Cerebrospinal Fluid Profile of Lipid Mediators in Alzheimer's Disease

Khanh V. Do, Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, 2020 Gravier Street, Suite D, New Orleans, LA, 70112, USA.
Erik Hjorth, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, BioClinicum J9:20, Visionsgatan 4, 171 64, Solna, Sweden.
Ying Wang, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, BioClinicum J9:20, Visionsgatan 4, 171 64, Solna, Sweden.
Bokkyoo Jun, Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, 2020 Gravier Street, Suite D, New Orleans, LA, 70112, USA.
Marie-Audrey I. Kautzmann, Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, 2020 Gravier Street, Suite D, New Orleans, LA, 70112, USA.
Makiko Ohshima, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, BioClinicum J9:20, Visionsgatan 4, 171 64, Solna, Sweden.
Maria Eriksdotter, Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska University Hospital, 141 86, Huddinge, Sweden.
Marianne Schultzberg, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, BioClinicum J9:20, Visionsgatan 4, 171 64, Solna, Sweden. Marianne.Schultzberg@ki.se.
Nicolas G. Bazan, Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, 2020 Gravier Street, Suite D, New Orleans, LA, 70112, USA. NBazan@lsuhsc.edu.

Abstract

Alzheimer's disease (AD) develops into dementia over a period of several years, during which subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) can be used as intermediary diagnoses of increasing severity. Chronic neuroinflammation resulting from insufficient resolution is involved in the pathogenesis of AD and is associated with cognitive impairment. Specialized pro-resolving lipid mediators (LMs) that promote the resolution of inflammation may be valuable markers in AD diagnosis and as therapeutic targets. Liquid chromatography-tandem mass spectrometry was used to analyze pro-resolving and pro-inflammatory LMs in cerebrospinal fluid (CSF) from patients with cognitive impairment ranging from subjective impairment to a diagnosis of AD and correlated to cognition, CSF tau, and β-amyloid. Resolvin (Rv) D4, RvD1, neuroprotectin D1 (NPD1), maresin 1 (MaR1), and RvE4 were lower in AD and/or MCI compared to SCI. The pro-inflammatory LTB and 15-HETE were higher in AD and MCI, respectively, while PGD2, PGE2, and PGF2a were decreased in AD, compared to SCI. RvD4 was also negatively correlated to AD tangle biomarkers, and positive correlations to cognitive test scores were observed for both pro-resolving LMs and their precursor fatty acids. In this exploratory study of the lipidome in CSF of AD, MCI, and SCI, the results indicate a shift in the LM profile from pro-resolving to pro-inflammatory in progression to AD, suggesting that it may be of use as a biomarker when followed by confirmation by replication studies.