Gyrification abnormalities in presymptomatic c9orf72 expansion carriers

Abstract

ObjectiveTo investigate in-vivo cortical gyrification patterns measured by the local gyrification index (lGI) in presymptomatic c9orf72 expansion carriers compared with healthy controls, and investigate relationships between lGI and cortical thickness, an established morphometric measure of neurodegeneration.MethodsWe assessed cortical gyrification and thickness patterns in a cohort of 15 presymptomatic c9orf72 expansion carriers (age 43.7 ± 10.2 years, 9 females) compared with 67 (age 42.4 ± 12.4 years, 36 females) age and sex matched healthy controls using the dedicated Freesurfer pipeline.ResultsCompared with controls, presymptomatic carriers showed significantly lower lGI in left frontal and right parieto-occipital regions. Interestingly, those areas with abnormal gyrification in presymptomatic carriers showed no concomitant cortical thickness abnormality. Overall, for both presymptomatic carriers and healthy controls, gyrification and cortical thickness measures were not correlated, suggesting that gyrification captures a feature distinct from cortical thickness.ConclusionsPresymptomatic c9orf72 expansion carriers show regions of abnormally low gyrification as early as their 30s, decades before expected symptom onset. Cortical gyrification represents a novel grey matter metric distinctive from grey matter thickness or volume and detects differences in presymptomatic carriers at an early age.

Faster Cortical Thinning and Surface Area Loss in Presymptomatic and Symptomatic C9orf72 Repeat Expansion Adult Carriers

“…Our results are in line with published studies on cortical gray matter volume showing relatively diffuse and symmetric loss in symptomatic subjects, 20 in addition to presymptomatic loss in several areas of the frontal, temporal, and parietal lobes up to 25 years prior to symptom onset. 8,21 In contrast to previous studies of CTh in C9orf72 mutation carriers that had not demonstrated accelerated thinning in presymptomatic subjects, 13,15 we are able to demonstrate that the differences in CTh and CSA observed in clinical subjects appear to be the result of faster decline in thickness and surface starting in early adulthood (compared to normative CTh and CSA loss over time with atrophy only around disease onset). Those differences from previous studies are probably explained by our larger sample size and wider age range of subjects.…”

“…There is limited literature on the topic of presymptomatic CTh changes in C9orf72 , with most studies having very small sample sizes (≤15 carriers) and, unsurprisingly, finding divergent results. Three of 4 studies found scattered cross‐sectional thinning, whereas 2 did not find differences in the rate of thinning versus noncarriers over time . One study reported no differences in CTh, but a lower gyrification index in presymptomatic carriers that did not change over time, suggesting an early developmental effect .…”

“…13,15 One study reported no differences in CTh, but a lower gyrification index in presymptomatic carriers that did not change over time, suggesting an early developmental effect. 15 To our knowledge, no study has explored the impact of the C9orf72 mutation on CSA.…”

Different CSF protein profiles in amyotrophic lateral sclerosis and frontotemporal dementia with C9orf72 hexanucleotide repeat expansion

“…In the validation step, we increased the number of C9orf72 HRE carriers and also investigated sporadic patients to determine whether the proteomic changes are specific for the C9orf72 HRE. Additionally, we included non-neurodegenertaive controls to identify any regulations in the CAR group before symptom onset, since anatomical changes were already described in presymptomatic CAR 12 13…”

Insights into disease mechanisms and potential therapeutics for C9orf72-related amyotrophic lateral sclerosis/frontotemporal dementia

“…cortical folding, and microstructural anomalies on MRI imaging as early as their 30s, decades before expected symptom onset (Bertrand et al, 2018;Caverzasi et al, 2019). Besides, PreSxC9 exhibit declined gyrification in regions atrophied during the symptomatic phase (Caverzasi et al, 2019) as well as decreased grey matter volume, impaired white matter integrity and early disruption of connectivity network (Bertrand et al, 2018;Lee et al, 2017;Rohrer et al, 2015). Whether these alterations represent early neurodegeneration or neurodevelopmental defects is unclear.…”