Journal
BRAIN
Volume 131, Issue -, Pages 2860-2869Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awn244
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Funding
- Medical Research Council [G0300723B, MC_U120036861] Funding Source: researchfish
- MRC [MC_U120036861] Funding Source: UKRI
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Recent studies have shown alterations in metabolism, sleep and circadian rhythms as well as in several neuropeptides derived from the hypothalamicpituitary axis in Huntingtons disease patients; however, the pathology underlying these abnormalities is not known. Our aim was to assess in vivo D(2) receptors loss/dysfunction and increases in microglial activation in the hypothalamus of symptomatic Huntingtons disease patients and premanifest Huntingtons disease gene carriers using PET with (11)C-raclopride (RAC), a specific D(2) receptor ligand and (11)C-(R)-PK11195 (PK), a marker of microglial activation. We have studied 9 symptomatic Huntingtons disease patients (age46.84.7 years; meanSD) and 10 premanifest Huntingtons disease gene carriers (age41.98.2 years; meanSD). RAC and PK findings for these subjects were compared with those of a group of normal controls (RAC, n9; PK, n10). In the symptomatic Huntingtons disease group, we found a significant decrease (P0.0012) in mean hypothalamic RAC binding potential (BP) and a significant increase in mean hypothalamic PK BP (P0.0008). Similarly, a significant decrease (P0.0143) in mean hypothalamic RAC BP and a significant increase in mean hypothalamic PK BP (P0.0057) were observed in the premanifest Huntingtons disease group. Hypothalamic RAC and PK BP values correlated with each other in combined Huntingtons disease groups (r0.6180, P0.0048) but not with striatal RAC and PK BP values. Our data demonstrate, for the first time, significant D(2) receptor loss and microglia activation in the hypothalamus of Huntingtons disease. These pathological changes occur very early in the course of the disease and may partly explain the development of commonly reported symptoms in Huntingtons disease including progressive weight loss, alterations in sexual behaviour and disturbances in the wakesleep cycle.
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