Anterior cingulate dopamine turnover and behavior change in Parkinson’s disease (original) (raw)
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Cognitive deficits and striato-frontal dopamine release in Parkinson's disease
Brain, 2007
Idiopathic Parkinson's disease (PD) is often accompanied by a pattern of executive deficits similar to those found in patients with frontal lobe lesions.We investigated whether such cognitive deficits are attributable to frontal lobe dysfunction as a direct consequence of impaired mesocortical dopaminergic transmission or an indirect consequence of impaired nigrostriatal dopaminergic function. For this purpose, changes in synaptic dopamine levels during task performance were monitored using a marker of dopamine D2-receptor availability 11 C-raclopride (RAC) PET. During RAC PET, seven patients with early symptomatic PD and seven age-matched healthy controls performed two types of behavioural task, a spatial working memory task (SWT) and a visuomotor control task (VMT).The SWT involves an executive process which is known to be impaired by both frontal lobe lesions and PD while theVMT is a controltest for the visuomotorcomponentofthe SWT.Parametric images of RAC bindingpotentialduring performance of eachtask were generated, andcomparedbetweenthe tasks using voxel-basedstatistical parametric mapping aswellasregion of interest analysis.In controls,RAC binding wasreducedinthe dorsalcaudate duringperformance ofthe SWT comparedwiththeVMT, compatiblewithincreasedlevels ofendogenous dopamine release due to the executive process.In PD patients, this RAC binding reductionwas not observed.In contrast,RAC binding in the anterior cingulate cortex within the medial prefrontal cortex was reduced by a comparable level during the SWT both in controls and PD patients. Statistical comparisons between controls and PD patients confirmed significantly attenuated dopamine release in the dorsal caudate in PD, but preserved levels of medial prefrontal dopamine release. Our data suggest that executive deficits in early patients with PD are associated with impaired nigrostriatal dopaminergic function resulting in abnormal processing in the cortico-basal ganglia circuit. In contrast, mesocortical dopaminergic transmission appears well preserved in early PD patients.
Journal of Cerebral Blood Flow & Metabolism, 2005
Conventional graphical analysis of positron emission tomography (PET) recordings of the cerebral uptake of the DOPA decarboxylase substrate [18F]fluorodopa (FDOPA) assumes irreversible trapping of [18F]fluorodopamine formed in the brain. However, 4-h long PET recordings allow the estimation of a rate constant for elimination of [18F]fluorodopamine from the brain ( kloss), from which can be calculated an effective distribution volume ( EDV1), which is an index of [18F]fluorodopamine storage capacity. We earlier developed a method employing 2-h long FDOPA recordings for the estimation of kloss and EDV, here defined as EDV2. This method is based on subtraction of the calculated brain concentrations of the FDOPA metabolite O-methyl-FDOPA, rather than the subtraction of the entire radioactivity in a reference region. We now extend this method for the parametric mapping of these parameters in the brain of healthy aged volunteers and patients with Parkinson's disease (PD), with asymmet...
Psychiatry Research: Neuroimaging, 2008
Frontostriatal cognitive dysfunction is common in Parkinson disease (PD), but the explanation for its heterogeneous expressions remains unclear. This study examined the dopamine system within the frontostriatal circuitry with positron emission tomography (PET) to investigate pre-and post-synaptic dopamine function in relation to the executive processes in PD. Fifteen non-demented PD patients and 14 healthy controls underwent [ 18 F]FDOPA (for dopamine synthesis) and [ 11 C]NNC 112 (for D 1 receptors) PET scans and cognitive testing. Parametric images of [ 18 F]FDOPA uptake (K i ) and [ 11 C]NNC 112 binding potential (BP ND ) were calculated using reference tissue models. Group differences in K i and BP ND were assessed with both volume of interest and statistical parametric mapping, and were correlated with cognitive tests. Measurement of [ 18 F]FDOPA uptake in cerebral cortex was questionable because of higher K i values in white than adjacent gray matter. These paradoxical results were likely to be caused by violations of the reference tissue model assumption rendering interpretation of cortical [ 18 F]FDOPA uptake in PD difficult. We found no regional differences in D 1 receptor density between controls and PD, and no overall differences in frontostriatal performance. Although D 1 receptor density did not relate to frontostriatal cognition, K i decreases in the putamen predicted performance on the Wisconsin Card Sorting Test in PD only. These results suggest that striatal dopamine denervation may contribute to some frontostriatal cognitive impairment in moderate stage PD.
