Plasma Concentrations of High Mobility Group Box 1 Proteins and Soluble Receptors for Advanced Glycation End-Products Are Relevant Biomarkers of Cognitive Impairment in Alcohol Use Disorder: A Pilot Study
Author:
Rodríguez de Fonseca Fernando12ORCID, Medina-Paz Francisco3ORCID, Sapozhnikov Mira3ORCID, Hurtado-Guerrero Isaac14, Rubio Leticia14ORCID, Martín-de-las-Heras Stella14ORCID, Requena-Ocaña Nerea15, Flores-López María15ORCID, Fernández-Arjona María del Mar12, Rivera Patricia15, Serrano Antonia15, Serrano Pedro12ORCID, C. Zapico Sara36ORCID, Suárez Juan14ORCID
Affiliation:
1. Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain 2. Servicio de Neurología, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain 3. Department of Chemistry and Environmental Sciences, New Jersey Institute of Technology, Tiernan Hall 365, Newark, NJ 07102, USA 4. Departamento de Anatomía Humana, Medicina Legal e Historia de la Ciencia, Facultad de Medicina, Universidad de Málaga, 29071 Málaga, Spain 5. UGC Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain 6. Anthropology Department, National Museum of Natural History, Smithsonian Institution, 10th and Constitution Ave. NW, Washington, DC 20560, USA
Abstract
Alcohol use disorder (AUD) is a major component in the etiology of cognitive decline and dementia. Underlying mechanisms by which long-term alcohol abuse causes cognitive dysfunction include excessive oxidative stress and inflammation in the brain, activated by increased reactive oxygen/nitrogen species (ROS/RNS), advanced glycation end-products (AGEs) and high-mobility group box 1 protein (HMGB1). In a pilot study, we examine the potential clinical value of circulating biomarkers of oxidative stress including ROS/RNS, HMGB1, the soluble receptor for AGE (sRAGE), the brain biomarker of aging apolipoprotein D (ApoD), and the antioxidant regulator nuclear factor erythroid 2-related factor 2 (NRF2) as predictive indices for cognitive impairment (CI) in abstinent patients with AUD (n = 25) compared to patients with established Alzheimer’s disease (AD, n = 26) and control subjects (n = 25). Plasma concentrations of sRAGE were evaluated with immunoblotting; ROS/RNS with a fluorometric kit; and HMGB1, ApoD, and NRF2 by ELISA. Abstinent AUD patients had higher sRAGE, ROS/RNS (p < 0.05), and ApoD (p < 0.01) concentrations, similar to those of AD patients, and lower NRF2 (p < 0.01) concentrations, compared to controls. These changes were remarkable in AUD patients with CI. HMGB1, and sRAGE correlated positively with duration of alcohol use (rho = 0.398, p = 0.022; rho = 0.404, p = 0.018), whereas sRAGE correlated negatively with periods of alcohol abstinence (rho = −0.340, p = 0.045). A predictive model including ROS/RNS, HMGB1, sRAGE, alcohol use duration, and alcohol abstinence periods was able to differentiate AUD patients with CI (92.3% of correct predictions, ROC-AUC= 0.90) from those without CI. In conclusion, we propose ROS/RNS, HMGB1, and sRAGE as stress biomarkers capable of predicting cognitive impairment in AUD patients.
Funder
Fulbright Visiting Scholar Program, United States Department of State and Ministerio de Educación y Formación Profesional Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación and European Regional Development Funds-European Union Instituto de Salud Carlos III RICORS RIAPAD RETICS RTA Ministerio de Sanidad, Delegación de Gobierno para el Plan Nacional sobre Drogas Consejería de Salud y Familia, Junta de Andalucía Consejería de Universidad, Investigación e Innovación, Junta de Andalucía Universidad de Málaga “María Zambrano” research contract from the Ministry of Universities “Miguel Servet I” research contract from the National System of Health, ERDF-EU-ISCIII
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