Metabolic Profiling of Dividing Cells in Live Rodent Brain by Proton Magnetic Resonance Spectroscopy (1HMRS) and LCModel Analysis

Abstract

RationaleDividing cells can be detected in the live brain by positron emission tomography or optical imaging. Here we apply proton magnetic resonance spectroscopy (1HMRS) and a widely used spectral fitting algorithm to characterize the effect of increased neurogenesis after electroconvulsive shock in the live rodent brain via spectral signatures representing mobile lipids resonating at ∼1.30 ppm. In addition, we also apply the same 1HMRS methodology to metabolically profile glioblastomas with actively dividing cells growing in RCAS-PDGF mice.Methods 1HMRS metabolic profiles were acquired on a 9.4T MRI instrument in combination with LCModel spectral analysis of: 1) rat brains before and after ECS or sham treatments and 2) RCAS-PDGF mice with glioblastomas and wild-type controls. Quantified 1HMRS data were compared to post-mortem histology.ResultsDividing cells in the rat hippocampus increased ∼3-fold after ECS compared to sham treatment. Quantification of hippocampal metabolites revealed significant decreases in N-acetyl-aspartate but no evidence of an elevated signal at ∼1.3 ppm (Lip13a+Lip13b) in the ECS compared to the sham group. In RCAS-PDGF mice a high density (22%) of dividing cells characterized glioblastomas. Nile Red staining revealed a small fraction (3%) of dying cells with intracellular lipid droplets in the tumors of RCAS-PDGF mice. Concentrations of NAA were lower, whereas lactate and Lip13a+Lip13b were found to be significantly higher in glioblastomas of RCAS-PDGF mice, when compared to normal brain tissue in the control mice.ConclusionsMetabolic profiling using 1HMRS in combination with LCModel analysis did not reveal correlation between Lip13a+Lip13b spectral signatures and an increase in neurogenesis in adult rat hippocampus after ECS. However, increases in Lip13a+Lip13b were evident in glioblastomas suggesting that a higher density of actively dividing cells and/or the presence of lipid droplets is necessary for LCModel to reveal mobile lipids.

Brain Biomarkers in Familial Alzheimer’s Disease Mouse Models

“…This discrepancy most likely arises from the poor spectral quality of cortical spectra when compared to DG and SVZ spectra, and contamination of the cortical voxel by extra-cortical lipids. A previous report has found that cortical spectra from the rat brain were generally of poor quality and many spectra had to be discarded and the remaining averaged before LCModel analysis could be used [23]. …”

Preventive brain radio‐chemotherapy alters plasticity associated metabolite profile in the hippocampus but seems to not affect spatial memory in young leukemia patients

“…2011; Park et al. 2014). However, we think that the metabolite profile detected with MR-spectroscopy might still be a powerful tool to trace cell proliferation and cellular plasticity in specific brain regions.…”

“…In the past, 1 H-MRS had raised the hope of some scientists to visualize or detect adult neural stem cells in the human brain (Manganas et al 2007), but the assumed stem cell specific peak at 1.28 ppm turned out not to be actually specific for a cell type but the cell state or more precisely apoptosis (Loewenbruck et al 2011;Park et al 2014). However, we think that the metabolite profile detected with MR-spectroscopy might still be a powerful tool to trace cell proliferation and cellular plasticity in specific brain regions.…”

In vivo imaging techniques: a new era for histochemical analysis

“…In biological studies, nuclei of interest are mainly 1 H and 31 P, the first one mainly used in brain studies and the second one in muscle studies. Several papers reported 1H-MRS studies in different brain pathologies, as stroke, tumors 13 and neurological diseases 14 (Figure 2 A-C); MR spectra of brain tumors generally report increased lactate and decreased N-Acetylaspartate content, 15 indicating neuronal loss. The lipids are the most easily detectable compounds given their high hydrogen content.…”

“…Indeed, in tumors there might be lipids signals (Figure 2 D, E) that are absent in healthy tissue. 13,16 In this contest, the type of adipose tissue in a particular area and also the composition of lipid accumulation, may represent two important factors in the genesis and progression of cancer. Studies on lipids in cancer revealed that the presence of accumulation of poly-unsaturated fatty acid lipids correlates with the presence of apoptotic cell death.…”