Assessment of brain cholesterol metabolism biomarker 24S-hydroxycholesterol in schizophrenia

Joshua Chiappelli,Patricio O’Donnell,Peter Kochunov,Dmitri Volfson,Michael Cwik,Ann Summerfelt,Eric Goldwaser,Wyatt Marshall,Heather Bruce,Mark Kvarta,Liyi Elliot Hong,Maria S Quinton

doi:10.1038/s41537-020-00121-4

Joshua Chiappelli, Patricio O’Donnell + Show 10 more

Open Access

https://doi.org/10.1038/s41537-020-00121-4

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Abstract

Plasma 24S-hydroxycholesterol mostly originates in brain tissue and likely reflects the turnover of cholesterol in the central nervous system. As cholesterol is disproportionally enriched in many key brain structures, 24S-hydroxycholesterol is a promising biomarker for psychiatric and neurologic disorders that impact brain structure. We hypothesized that, as schizophrenia patients have widely reported gray and white matter deficits, they would have abnormal levels of plasma 24S-hydroxycholesterol, and that plasma levels of 24S-hydroxycholesterol would be associated with brain structural and functional biomarkers for schizophrenia. Plasma levels of 24S-hydroxycholesterol were measured in 226 individuals with schizophrenia and 204 healthy controls. The results showed that levels of 24S-hydroxycholesterol were not significantly different between patients and controls. Age was significantly and negatively correlated with 24S-hydroxycholesterol in both groups, and in both groups, females had significantly higher levels of 24S-hydroxycholesterol compared to males. Levels of 24S-hydroxycholesterol were not related to average fractional anisotropy of white matter or cortical thickness, or to cognitive deficits in schizophrenia. Based on these results from a large sample and using multiple brain biomarkers, we conclude there is little to no value of plasma 24S-hydroxycholesterol as a brain metabolite biomarker for schizophrenia.

Highlights

The brain has the highest level of cholesterol among all organs of the human body and contains about a quarter of the body’s cholesterol despite the fact that it has only about 2% of the total body weight
When body surface area is included as a covariate in this model, the sex effect is no longer significant (p = 0.08), and instead, body surface area is significantly related to 24-OHC levels (F = 9.67, p = 0.002)
This study found no evidence to indicate that plasma levels of 24-OHC are abnormal in people with schizophrenia compared to healthy controls

Summary

Introduction

The brain has the highest level of cholesterol among all organs of the human body and contains about a quarter of the body’s cholesterol despite the fact that it has only about 2% of the total body weight. The brain contains such a disproportionate amount of the total cholesterol in large part due to the key role of cholesterol in myelin sheath and neuronal cell membranes[1]. A key mechanism for the excretion of cholesterol maybe conversion to the oxysterol 24S-hydroxycholesterol (24-OHC), which enters circulation from the brain to be further metabolized by the liver at a rate roughly equivalent to de novo synthesis of cholesterol within the brain[3].

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