Brain, 1999
Parkinson's disease by applying statistical parametric mapping (SPM) to 3D [ 18 F]dopa-PET. Data from seven early hemi-Parkinson's disease and seven advanced bilateral Parkinson's disease patients were compared with that from 12 normal controls. Parametric images of [ 18 F]dopa influx rate constant (K i o ) were generated for each subject from dynamic 3D [ 18 F]dopa datasets and transformed into standard stereotactic space. Significant changes in mean voxel [ 18 F]dopa K i o values between the normal control group and each Parkinson's disease group were localized with SPM. Conventional region of interest analysis was also applied to comparable regions on the untransformed image datasets. In early left hemi-Parkinson's disease, significant extrastriatal increases in [ 18 F]dopa K i o were observed in the left anterior cingulate gyrus and the dorsal midbrain region (P < 0.05, corrected) along with decreases in striatal [ 18 F]dopa K i o . In advanced Parkinson's disease, significant extrastriatal decreases in [ 18 F]dopa K i o were observed in the ventral and dorsal
The aim of the study was to estimate normal ranges and test-retest measures for various parameters characterising dopamine metabolism from a prolonged (18)F-dopa positron emission tomography (PET) measurement using a reference tissue model and compare their value for the detection of early Parkinson's disease (PD). Healthy volunteers (n = 9) and patients (n = 36) in an early stage of PD underwent an (18)F-dopa PET measurement lasting 4 h. The influx rate constant k(occ) and the effective distribution volume ratio (EDVR, its inverse is an indicator for dopamine turnover) were estimated by a graphical approach using dynamic data in the striatum and, as a reference region, the occipital cortex. Furthermore, ratios of activity concentrations between striatum and occipital brain taken for three time intervals completed the data analysis. All parameters were determined both in eight small volumes of interest placed in the striatum as well as averaged for caudate nucleus and putamen. For the control group, reproducibility was checked in a second study 3 months later and ranges for normal values were derived from mean ± 2 standard deviations. Receiver-operating characteristic (ROC) analyses were performed to assess the value of the parameters for diagnostic purposes. Patients with early-stage PD and healthy volunteers could be separated by the values of the putamen, not the caudate nucleus. The normal ranges of the putamen were 0.0151-0.0216/min for the influx rate constant k(occ) and 2.02-3.00 for EDVR. For the various time intervals used the striato-occipital ratios yielded 2.24-3.06, 2.43-3.42 and 2.35-3.21, respectively. Patients were characterised by significantly lower values (p < 0.001) and significant differences between ipsi- and contralateral sides (p < 0.001) with regard to their clinical symptoms and a rostrocaudal gradient. EDVR as well as k(occ) for the putamen were able to effectively differentiate between groups (sensitivity >97%, specificity 100%). In contrast, striato-occipital ratios showed a sensitivity of about only 85%. For clinical applications, our data do not demonstrate any superiority of the EDVR determination compared to influx rate constant, while requiring long and tedious acquisition protocols. The normal range estimates do not represent absolute quantitative measures for dopamine metabolism but are specific for the chosen acquisition and processing procedures.
