Serial C-11-raclopride PET in the longitudinal assessment of Huntington's disease (original) (raw)
Related papers
Annals of Neurology, 1998
We used [ "C] raclopride and positron emission tomography (PET) to assess the relationship between striatal dopamine D2 receptor binding, trinucleotide repeat number (CAG), and subject age in 10 asymptomatic and 8 symptomatic carriers of the Huntington's disease (HD) mutation. In both preclinical and symptomatic gene carriers, we found significant correlations between CAG repeat length and the ratio of percent loss in striatal D2 receptor binding divided by age. In accord with neuropathological studies, we obtained an intercept at 35.5 CAG repeats in the symptomatic HD patients. Nonetheless, we noted that the slopes of the correlation lines differed significantly for the presymptomatic and symptomatic cohorts. These PET results support the notion that the HD disease process is a function of trinucleotide length and age, and that the development of clinical signs and symptoms is associated with CAG repeat lengths greater than 35.5. However, our analysis also suggests that striatal degeneration may proceed in a nonlinear fashion. These findings have implications for the design of neuroprotective strategies for the treatment of 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.
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.
Extrastriatal dopamine D 2 receptor binding in Huntington's disease
Human Brain Mapping, 2011
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. Hum Brain Mapp 32:1626-1636,
Journal of Nuclear Medicine, 2016
Since the discovery of the HTT gene in 1993, numerous animal models have been developed to study the progression of Huntington disease (HD) and to evaluate potential new therapeutics. In the present study, we used small-animal PET to characterize the expression of molecular targets in the recently reported HD animal model, the zQ175 mouse model. Methods: Male heterozygous zQ175 (Htt tm1Mfc /190JChdi, CHDI-81003003) and wild-type (WT, C57BL/6J) animals were imaged with the dopamine D 2 receptor radioligand 11 C-raclopride, the PDE10A radioligand 18 F-MNI-659, the dopamine D 1 receptor radioligand 11 C-NNC 112, and the 5-HT 2A radioligand 11 C-MDL 100907 at 6 and 9 mo of age. The outcome measure was the binding potential (BP ND), using the cerebellum as the reference region. Selected regions of interest were the striatum for all radioligands and additionally the striatum, rostral cortex, caudal cortex, and hippocampus for 11 C-NNC 112 and 11 C-MDL 100907. Results: At 6 mo of age, the BP ND in the striatum was lower in zQ175 than WT animals by 40% for 11 C-raclopride, by 52% for 18 F-MNI-659, by 28% for 11 C-NNC, and by 11% for 11 C-MDL 100907. In the rostral cortex, D 1 receptor binding was 22% lower in zQ175 than WT animals. We found an overall reduction in D 1 and 5-HT 2A binding in the hippocampus of zQ175 compared with WT animals. The BP ND of 11 C-MDL 100907 in the caudal cortex was also lower in zQ175 WT animals. At 9 mo, there was a slight further reduction of D 1 , D 2 , and 5-HT 2A BP ND in the striatum, whereas PDE10A reached a plateau. Cortical markers were also slightly further decreased at 9 mo in zQ175 animals. Conclusion: Our study indicates a marked reduction of ligand binding to D 1 and D 2 and 5-HT 2A receptors as well as loss of PDE10A enzyme in the striatum of zQ175 mice as compared with WT animals, in agreement with data obtained in clinical PET studies of patients with HD. The zQ175 mouse model recapitulates the expression pattern seen in humans with HD and may have value in further elucidating pathophysiologic events and therapeutic strategies.
Journal of Nuclear Medicine, 2016
Since the discovery of the HTT gene in 1993, numerous animal models have been developed to study the progression of Huntington disease (HD) and to evaluate potential new therapeutics. In the present study, we used small-animal PET to characterize the expression of molecular targets in the recently reported HD animal model, the zQ175 mouse model. Methods: Male heterozygous zQ175 (Htt tm1Mfc /190JChdi, CHDI-81003003) and wild-type (WT, C57BL/6J) animals were imaged with the dopamine D 2 receptor radioligand 11 C-raclopride, the PDE10A radioligand 18 F-MNI-659, the dopamine D 1 receptor radioligand 11 C-NNC 112, and the 5-HT 2A radioligand 11 C-MDL 100907 at 6 and 9 mo of age. The outcome measure was the binding potential (BP ND), using the cerebellum as the reference region. Selected regions of interest were the striatum for all radioligands and additionally the striatum, rostral cortex, caudal cortex, and hippocampus for 11 C-NNC 112 and 11 C-MDL 100907. Results: At 6 mo of age, the BP ND in the striatum was lower in zQ175 than WT animals by 40% for 11 C-raclopride, by 52% for 18 F-MNI-659, by 28% for 11 C-NNC, and by 11% for 11 C-MDL 100907. In the rostral cortex, D 1 receptor binding was 22% lower in zQ175 than WT animals. We found an overall reduction in D 1 and 5-HT 2A binding in the hippocampus of zQ175 compared with WT animals. The BP ND of 11 C-MDL 100907 in the caudal cortex was also lower in zQ175 WT animals. At 9 mo, there was a slight further reduction of D 1 , D 2 , and 5-HT 2A BP ND in the striatum, whereas PDE10A reached a plateau. Cortical markers were also slightly further decreased at 9 mo in zQ175 animals. Conclusion: Our study indicates a marked reduction of ligand binding to D 1 and D 2 and 5-HT 2A receptors as well as loss of PDE10A enzyme in the striatum of zQ175 mice as compared with WT animals, in agreement with data obtained in clinical PET studies of patients with HD. The zQ175 mouse model recapitulates the expression pattern seen in humans with HD and may have value in further elucidating pathophysiologic events and therapeutic strategies.
Brain Research, 2000
It has been demonstrated that withdrawal from chronic treatment with haloperidol is associated with a long-lasting increase in the number of striatal dopamine D receptors and variable changes in D receptors. We have investigated the effect of withdrawal from 2 1 sub-chronic administration of haloperidol on the density of dopamine receptors, dopamine receptor gene expression, and spontaneous Ž. locomotor activity. Following a 3-week treatment period with haloperidol 1.5 mgrkg, i.p. , spontaneous locomotor activity measurements, autoradiography of D and D receptors and in situ hybridisation histochemistry of D and D mRNA were performed. Using 1 2 1 2 w 3 x H raclopride as the ligand, sub-chronic haloperidol administration produced a robust upregulation in D binding in the striatum of rats 2 w 3 x which correlated with parallel increases in spontaneous locomotor activity from 24 h to 4 weeks. Using, H SCH23390 as the ligand, D 1 binding was largely unaffected by the drug treatment. Non-significant changes were measured in the striatal expression of D receptor 1 mRNA or the nigral or striatal expression of D receptor mRNA. Our findings have implications for the use of dopaminergic ligands in 2 Ž. positron emission tomography PET imaging of patients under regimens of chronic neuroleptics in particular in the context of Ž. forthcoming trials of neural grafts in Huntington's disease HD striatum.
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.