Advancing functional dysconnectivity and atrophy in progressive supranuclear palsy

Abstract

Progressive supranuclear palsy syndrome (PSP-S) results from neurodegeneration within a network of brainstem, subcortical, frontal and parietal cortical brain regions. It is unclear how network dysfunction progresses and relates to longitudinal atrophy and clinical decline. In this study, we evaluated patients with PSP-S (n = 12) and healthy control subjects (n = 20) at baseline and 6 months later. Subjects underwent structural MRI and task-free functional MRI (tf-fMRI) scans and clinical evaluations at both time points. At baseline, voxel based morphometry (VBM) revealed that patients with mild-to-moderate clinical symptoms showed structural atrophy in subcortex and brainstem, prefrontal cortex (PFC; supplementary motor area, paracingulate, dorsal and ventral medial PFC), and parietal cortex (precuneus). Tf-fMRI functional connectivity (FC) was examined in a rostral midbrain tegmentum (rMT)-anchored intrinsic connectivity network that is compromised in PSP-S. In healthy controls, this network contained a medial parietal module, a prefrontal-paralimbic module, and a subcortical-brainstem module. Baseline FC deficits in PSP-S were most severe in rMT network integrative hubs in the prefrontal-paralimbic and subcortical-brainstem modules. Longitudinally, patients with PSP-S had declining intermodular FC between the subcortical-brainstem and parietal modules, while progressive atrophy was observed in subcortical-brainstem regions (midbrain, pallidum) and posterior frontal (perirolandic) cortex. This suggested that later-stage subcortical-posterior cortical change may follow an earlier-stage subcortical-anterior cortical disease process. Clinically, patients with more severe baseline impairment showed greater subsequent prefrontal-parietal cortical FC declines and posterior frontal atrophy rates, while patients with more rapid longitudinal clinical decline showed coupled prefrontal-paralimbic FC decline. VBM and FC can augment disease monitoring in PSP-S by tracking the disease through stages while detecting changes that accompany heterogeneous clinical progression.

Keywords: Intrinsic connectivity network; Longitudinal; Modularity; Progressive supranuclear palsy.

Fig. 1

Rostral midbrain tegmentum-anchored intrinsic connectivity network configuration in healthy control subjects. A. The 27 regions comprising the network, colored according to their membership in Module 1 (blue), Module 2 (red), or Module 3 (green). B. Group mean functional connectivity matrix at baseline (upper triangle) and longitudinal follow-up (lower triangle). Nodes are ordered according to module membership. C. Spring-embedded graph illustrates the modular connectivity of the network. D. Scatter plot of each node's within-module functional connectivity strength vs. its between-module functional connectivity strength. The nodes with the highest combination of intramodular and intermodular connectivity, the hubs, are located in the thalamus, paracingulate cortex, and posterior midcingulate cortex. The other major nodes with high intermodular connectivity, the connector hubs, are the basal ganglia (Module 3 to Module 2) and anterior cingulate cortex (Module 2 to Module 1). PreCu: precuneus, RSC: retrosplenial cortex, pMCC: posterior midcingulate cortex, MFG: middle frontal gyrus, paracing: paracingulate cortex, SMG: supramarginal gyrus, pACC: pregenual anterior cingulate cortex, Ins: insula, BG: basal ganglia, Thal: thalamus, MTJ: mesothalamic junction, rosPons: rostral pons, cauPons: caudal pons; DentN: dentate nucleus, Vermis: cerebellar vermis. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Intra and intermodular mean functional connectivity strengths at baseline and follow-up for PSP-S patients and healthy controls. Significant baseline reductions in PSP-S patients with respect to controls (*, p < 0.0083) were detected for module 1 to module 2, intra-module 2, module 2 to module 3, and intra-module 3. A significant longitudinal decline in PSP-S patients was found for module 1 to module 3.

Fig. 3

Baseline differences in whole brain functional connectivity and tissue volume. A. Whole brain weighted degree deficits in PSP-S with respect to healthy controls, shown with and without correction for voxelwise gray matter volume (green and blue, respectively). The strongest reductions were found in the right inferior frontal gyrus, insula, middle frontal gyurs, precuneus, and caudate. Voxels that showed reduction after atrophy correction (AC; green) were nearly a perfect subset of voxels showing reduction with no AC (blue) and are therefore shown superimposed on top of the no AC map. B. Voxel based morphometry volume reductions in PSP-S were apparent in gray matter areas including the paracingulate cortex, supplementary motor area, and precuneus; and white matter areas including the mesothalamic junction and corona radiata. C. The 27 rMT-ICN regions shown for anatomical correspondence with functional and structural deficits. AC: atrophy correction. GM: gray matter. WM: white matter. Colorbars indicate t-statistic range. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Group-level longitudinal atrophy in PSP-S with respect to healthy controls. A. Longitudinal atrophy compared to controls was identified in the perirolandic gray and white matter, pallidum, and midbrain. GM: gray matter. WM: white matter. Colorbars indicate t-statistic range.

Fig. 5

Longitudinal atrophy that correlates with clinical worsening. A. Areas where gray or white matter longitudinal atrophy negatively correlate with PSPRS baseline score included the perirolandic cortex, supplementary motor area, midcingulate cortex, thalamus, midbrain, corona radiata, superior longitudinal fasicuclus, and superior cerebellar peduncle. Line plot shows mean VBM change (longitudinal atrophy) in the gray matter map as a function of increasing PSPRS baseline. GM: gray matter. WM: white matter. Colorbars indicate t-statistic range. (For interpretation of the references to color in this figure, the reader is referred to the web version of this article.)