Dementia is a devastating age-related disorder. Its therapy would largely benefit from the identification of susceptible subjects at early, prodromal stages of the disease. To search for such prognostic markers of cognitive impairment, we studied spatial navigation in male BALBc vs. B6N mice in combination with in vivo magnetic resonance spectroscopy (1H-MRS). BALBc mice consistently showed higher escape latencies than B6N mice, both in the Water Cross Maze (WCM) and the Morris water maze (MWM). These performance deficits coincided with higher levels of myo-inositol (mIns) in the dorsal hippocampus before and after training. Subsequent biochemical analyses of hippocampal specimens by capillary immunodetection and liquid chromatography mass spectrometry-based (LC/MS) metabolomics revealed a higher abundance of glial markers (IBA-1, S100B, and GFAP) as well as distinct alterations in metabolites including a decrease in vitamins (pantothenic acid and nicotinamide), neurotransmitters (acetylcholine), their metabolites (glutamine), and acetyl-L-carnitine. Supplementation of low abundant acetyl-L-carnitine via the drinking water, however, failed to revert the behavioral deficits shown by BALBc mice. Based on our data we suggest (i) BALBc mice as an animal model and (ii) hippocampal mIns levels as a prognostic marker of mild cognitive impairment (MCI), due to (iii) local changes in microglia and astrocyte activity, which may (iv) result in decreased concentrations of promnesic molecules.

Central Nervous System Diseases Research Boehringer Ingelheim Pharma GmbH and Co KG Biberach an der Riss Germany

Department of Pharmacology Faculty of Medicine Masaryk University Brno Czechia

Department of Translational Research in Psychiatry Max Planck Institute of Psychiatry Munich Germany

Max Planck School of Cognition Leipzig Germany

Proteomics and Biomarkers Max Planck Institute of Psychiatry Munich Germany

Research Group Neurohomeostasis Department of Psychiatry and Psychotherapy University Hospital Bonn Bonn Germany

Research Group Neuronal Plasticity Max Planck Institute of Psychiatry Munich Germany

Scientific Core Unit Neuroimaging Max Planck Institute of Psychiatry Munich Germany

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