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Response monitoring in de novo patients with Parkinson's disease.

ABSTRACT: BACKGROUND: Parkinson's disease (PD) is accompanied by dysfunctions in a variety of cognitive processes. One of these is error processing, which depends upon phasic decreases of medial prefrontal dopaminergic activity. Until now, there is no study evaluating these processes in newly diagnosed, untreated patients with PD ("de novo PD"). METHODOLOGY/PRINCIPAL FINDINGS: Here we report large changes in performance monitoring processes using event-related potentials (ERPs) in de novo PD-patients. The results suggest that increases in medial frontal dopaminergic activity after an error (Ne) are decreased, relative to age-matched controls. In contrast, neurophysiological processes reflecting general motor response monitoring (Nc) are enhanced in de novo patients. CONCLUSIONS/SIGNIFICANCE: It may be hypothesized that the Nc-increase is at costs of dopaminergic activity after an error; on a functional level errors may not always be detected and correct responses sometimes be misinterpreted as errors. This pattern differs from studies examining patients with a longer history of PD and may reflect compensatory processes, frequently occurring in pre-manifest stages of PD. From a clinical point of view the clearly attenuated Ne in the de novo PD patients may prove a useful additional tool for the early diagnosis of basal ganglia dysfunction in PD.

SUBMITTER: Willemssen R

PROVIDER: S-EPMC2657830 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Response monitoring in de novo patients with Parkinson's disease.

Willemssen Rita R Müller Thomas T Schwarz Michael M Falkenstein Michael M Beste Christian C

PloS one 20090327 3

<h4>Background</h4>Parkinson's disease (PD) is accompanied by dysfunctions in a variety of cognitive processes. One of these is error processing, which depends upon phasic decreases of medial prefrontal dopaminergic activity. Until now, there is no study evaluating these processes in newly diagnosed, untreated patients with PD ("de novo PD").<h4>Methodology/principal findings</h4>Here we report large changes in performance monitoring processes using event-related potentials (ERPs) in de novo PD- ...[more]

PMID: 19325909

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Project description:The most common genetic risk factors for Parkinson's disease are GBA1 mutations, encoding the lysosomal enzyme glucocerebrosidase. Patients with GBA1 mutations (GBA-PD) exhibit earlier age of onset and faster disease progression with more severe cognitive impairments, postural instability and gait problems. These GBA-PD features suggest more severe cholinergic system pathologies. PET imaging with the vesicular acetylcholine transporter ligand 18F-F-fluoroethoxybenzovesamicol (18F-FEOBV PET) provides the opportunity to investigate cholinergic changes and their relationship to clinical features in GBA-PD. The study investigated 123 newly diagnosed, treatment-naïve Parkinson's disease subjects-with confirmed presynaptic dopaminergic deficits on PET imaging. Whole-gene GBA1 sequencing of saliva samples was performed to evaluate GBA1 variants. Patients underwent extensive neuropsychological assessment of all cognitive domains, motor evaluation with the Unified Parkinson's Disease Rating Scale, brain MRI, dopaminergic PET to measure striatal-to-occipital ratios of the putamen and 18F-FEOBV PET. We investigated differences in regional cholinergic innervation between GBA-PD carriers and non-GBA1 mutation carriers (non-GBA-PD), using voxel-wise and volume of interest-based approaches. The degree of overlap between t-maps from two-sample t-test models was quantified using the Dice similarity coefficient. Seventeen (13.8%) subjects had a GBA1 mutation. No significant differences were found in clinical features and dopaminergic ratios between GBA-PD and non-GBA-PD at diagnosis. Lower 18F-FEOBV binding was found in both the GBA-PD and non-GBA-PD groups compared to controls. Dice (P < 0.05, cluster size 100) showed good overlap (0.7326) between the GBA-PD and non-GBA-PD maps. GBA-PD patients showed more widespread reduction in 18F-FEOBV binding than non-GBA-PD when compared to controls in occipital, parietal, temporal and frontal cortices (P < 0.05, FDR-corrected). In volume of interest analyses (Bonferroni corrected), the left parahippocampal gyrus was more affected in GBA-PD. De novo GBA-PD show a distinct topography of regional cholinergic terminal ligand binding. Although the Parkinson's disease groups were not distinguishable clinically, in comparison to healthy controls, GBA-PD showed more extensive cholinergic denervation compared to non-GBA-PD. A larger group is needed to validate these findings. Our results suggest that de novo GBA-PD and non-GBA-PD show differential patterns of cholinergic system changes before clinical phenotypic differences between carriers versus non-carrier groups are observable.

Project description:BackgroundParkinson's disease (PD) manifests with the appearance of non-motor symptoms before motor symptoms onset. Among these, dysfunctioning visual structures have recently been reported to occur at early disease stages.ObjectiveThis study addresses effective connectivity in the visual network of PD patients.MethodsUsing functional MRI and dynamic causal modeling analysis, we evaluated the connectivity between the superior colliculus, the lateral geniculate nucleus and the primary visual area V1 in de novo untreated PD patients (n = 22). A subset of the PD patients (n = 8) was longitudinally assessed two times at two months and at six months after starting dopaminergic treatment. Results were compared to those of age-matched healthy controls (n = 22).ResultsOur results indicate that the superior colliculus drives cerebral activity for luminance contrast processing both in healthy controls and untreated PD patients. The same effective connectivity was observed with neuromodulatory differences in terms of neuronal dynamic interactions. Our main findings were that the modulation induced by luminance contrast changes of the superior colliculus connectivity (self-connectivity and connectivity to the lateral geniculate nucleus) was inhibited in PD patients (effect of contrast: p = 0.79 and p = 0.77 respectively). The introduction of dopaminergic medication in a subset (n = 8) of the PD patients failed to restore the effective connectivity modulation observed in the healthy controls.InterpretationThe deficits in luminance contrast processing in PD was associated with a deficiency in connectivity adjustment from the superior colliculus to the lateral geniculate nucleus and to V1. No differences in cerebral blood flow were observed between controls and PD patients suggesting that the deficiency was at the neuronal level. Administration of a dopaminergic treatment over six months was not able to normalize the observed alterations in inter-regional coupling. These findings highlight the presence of early dysfunctions in primary visual areas, which might be used as early markers of the disease.

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Response monitoring in de novo patients with Parkinson's disease.

Publications

Response monitoring in de novo patients with Parkinson's disease.

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