Thalamic and Cerebellar Regional Involvement across the ALS–FTD Spectrum and the Effect of C9orf72

Abstract

Data Availability Statement: Data will be available on request from the authors until 2030.Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/brainsci12030336/s1, Table S1: Spearman’s correlations between w-scores and behavioural and cognitive total scores across the clinical and genetic groups. Table S2: Spearman’s correlations between w-scores and behavioural and cognitive subscores across the clinical and genetic groups.Copyright © 2022 by the authors. . Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of the same disease spectrum. While thalamic–cerebellar degeneration has been observed in C9orf72 expansion carriers, the exact subregions involved across the clinical phenotypes of the ALS–FTD spectrum remain unclear. Using MRIs from 58 bvFTD, 41 ALS–FTD and 52 ALS patients compared to 57 controls, we aimed to delineate thalamic and cerebellar subregional changes across the ALS–FTD spectrum and to contrast these profiles between cases with and without C9orf72 expansions. Thalamic involvement was evident across all ALS–FTD clinical phenotypes, with the laterodorsal nucleus commonly affected across all groups (values below the 2.5th control percentile). The mediodorsal nucleus was disproportionately affected in bvFTD and ALS–FTD but not in ALS. Cerebellar changes were only observed in bvFTD and ALS–FTD predominantly in the superior–posterior region. Comparison of genetic versus sporadic cases revealed significantly lower volumes exclusively in the pulvinar in C9orf72 expansion carriers compared to non-carriers, irrespective of clinical syndrome. Overall, bvFTD showed significant correlations between thalamic subregions, level of cognitive dysfunction and severity of behavioural symptoms. Notably, strong associations were evident between mediodorsal nucleus atrophy and severity of behavioural changes in C9orf72-bvFTD (r = −0.9, p < 0.0005). Our findings reveal distinct thalamic and cerebellar atrophy profiles across the ALS–FTD spectrum, with differential impacts on behaviour and cognition, and point to a unique contribution of C9orf72 expansions in the clinical profiles of these patients.This work was supported in part by funding to ForeFront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neurone disease, from the National Health and Medical Research Council of Australia (NHMRC) program grant (GNT1037746 to O.P., M.C.K. and J.R.H.) and the Australian Research Council Centre of Excellence in Cognition and Its Disorders Memory Program (#CE110001021 to O.P. and J.R.H.) and other grants/sources (NHMRC project grant GNT1003139 to O.P.), and Royal Australasian College of Physicians, MND Research Institute of Australia. We are grateful to the research participants involved with the ForeFront research studies. R.M.A. is an NHMRC Early Career Fellow (#1120770). O.P. was an NHMRC Senior Research Fellow (GNT1103258). M.B. is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). M.B.’s work was also supported by the UK Dementia Research Institute, which receives its funding from DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. M.I. is supported by an Australian Research Council Future Fellowship (FT160100096). J.D.R. has received funding from an MRC Clinician Scientist fellowship (MR/M008525/1) as well as from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration. M.C.K. receives funding from the NHMRC Partnership Project (APP1153439) and Practitioner Fellowship (APP1156093) schemes