Dopaminergic pathways and resting-state functional connectivity in Parkinson's disease with freezing of gait
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-...
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|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.
|Gefördert durch den Open-Access-Publikationsfonds der UB Marburg.