Striatal glucose metabolism and dopamine D₂ receptor binding in asymptomatic gene carriers and patients with Huntington's disease

Abstract

We used PET scans with the tracers [18F]fluorodeoxyglucose (FDG) and [11C]raclopride (RACLO) to study glucose metabolism and dopamine D2 receptor binding in the caudate nucleus and putamen of 18 carriers of the Huntington's disease gene mutation (10 asymptomatic subjects and eight untreated symptomatic Huntington's disease patients in an early disease stage). We also performed MRI scans and measured the bicaudate ratio (BCR) in the same subjects. Data were compared with those from nine mutation-negative members of Huntington's disease families and separate groups of age matched controls. The PET scans were repeated 1.5-3 years later in six of the asymptomatic gene carriers. Symptomatic Huntington's disease patients showed a marked reduction of FDG and RACLO uptake in the caudate nucleus and putamen and a significant increase of BCR. Asymptomatic mutation carriers revealed significant hypometabolism in the caudate nucleus and putamen. The RACLO binding was significantly decreased in the putamen. Decrements of caudate nucleus tracer uptake, particularly RACLO, correlated significantly with BCR increases in both symptomatic and asymptomatic gene carriers. In asymptomatic carriers, metabolic and receptor binding decreases were also significantly associated with the CAG repeat number but not with the individual's age. Discriminant function analysis correctly classified clinical and genetic status in 24 of 27 subjects on the basis of their striatal PET values (83% sensitivity and 100% specificity). Three asymptomatic mutation carriers were classified/grouped together with mutation-negative subjects, indicating that these individuals had normal striatal RACLO and FDG uptake. Follow-up PET data from gene-positive subjects showed a significant reduction in the mean striatal RACLO binding of 6.3% per year. Striatal glucose metabolism revealed an overall non significant 2.3% decrease per year. These data indicate that asymptomatic Huntington's disease mutation carriers may show normal neuronal function for a long period of life. These findings also suggest that it may be possible to predict when an asymptomatic gene carrier will develop clinical symptoms from serial PET measurements of striatal function.

Type 1 cannabinoid receptor mapping with [18F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism

“…Radiotracer synthesis CB 1 receptor imaging was performed in all animals (n=21) using the radioligand [ 18 …”

“…Functional images of the striatal dopamine system were obtained from each surviving rat using the D 2 receptor radioligand [ 11 C]raclopride (n=20) [25], while glucose metabolism was assessed using [ 18 GBq/ μmol; injection volume: 500 μl) were injected into the tail vein using an infusion needle set.…”

“…Imaging studies were performed on age-matched animals within 11-13 weeks post-lesioning for [ 18 The acquisition timing rationale and kinetics of the radioligands in rats have been described previously [24,26].…”

“…SPM analysis was carried out using a categorical subject design (conditions: disease vs controls) on parametric [ 18 To minimize false-positive findings, T-map data were interrogated at a peak level of p<0.005 (uncorrected) and extent threshold k E >200 voxels (1.6 mm 3 ), as described previously [30]. Only those clusters that were significant at the p<0.05 (corrected) level were considered.…”

“…Also, dopamine D 2 receptor availability and glucose metabolism, all shown to be altered (early) in patients and animal models of HD [18,19], were investigated in the same animals and correlated to the regional CB 1 receptor status.…”