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.

How reliable is 18FDG PET for predicting the onset of Huntington’s disease?

“…A similar finding has been reported in the thalamus that shows an early compensatory hypermetabolism resulting from striatal dysfunction followed by decreased uptake when signs of disease become clinically evident [18].…”

“…In conclusion, the results of this paper that highlight the value of molecular imaging in HD also suggest that 18 FDG PET could be a reliable tool to provide a better understanding of the biological process in other neurodegenerative disease, thus providing additional data to clinicians to support diagnoses and treatment strategies.…”

“…The authors found a progressive metabolic striatal decrease in subjects with preclinical HD as compared with controls and subjects with manifest HD, indicating the value of 18 F-FDG PET/CT as a possible predictor of the onset of HD. The findings are consistent with those of previous studies highlighting early striatal involvement in gene mutation carriers without motor symptoms and, therefore, still clinically considered far from onset.…”

“…In the current issue of the European Journal of Nuclear Medicine and Molecular Imaging, López-Mora et al present a study evaluating the cortical and striatal 18 F-FDG PET/CT uptake in a cohort of Huntington's disease (HD) mutation carriers in preclinical and manifest stages of the disease. The authors found a progressive metabolic striatal decrease in subjects with preclinical HD as compared with controls and subjects with manifest HD, indicating the value of 18 F-FDG PET/CT as a possible predictor of the onset of HD.…”

Treatment of Huntington's Disease

“…It is not known if the accumulation of mhtt conglomerate results in cell death, or if the soluble form of the protein is the toxic form [8,9]. Dopamine, glutamate, and γ-aminobutyric acid are thought to be the most affected neurotransmitters in HD and are currently the focus of pharmacotherapy (Table 1) [10][11][12][13][14][15][16][17][18][19][20][21][22][23].…”