H03 Cerebral and extracerebral cholesterol biosynthesis is impaired in Huntington's disease patients

Background Cholesterol in the CNS is fundamental for membrane trafficking, signal transduction and synaptogenesis and almost all the brain cholesterol is synthetised locally. Homeostasis is maintained through a neuronal specific cholesterol 24-hydroxylase which converts cholesterol into 24-hydroxycholesterol (24OHC). The levels of 24OHC in blood thus reflect the number of active neurons and the volume of the grey matter. We previously found that plasma levels of 24OHC were progressively reduced in early Huntington's disease (HD)1 and that cholesterol biosynthesis was significantly impaired in the brain of multiple mouse HD models, and in fibroblasts of HD patients.2 Methods We analysed by mass spectrometry plasma levels of the cholesterol precursor lathosterol and lanosterol (marker of cholesterol biosynthesis), 24OHC and bile acid precursor 27-hydroxycholesterol, in 130 HD gene positive subjects (from presymptomatic to advanced stage of disease). Results We found that plasma levels of lathosterol and lanosterol, together with 24OHC and 27OHC, were reduced in all HD patients compared with healthy controls (p