Multivariate Assessment of Lipoxidative Metabolites, Trace Biometals, and Antioxidant and Detoxifying Activities in the Cerebrospinal Fluid Define a Fingerprint of Preclinical Stages of Alzheimer’s Disease

Article type: Research Article

Authors: Mesa-Herrera, Fátima^a | Marín, Raquel^{b; c} | Torrealba, Eduardo^d | Díaz, Mario^{e; f; *}

Affiliations: [a] Laboratory of Membrane Physiology and Biophysics, Department of Animal Biology, Edaphology and Geology, Biology Section, Science School, Universidad de La Laguna, Santa Cruz de Tenerife, Spain | [b] Laboratory of Cellular Neurobiology, Department of Basic Medical Sciences, Health Sciences School, Universidad de La Laguna, Santa Cruz de Tenerife, Spain | [c] Associate Research Unit ULL-CSIC Membrane Physiology and Biophysics in Neurodegenerative and Cancer Diseases, University of La Laguna, Santa Cruz de Tenerife, Spain | [d] Department of Neurology, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain | [e] Department of Physics, Faculty of Sciences, Universidad de La Laguna, Santa Cruz de Tenerife, Spain | [f] IUETSP (Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias), Universidad de La Laguna, Santa Cruz de Tenerife, Spain

Correspondence: [*] Correspondence to: Mario Diaz, PhD, Department of Physics, Faculty of Sciences, Universidad de La Laguna, Spain. E-mail: madiaz@ull.es.

Abstract: Background:There exists considerable interest in the identification of molecular traits during early stages of Alzheimer’s disease (AD). Mild cognitive impairment (MCI) is considered the closest prodromal stage of AD, and to develop gradually from earlier stages although not always progresses to AD. Classical cerebrospinal fluid (CSF) AD biomarkers, amyloid-β peptides and tau/p-tau proteins, have been measured in prodromal stages yet results are heterogeneous and far from conclusive. Therefore, there exists a pressing need to identify a neurochemical signature for prodromal stages and to predict which cases might progress to AD. Objective:Exploring potential CSF biomarkers related to brain oxidative and inorganic biochemistry during prodromal stages of the disease. Methods:We have analyzed CSF levels of lipoxidative markers (MDA and 8-isoF2α), biometals (Cu, Zn, Se, Mn, and Fe), iron-transport protein transferrin (TFER), antioxidant enzymes (SOD and GPx4), detoxifying enzymes (GST and BuChE), as well as classical amyloid-β and total and phosphorylated tau, in cognitively healthy controls, patients with MCI, and subjects exhibiting subjective memory complaints (SMC). Results:Inter-group differences for several variables exhibit differentiable trends along the HC ⟶ SMC ⟶ MCI sequence. More interestingly, the combination of Se, Cu, Zn, SOD, TFER, and GST variables allow differentiable fingerprints for control subjects and each prodromal stage. Further, multivariate scores correlate positively with neurocognitive In-Out test, hence with both episodic memory decline and prediction to dementia. Conclusion:We conclude that changes in the CSF biochemistry related to brain oxidative defense and neurometallomics might provide more powerful and accurate diagnostic tools in preclinical stages of AD.

Keywords: Alzheimer’s disease, butyrylcholinesterase, extracellular superoxide dismutase, glutathione-S-transferase, lipoxidative markers, mild cognitive impairment, neurometalomics, oxidative stress, subjective memory complaints, transferrin

DOI: 10.3233/JAD-215437

Journal: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 387-402, 2022