Extrastriatal dopamine D 2 receptor binding in Huntington's disease (original) (raw)
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Extrastriatal dopamine D2receptor binding in Huntington's disease
Human Brain Mapping, 2010
Huntington's disease (HD) is a neurodegenerative disorder, primarily affecting medium spiny neurones in the striatum. The density of striatal dopamine D 2 receptors is reduced in HD but there is little known about this biomarker in brain regions outside the striatum. The primary objective of this study was to compare extrastriatal dopamine D 2 receptor binding, in age-matched control subjects and patients with HD. All subjects were examined using a high-resolution positron emission tomography system and the highaffinity dopamine D 2 receptor radioligand [ 11 C]FLB 457. A ROI based analysis was used with an atrophy correction method. Dopamine D 2 receptor binding potential was reduced in the striatum of patients with HD. Unlike the striatum, dopamine D 2 receptor binding in thalamic and cortical subregions was not significantly different from that in control subjects. A partial least square regression analysis which included binding potential values from all investigated cortical and subcortical regions revealed a significant model separating patients from controls, conclusively dependent on differences in striatal binding of the radioligand. Some clinical assessments correlated with striatal dopamine D 2 receptor binding, including severity of chorea and cognitive test performance. Hence, the present study demonstrates that dopamine D 2 receptors extrinsic to the striatum are well preserved in early to mid stage patients with HD. This observation may have implication for the development of therapy for HD.
Changes in striatal dopamine D2 receptor binding in pre-clinical Huntington’s disease
European Journal of Neurology, 2009
Background: Carriers of the Huntington disease (HD) mutation develop a progressive neurodegenerative disorder after a pre-clinical phase. We examined the value of 11 C-raclopride PET (RAC) as a biomarker for pre-clinical HD pathophysiology. Methods: In a prospective cohort study with clinical and neuropsychological assessment we collected complete RAC data in 18 pre-clinical mutation carriers (HD-PMC) and 11 controls. Follow-up was 2 years. We calculated striatal RAC binding potential (BP) to measure dopamine D2 receptor availability. Results: No HD-PMC had overt neuropsychological dysfunction. RAC-BP in putamen was abnormal in up to 44% of HD-PMC. The rate of RAC-BP decline (2.6% per year) was not significantly higher than in controls. Follow-up putaminal BP correlated weakly with predicted distance to onset of clinical HD (P = 0.034), but the rate of decline did not. Three HD-PMC developed motor abnormalities suspect for HD but did not show an increased rate of decline of putaminal BP. Conclusions: Many HD-PMC have striatal abnormalities but we found no clearly increased rate of D2 receptor changes around the onset of clinical HD. A longer follow-up of the present study cohort is needed to establish the value of RAC-BP in assessing the risk of clinical conversion from striatal D2 binding data.
Brain, 1997
PET and markers for the pre-and postsynaptic neurons striatum correlated significantly with increasing duration of illness. The correlation between the duration of illness were used to study the dopamine system in vivo in Huntington's disease. The radioligands used were [ 11 C]SCH and decline of D1-and D2-receptors make these receptors valuable as quantitative markers for the Huntington's disease 23390 for D1-receptors, [ 11 C]raclopride for D2-receptors and [ 11 C]β-CIT for dopamine transporters. Five patients degenerative process. Besides postsynaptic changes, a significant 50% decrease of [ 11 C]β-CIT binding to the with Huntington's disease and five matched controls were recruited. Brain anatomy was examined by MRI. The findings dopamine transporter was found in the striatum. A reduced striatal blood flow in Huntington's disease cannot be excluded in patients were as follows. Postsynaptic D1-and D2-receptor densities were similarly reduced in the striatum. A reduction and could account for a small part of the decrease in [ 11 C]β-CIT binding. We suggest that the finding reflects a loss of in D1-receptor density was shown in the temporal cortex; it draws attention to the cortical degeneration in relation to presynaptic terminals or a reduced expression of dopamine transporter in the nigrostriatal dopaminergic system in the cognitive deficits observed in Huntington's disease. The reduction of D1-and D2-receptor binding potentials in the Huntington's disease.
Dopamine D1 and D2 receptor gene expression in the striatum in Huntington's disease
Annals of Neurology, 1997
The cellular expression of dopamine D, and D, receptor mRNAs was investigated in the postmortem human caudate nucleus of control cases and genetically and pathologically confirmed cases of Huntington's disease (HD) by using quantitative in situ hybridization. The HD cases were categorized (0-4) by severity of striatal neuropathology according to the Vonsattel scale. For the HD grade 0 case, a pronounced reduction in the number of D, and D, mRNA-positive cells was observed compared with controls; however, the abundance of both receptor mRNAs per remaining cell was within the control range. For D, receptor mRNA, the number of detectable D,-positive medium-sized cells decreased with increasing pathology; this decrease was accompanied by a gradual reduction in the intensity of D, signal per cell. By contrast, for D, receptor mRNA, despite a decrease in the number of D, mRNA-positive cells detected, the average cellular expression of D, mRNA was markedly reduced in the HD grade 1 case and then increased (relative to the grade 1 case) with increasing pathology, presumably reflecting the relative survival of D,-expressing striatal interneurons. The implications of these findings for providing further information on the neurodegenerative process in HD are discussed.
