Anterior cingulate dopamine turnover and behavior change in Parkinson’s disease

Abstract

Subtle cognitive and behavioral changes are common in early Parkinson’s disease. The cause of these symptoms is probably multifactorial but may in part be related to extra-striatal dopamine levels. 6-[18F]-Fluoro-L-dopa (FDOPA) positron emission tomography has been widely used to quantify dopamine metabolism in the brain; the most frequently measured kinetic parameter is the tissue uptake rate constant, Ki. However, estimates of dopamine turnover, which also account for the small rate of FDOPA loss from areas of specific trapping, may be more sensitive than Ki for early disease-related changes in dopamine biosynthesis. The purpose of the present study was to compare effective distribution volume ratio (eDVR), a metric for dopamine turnover, to cognitive and behavioral measures in Parkinson’s patients. We chose to focus the investigation on anterior cingulate cortex, which shows highest FDOPA uptake within frontal regions and has known roles in executive function. 15 Non-demented early-stage PD patients were pretreated with carbidopa and tolcapone, a central catechol-O-methyl transferase (COMT) inhibitor and then underwent extended imaging with FDOPA PET. Anterior cingulate eDVR was compared with composite scores for language, memory, and executive function measured by neuropsychological testing, and behavior change measured using two informant-based questionnaires, the Cambridge Behavioral Inventory and the Behavior Rating Inventory of Executive Function- Adult Version. Lower mean eDVR (thus higher dopamine turnover) in anterior cingulate cortex was related to lower (more impaired) behavior scores. We conclude that subtle changes in anterior cingulate dopamine metabolism may contribute to dysexecutive behaviors in Parkinson’s disease.

Neurophysiological Biomarkers of Parkinson’s Disease

“…EEG analytics reliably characterized alterations in neurophysiological oscillatory activity associated with PD, and specific changes in the cortico-cortical and cortico-thalamic coupling were observable in the surface EEG recording during resting state. Abnormally high levels of beta (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and gamma (25-40 Hz) frequency synchronization were observed across multiple cortico-cortical regions in the PD patients. The high levels of beta and gamma coherence were significantly positively correlated with UPDRS scores and [ 11 C]PE2I DAT PET, confirming that excessive high coherence is associated with higher disease severity and underlying pathophysiology [8].…”

“…The anterior cingulate is a critically important component of the neural network controlling attention, orienting, and vigilance [25]. Additionally, alterations in dopamine metabolism within the anterior cingulate have been linked with cognitive decline in PD [26]. Attention deficits are often detected in the early stages of PD, and have been suggested as a component of the fluctuations in cognition that are one of the hallmarks of PD [27][28][29].…”

Dopaminergic correlates of metabolic network activity in Parkinson's disease

“…Indeed, FDOPA PET can be used to accurately assess integrity of the serotonergic system in PD [Pavese et al, 2012]. Similarly, low cortical signal may be an important reason why prior efforts to quantify extra-striatal FDOPA uptake have relied almost exclusively on regional (ROI/VOI) as opposed to voxelbased methods [Gallagher et al, 2014;Kumakura et al, 2010;Pavese et al, 2011Pavese et al, , 2012. Substantially lower AADC expression in cortical regions with concomitantly lower PET signal may explain why correlations were not found in these areas even after lowering the voxel threshold to a minimum (P < 0.05, uncorrected).…”

“…Substantially lower AADC expression in cortical regions with concomitantly lower PET signal may explain why correlations were not found in these areas even after lowering the voxel threshold to a minimum (P < 0.05, uncorrected). Similarly, low cortical signal may be an important reason why prior efforts to quantify extra-striatal FDOPA uptake have relied almost exclusively on regional (ROI/VOI) as opposed to voxelbased methods [Gallagher et al, 2014;Kumakura et al, 2010;Pavese et al, 2011Pavese et al, , 2012. Thus, it may be predictive to use ROI-based methods to study relationships between network activity and FDOPA uptake in regions rich in serotonergic terminals.…”

Dopamine, time perception, and future time perspective

“…In summary, previous research indicates that lower frontal dopamine levels result in poorer executive control (Boettiger et al 2007 ; Gallagher et al 2015 ) and difficulties with impulsivity and time perception (Blum et al 2007 ; Gold et al 2015 ). Our current findings suggest that compressed time perception, a hypothesized component of impulsivity (Peters and Buchel 2011 ), can be improved by administration of the COMT inhibitor tolcapone, perhaps by decreasing connectivity between RIFG and R putamen.…”