Differential intrinsic functional connectivity changes in semantic variant primary progressive aphasia

Abstract

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by semantic memory deficits with relatively preserved motor speech, syntax, and phonology. There is consistent evidence linking focal neurodegeneration of the anterior temporal lobes (ATL) to the semantic deficits observed in svPPA. Less is known about large-scale functional connectivity changes in this syndrome, particularly regarding the interplay between affected and spared language networks that leads to the unique cognitive dissociations typical of svPPA. Using whole-brain, seed-based connectivity on task-free Magnetic Resonance Imaging (MRI) data, we studied connectivity of networks anchored to three left-hemisphere regions crucially involved in svPPA symptomatology: ATL just posterior to the main atrophic area, opercular inferior frontal gyrus, and posterior inferior temporal lobe. First, in 32 healthy controls, these seeds isolated three networks: a ventral semantic network involving anterior middle temporal and angular gyri, a dorsal articulatory-phonological system involving inferior frontal and supramarginal regions, and a third functional connection between posterior inferior temporal and intraparietal regions likely involved in linking visual and linguistic processes. We then compared connectivity strength of these three networks between 16 svPPA patients and the 32 controls. In svPPA, decreased functional connectivity in the ventral semantic network correlated with weak semantic skills, while connectivity of the network seeded from the posterior inferior temporal lobe, though not significantly different between the two groups, correlated with pseudoword reading skills. Increased connectivity between the inferior frontal gyrus and the superior portion of the angular gyrus suggested possible adaptive changes. Our findings have two main implications. First, they support a functional subdivision of the left IPL based on its connectivity to specific language-related regions. Second, the unique neuroanatomical and linguistic profile observed in svPPA provides a compelling model for the functional interplay of these networks, being either up- or down- regulated in response to disease.

Keywords: Functional connectivity; Language; Parietal lobe; Primary progressive aphasia; Resting-state connectivity.

Fig. 1

Atrophy pattern in svPPA patients. The map was thresholded at p(FWE) < .05 using a permutation approach, and is shown on a rendered surface of the Montreal Neurological Institute (MNI) template. Colorbar represents T-score.

Fig. 2

Functional connectivity networks in healthy controls (p < .05, FWE corrected; height threshold T = 5.88). Right upper panel shows the location of the three seeds in the left opIFG (red), left aMTG (green), and the left pITG (blue). Arrows point to the network revealed by each of these seeds. Left hemispheres are shown.

Fig. 3

The three language networks in the two subject groups. Networks are colored according to the colors of the seeds shown in Fig. 2: opIFG network (red); aMTG network (green); pITG network (blue). Maps in HC, (panel A) are thresholded at p < .05, FWE corrected (height threshold T = 5.88), and voxel-wise at p < .001 for the svPPA patients (height threshold T = 3.73, panel B) to account for the smaller number of svPPA patients. A surface rendering, as well as coronal IPL sections, is shown for the left hemisphere.

Fig. 4

Comparison of functional connectivity between svPPA patients and HC. SvPPA patients showed stronger connectivity with the opIFG seed in the upper part of the angular gyrus (panel A). Decreased connectivity with the aMTG seed was found in the lower part of the angular gyrus (panel B). Results were thresholded voxel-wise at p < .01 and corrected for family-wise error rate p < .05 at cluster level. Seeds are shown as red (opIFG seed) and green (aMTG seed) boxes on the surface rendering of the left hemisphere. Coronal IPL sections are shown for the left hemisphere.

Fig. 5

Functional connectivity-behavioral correlations. Panel A highlights the dissociation of the language networks by showing that patients' performance only on the PPVT score significantly correlated with functional connectivity in the aMTG-to-AG network, while performance on Pseudoword reading correlated with pITG-to-IPS connectivity. The horizontal axis displays the Spearman correlation coefficients, and the vertical axis lists the names of the behavioral measures. Panel B shows the scatter plots of the significant correlations. The % of correct items in the behavioral scores (horizontal axes) were plotted against the residual of the functional connectivity scores after removing the effect of disease severity through the CDR score. The reported p-value is not corrected for multiple comparisons due to the small sample size.