Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

Abstract

Introduction: The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial frontotemporal dementia (FTD).

Methods: We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data-driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset.

Results: There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviorally relevant structural and functional network differences. Structure-function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non-carriers, and increased with proximity to the expected onset of disease.

Discussion: Our findings suggest that the maintenance of functional network connectivity enables carriers to maintain cognitive performance.

Keywords: frontotemporal dementia (FTD); functional magnetic resonance imaging (fMRI); network connectivity; presymptomatic.

Figure 1

Schematic representation of data processing and analysis pipeline to test for brain-behaviour differences between presymptomatic carriers (PSC) and non-carriers (NC) as a function of expected years to onset (EYO) of symptoms, while controlling for covariates of no interest (Covs). Brain structural measures were based on the mean grey matter volume (GMV) in 246 nodes, as defined in the Brainnetome atlas [35]. Brain functional measures were based on the functional connectivity between 15 nodes as part of four large-scale networks, which were defined in an independent cohort of 298 age-matched individuals part of the Cam-CAN dataset.

Figure 2

Visualisation of spatial localisation of the nodes part of the four large-scale networks and their mean functional connectivity (circular plot) across all participants in this study. Nodes and networks were defined in an independent cohort of 298 age-matched individuals part of the Cam-CAN dataset [30].The default mode network (DMN) contained five nodes: the ventral anterior cingulate cortex (vACC), dorsal and ventral posterior cingulate cortex (vPCC and dPCC), and right and left inferior parietal lobes (rIPL and lIPL). The salience network (SN) was defined using right and left anterior insular (rAI and lAI) and dorsal anterior cingulate cortex (dACC). The frontoparietal network (FPN) was defined using right and left anterior superior frontal gyrus (raSFG and laSFG), and right and left angular gyrus (rAG and lAG). The dorsal attention Network (DAN) was defined using right and left intraparietal sulcus (rIPS and lIPS).

Figure 3

Group differences between PSC and NC in grey matter volume (left panel) and functional connectivity between nodes within four large scale networks (right panel). Hot colour scheme indicates the strength of effect size of PSC showing higher GMV and FC than NC, while cold colour scheme indicates the opposite effect (i.e. NC > PSC).

Figure 4

PLS analysis of grey matter volume (GMV) and cognition indicating the spatial distribution of GMV loading values (a), where hot and cold colour schemes are used for the strength of positive and negative correlations with the profile of Cognitive LV (b). (c) The scatter plot on the left represents the relationship between subjects scores of GMV LV and Cognition LV for presymptomatic carriers (PSC) and non-carriers (NC). The scatter plots in the middle and right hand-side represent GMV-Cognition LV relationship as a function of expected years to onset (EYO, split in two groups, Near and Far, see text) in each genetic status group separately.

Figure 5

PLS analysis of functional connectivity and cognition indicating the connectivity pattern of loading values (a), where hot and cold colour schemes are used for the strength of positive and negative correlations with the profile of Cognitive LV (b). (c) The scatter plot on the left represents the relationship between subjects scores of Function LV and Cognition LV for presymptomatic carriers (PSC) and non-carriers (NC). The scatter plots in the middle and right hand-side represents Function-Cognition LV relationship as a function of expected years to onset (EYO split in two groups, Near and Far, see text) in each genetic status group separately. This is also represented using a bar chart in (d), where continuous and dashed lines indicate significance of effect differences and difference in differences, respectively. † and * denote significant tests at p-value < 0.05 (one-and two-sided, respectively).