Thalamic metabolism and symptom onset in preclinical Huntington's disease

Abstract

The neural basis for the transition from preclinical to symptomatic Huntington's disease (HD) is unknown. We used serial positron emission tomography (PET) imaging in preclinical HD gene carriers (p-HD) to assess the metabolic changes that occur during this period. Twelve p-HD subjects were followed longitudinally with [11C]-raclopride and [18F]-fluorodeoxyglucose PET imaging, with scans at baseline, 18 and 44 months. Progressive declines in striatal D2-receptor binding were correlated with concurrent changes in regional metabolism and in the activity of an HD-related metabolic network. We found that striatal D2 binding declined over time (P < 0.005). The activity of a reproducible HD-related metabolic covariance pattern increased between baseline and 18 months (P < 0.003) but declined at 44 months (P < 0.04). These network changes coincided with progressive declines in striatal and thalamic metabolic activity (P < 0.01). Striatal metabolism was abnormally low at all time points (P < 0.005). By contrast, thalamic metabolism was elevated at baseline (P < 0.01), but fell to subnormal levels in the p-HD subjects who developed symptoms. These findings were confirmed with an MRI-based atrophy correction for each individual PET scan. Increases in network expression and thalamic glucose metabolism may be compensatory for early neuronal losses in p-HD. Declines in these measures may herald the onset of symptoms in gene carriers.

Fig. 1

Huntington’s disease-related pattern. This spatial covariance pattern was identified by network analysis of baseline FDG PET scans from 12 p-HD gene carriers and 12 age-matched healthy volunteer subjects. This pattern, representing the PC1 in the combined group analysis, accounted for 18% of the subject × voxel variation. Subject scores for this HD-related pattern (HDRP), representing network expression in individual subjects, discriminated the p-HD subjects from the controls (P<0.01). The HDRP is characterized by relative metabolic decreases in the striatum and cingulate cortex, associated with relative increases in the ventral thalamus, motor cortex (BA 4) and occipital lobe (BA17, 18). [The display represents voxels that contribute significantly to the network at P =0.005 and that were demonstrated to be reliable by bootstrap resampling procedures [inverse coefficient of variation (ICV)>3.5; P<0.001].Voxels with positive region weights (metabolic increases) are colour coded from red to yellow; those with negative region weights (metabolic decreases) are colour coded from blue to purple. The numbers under each slice are in millimeters, relative to the anterior-posterior commissure line.]

Fig. 2

Changes in HDRP expression. Individual subject HDRP expression for the 12 p-HD subjects scanned at baseline, and following 18 and 44 months. Network activity is represented separately for the four p-HD subjects (filled triangles) who subsequently developed symptoms (bold lines), and for the eight remaining p-HD subjects (filled circles) who had not phenoconverted by the third time point (fine lines, see text). Values for 12 age-matched healthy control subjects (CN, open circles) are presented for reference. [Bar represents the SE of the control values.]

Fig. 3

Regional glucose metabolism measured at representative nodes of the HDRP network. (A, B) In the striatum (putamen represented) normalized glucose metabolism declined over time (P<0.005). Significant reductions in striatal (putamen represented) metabolism are present at the baseline and follow-up PET visits in the p-HD cohort (filled squares). These reductions were comparatively greater in the p-HD subgroup who subsequently phenoconverted (open triangles). Regional glucose utilization was also reduced in the cingulate cortex throughout the period of observation. However, metabolism in this region did not change significantly over time. (C, D) In the thalamus (mediodorsal nucleus represented), normalized glucose utilization declined over time (P<0.01). In this region, baseline metabolic activity was abnormally elevated, particularly in the subgroup of gene carriers who did not phenoconvert during the course of the study (open circles). Although thalamic metabolism was also elevated at baseline in the subjects who subsequently phenoconverted (open triangles), metabolic activity in this region fell to normal levels as clinical signs emerged. By contrast, in the cerebellar vermis, metabolism was also elevated, but did not change over time. [The mean (±SE) for the 12 healthy control subjects is represented by broken lines.]

Fig. 4

Hypothesized time course of changes in striatal D₂ binding, metabolic activity and clinical ratings in preclinical Huntington’s disease. We used regression analysis of the data to estimate the time of onset (in years) of these functional changes prior to HD diagnosis (zero). Our data suggest that a decline in striatal D2 receptor binding (black) begins approximately 25 years before diagnosis. About five years later, striatal metabolism (green), an index of local neuronal viability, begins to fall. To compensate for striatal cell loss, thalamic metabolism (blue) increases (exactly when remains unknown) and with it, HDRP network activity (red). The latter measure peaks approximately 9 years before diagnosis. As thalamic metabolism declines, subtle clinical signs of disease (UHDRS, purple) emerge, beginning approximately 12 years before diagnosis. Concurrently, HDRP expression also falls, although remaining at supranormal levels (Feigin et al., 2001). The horizontal dashed line represents the normal mean. The arrows represent the estimated period of time of the current study.