RESUMEN
Non-invasive methods of detecting early-stage Alzheimer's disease (AD) can provide valuable insight into disease pathology, improving the diagnosis and treatment of AD. Nuclear Overhauser enhancement (NOE) MRI is a technique that provides image contrast sensitive to lipid and protein content in the brain. These macromolecules have been shown to be altered in Alzheimer's pathology, with early disruptions in cell membrane integrity and signaling pathways leading to the buildup of amyloid-beta plaques and neurofibrillary tangles. We used template-based analyzes of NOE MRI data and the characteristic Z-spectrum, with parameters optimized for increase specificity to NOE, to detect changes in lipids and proteins in an AD mouse model that recapitulates features of human AD. We find changes in NOE contrast in the hippocampus, hypothalamus, entorhinal cortex, and fimbria, with these changes likely attributed to disruptions in the phospholipid bilayer of cell membranes in both gray and white matter regions. This study suggests that NOE MRI may be a useful tool for monitoring early-stage changes in lipid-mediated metabolism in AD and other disorders with high spatial resolution.
RESUMEN
Alzheimer's disease (AD) is a very common neurodegenerative disorder. Although a majority of the AD cases are sporadic, most of the studies are conducted using transgenic models. Intracerebroventricular (ICV) administered streptozotocin (STZ) animals have been used to explore mechanisms in sporadic AD. In this study, we have investigated memory and neurometabolism of ICV-STZ-administered C57BL6/J mice. The neuronal and astroglial metabolic activity was measured in 1H-[13C]-NMR spectrum of cortical and hippocampal tissue extracts of mice infused with [1,6-13C2]glucose and [2-13C]acetate, respectively. STZ-administered mice exhibited reduced (p = 0.00002) recognition index for memory. The levels of creatine, GABA, glutamate and NAA were reduced (p ≤ 0.04), while that of myo-inositol was increased (p < 0.05) in STZ-treated mice. There was a significant (p ≤ 0.014) reduction in aspartate-C3, glutamate-C4/C3, GABA-C2 and glutamine-C4 labeling from [1,6-13C2]glucose. This resulted in decreased rate of glucose oxidation in the cerebral cortex (0.64 ± 0.05 vs. 0.77 ± 0.05 µmol/g/min, p = 0.0008) and hippocampus (0.60 ± 0.04 vs. 0.73 ± 0.07 µmol/g/min, p = 0.001) of STZ-treated mice, due to similar reductions of glucose oxidation in glutamatergic and GABAergic neurons. Additionally, reduced glutamine-C4 labeling points towards compromised synaptic neurotransmission in STZ-treated mice. These data suggest that the ICV-STZ model exhibits neurometabolic deficits typically observed in AD, and its utility in understanding the mechanism of sporadic AD.