Dataset Information

Anomia is present pre-symptomatically in frontotemporal dementia due to MAPT mutations.

ABSTRACT:

Introduction

A third of frontotemporal dementia (FTD) is caused by an autosomal-dominant genetic mutation in one of three genes: microtubule-associated protein tau (MAPT), chromosome 9 open reading frame 72 (C9orf72) and progranulin (GRN). Prior studies of prodromal FTD have identified impaired executive function and social cognition early in the disease but few have studied naming in detail.

Methods

We investigated performance on the Boston Naming Test (BNT) in the GENetic Frontotemporal dementia Initiative cohort of 499 mutation carriers and 248 mutation-negative controls divided across three genetic groups: C9orf72, MAPT and GRN. Mutation carriers were further divided into 3 groups according to their global CDR plus NACC FTLD score: 0 (asymptomatic), 0.5 (prodromal) and 1 + (fully symptomatic). Groups were compared using a bootstrapped linear regression model, adjusting for age, sex, language and education. Finally, we identified neural correlates of anomia within carriers of each genetic group using a voxel-based morphometry analysis.

Results

All symptomatic groups performed worse on the BNT than controls with the MAPT symptomatic group scoring the worst. Furthermore, MAPT asymptomatic and prodromal groups performed significantly worse than controls. Correlates of anomia in MAPT mutation carriers included bilateral anterior temporal lobe regions and the anterior insula. Similar bilateral anterior temporal lobe involvement was seen in C9orf72 mutation carriers as well as more widespread left frontal atrophy. In GRN mutation carriers, neural correlates were limited to the left hemisphere, and involved frontal, temporal, insula and striatal regions.

Conclusion

This study suggests the development of early anomia in MAPT mutation carriers, likely to be associated with impaired semantic knowledge. Clinical trials focused on the prodromal period within individuals with MAPT mutations should use language tasks, such as the BNT for patient stratification and as outcome measures.

SUBMITTER: Bouzigues A

PROVIDER: S-EPMC9294015 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Anomia is present pre-symptomatically in frontotemporal dementia due to MAPT mutations.

Bouzigues Arabella A Russell Lucy L LL Peakman Georgia G Bocchetta Martina M Greaves Caroline V CV Convery Rhian S RS Todd Emily E Rowe James B JB Borroni Barbara B Galimberti Daniela D Tiraboschi Pietro P Masellis Mario M Tartaglia Maria Carmela MC Finger Elizabeth E van Swieten John C JC Seelaar Harro H Jiskoot Lize L Sorbi Sandro S Butler Chris R CR Graff Caroline C Gerhard Alexander A Langheinrich Tobias T Laforce Robert R Sanchez-Valle Raquel R de Mendonça Alexandre A Moreno Fermin F Synofzik Matthis M Vandenberghe Rik R Ducharme Simon S Le Ber Isabelle I Levin Johannes J Danek Adrian A Otto Markus M Otto Markus M Pasquier Florence F Santana Isabel I Rohrer Jonathan D JD

Journal of neurology 20220329 8

<h4>Introduction</h4>A third of frontotemporal dementia (FTD) is caused by an autosomal-dominant genetic mutation in one of three genes: microtubule-associated protein tau (MAPT), chromosome 9 open reading frame 72 (C9orf72) and progranulin (GRN). Prior studies of prodromal FTD have identified impaired executive function and social cognition early in the disease but few have studied naming in detail.<h4>Methods</h4>We investigated performance on the Boston Naming Test (BNT) in the GENetic Fronto ...[more]

PMID: 35348856

Similar Datasets

Project description:Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on β-glucocerebrosidase outside of the context of neurodegeneration, we investigated β-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn-/- mice had lower β-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs β-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired β-glucocerebrosidase processing.

Dataset Information

Anomia is present pre-symptomatically in frontotemporal dementia due to MAPT mutations.

Introduction

Methods

Results

Conclusion

Publications

Anomia is present pre-symptomatically in frontotemporal dementia due to MAPT mutations.

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