Objective: To investigate the involvement of dopaminergic systems in Parkinson’s disease (PD) patients with freezing of gait (FOG) using a multimodal assessment involving ¹⁸ F-DOPA-PET and resting state-fMRI.

Background: FOG is a common phenomenon of advanced PD and has been shown to severely affect the quality of life of patients^1,2. It has been thoroughly studied by ¹⁸ FDG-PET imaging as well as fMRI. A growing body of evidence suggests involvement of frontal executive, visuospatial, limbic and locomotor networks with right hemispheric predominance. The reported changes in functional connectivity between and within these networks have been various. A multimodal approach combining DOPA-PET and fMRI modalities might shed further light on the underlying mechanisms.

Method: We compared a subset of 29 PD patients with FOG (FOG+) with one of 33 Patients without FOG (FOG-), who did not significantly differ in disease duration, using ¹⁸ F-DOPA-PET and rs-fMRI. The Freezing of Gait Questionnaire (FOG-Q) was used to identify FOG+ patients as well as to assess FOG severity. A whole brain group comparison of the PET scans was performed, followed by a seed-to-voxel resting state fMRI approach using masks obtained in the PET analysis to identify differences in functional connectivity (FC).

Results: Impaired dopamine metabolism in FOG+ compared with FOG- patients occurred in the left caudate nucleus and in both left and right ventral tegmental areas (VTA).¹⁸F-DOPA uptake in the left VTA was inversely correlated with FOG severity among PD patients. The fMRI analysis revealed reduced functional connectivity (FC) between the left VTA and the left ventromedial prefrontal cortex. FC in this part of the mesocortical dopamine system was significantly correlated with FOG severity as well.

Conclusion: We demonstrated an impaired dopamine uptake and functional connectivity in the left mesocortical dopamine system, which is strongly associated with prefrontal function³, in a well-defined cohort, using a multimodal imaging approach. A common limitation of past studies was a significantly longer disease duration in FOG+ patients, which did not occur in our cohort. The reported mesocortical pathway alterations correlated with FOG severity. This aligns well with the previous findings that FOG+ patients perform poorer in executive tasks^4,5 and that an abnormal FC of frontal networks contributes to FOG^6,7.

References: 1. Giladi, N. et al. Freezing of gait in PD: Prospective assessment in the DATATOP cohort. Neurology 56, 1712–1721 (2001). 2. Moore, O., Peretz, C. & Giladi, N. Freezing of gait affects quality of life of peoples with Parkinson’s disease beyond its relationships with mobility and gait. Mov. Disord. 22, 2192–2195 (2007). 3. Weele, C. M. V., Siciliano, C. A. & Tye, K. M. Dopamine tunes prefrontal outputs to orchestrate aversive processing. Brain Research vol. 1713 16–31 (2019). 4. Kostić, V. S. et al. Pattern of brain tissue loss associated with freezing of gait in Parkinson disease. Neurology 78, 409–416 (2012). 5. Amboni, M., Cozzolino, A., Longo, K., Picillo, M. & Barone, P. Freezing of gait and executive functions in patients with Parkinson’s disease. Mov. Disord. 23, 395–400 (2008). 6. Tessitore, A. et al. Resting-state brain connectivity in patients with Parkinson’s disease and freezing of gait. Park. Relat. Disord. 18, 781–787 (2012). 7. Fling, B. W. et al. Functional reorganization of the locomotor network in parkinson patients with freezing of gait. PLoS One 9, (2014).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impairment-of-the-mesocortical-dopamine-system-in-parkinsons-disease-patients-with-freezing-of-gait-in-a-multimodal-imaging-approach/