Brain Advance Access published online on October 1, 2008
Brain, doi:10.1093/brain/awn244
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Hypothalamic involvement in Huntington's disease: an in vivo PET study
1Division of Clinical Neurosciences and MRC Clinical Sciences Centre, Faculty of Medicine, Hammersmith Hospital, Imperial College London, 2Department of Neurodegenerative Disease, Institute of Neurology, London and 3Centre for Brain Repair and Department of Neurology, University of Cambridge, Cambridge, UK
Correspondence to:
Prof. Paola Piccini, Cyclotron Building, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK E-mail: paola.piccini{at}imperial.ac.uk
Recent studies have shown alterations in metabolism, sleep and circadian rhythms as well as in several neuropeptides derived from the hypothalamic–pituitary axis in Huntington's disease patients; however, the pathology underlying these abnormalities is not known. Our aim was to assess in vivo D2 receptor's loss/dysfunction and increases in microglial activation in the hypothalamus of symptomatic Huntington's disease patients and premanifest Huntington's disease gene carriers using PET with 11C-raclopride (RAC), a specific D2 receptor ligand and 11C-(R)-PK11195 (PK), a marker of microglial activation. We have studied 9 symptomatic Huntington's disease patients (age = 46.8 ± 4.7 years; mean ± SD) and 10 premanifest Huntington's disease gene carriers (age = 41.9 ± 8.2 years; mean ± SD). RAC and PK findings for these subjects were compared with those of a group of normal controls (RAC, n = 9; PK, n = 10). In the symptomatic Huntington's disease group, we found a significant decrease (P = 0.0012) in mean hypothalamic RAC binding potential (BP) and a significant increase in mean hypothalamic PK BP (P = 0.0008). Similarly, a significant decrease (P = 0.0143) in mean hypothalamic RAC BP and a significant increase in mean hypothalamic PK BP (P = 0.0057) were observed in the premanifest Huntington's disease group. Hypothalamic RAC and PK BP values correlated with each other in combined Huntington's disease groups (r = –0.6180, P = 0.0048) but not with striatal RAC and PK BP values. Our data demonstrate, for the first time, significant D2 receptor loss and microglia activation in the hypothalamus of Huntington's disease. These pathological changes occur very early in the course of the disease and may partly explain the development of commonly reported symptoms in Huntington's disease including progressive weight loss, alterations in sexual behaviour and disturbances in the wake–sleep cycle.
Key Words: hypothalamus; Huntington's disease; positron emission tomography (PET); raclopride; PK11195
Abbreviations: BP, binding potential; PET, positron emission tomography; PK, 11C-(R)-PK11195; RAC, 11C-raclopride; ROI, region of interest; SD, standard deviation; SPM, statistical parametric mapping; VOI, volume of interest
Received March 24, 2008. Revised August 10, 2008. Accepted September 7, 2008.