Proton and Phosphorus Magnetic Resonance Spectroscopy of a Mouse Model of Alzheimer's Disease

Abstract

The development of new diagnostic criteria for Alzheimer's disease (AD) requires new in vivo markers reflecting early pathological changes in the brain of patients. Magnetic resonance (MR) spectroscopy has been shown to provide useful information about the biochemical changes occurring in AD brain in vivo. The development of numerous transgenic mouse models of AD has facilitated the evaluation of early biomarkers, allowing researchers to perform longitudinal studies starting before the onset of the pathology. In addition, the recent development of high-field animal scanners enables the measurement of brain metabolites that cannot be reliably quantified at lower magnetic fields. In this report, we studied a new transgenic mouse model of AD, the 5xFAD model, by in vivo proton and phosphorus MR spectroscopy. This model, which is characterized by an early-onset and a robust amyloid pathology, developed changes in the neurochemical profile, which are typical in the human disease, i.e., an increase in myo-inositol and a decrease in N-acetylaspartate concentrations, as early as in the 40th week of age. In addition, a significant decrease in the γ-aminobutyrate concentration was observed in transgenic mice at this age compared to controls. The pseudo-first-order rate constant of the creatine kinase reaction as well as relative concentrations of phosphorus-containing metabolites were not changed significantly in the 36 and 72-week old transgenic mice. Overall, these results suggest that mitochondrial activity in the 5 × FAD mice is not substantially affected but that the model is relevant for studying early biomarkers of AD.

Altered neurochemical profile in the McGill‐R‐Thy1‐APP rat model of Alzheimer's disease: a longitudinal in vivo1H MRS study

“…Although GABA levels in McGill-R-Thy1-APP rats remained stable during the study period, the difference in GABA levels at age 9 months in both brain areas might be of pathophysiological importance as GABA is the major inhibitory neurotransmitter of the brain and regulates neuronal excitability. This is also in accordance with a recent study that demonstrated a lower GABA concentration in the dorsal hippocampus of 5xFAD mice at age 40 and 44 weeks (Mlynarik et al 2012). Thus, both glutamatergic and GABAergic neurons were affected in both brain areas analysed in McGill-R-Thy1-APP rats at 9 months of age.…”

“…Others, however, found an increase in later stages after the appearance of amyloid plaques (Marjanska et al 2005). As suggested by Mlynarik et al (2012), this could mean that an increase in mIns is only detected when the pathology is severe, and that the early pre-plaque increase in mIns reported by Chen et al (2009) might indicate that they have a better animal model or could be a result of subtle effects of transgenes during embryogenesis. Our results support that hippocampal mIns increased after the appearance of plaques, and the level was also elevated in frontal cortex around the time of cortical plaque appearance in the McGill-R-Thy1-APP rat model.…”

“…The higher level of taurine in McGill-R-Thy1-APP rats could be related to any of these suggested roles. Elevated taurine/tCr has previously been demonstrated in hippocampus and cingulate cortex of APP Tg2576 mice at age 19-20 months (Dedeoglu et al 2004;Marjanska et al 2005), whereas dorsal hippocampal taurine has been shown to remain unaltered between age 36 and 44 weeks in 5xFAD mice (Mlynarik et al 2012).Total choline and creatine Differences in tCho levels were found in the dorsal hippocampus at age 3 and 9 months. Alterations in membrane synthesis and degradation can produce changes in the tCho peak, as GPC and PCh are breakdown products, and PCh is a precursor for phosphatidylcholine, a major component of cell membranes.…”

“…Alterations in membrane synthesis and degradation can produce changes in the tCho peak, as GPC and PCh are breakdown products, and PCh is a precursor for phosphatidylcholine, a major component of cell membranes. Previous studies on tCho levels in AD are conflicting (Mlynarik et al 2012) and have shown tCho to be either increased (Pfefferbaum et al 1999;Griffith et al 2008;Forster et al 2012), decreased (Jessen et al 2000 or unaltered (Block et al 2002;Wang et al 2009). The tCr level reflects high-energy phosphate metabolism, and we found that it changed with age in both dorsal hippocampus and frontal cortex and also differed between McGill-RThy1-APP rats and controls in frontal cortex.…”

“…The higher level of taurine in McGill-R-Thy1-APP rats could be related to any of these suggested roles. Elevated taurine/tCr has previously been demonstrated in hippocampus and cingulate cortex of APP Tg2576 mice at age 19-20 months (Dedeoglu et al 2004;Marjanska et al 2005), whereas dorsal hippocampal taurine has been shown to remain unaltered between age 36 and 44 weeks in 5xFAD mice (Mlynarik et al 2012).…”