Prefrontal dopaminergic receptor abnormalities and executive functions in Parkinson's disease
Human Brain Mapping, 2012
The main pattern of cognitive impairments seen in early to moderate stages of Parkinson's disease (PD) includes deficits of executive functions. These nonmotor complications have a significant impact on the quality of life and day-today activities of PD patients and are not effectively managed by current therapies, a problem which is almost certainly due to the fact that the disease extends beyond the nigrostriatal system. To investigate the role of extrastriatal dopamine in executive function in PD, PD patients and a control group were studied with positron-emission-tomography using a high-affinity dopamine D2/D3 receptor tracer, [ 11 C]FLB-457. All participants were scanned twice while performing an executive task and a control task. Patients were off medication for at least 12 h. The imaging analysis revealed that parkinsonian patients had lower [ 11 C]FLB-457 binding than control group independently of task conditions across different brain regions. Cognitive assessment measures were positively correlated with [ 11 C]FLB-457 binding in the bilateral dorsolateral prefrontal cortex and anterior cingulate cortex only in control group, but not in PD patients. Within the control group, during the executive task (as compared to control task), there was evidence of reduced [ 11 C]FLB-457 binding (indicative of increased dopamine release) in the right orbitofrontal cortex. In contrast, PD patients did not show any reduction in binding during the executive task (as compared with control task). These findings suggest that PD patients present significant abnormalities in extrastriatal dopamine associated with executive processing. These observations provide important insights on the pathophysiology of cognitive dysfunction in PD.
Journal of Neurology, Neurosurgery & Psychiatry, 1999
Objective-To apply statistical parametric mapping to 18 F-dopa PET data sets, to examine the regional distribution of changes in dopaminergic metabolism in early asymmetric Parkinson's disease. Methods-Thirteen normal volunteers (age 57.7 (SD 16.5) years; four women, nine men ) and six patients (age 50.3 (SD 13.5) years; three women, three men) with asymmetric (right sided) Parkinson's disease were studied. Images from each dynamic dopa PET dataset were aligned and parametric images of 18 F-dopa influx (Ki) were created for each subject. The Ki images were transformed into standard stereotactic space. The Ki values of the caudate and putamen on spatially normalised images were compared with the Ki values before normalisation. The application of statistical parametric mapping (SPM) allowed statistical comparison of regional Ki values on a voxel by voxel basis between healthy volunteers and patients with Parkinson's disease. Results-There was a strong correlation between the Ki values before and after spatial normalisation (r=0.898, p=0.0001). Significant decreases in the Ki values were found for the Parkinson's desease group throughout the entire left putamen (p< 0.001) and focally in the dorsal right putamen (p< 0.001). Decreased Ki values were also shown bilaterally in the substantia nigra (p< 0.01). Conclusion-Using (SPM) and 18 F-dopa PET, reductions in both striatal and nigral brain dopaminergic function could be demonstrated in early Parkinson's disease. (J Neurol Neurosurg Psychiatry 1999;66:754-758)
Brain, 2002
We investigated the relative differences in dopaminergic function through the whole brain in patients with Parkinson's disease without dementia (PD) and with dementia (PDD) using 6-[ 18 F]¯uoro-L-dopa ( 18 F-dopa) PET and a voxel-by-voxel analysis. The 10 PD and 10 PDD patients were equivalently disabled, having mean scores of 3.2 T 0.6 and 3.2 T 0.7, respectively, on the Hoehn and Yahr rating scale. 18 F-dopa in¯ux constant (Ki) images of those patients and 15 normal age-matched subjects were transformed into standard stereotactic space. The signi®cant differences between the groups (expressed in mean regional Ki values) were localized with statistical parametric mapping (SPM) on a voxelby-voxel basis. Compared with the normal group, SPM localized declines of the 18 F-dopa Ki bilaterally in the putamen, the right caudate nucleus and the left ventral midbrain for the PD group (P < 0.01, corrected). Compared with the normal group, the PDD group showed reduced 18 F-dopa Ki bilaterally in the striatum, midbrain and anterior cingulate area (P < 0.01, corrected). A relative difference in 18 F-dopa uptake between PD and PDD was the bilateral decline in the anterior cingulate area and ventral striatum and in the right caudate nucleus in the PDD group (P < 0.001, corrected). Accordingly, we conclude that dementia in PD is associated with impaired mesolimbic and caudate dopaminergic function.
