On the possible use of oxysterols for the diagnosis and evaluation of patients with neurological and neurodegenerative diseases

Abstract: Oxysterols are monooxygenated derivatives of cholesterol with a unique ability to pass lipophilic membranes and are involved in a number of elimination pathways for cholesterol. One of the major oxysterols in the circulation, 24S-hydroxycholesterol, is formed exclusively in the brain, mainly in neuronal cells. There is a continuous flux of this oxysterol from the brain over the blood-brain barrier (BBB) into the circulation, and the levels of 24S-hydroxycholesterol may thus reflect cholesterol homeostasis in the brain. Another major oxysterol in the circulation, 27hydroxycholesterol is formed by most cells in the body. The levels of this oxysterol are relatively low in the brain, and the possibility must be considered that part of it may originate from the circulation. In the present thesis the following hypotheses were tested: 1) Patients with multiple sclerosis (MS) have increased flux of 24S-hydroxycholesterol during active periods of the disease and may then have increased plasma levels of this oxysterol; 2) the plasma levels of 24Shydroxycholesterol in circulation are correlated with the degree of brain atrophy; 3) Patients with neuronal damage and/or demyelination have an increased flux of 24S-hydroxychole sterol from the brain into the cerebrospinal fluid (CSF); 4) A defect BBB causes increased flux of 27-hydroxycholesterol from the circulation into the CSF; 5) Patients with MS may have increased CSF-levels of 7-oxocholesterol, an oxysterol formed from cholesterol as a consequence of lipid peroxidation and oxidative stress. Isotope dilution - mass spectrometry was used to assay the different oxysterols in CSF and plasma from more than 300 patients with different neurological and geriatric diseases. The amount of the disease burden and the degree of brain atrophy was evaluated in some of the MS patients by Magnetic Resonance Imaging (MRI). The 95% confidence interval for 24S- and 27-hydroxycholesterol in CSF from a normal population was found to be 0.4-2.5 µg/L and 0.2-1 µg/L, respectively. In the course of the investigations it was found that: 1) plasma levels of 24S-hydroxycholesterol are significantly decreased in MS patients with advanced disease, and are likely to reflect the degree of brain atrophy; 2) neuronal damage or demyelination are associated with increased levels of 24S-hydroxycholesterol in CSF; 3) most of the 27-hydroxycholesterol in CSF originates from the circulation and a compromised BBB is associated with increased CSF levels of this oxysterol; 4) patients with MS have slightly increased levels of 7-oxocholesterol in CSF, possibly reflecting an increased lipid peroxidation. The high proportion of the neurological patients with increased CSF levels of one or both of the two side-chain oxidized oxysterols is consistent with the contention that a normal level of these two oxysterols has a high negative predictive value. In conclusion, the determination of both plasma and CSF oxysterol levels may offer important information for a better understanding of the different processes active in central nervous system diseases.