Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease
Department of Neurology, Groningen University Medical Center, Groningen, The Netherlands.Neurology (Impact Factor: 8.29). 09/2005; 65(6):941-3. DOI: 10.1212/01.wnl.0000176071.08694.cc
Among 27 preclinical carriers of the Huntington disease mutation (PMC), the authors found normal striatal values for MRI volumetry in 88% and for fluorodesoxyglucose PET metabolic index in 67%. Raclopride PET binding potential (RAC-BP) was decreased in 50% and correlated with increases in the product of age and CAG repeat length (p < 0.0005). Dopamine D2 receptor availability measured by RAC-BP seems the most sensitive indicator of early neuronal impairment in PMC.
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- "An up to 60% loss of the cross-sectional area of the striatum has been reported in patients in the progressive stages of HD  . However, decreases in D2 receptor binding in the striatum emerge before significant volumetric changes in HD gene carriers  and a 49.2% decrease in PDE10A binding density was correlated with only a 21.6% decrease in mean caudate volume in manifest HD patients at relatively early stages of disease . Therefore, the R6/2 model may reflect these earlier pathological stages of HD with pronounced decreases in binding density of PDE10A and dopaminergic markers, but a smaller decrease in striatal cross-sectional area. "
ABSTRACT: Background: Phosphodiesterase 10A (PDE10A) is expressed at high levels in the striatum and has been proposed both as a biomarker for Huntington's disease pathology and as a target for intervention. Objective: PDE10A radiotracers have been successfully used to measure changes in binding density in Huntington's disease patients, but little is known about PDE10A binding in mouse models that are used extensively to model pathology and test therapeutic interventions. Methods: Our study investigated changes in PDE10A binding using the selective tracer 3 H-7980 at specific ages of two Huntington's disease transgenic mouse models: R6/2, a short-lived model carrying exon-1 of mutant HTT and BACHD, a longer-lived model carrying full-length mutant HTT. PDE10A binding was compared to binding of known markers of striatal atrophy in Huntington's disease, e.g. dopamine transporter (DAT) and dopamine receptors D1 and D2. Results: We found that in the R6/2 model at 6 weeks of age, mice showed high variability of binding, however binding of all ligands was significantly decreased at 8 and 12 weeks of age. In contrast, no changes were detectable in the BACHD model at 8, 10 or 12 month of age. Conclusions: These findings suggest that radiotracer binding of PDE10A, DAT, D1 and D2 receptor in the R6/2 model may be a good indicator of striatal pathological changes that are observed in Huntington's disease patients, and that the first 12 months in the BACHD model may be more reflective of early stages of the disease.Journal of Huntington's disease 12/2014; 3(4):333-341. DOI:10.3233/JHD-140129
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- "Moreover, the decline in the striatal dopamine receptor system is likely to be gene-associated in HD (e.g. Antonini et al., 1998; van Oostrom et al., 2005). Due to the dependence of the Nogo-N2 and/or Nogo-P3 on the DA-system as well as medial frontal systems, which are dysfunctional in symptomatic HD, we would expect an attenuation of Nogo-potential amplitudes in HD compared to healthy controls. "
ABSTRACT: Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder, with neurodegeneration mainly affecting the striatum. We investigated executive functions related to response inhibition in (HD) and healthy controls by means of event-related potentials (ERP) in a simple Go/Nogo-task. In Nogo as opposed to Go trials two fronto-central ERP components are elicited: the Nogo-N2 and Nogo-P3. These components are supposed to depend on (medial) prefrontal regions, especially the anterior cingulate cortex (ACC). The results show that the Nogo-N2 did not differ between the groups, while the Nogo-P3 demonstrated a strong attenuation in the HD-group, which also showed more false alarms in the Nogo-condition. Using sLORETA it is shown that this attenuation was related to the medial frontal cortex, especially the ACC, and superior frontal cortex areas. Moreover, the attenuation was related to the underlying genetic disease load (CAG-index). The decline in inhibition is likely mediated via a dysfunction in the ACC, which is known to be dysfunctional in HD. Moreover, the results may be interpreted that the decline in response inhibition in HD is gene-associated. The differentially affected Nogo-components suggest that they rely on different neuronal circuits, even within the ACC. For HD this suggests that this structure is not entirely dysfunctional.Neuropsychologia 05/2008; 46(5):1290-7. DOI:10.1016/j.neuropsychologia.2007.12.008 · 3.30 Impact Factor
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- "Regarding the processes (degeneration and/or compensation) that possibly occur in pHD, two hypothesis can be formulated: (i) The dopamine striatal system (D2-system) is dysfunctional in pHD (Augood et al., 1997; Backman et al., 1997; Van Oostrom et al., 2005) and/or the adenosine A2A-receptors express their pathogenic effects. Accordingly, the Ne should be reduced in pHD compared to healthy controls, since a suppression of the DA system and cortico-subcortical interaction by pathological or pharmacological factors has been consistently shown to decrease the Ne (de Bruijn, Sabbe, Hulstjin, Ruigt, & Verkes, 2006; Zirnheld et al., 2004) as has recently been shown in symptomatic HD (Beste, Saft, Andrich, Gold, & Falkenstein, 2006; Beste et al., in press). "
ABSTRACT: Huntington's disease (HD) is an autosomal dominant neurological disorder, with degeneration amongst others affecting the basal ganglia dopaminergic system. Recent findings suggest compensatory as well as pathogenetic mechanisms mediated via the adenosine receptor system in the presymptomatic stage (pHD) of HD. The adenosine receptor system is functionally related to the dopaminergic system. In this study, we assessed error processing, a dopamine-dependent cognitive function, using an event-related potential the error negativity (Ne/ERN) in pHD and controls. This was done by means of a flanker task. The Ne consists of a cognitive and a motor component, expressed via different frequency bands. Time-frequency decomposition of the Ne into delta and theta sub-components was applied to assess if degeneration or compensation predominantly involve cognitive or motor processes. No parameter of the behavioral data (reaction times, error frequency, corrections, post-error slowing) differed between the groups. A selective increase in the power of the cognitive delta-Ne component was found in pHD relative to controls inversely related to the estimated age of onset (eAO). Thus, the increase in the power of the cognitive delta-Ne component was stronger in pHD with an earlier eAO. An earlier eAO implies stronger pathogenetic mechanisms. Due to the behavioral data our results speak for a solely cognitive compensating-mechanism controlling performance monitoring in pHD. In contrast, correlations with eAO suggest that the increase in delta-Ne activity is also related to pathogenesis. It is proposed that compensation is a transient effect of the whole pathogenetic dynamics of HD, with these two processes not foreclosing each other.Neuropsychologia 11/2007; 45(13):2922-30. DOI:10.1016/j.neuropsychologia.2007.06.004 · 3.30 Impact Factor
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