affects executive function through regional disruption of the frontal and temporal lobes (44), where the more severely disrupted WM tracts were found in T2DM. Therefore, we predict that T2DM might be associated with FTD.…”

Novel progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration

“…Mutations in GRN account for 5-10% of all the FTLD cases. 10,11 Deletions of one copy of GRN have been reported, 12,13 but the majority of mutations result in null alleles, leading to an approximately 50% reduction of the precursor protein GRN, which can be measured in serum, plasma and CSF. [14][15][16] Mutations in GRN have been reported in different clinical phenotypes including Alzheimer disease (AD) and corticobasal syndrome (CBS).…”

Functional neuroimaging for dementia: commissioning and evaluating a service

“…Patients referred for FDG-PET had a younger mean age than patients referred for DaTscan, consistent with the younger age at onset of FTD. 1 The gender spread was biased towards male patients, particularly in the group referred for DaTscan. This may reflect the small sample size, but also suggests a preponderance of suspected DLB in male patients, as has been described previously.…”

“…For example, fronto-temporal dementia (FTD) is different from Alzheimer's disease (AD) in terms of earlier age of onset, higher genetic burden, prominent behavioural symptoms and poor response to acetylcholine-esterase inhibitors (ACIs). 1 NICE clinical guidelines recommend that structural neuroimaging with CT or MRI should be performed at least once in ever y patient with suspected dementia and that functional neuroimaging with HMPAO-SPECT or FDG-PET should be considered to help differentiate between AD, vascular dementia (VaD) and FTD if the diagnosis is in doubt. 2 European guidelines state that FDG-PET is particularly useful in differentiating AD from FTD with more than 95% specificity in young onset dementia.…”