Genetic Frontotemporal Dementia Initiative’s scientific contributions

BACKGROUND AND AIMS: A robust feature characterizing frontotemporal dementia from other dementias are early deficits in social cognition. The salience and default networks, comprising groups of brain regions studied using resting-state functional connectivity (RSFC), are linked to the processing of emotionally salient stimuli and inferring others’ mental states, respectively. Recently, differences across presymptomatic frontotemporal dementia groups have been detected in RSFC and empathy separately. The present study evaluates the relationship between RSFC and empathy in presymptomatic frontotemporal dementia. We hypothesize that empathy-associated patterns of RSFC may be sensitive to group differences in the presymptomatic phase of frontotemporal dementia. METHODS: The GENFI cohort recruited 840 presymptomatic adults (Mage=44y±13; 59%F, 41%M) including pathogenic mutation carriers C9orf72 (n=180), GRN (n=178), MAPT (n=72) and non-mutation carriers (NMC, n=410). RSFC data was processed using CONN and divided into networks using a parcellation method based on the Yeo 17 network solution. A subsample completed the modified Interpersonal Reactivity Index, a measure of empathy comprising the emotional concern and perspective-taking subscales. Partial least squares, a multivariate analysis, was conducted to evaluate group differences in patterns of RSFC as well as empathy-RSFC relationships. RESULTS: A distributed pattern of RSFC dissociated NMC from the mutation carrier groups, revealing a number of edge-level differences (20.08% covariance explained, p=.02). The salience and default networks emerged as part of the broad pattern of RSFC differences. Additionally, stronger within salience network RSFC contrasted C9orf72 from GRN (31.08% covariance explained, p=0.04). As hypothesized, empathy-related patterns of RSFC revealed group differences (23.95% covariance explained, p=.04). Specifically, GRN exhibited a positive relationship between empathy and RSFC in both salience and default networks. CONCLUSIONS: We provide evidence that networks associated with social cognition revealed group differences among presymptomatic frontotemporal dementia groups and that the GRN genetic group may show stronger empathy-related associations with these networks. Early between group differences among presymptomatic mutation carriers allude to variability in disease progression and trajectory prior to onset of clinical frontotemporal dementia. Future longitudinal work examining the relationship between social cognition and RSFC change over time may provide greater sensitivity for identifying at-risk individuals converting to early stage frontotemporal dementia. ACKNOWLEDGEMENTS AND FUNDING: This research was undertaken thanks in part to funding from the Canada First Research Excellence Fund and Fonds de recherche du Québec, awarded to the Healthy Brains, Healthy Lives initiative at McGill University.

INTRODUCTION. The salience network (SN) is central for processing salient stimuli and plays an interactive role with neurocognitive networks relevant to goal-oriented behaviour. A robust feature characterising frontotemporal dementia (FTD) from other dementias are early deficits in social cognition and atrophy in the anterior insula (aINS). Resting-state functional connectivity (RSFC) of aINS, a core SN node, has been associated with FTD disease progression and disease severity. We investigated the interaction between RSFC and aINS cortical thickness across non-symptomatic and symptomatic FTD groups. METHODS. Adult participants (N=981; mean age=48.9y±14; 55%F, 45%M) of a first-degree relative with a known pathogenic mutation were recruited as part of a large-scale, multi-site genetic FTD initiative. The sample comprised healthy control non-mutation carriers (n=374) and mutation carriers (presymptomatic n=392; symptomatic n=215). A common MRI protocol was used. T2-weighted single echo planar imaging sensitized to BOLD for resting-state fMRI data (TRs: 2200-2500ms; TE: 30ms; voxel dimension range 2.7-3.4mm) were processed in CONN toolbox (v.21a) and segmented into 200 parcels (Schaeffer et al., 2017) using the Yeo-17 network solution. T1-weighted anatomical scans from the GENFI protocol were processed in Freesurfer (v.7.3.2). Partial least squares was conducted to identify differences in patterns of RSFC between groups. The significance of each latent variable was determined by permutation testing (1000 permutations) and its reliability with bootstrap resampling (1000 bootstraps). The aINS cortical thickness was averaged between hemispheres and compared between groups with ANCOVA. A second PLS analysis was performed to determine the association between INS cortical thickness and RSFC between groups. RESULTS. A distributed pattern of RSFC dissociated the non-symptomatic groups from the symptomatic FTD group (Figure C; 93.55% covariance explained, p<.0001). Of note, presymptomatic FTD patients had weaker RSFC within the SN. Because the aINS is a central processing hub of the SN, we next examined aINS cortical thickness between groups. The symptomatic FTD group had lower aINS cortical thickness than both non-symptomatic groups (F(1,544)=37.37, p<.001, ηp2=.12, Figure B). To examine how aINS cortical thickness was related to RSFC, we conducted a second PLS analysis. A single latent variable emerged (Figure D; 39.58% covariance explained, p=0.05), driven by the presymptomatic FTD group, which revealed that aINS thickness is associated with both higher and lower magnitude RSFC across the brain. CONCLUSIONS. We provide evidence that early structural differences are related to functional differences in symptomatic FTD. Weaker within-network connectivity potentially reflects disruption to efficient brain organization in FTD. The aINS and the broader SN, most prominently affected, has been linked to deficits in social cognition both in FTD and non-clinical samples. The association between structure and function in symptomatic FTD may thus reveal a disease-specific pathological process specifically disrupting communication between neurocognitive networks central to executive control and decision-making.

