Lombardi, Jolina

ABSTRACT Background and Objectives Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results Variant carriers ( n =147) and familial non-carriers ( n =113) did not differ in age (mean±SD, 25.9±3.2 years), sex (53% female), or number of visits (2.1±1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years ( b =-982.8mm 3 , SE=317.0, p= 0.0046, f 2 =0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines ( b =64.4mm 3 , SE=29.9, p= 0.035, f 2 =0.07). For MAPT and GRN , there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.

AbstractBackgroundPresymptomatic frontotemporal lobar degeneration (FTLD) mutation carriers as young as their thirties display gray matter (GM) deficits and alterations in the specific neural networks targeted during the symptomatic phase (Lee et al. NeuroImage Clin 2017; Bertrand et al. JAMA Neurol 2018). These studies raise the question of a potential neurodevelopmental role of pathogenic mutations in FTLD, yet sufficient research in young adults is lacking.MethodLeveraging 3T MRI brain scans from UCSF and the ALLFTD Consortia, we studied structural and functional connectivity alterations in 31 presymptomatic mutation carriers [PreSxAll; 12 C9orf72,13 MAPT, 6 GRN, mean age: 25.2±3.9, range 18‐30 years] and 28 demographically‐matched healthy controls [HC; mean age: 26.5±3.1, range 18‐30 years]. We performed voxel‐based morphometry (VBM) to compare GM volume between HC and PreSxAll, and HC and each mutation carrier subgroup using ANCOVA (SPM12). VBM statistical results were thresholded at a height of p<0.001 uncorrected or p<0.05 familywise error corrected. We used seed‐based task‐free functional MRI (tf‐fMRI) analysis to examine salience network (SN) and default mode network (DMN) connectivity. Single‐subject connectivity maps were analyzed using ANCOVA in SPM for group comparisons and masked to the relevant network. Tf‐fMRI results were thresholded at a height of p<0.05 and extent of p<0.05. For all analyses, nuisance covariates included age, sex, education, handedness, scanner and TIV (GM only).ResultWe found no significant GM differences between groups. PreSxAll showed regions of SN hyperconnectivity compared with HC, specifically in the bilateral insula, right superior frontal gyrus, bilateral midcingulate cortex, and the left cerebellum. Compared to controls, each mutation carrier subgroup featured SN hyperconnectivity within key network hubs, such as the insula and anterior cingulate cortex. The DMN showed no significant alterations for PreSxAll vs. HC. Scattered small clusters of DMN alterations were noted in subcortical regions and the cerebellum in presymptomatic C9orf72 and GRN.ConclusionDespite the absence of GM deficits in young adult FTLD mutation carriers, tf‐fMRI detected SN alterations in these carriers compared with healthy controls. Future studies focused on other neuroimaging measures will further explore differences in young adult FTLD mutation carriers.

AbstractBackgroundPresymptomatic C9orf72 expansion carriers show regions of low local gyrification index (lGI) as early as their thirties (Caverzasi et al. JNNP 2019) and regions of gyrification decline have been reported (van Veenhuijzen et al. Ann Neurol 2022). These findings raise the question as to whether abnormal gyrification represents a neurodevelopmental difference or early neurodegeneration in frontotemporal lobar degeneration (FTLD) mutation carriers. Yet, previous studies focusing on young adults is lacking and no study has explored gyrification in the two other common FTLD mutations, GRN and MAPT. Here, we analyzed lGI in young adult presymptomatic FTLD mutation carriers.MethodLGI quantifies buried cortex within the sulcal folds compared to the visible cortex on the outer surface, with larger values indicating more folding (Schaer et al. IEEE trans med imaging 2008). Mean lGI values, as measured by a parcel‐wise analysis implemented in FreeSurfer v.6.0, were compared between 31 presymptomatic (preSx) carriers (12 C9orf72, 13 MAPT, 6 GRN, mean age: 25.2 ± 3.91 years) and 28 demographically‐matched healthy controls (HC: mean age: 25.6 ± 3.8 years). We used ANCOVA to compare all presymptomatic carriers combined (preSxAll) and HC to identify regions with significant lGI differences regressing age, sex, education, handedness, total intracranial volume and scanner type as nuisance covariates. Significant group differences were analyzed by Dunnett’s post‐hoc tests between each mutation subgroup and HC (p<0.05).ResultCompared to HC, preSxAll had higher mean gyrification in the right caudal (F = 5.07, p = 0.03) and rostral anterior cingulate (F = 6.22, p = 0.17), and lower lGI in the left middle temporal gyrus (F = 4.22, p = 0.046). Within these regions, post‐hoc analyses showed that preSx GRN had greater gyrification in the right caudal anterior cingulate (t = 2.57, p = 0.039, 95% CI = [0.005, 0.248]) and preSx C9orf72 had lower lGI in the left middle temporal gyrus (t = ‐3.14, p = 0.009, 95% CI = [‐0.37, ‐0.04]) vs. HC.ConclusionYoung adult FTLD mutation carriers displayed higher gyrification in the right anterior cingulate and lower gyrification in the left middle temporal gyrus compared to HC. Future studies in children will confirm the extent to which these gyrification abnormalities represent neurodevelopmental differences.