Article

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
Source: PubMed

ABSTRACT

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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    • "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. "
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    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.
    Full-text · Article · May 2008 · Neuropsychologia
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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). "
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    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.
    Full-text · Article · Nov 2007 · Neuropsychologia
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    • "As such the Ne migth serve as an easy deriveable measure of the integrity of the dopaminergic striatial output function. The fact that the Ne was related to the CAG repeat mutation, which is in turn related to the receptor density/integrity [7]–[9], further supports the dependence of the Ne on striatal DA system (receptor) functioning. This interpretation is supported by older findings in HD in which there was no change in the levels of free-available dopamine [38], [39] that could have influenced the results. "
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    ABSTRACT: Huntington's disease (HD) is a genetic disorder expressed by a degeneration of the basal ganglia inter alia accompanied with dopaminergic alterations. These dopaminergic alterations are related to genetic factors i.e., CAG-repeat expansion. The error (related) negativity (Ne/ERN), a cognitive event-related potential related to performance monitoring, is generated in the anterior cingulate cortex (ACC) and supposed to depend on the dopaminergic system. The Ne is reduced in Parkinson's Disease (PD). Due to a dopaminergic deficit in HD, a reduction of the Ne is also likely. Furthermore it is assumed that movement dysfunction emerges as a consequence of dysfunctional error-feedback processing. Since dopaminergic alterations are related to the CAG-repeat, a Ne reduction may furthermore also be related to the genetic disease load. We assessed the error negativity (Ne) in a speeded reaction task under consideration of the underlying genetic abnormalities. HD patients showed a specific reduction in the Ne, which suggests impaired error processing in these patients. Furthermore, the Ne was closely related to CAG-repeat expansion. The reduction of the Ne is likely to be an effect of the dopaminergic pathology. The result resembles findings in Parkinson's Disease. As such the Ne might be a measure for the integrity of striatal dopaminergic output function. The relation to the CAG-repeat expansion indicates that the Ne could serve as a gene-associated "cognitive" biomarker in HD.
    Full-text · Article · Feb 2006 · PLoS ONE
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