(Awarded Best Poster at 5th Annual Healthy Brains, Healthy Lives 2023 Research Symposium). BACKGROUND AND AIM. The salience network (SN), comprising the anterior insula, dorsal anterior cingulate and other structures, is central in the processing of emotionally salient stimuli and directly influences other neurocognitive networks relevant to goal-oriented behaviours. A robust feature specifically characterising clinical frontotemporal dementia (FTD) are deficits in social cognition and atrophy to the insula, which has been associated with core FTD symptoms such as loss of empathy. Furthermore, changes in insular resting-state functional connectivity (RSFC) have been associated with FTD disease progression and disease severity. We investigated differences in measures of both social cognition and RSFC in non-mutation carriers (NMC), presymptomatic mutation carriers (PMC) and symptomatic mutation carriers (SMC). METHODS. Nine hundred adult participants of a first-degree relative with a known pathogenic mutation in MAPT, GRN, or C9orf72 were recruited as part of a large-scale genetic FTD initiative among research centres across Europe and Canada. One-third of the sample comprised SMC and two-thirds were classified as at-risk PMC or NMC. A common MRI protocol of structural and functional MRI was used across sites. Resting state data was processed using the CONN toolbox default pipeline (v. 21a) based on SPM12 in Matlab 2021b. We conducted partial-least squares (PLS)mcgto identify differences in the RSFC patterns between NMC, PMC, SMC groups. Measures of social cognition (MiniSEA, Interpersonal Reactivity Index, Revised Self-Monitoring Scale, Faux Pas Recognition Test, Ekman 60 Faces) were collected in a subsample of participants (n = 448) and analysis of covariance (ANCOVA) was conducted to evaluate differences between groups. RESULTS. The PLS analysis revealed a significant latent variable that dissociated patterns of RSFC in the NMC and PMC groups from SMC (p < .001). Robust differences were observed in the SN, with reduced coupling among distributed nodes in the symptomatic FTD patients. The ANCOVAs on social cognition scores reflected similar between group differences, with higher mean scores in the NMC and PMC groups compared to the SMC group. Baseline differences were not detected between the NMC and PMC groups. CONCLUSIONS. RSFC differences, particularly within the SN, distinguished symptomatic FTD from non-symptomatic FTD. Similar between group differences were observed in social cognition. FTD presents with characteristics resembling other neurological or psychiatric disorders and is thus a challenge for diagnosis and disease staging9 reflecting a need for more refined diagnostic processes. The findings of this study provide insight into FTD disease staging. Future longitudinal work examining pathogenic mutations may provide greater sensitivity in identifying individuals at risk for developing FTD symptoms.