Abstract
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.
Highlights
Today approximately 50 million people worldwide suffer from dementia, which renders this neurodegenerative disease one of the major causes of cognitive impairment, immobility and dependency among elderly people
To compare cognitive abilities of both mice strains, 8 weeks old B6N and BALBc mice were trained in the Water Cross Maze (WCM) using the place-learning protocol over the course of 5 days
Due to its simplicity, mice more reach the platform compared to training in the Water maze, which reduces the stress load and frustration
Summary
Today approximately 50 million people worldwide suffer from dementia, which renders this neurodegenerative disease one of the major causes of cognitive impairment, immobility and dependency among elderly people. Patients have to be identified at early, ideally at prodromal stages of the disease, in order to permit preventive interventions (Hampel et al, 2014). Such attempts should include longitudinal studies on prognostic markers, which directly relate to the pathology of dementia (e.g., cognitive changes and altered neurochemistry/anatomy of distinct brain structures) rather than surrogate markers (e.g., lifestyle factors, blood analytes, etc.). MCI is defined as an intermediate stage of cognitive impairment that may evolve into dementia (Petersen, 2004). MCI patients are still able to handle their daily routine and preserve general cognitive and functional abilities
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