Thalamic volume as a susceptibility/risk biomarker for C9orf72 phenoconversion

BackgroundC9orf72 repeat expansions are the most frequent genetic risk factor of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). With growing interest in the prospect of preventing clinically manifest disease, there is a pressing need to identify susceptibility/risk biomarkers that might predict the short-term risk of phenoconversion. This study sought to identify such neuroimaging biomarkers that predict the risk of ALS or FTD among unaffected C9orf72 carriers. MethodsOur cohort comprised 4 groups of participants genotyped for C9orf72 repeat expansions, including 73 pre-symptomatic carriers, 8 phenoconverters, 49 affected carriers, and 99 non-carrier controls. Pre-symptomatic carriers remained unaffected throughout the follow-up period, while phenoconverters were those who transitioned from pre-symtpomatic to the clinically manifest phase during follow-up. Affected carriers were already diagnosed with ALS and/or FTD at baseline. All participants underwent an initial MRI scan, with a subset receiving follow-up MRI scans. Regional gray matter volumes were analyzed to assess initial differences across groups, to predict phenoconversion from a pre-symptomatic to clinically manifest state, and to explore progression over time. ResultsGroup comparisons revealed an increasing extent and magnitude of reduced gray matter volume across the clinical continuum, from pre-symptomatic to clinically manifest stages, with phenoconverters who were imaged when pre-symptomatic and later developed clinically manifest disease intermediate between the two. The thalamus demonstrates the largest effect and the least variability across centers and MRI protocols. Thalamic volume is, on average, lower among pre-symptomatic carriers than non-carrier controls, though with wide overlapping distributions. Phenoconverters exhibited thalamic volumes in the range of affected carriers, both before and after phenoconversion. Mean thalamic volume discriminated between phenoconverters and carriers who remained pre-symptomatic during follow-up with an area under the curve of 0.854 (p<0.001), and time-to-phenoconversion analysis demonstrated that individuals with a lower baseline thalamic volume had an increased hazard for phenoconversion (HR=17.6; CI=2.2-143.3; p<0.001). Other regions, including the amygdala, somatomotor cortex, postcentral gyrus, and parietal cortex, demonstrated less consistent signals across centers and MRI protocols, but generally followed trends similar to the thalamus. Longitudinal observations further indicated that these regions, particularly the thalamus, demonstrated consistent downward trajectories over time, with more rapid atrophy observed in phenoconverters and affected carriers. ConclusionsLower thalamic volume is a promising susceptibility/risk biomarker predicting phenoconversion to clinically manifest ALS or FTD among clinically unaffected C9orf72 repeat expansion carriers, with potential utility to aid the design and implementation of early intervention and preventative clinical trials.