Patterns of regional cerebellar atrophy in genetic frontotemporal dementia.

Martina Bocchetta,David M Cash,Sebastien Ourselin,M Jorge Cardoso,Jonathan D Rohrer,Jason D Warren

doi:10.1016/j.nicl.2016.02.008

Abstract

BackgroundFrontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder with a strong genetic component. The cerebellum has not traditionally been felt to be involved in FTD but recent research has suggested a potential role.MethodsWe investigated the volumetry of the cerebellum and its subregions in a cohort of 44 patients with genetic FTD (20 MAPT, 7 GRN, and 17 C9orf72 mutation carriers) compared with 18 cognitively normal controls. All groups were matched for age and gender. On volumetric T1-weighted magnetic resonance brain images we used an atlas propagation and label fusion strategy of the Diedrichsen cerebellar atlas to automatically extract subregions including the cerebellar lobules, the vermis and the deep nuclei.ResultsThe global cerebellar volume was significantly smaller in C9orf72 carriers (mean (SD): 99989 (8939) mm3) compared with controls (108136 (7407) mm3). However, no significant differences were seen in the MAPT and GRN carriers compared with controls (104191 (6491) mm3 and 107883 (6205) mm3 respectively). Investigating the individual subregions, C9orf72 carriers had a significantly lower volume than controls in lobule VIIa-Crus I (15% smaller, p < 0.0005), whilst MAPT mutation carriers had a significantly lower vermal volume (10% smaller, p = 0.001) than controls. All cerebellar subregion volumes were preserved in GRN carriers compared with controls.ConclusionThere appears to be a differential pattern of cerebellar atrophy in the major genetic forms of FTD, being relatively spared in GRN, localized to the lobule VIIa-Crus I in the superior-posterior region of the cerebellum in C9orf72, the area connected via the thalamus to the prefrontal cortex and involved in cognitive function, and localized to the vermis in MAPT, the ‘limbic cerebellum’ involved in emotional processing.

Highlights

Frontotemporal dementia (FTD) is a clinically, pathologically and genetically heterogeneous neurodegenerative disorder, commonly presenting with progressive impairment in behaviour or language
No other subregion reached statistical significance but there was a trend for lower volumes of the interposed nuclei in both the chromosome 9 open reading frame 72 (C9orf72) and microtubule-associated protein tau (MAPT) groups compared with controls (p = 0.004 and p = 0.007, respectively)
We found a differential pattern of regional cerebellar involvement in the different genetic forms of FTD: lobule VIIA-Crus I in C9orf72, the vermis in MAPT, and sparing in the GRN group

Summary

Introduction

Frontotemporal dementia (FTD) is a clinically, pathologically and genetically heterogeneous neurodegenerative disorder, commonly presenting with progressive impairment in behaviour (behavioural variant FTD, bvFTD) or language (primary progressive aphasia, PPA). Its function has traditionally been felt to be related solely to the co-ordination of movement, research over the past twenty years has highlighted a role for the cerebellum in cognitive and emotional processing (Schmahmann, 1991; D'Angelo and Casali, 2013; Middleton and Strick, 2000; Strick et al, 2009; Makris et al, 2003) It is extensively connected with different brain regions, including key areas involved in FTD, e.g. via the thalamus to the prefrontal cortex (Behrens et al, 2003; Palesi et al, 2015), and to the limbic system via a direct cerebello-limbic pathway (Arrigo et al, 2014). Conclusion: There appears to be a differential pattern of cerebellar atrophy in the major genetic forms of FTD, being relatively spared in GRN, localized to the lobule VIIa-Crus I in the superior-posterior region of the cerebellum in C9orf, the area connected via the thalamus to the prefrontal cortex and involved in cognitive function, and localized to the vermis in MAPT, the ‘limbic cerebellum’ involved in emotional processing

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