Abstract
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.
Highlights
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are often conceptualised as lying on a disease spectrum, with motor changes at one end and cognitive– behavioural changes at the other [1]
The current study employed automated segmentation methods on T1-weighted MR images to examine the pattern of involvement of thalamic and cerebellar regions in a well-characterised cohort of patients diagnosed with bvFTD, ALS–FTD and ALS, with and without chromosome 9 open reading frame 72 (C9orf72) expansions
The study found significant thalamic subregions and cerebellar involvement across the ALS–FTD spectrum, with significant associations with cognitive and behavioural change, reinforcing the pivotal role that the thalamus and cerebellum play in the neurodegenerative process across the ALS–FTD spectrum
Summary
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are often conceptualised as lying on a disease spectrum, with motor changes at one end and cognitive– behavioural changes at the other [1]. The syndrome of ALS–FTD lies somewhere in between these two phenotypes, with about 15% of ALS cases satisfying diagnostic criteria for bvFTD [2] and 10–15% of bvFTD patients eventually developing ALS [3–5] These clinical syndromes share common neuropathological and genetic features, with the presence of 43 kDa TAR DNA-binding (TDP-43) protein deposition in the brain [6–8] and expansions in the chromosome 9 open reading frame 72 (C9orf72) gene [9,10]. Mounting evidence suggests that the thalamus and cerebellum play an important role in several relevant behavioural and clinical phenotypes in FTD and ALS, including neuropsychiatric and behavioural changes [12–14] and altered eating behaviour [15] Both structures undergo significant atrophy in FTD, especially in C9orf expansion carriers [16,17], and in ALS patients with and without C9orf expansions [17–21]. No study has explored how subregions of the thalamus and cerebellum are differentially impacted across the ALS–FTD spectrum or studied the impact of the C9orf expansion on these structures
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