Mild behavioral impairment in Parkinson's disease is associated with altered corticostriatal connectivity

Abstract

Background: Mild behavioral impairment (MBI) is a syndrome characterized by later life onset, sustained neuropsychiatric symptoms as a marker of dementia risk. In Parkinson's disease (PD), MBI has been associated with worse cognitive abilities and increased cortical atrophy. However, the circuit level correlates of MBI have not been investigated in this population. Our objective was to investigate the relationship between MBI and corticostriatal connectivity in PD patients. This emphasis on corticostriatal connectivity was due to the significant role of these circuits in neuropsychiatric and cognitive symptoms across disease conditions.

Methods: Seventy-four non-demented patients with PD were administered the MBI-checklist, and classified as having high MBI (PD-MBI; n = 21) or low MBI scores (PD-noMBI; n = 53). Corticostriatal connectivity was assessed with both an atlas and seed-based analysis. The atlas analysis consisted of calculating the average connectivity between the striatal network and the default mode (DMN), central executive (CEN), and saliency networks (SAN). Structural measurements of cortical thickness and volume were also assessed. PD-MBI and PD-noMBI patients were compared, along with a group of age matched healthy control subjects (HC; n = 28). Subsequently, a seed analysis assessed the relationship of MBI scores with the connectivity of twelve seeds within the striatum while controlling for cognitive ability. A complementary analysis assessed the relationship between striatal connectivity and cognition, while controlling for MBI-C.

Results: PD-MBI demonstrated decreased connectivity between the striatum and both the DMN and SAN compared to PD-noMBI and HC. The decreased connectivity between the striatum and the SAN was explained partly by increased atrophy within the SAN in PD-MBI. The seed analysis revealed a relationship between higher MBI scores and lower connectivity of the left caudate head to the dorsal anterior cingulate cortex and left middle frontal gyrus. Higher MBI-C scores were also related to decreased connectivity of the right caudate head with the anterior cingulate cortex, precuneus, and left supramarginal gyrus, as well as increased connectivity to the left hippocampus and right cerebellar hemisphere. Caudate-precuneus connectivity was independently associated with both global behavioural and cognitive scores.

Conclusion: These results suggest PD-MBI is associated with altered corticostriatal connectivity, particularly between the head of the caudate and cortical regions associated with the DMN and SAN. In particular, caudate-precuneus connectivity is associated with both global behavioral and cognitive symptoms in PD.

Keywords: Basal ganglia; Cognition; Corticostriatal connectivity; Default mode network; Mild behavioral impairment; Parkinson's disease; Resting state.

Fig. 1

Regions of interest for Atlas-based analysis. A) Default mode network (DMN); B) Central executive network (CEN); C) Saliency network (SAN); D) Striatal network. All networks adopted from (Lang et al., 2019).

Fig. 2

Striatal subdivisions for seed-based analysis, adopted from a model-based functional parcellation (Janssen et al., 2015). This parcellation included 12 regions of interest (six per hemisphere): (1) caudate tail, (2) caudate head, (3) ventral striatum, (4) anterior putamen, (5) dorsal putamen, and (6) posterior putamen.

Fig. 3

Group differences in Striatal-Cortical Network connectivity. A) Striatal network to DMN connectivity; B) Striatal network to SAN connectivity; C) Striatal network to CEN connectivity. Welch's ANOVA controlling for education with significance set at p < 0.0167. Post-hoc comparison using Games-Howell test with significance set at p < 0.05. All direct post-hoc comparisons between PD-MBI and PD-noMBI adjusted for the effect of UPDRS-III. For visualization, the diameter of each data point is representative of the MBI-C score: large data points equal higher scores.

Fig. 4

Relationship between MBI-C and striatal subdivision connectivity, adjusting for MoCA and UPDRS-III. A) Seed: Left caudate head. MBI-C was independently associated with left caudate head connectivity to the dorsal ACC (cluster 1) and the left MFG (cluster 2); B) Seed: Left dorsal putamen. MBI-C was independently associated with left dorsal putamen connectivity to the left ITG (cluster 1). Panels (left to right) represent: (1) 3-D volume rendering of significant clusters; (2) selected axial and sagittal slices for visualization; and (3) extracted relationship between MBI-C and connectivity for each cluster (seeTable 2for cluster details).

Fig. 5

Relationship between MBI-C and right caudate head connectivity, adjusting for MoCA and UPDRS-III. MBI-C was independently associated with right caudate head connectivity to the precuneus/SOC (cluster 1), the dorsal ACC (cluster 2), left SMG/AG (cluster 3), right preCG (cluster 4), left pHG (cluster 5), and right cerebellar hemisphere (cluster 6). Panels (left to right) represent: (1) 3-D volume rendering of significant clusters; (2) selected axial and sagittal slices for visualization; and (3) extracted relationship between MBI-C and connectivity for each cluster (seeTable 2for cluster details).

Fig. 6

Relationship between MoCA and striatal subdivision connectivity, adjusting for MBI-C and UPDRS-III. A) Seed: Left caudate head. MoCA was independently associated with left caudate head connectivity to the left OP/LG (cluster 1), precuneus/SOC (cluster 2), and the left IOC (cluster 3); B) Seed: Right caudate head. MoCA was independently associated with right caudate head connectivity to the precuneus/SOC (cluster 1), and the right OP/IOC/FG (cluster 2). Panels (left to right) represent: (1) 3-D volume rendering of significant clusters; (2) selected axial and sagittal slices for visualization; and (3) extracted relationship between MBI-C and connectivity for each cluster (seeTable 3for cluster details).