Parkinson's disease cognitive network correlates with caudate dopamine
NeuroImage, 2013
Prior evidence has suggested a link between caudate dopaminergic functioning and cognition in Parkinson's disease (PD). In this dual tracer study we analyzed the relationship between nigrostriatal dopaminergic dysfunction and the expression of the previously validated PD cognition-related metabolic pattern (PDCP). In this study, 17 non-demented PD patients underwent positron emission tomography (PET) imaging with [ 18 F]-fluorodeoxyglucose to measure PDCP expression, and [ 18 F]-fluoropropyl-β-CIT (FPCIT) to measure dopamine transporter (DAT) binding. Automated voxel-by-voxel searches of the FPCIT PET volumes were performed to identify regions in which DAT binding significantly correlated with PDCP expression values. The findings were validated using prespecified anatomical regions-of-interest (ROIs). Voxel-wise interrogation of the FPCIT PET scans revealed a single significant cluster in which DAT binding correlated with PDCP expression (p b 0.05, corrected). This cluster was localized to the left caudate nucleus; an analogous correlation (r = − 0.63, p b 0.01) was also present in the "mirror" region of the right hemisphere. These findings were confirmed by the presence of a significant correlation (r = −0.67, p b 0.005) between PDCP expression and DAT binding in caudate ROIs, which survived adjustment for age, disease duration, and clinical severity ratings. Correlation between caudate DAT binding and subject expression of the PD motor-related metabolic pattern was not significant (p > 0.21). In summary, this study demonstrates a significant relationship between loss of dopaminergic input to the caudate nucleus and the expression of a cognition-related disease network in unmedicated PD patients. These baseline measures likely function in concert to determine the cognitive effects of dopaminergic therapy in PD.
Journal of the Neurological Sciences, 1999
The contribution of striatal (caudate nucleus-putamen) dopaminergic deficiency to the severity of motor signs is well established in Parkinson&amp;amp;amp;#39;s disease (PD), while its role in the occurrence of cognitive and mood changes remains unresolved. We therefore measured in 27 non-demented PD patients and 10 age-matched controls striatal uptake of [18F]-6-fluoro-L-Dopa (F-Dopa) with PET, and mood (Beck depression), memory (Grober-Buschke), frontal executive functions (verbal fluency and Wisconsin card sorting), and attentional processing of sensory stimuli (N2-P3 auditory event-related potentials--ERPs). Locomotor disability of patients was assessed by Hoehn and Yahr score and Unified Parkinson&amp;amp;amp;#39;s Disease Rating Scale (UPDRS). ANOVA showed that memory, but neither frontal lobe functions nor ERPs, was significantly altered in PD patients, whereas indices of depression were found only in advanced PD. The F-Dopa rate constant Ki was significantly reduced in the striatum, more in putamen than caudate nucleus, and inversely correlated with disease duration. A significant inverse correlation was found between both putamen and caudate nucleus Ki and Hoehn and Yahr score, and between putamen--but not caudate nucleus Ki --and UPDRS motor score. Principal components analysis (PCA) of PD patients Ki values and mood, cognitive and ERP parameters gave a three-factor solution. Variables contributing to factor 1 were memory score and N2-P3 ERP latencies, those to factor 2 were striatal Ki values, and those to factor 3 frontal executive performances. Depression did not segregate with any variable. Our findings suggest that unlike locomotor disability, cognitive abilities and mood state of non-demented PD patients are for the most part unrelated to striatal dopaminergic depletion and may result from dysfunction of extra-striatal dopaminergic or from non-dopaminergic systems.