Distinct clinical and pathological phenotypes in frontotemporal dementia associated with MAPT, PGRN and C9orf72 mutations

Abstract

Our objective was to compare the clinical and pathological characteristics of frontotemporal dementia patients with MAPT, GRN and C9orf72 gene mutations. We carried out a cross-sectional comparative study of 74 gene-positive patients (15 MAPT, 17 GRN and 42 C9orf72). Thirty had post mortem pathological data permitting clinico-pathological correlation. MAPT patients were younger than other groups, and showed more frequent behavioural disinhibition, repetitive and stereotyped behaviours, semantic impairment and temporal predominance of atrophy. GRN patients were older at death and more likely to present with non-fluent aphasia. C9orf72 patients alone showed a co-occurrence of ALS. They showed more psychotic symptoms and irrational behaviour, yet were more often reported clinically as socially appropriate and warm. They showed less dietary change than other groups. C9orf72 patients with and without ALS differed only in frequency of psychosis. Greater clinical overlap was observed between GRN and C9orf72 compared to MAPT cases. MAPT cases had tau and GRN and C9orf72, with one exception, TDP-43 pathology. Non-fluent aphasia was linked to TDP subtype A in both GRN and C9orf72 cases and ALS with subtype B. In conclusion, the findings reinforce clinical heterogeneity in FTD and strengthen evidence that genotype influences clinical presentation. Clinical features may inform targeted genetic testing.

Key words:

• Frontotemporal dementia
• clinical phenotype
• behaviour
• gene mutation
• neuropathology

Acknowledgements

We thank the patients and their families for their participation and support of this study. We are grateful to colleagues who have referred patients and contributed to their original clinical evaluation. We thank Steve Chew-Graham for his role as coordinator of the Manchester brain donation scheme. The scheme and work of the Manchester Brain Bank is supported by Alzheimer’s Research UK and the Alzheimer’s Society through the Brains for Dementia Research Initiative.

Declaration of interest

SPB is named as co-inventor of patents covering MAPT, GRN and C9orf72. SPB receives funding from the Medical Research Council (The Molecular Genetics of Dementia and other Neurodegenerative Disorders MRC G0701441).