European Journal of Nuclear Medicine and Molecular Imaging, 1999
Huntington disease (HD) is characterized by severe abnormalities in neurotransmitter concentrations and neuroreceptor density. Quantitative changes in dopamine D 2 receptors occur in the early stages of HD and may be detectable with functional neuroimaging techniques. The aim of this study was to determine whether dopamine D 2 receptor imaging with single-photon emission tomography (SPET) identifies preclinical abnormalities in HD. The study population comprised 32 subjects from families affected by HD: 11 were genetically normal while 21 were genetically positive for HD (seven asymptomatic, six early, three moderate and five advanced findings). Disease severity was determined using a standardized quantitative neurological examination (QNE) and the mini-mental status examination (MMSE). Subjects underwent brain SPET imaging 120 min following intravenous injection of iodine-123 epidepride. Ratios of target (striatal) to nontarget (occipital or whole-brain) uptake were calculated from the reconstructed image data. Striatum to occiput and striatum to whole-brain count ratios correlated negatively with disease stage (P=0.002 and P=0.0002) and QNE (P<0.002 and P=0.0002), and positively with the MMSE (P=0.001 and P<0.001). Uptake was significantly reduced in the moderate-advanced subjects but was still normal for the asymptomatic and early symptomatic stages. It is concluded that reductions in striatal dopamine D 2 receptor density can be detected with 123 I epidepride at moderate or advanced stages of HD. In contrast to other reports, we could not identify abnormalities in clinically unaffected or early stages of HD.
Synapse, 1988
The technique of quantitative autoradiography was used to examine the effects of Huntington's disease (HD) and schizophrenia on the organization of striatal dopamine (DA) D1 and D2 receptors. Whereas the striatum of HD cases showed a reduction in the density of D1 ([3H]SCH 23390) and D2 ([3H]spiroperidol) receptors, the patterning of D2 receptor loss did not match that of the D1 receptor loss. The HD loss of D1 D1 receptors (65%) is far greater than the loss of D2 receptors (28%). Whereas there was a dorsal-ventral gradient of effect on both receptor subtypes, the effects of HD on D2 receptors in the ventral putamen (PUT) and nucleus accumben septi (NAS) were minimal. Similarly, muscarinic M1 and M2 receptors demonstrate different patterns of alteration in HD. The M2 subtype, labeled with [3H]N-methylscopolamine (in the presence of excess pirenzepine to occlude M1 sites), was depleted far more than the M1 receptor subtype, labeled with [3H]pirenzepine. Although the effects of HD on [3H]mazindol labeling of DA terminals were more heterogeneous, there appeared to be a relative preservation of this afferent input to the striatum of the HD cases. In the schizophrenic cases, our autoradiographic studies confirm previous reports of an elevation of D2 receptor density in the striata of many schizophrenics. This increase was evident even though two of the three cases were known to have not been treated with neuroleptics, and the third case may also have been drug naive. However, the increase was far greater in the NAS (164%) and ventral PUT (173%) than more dorsally in the striatum (68%). The density of D1 receptors and DA terminals labeled with [3H]mazindol in the striatum of schizophrenics was not significantly different from that of control cases. Thus in both HD and schizophrenia, the ratio of D2D1 receptors is altered in favor of the D2 population, particularly in the NAS.
Background: Values of binding potentials (BPND) of dopamine D2/3 receptors differ in different regions of the brain, but we do not know with certainty how much of this difference is due either to different receptor numbers, or to different affinities of tracers to the receptors, or to both. Method: We tested the claim that both striatal and extrastriatal dopamine D2/3 receptor availabilities vary with age in vivo in humans by determining the values of BPND of the specific radioligand [11C]raclopride. We determined values of BPND in striatal and extrastriatal volumes-of-interest (VOI) with the same specific receptor radioligand. Results: We estimated values of BPND in individual voxels of brains of healthy volunteers in vivo, and we obtained regional averages of VOI by dynamic positron emission tomography (PET). We calculated average values of BPND in caudate nucleus and putamen of striatum, and in frontal, occipital, parietal, and temporal cortices of the forebrain, by means of four...
Acta Neurologica Scandinavica, 1987
Dopaminergic receptor properties in the striatum of patients with Parkinson's disease (PD) and Huntington's chorea (HD) were studied by positron emission tomography (PET), using "C-N-methyl-spiperone as a dopamine D, receptor ligand. The time-dependent regional radioactive uptake in the caudate nucleus and the putamen was measured and fitted to a 3-compartment pharmacokinetic model. The rate constant k, for specific binding to the receptor compartment in the striatum was determined in relation to the binding in regions with a low density of specific binding sites, such as the cerebellum and the frontal cortex. k,, which is a measure of the receptor density, was reduced in one patient with HD but less affected in PD in comparison with healthy controls. The pattern of k, values calculated from the 6 PD patients is discussed in relation to any side-to-side differences in dopamine receptor densities in hemiparkinsonism and to possible "hypersensitivity" of dopamine receptors in the early stage of the disease and down-regulation in more advanced disease.