Different patterns of functional network reorganization across the variants of primary progressive aphasia: a graph-theoretic analysis

Abstract

Primary progressive aphasia (PPA) is a neurodegenerative syndrome with three main variants (nonfluent, logopenic, semantic) that are identified primarily based on language deficit profiles and are associated with neurotopographically distinct atrophic patterns. We used a graph-theoretic analytic approach to examine changes in functional network properties measured with resting-state fMRI in all three PPA variants compared with age-matched healthy controls. All three variants showed a more segregated network organization than controls. To better understand the changes underlying the increased segregation, we examined the distribution of functional "hubs". We found that while all variants lost hubs in the left superior frontal and parietal regions, new hubs were recruited in different areas across the variants. In particular, both logopenic and semantic variants recruited significant numbers of hubs in the right hemisphere. Importantly, these functional characteristics could not be fully explained by local volume changes. These findings indicate that patterns of functional connectivity can serve as further evidence to distinguish the PPA variants, and provide a basis for longitudinal studies and for investigating treatment effects. This study also highlights the utility of graph-theoretic approaches in understanding the brain's functional reorganization in response to neurodegenerative disease.

Trial registration: ClinicalTrials.gov NCT02606422.

Keywords: Graph theory; Network analysis; Primary progressive aphasia; Resting-state functional connectivity.

Conflict of interest statement

Disclosure statement

The authors declare no potential of actual conflicts of interest.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Figure 1.. Regions-of-interest (ROI) parcellation and atrophy.

a) A lateral view of the atlas used for the parcellation (76 ROIs, the same 38 ROIs in each hemisphere. See section 2.3). ROIs that are visible on this view are labelled.b) Comparison of the grey matter volumes of the 76 ROIs between HC (N=17) and each variant (nfv N=18, lv N=15, sv N=9). The color scale indicates the t-value, thresholded by one-tailed p-values < 0.01 (uncorrected). Left hemisphere is on the left and the right is on the right.

Figure 2.. Graph-theoretic measures for which PPA groups exhibited statistically significant differences from the healthy control (HC) group.

a) Left to right: characteristic path length, mean clustering coefficient, andmodularity(i), all indicate that the PPA group had greater segregation (or lower integration) than the HC group. No difference was found among the three PPA variants. See Table 2 for results for all graph-theoretic measures evaluated. The boxplots show the lower to upper quartile of the data with a line indicating the median, the diamonds indicate the mean. *: p<0.05; **: p<0.01 Bonferroni corrected.b) ROIs that show higher nodal clustering coefficient in PPA than HC. The node sizes are proportional to the t-values and the colors indicate their module membership as in Supp Fig. 1. The nodes are found in three modules. Note that we color-code the module membership only to facilitate visual inspection and that module membership is not considered in this analysis.SFG_pole: superior frontal gyrus pole; SFG_PFC: superior frontal gyrus (prefrontal cortex), MFG: middle frontal gyrus, PCC: posterior cingulate cortex, IFG_tria: inferior frontal gyrus triangluaris, RG: rectus gyrus, LFOG: lateral frontal orbital gyrus.

Figure 3.. Connector hub distributions.

a) Connector hubs identified in the healthy control (HC) group which correspond to ROIs with the highest participation coefficient (PC) scores across the whole brain (>1SD above the mean). b) Connector hubs identified for each variant group, top to bottom: non-fluent (nfvPPA), logopenic (lvPPA), semantic (svPPA). Compared to the HC, all three variants “lost” the left SFG and the left SPG (circled) and the bilateral S/MTG are retained (circled). On the right panel the new hubs (present in PPA but not in the HC) for each variant are shown.SFG: superior frontal gyrus, SPG: superior parietal gyrus, S/MTG: superior/middle and temporal gyri, MFG: middle frontal gyrus, MFG_DPFC: middle frontal dorsal prefrontal cortex. ITG: inferior temporal gyrus, FuG: fusiform gyrus, PrCG: precentral gyrus, PrCu: precuneus.

Figure 4.. Global connectivitiy (PC) and gray matter volume of the lost, retained and new connector hubs.

a) Comparison of PC values between healthy controls (HC) and PPA. For the two lost hubs shared by all variants (see Fig. 3), PPA had significantly lower average PC (p=0.028). For the four retained hubs that were also shared by all variants (see Fig. 3), PPA did not differ from the HC in terms of average PC (p=0.88). For the new hubs of each variant (see Fig. 3b), all variants showed higher (or numerically higher) PC values than HC (Top to bottom: nfv: p=0.25; lv:p=0.0384; sv: p=0.0408, Bonferroni corrected). b) Comparison of gray matter volume: Compared to the HC group, the PPA group showed marginally smaller volume (p=0.06) for the lost hubs and also significantly smaller volume for the retained hubs (p=0.0006). No significant differences between the groups was found for the new hubs. The boxplots show the lower to upper quartile of the data with a line indicating the median, the diamonds indicate the mean.c) Correlations between hub connectivity (PC, y-axis) and volume (x-axis) for the three types of hubs combining all PPA variants (N=42).~: p<0.1, *: p<0.05, **: p<0.01, ***: p<0.001.