Brain Advance Access originally published online on September 24, 2007
Brain 2007 130(11):2858-2867; doi:10.1093/brain/awm217
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Thalamic metabolism and symptom onset in preclinical Huntington's disease
1Center for Neurosciences, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY, 2Department of Neurology, North Shore University Hospital and New York University School of Medicine, New York, 3Department of Psychiatry, North Shore-Long Island Jewish Health System, Manhasset, NY, 4Department of Neuropsychology, Transitional Learning Centre, Galveston, TX, USA, 5Department of Neurology, University of Toronto, Toronto, Canada and 6Department of Neurology, University of Iowa, Des Moines, IA, USA
Correspondence to: Dr David Eidelberg, Center for Neurosciences, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, 350 Community Drive, Manhasset, NY 11030, USA E-mail: david1{at}nshs.edu
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.
Key Words: preclinical Huntington's disease (p-HD); brain metabolism; positron emission tomography (PET)
Abbreviations: BA, Brodmann area; FDG, 18F-fluorodeoxyglucose; HD, Huntington's disease; HDRP, HD-related metabolic covariance pattern; IVA, integrated visual and auditory continuous performance test; MD, mediodorsal; PCA, principal components analysis; PC1, first principal component; PCs, principal components; PET, positron emission tomography; p-HD, preclinical Huntington's disease; RAC, 11C-raclopride; RMANOVA, repeated measures analysis of variance; ROI, region-of-interest; UHDRS, unified Huntington's disease rating scale; VL, ventrolateral; VOI, volume-of-interest; VPL, ventrolateral posterolateral
Received April 20, 2007. Revised August 14, 2007. Accepted August 16, 2007.
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