(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.

Frontotemporal dementia (FTD) is a neurodegenerative disease impacting 50% of people with dementia under the age of 60. A core feature of FTD is a deficit in social cognition. The salience network, a functionally connected assembly of brain regions including the anterior insula (aINS) and anterior cingulate, is impacted by FTD. The Genetic FTD Initiative (GENFI) participants (n=949, females=520, males=429, mean age=48.75 +/- 14 years) includes patients and family members with FTD-associated pathogenic mutations. Baseline analyses showed lower volume of the aINS and lower social cognitive functioning in symptomatic mutation carriers compared to both presymptomatic and healthy controls. In FTD patients, aINS volume was correlated with social cognition scores (r=0.36, p<0.01). Future research mapping the longitudinal relationship between social cognition and the salience network may provide novel insights into FTD onset and progression to expand treatment windows for improved intervention outcomes.

The intrinsic functional organization of the brain changes into older adulthood. Age differences are observed at multiple spatial scales, from global reductions in modularity and segregation of distributed brain systems, to network-specific patterns of dedifferentiation. Whether dedifferentiation reflects an inevitable, global shift in brain function with age, circumscribed, experience-dependent changes, or both, is uncertain. We employed a multimethod strategy to interrogate dedifferentiation at multiple spatial scales. Multi-echo (ME) resting-state fMRI was collected in younger (n = 181) and older (n = 120) healthy adults. Cortical parcellation sensitive to individual variation was implemented for precision functional mapping of each participant while preserving group-level parcel and network labels. ME-fMRI processing and gradient mapping identified global and macroscale network differences. Multivariate functional connectivity methods tested for microscale, edge-level differences. Older adults had lower BOLD signal dimensionality, consistent with global network dedifferentiation. Gradients were largely age-invariant. Edge-level analyses revealed discrete, network-specific dedifferentiation patterns in older adults. Visual and somatosensory regions were more integrated within the functional connectome; default and frontoparietal control network regions showed greater connectivity; and the dorsal attention network was more integrated with heteromodal regions. These findings highlight the importance of multiscale, multimethod approaches to characterize the architecture of functional brain aging.

The intrinsic network architecture of the brain is continuously shaped by biological and behavioral factors from younger to older adulthood. Differences in functional networks can reveal how a lifetime of learning and lived experience can alter large-scale neurophysiological dynamics, offering a powerful lens into brain and cognitive aging. Quantifying these differences has been hampered by significant methodological challenges. Here, we use multi-echo fMRI and multi-echo ICA processing, individualized cortical parcellation methods, and multivariate (gradient and edge-level) functional connectivity analyses to provide a definitive account of the intrinsic functional architecture of the brain in older adulthood. Twenty minutes of resting-state multi-echo fMRI data were collected in younger (n=181) and older (n=120) adults. Dimensionality, the number of independent, non-noise BOLD components in the fMRI signal, was significantly reduced for older adults. Macroscale functional gradients were largely preserved. In contrast, edge-level functional connectivity was significantly altered. Within-network connections were weaker while connections between networks were stronger for older adults, and this connectivity pattern was associated with lower executive control functioning. Greater integration of sensory and motor regions with transmodal association cortices also emerged as a prominent feature of the aging connectome. These findings implicate network dedifferentiation, reflected here as reduced dimensionality within the BOLD signal and altered edge-level connectivity, as a global and putatively maladaptive feature of functional brain aging. However, greater coherence among specific networks may also signal adaptive functional reorganization in later life. By overcoming persistent and pervasive methodological challenges that have confounded previous research, the results provide a comprehensive account of the intrinsic functional architecture of the aging brain.