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Transient MRI-detected water apparent diffusion coefficient reduction correlates with c-fos mRNA but not hsp70 mRNA
1Department of Neurological Surgery, University of California at San Francisco and the Department of Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA 94121, USA. tony@mail.mmrrcc.upenn.edu
Abstract:
Cerebral ischemia induces immediate early genes such as c-fos and stress genes such as hsp70. In this study, the spatial relationships between c-fos and hsp70 mRNA expression and changes detectable with diffusion and perfusion magnetic resonance (MR) imaging were examined. The middle cerebral artery (MCA) of young adult rats was occluded for 30 or 60 min. Diffusion MR (D-MR) images were acquired continuously during the ischemic period and dysprosium-contrast perfusion (P-MR) images were acquired at the end of the ischemic period. C-fos and hsp70 mRNA expression were examined with in situ hybridization. The most significant finding of this work was that for both durations of ischemia, c-fos induction was observed in cortical and sub-cortical regions exhibiting a transient reduction in the apparent diffusion coefficient of water (ADC). Transients which occurred on a time scale of 3 min may have been caused by spreading depression. Those occurring on a 10-min time scale may have been caused by an initial reduction in blood flow with occlusion that was followed by an ischemia-induced increase in collateral blood flow. P-MR imaging showed that perfusion in c-fos positive regions was higher than in regions with persistently reduced ADC. Hsp70 induction did not correlate with transient ADC reduction. It was induced in the MCA territory in regions showing persistent ADC changes, with induction being greatest at the periphery of these regions. It was also induced in regions that exhibited both spontaneous reversal of the diffusion changes and decreased perfusion.
Insights
Cerebral ischemia triggers c-fos gene expression in areas with temporary water diffusion changes. Heat shock protein 70 (HSP70) expression, however, correlated with persistent diffusion changes and altered perfusion.
Area of Science:
- Neuroscience
- Medical Imaging
- Molecular Biology
Background:
- Cerebral ischemia triggers immediate early genes like c-fos and stress genes like hsp70.
- Understanding the spatial relationship between gene expression and MR imaging changes is crucial for stroke research.
Purpose of the Study:
- To investigate the spatial correlation between c-fos and hsp70 mRNA expression and diffusion/perfusion MR imaging changes during cerebral ischemia in rats.
- To elucidate the temporal dynamics of gene expression in relation to apparent diffusion coefficient (ADC) and perfusion changes.
Main Methods:
- Middle cerebral artery occlusion (MCAO) in rats for 30 or 60 minutes.
- Continuous diffusion MR (D-MR) imaging during ischemia and dysprosium-contrast perfusion MR (P-MR) imaging at the end of ischemia.
- In situ hybridization to examine c-fos and hsp70 mRNA expression.
Main Results:
- c-fos mRNA induction was observed in cortical and sub-cortical regions with transient apparent diffusion coefficient (ADC) reductions.
- Transient ADC changes on 3-min and 10-min timescales were potentially linked to spreading depression and initial hypoperfusion followed by collateral flow, respectively.
- Perfusion MR imaging indicated higher perfusion in c-fos positive regions compared to regions with persistently reduced ADC.
- Hsp70 mRNA induction did not correlate with transient ADC reduction but was observed in MCA territory regions with persistent ADC changes and in areas with reversed diffusion changes and decreased perfusion.
Conclusions:
- c-fos induction is associated with transient ADC changes during cerebral ischemia, potentially reflecting early cellular responses or altered blood flow dynamics.
- Hsp70 induction is linked to more persistent ischemic changes and complex perfusion patterns, indicating a delayed or different response mechanism.
- The study highlights the utility of combining diffusion and perfusion MR imaging with molecular markers for a comprehensive understanding of ischemic brain injury.