Dopaminergic pathways and resting-state functional connectivity in Parkinson's disease with freezing of gait

Abstract

Freezing of gait is a common phenomenon of advanced Parkinson's disease. Besides locomotor function per se, a role of cognitive deficits has been suggested. Limited evidence of associated dopaminergic deficits points to caudatal denervation. Further, altered functional connectivity within resting-state networks with importance for cognitive functions has been described in freezers. A potential pathophysiological link between both imaging findings has not yet been addressed. The current study sought to investigate the association between dopaminergic pathway dysintegrity and functional dysconnectivity in relation to FOG severity and cognitive performance in a well-characterized PD cohort undergoing high-resolution 6-[18F]fluoro-L-Dopa PET and functional MRI. The freezing of gait questionnaire was applied to categorize patients (n = 59) into freezers and non-freezers. A voxel-wise group comparison of 6-[18F]fluoro-L-Dopa PET scans with focus on striatum was performed between both well-matched and neuropsychologically characterized patient groups. Seed-to-voxel resting-state functional connectivity maps of the resulting dopamine depleted structures and dopaminergic midbrain regions were created and compared between both groups. For a direct between-group comparison of dopaminergic pathway integrity, a molecular connectivity approach was conducted on 6-[18F]fluoro-L-Dopa scans. With respect to striatal regions, freezers showed significant dopaminergic deficits in the left caudate nucleus, which exhibited altered functional connectivity with regions of the visual network. Regarding midbrain structures, the bilateral ventral tegmental area showed altered functional coupling to regions of the default mode network. An explorative examination of the integrity of dopaminergic pathways by molecular connectivity analysis revealed freezing-associated impairments in mesolimbic and mesocortical pathways. This study represents the first characterization of a link between dopaminergic pathway dysintegrity and altered functional connectivity in Parkinson's disease with freezing of gait and hints at a specific involvement of striatocortical and mesocorticolimbic pathways in freezers.

Keywords: Freezing of gait; Functional connectivity; Molecular connectivity; Multimodal imaging; PET.

Graphical abstract

Fig. 1

Schematic representation of the workflow of molecular connectivity and resting-state functional connectivity analyses applied to FDOPA-PET scans and fMRI scans of FOG+ and FOG- patients in the current study. Initially, a group comparison of FDOPA-PET scans was performed between FOG+ and FOG- patients, which revealed more profound dopaminergic deficits in FOG+ patients. Seed regions of interest (ROIs) for subsequently performed functional connectivity analyses were placed based on the hypodopaminergic regions or represented atlas-based definitions of dopaminergic midbrain nuclei. Mean tracer uptake of regions constituting the mesocorticolimbic system (AALv3) was extracted from normalized FDOPA-PET scans and ROI-wise correlations were calculated between the seed ROI‘s tracer uptake and every other ROI to obtain covariant dopaminergic pathways. Resulting correlations were compared between FOG+ and FOG- patients by fisher’s z test to evaluate impairments in dopaminergic pathway integrity in FOG. Significant differences in correlation coefficients were visualized by a connectogram. Similarly, mean BOLD time series were extracted from defined seed ROIs for each subject and voxel-wise correlations were examined and compared between both patient groups for the whole brain.

Fig. 2

(A) Results of voxel-wise two-sample t-test of FDOPA-PET with the contrast FOG+<FOG- (p_FWE < 0.05). FOG + patients display lower dopamine metabolism in the left caudate nucleus. Coordinates in respective planes are displayed above. (B) Multiple boxplots with group comparisons of BP_d in the left caudate between FOG+ and FOG- patients in left- respectively right-lateralized individuals. * indicate significance at p < 0.05 in Welch’s t-test. (C) Boxplot with group comparison of BP_d in the left caudate between left and right lateralized FOG+ patients.

Fig. 3

Connectogram with atlas based ROIS (AALv3) of mesocortical and mesolimbic dopamine pathways with the bilateral VTA as seed volume. Solely the significantly reduced interregional correlations in FOG+ compared to FOG- are displayed (p-values after FDR-correction for multiple testing). Differences in z-values after Fisher’s z-test are indicated by color scale, lower values indicate higher impairment of connectivity in FOG+ . Abbreviations: L/R: left/right, ACC: anterior cingulate cortex, ACC: anterior cingulate cortex, MCC: mid cingulate cortex, PCC; posterior cingulate cortex, HIP: hippocampus, PHG: parahippocampal gyrus, AMYG: amygdala, NAcc: nucleus accumbens, SFG: dorsolateral superior frontal gyrus, SFGmed: medial superior frontal gyrus, PFCventmed: ventromedial prefrontal gyrus, IFGorb: orbital inferior frontal gyrus, OFC: orbitofrontal cortex.

Fig. 4

Results of rs-fMRI analysis with the applied contrast FOG+FWE < 0.05). (A) Increased functional connectivity between left caudate nucleus and bilateral visual cortex, and (B) increased functional connectivity between bilateral VTA and bilateral precuneus, bilateral superior lateral occipital cortex and right superior frontal gyrus was observed in freezers.