Evaluation of CA1 damage using single-voxel 1H-MRS and un-biased stereology: Can non-invasive measures of N-acetyl-asparate following global ischemia be used as a reliable measure of neuronal damage?
Global brain ischemia provoked by transient occlusion of the carotid arteries (2VO) in gerbils results in a severe loss of neurons in the hippocampal CA1 region. We measured the concentration of the neuron specific N-acetyl-aspartate, [NAA], in the gerbil dorsal hippocampus by proton MR spectroscopy (1H-MRS) in situ, and HPLC, 4 days after global ischemia. The [NAA] was correlated with graded hippocampus damage scoring and stereologically determined neuronal density. A basal hippocampal [NAA] of 8.37+/-0.10 and 9.81+/-0.44 mmol/l were found from HPLC and 1H-MRS, respectively. HPLC measurements of [NAA] obtained from hippocampus 4 days after 2VO showed a 20% reduction in the [NAA] following 4 min of ischemia (P<0.001). 1H-MRS measurements on gerbils subjected to 4 or 8 min of ischemia showed a similar 24% decline in the [NAA] (P<0.05). Thus, there was correlation between the HPLC and 1H-MRS determined NAA decline. There was also a significant correlation between 1H-MRS [NAA] and the corresponding reduction in CA1 neuronal density (P<0.004). In summary our findings show that single voxel 1H-MRS can be used as a supplement to histological evaluation of neuronal injury in studies after global brain ischemia. Accordingly, volume selective spectroscopy has a potential for assessment of neuroprotective therapeutic compounds/strategies with respect to neuronal rescue for delayed ischemic brain damage.
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Department of Neurodegeneration and Recovery, NeuroSearch A/S, Ballerup, Denmark. tsa@lundbeck.com
Topp
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Torup
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Hanson
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Egestad
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Møller
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D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism*; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000473:pathology*; D002851:Chromatography, High Pressure Liquid; D005849:Gerbillinae; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006859:Hydrogen; D002546:Ischemic Attack, Transient / Q000473:pathology*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D015203:Reproducibility of Results; D013997:Time Factors
D015415:Biomarkers; D001224:Aspartic Acid; D006859:Hydrogen; C000179:N-acetylaspartate