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Quantification of Relative Cerebral Blood Volume in Aging Collapsin Response Mediator Protein 1 Gene Knockout Mice1Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan, 2Institute of biomedical engineering and nanomedicine, National Health Research Institutes, Miaoli, Taiwan, 3Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, 4Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan, Taiwan
Synopsis
Mice deficient of collapsin response mediator protein 1 (CRMP-1) gene may cause neural disorganization in hippocampus and demonstrate memory and spatial learning dysfunction. Relative cerebral blood volume (rCBV) can reflect the blood volume within the tissue and was served as an index to correlate with psychosis progression. The purpose of this study was to quantify the rCBV of hippocampus and to explore the difference of vascular distribution in wild type (WT) and aging CRMP-1 knockout (KO) mice. KO mice possessed significantly higher rCBV in the hippocampus than WT mice, indicating the increased blood volume in the hippocampus of KO mice.
Introduction
Collapsin response mediator protein 1 (CRMP-1) gene involves in the neurite outgrowth of hippocampus and may be related to the pathological mechanism of psychotic disorder such as schizophrenia (1,2). Mice deficient in CRMP-1 gene may result in neural disorganization in the hippocampus and demonstrate memory and spatial learning dysfunction (1,3). Previous studies have shown that neurogenesis and several central nervous system diseases may influence the biomechanics of angiogenesis (4-6).Relative cerebral blood volume (rCBV) map, reflecting the amount of blood volume within the tissue (7), can be computed from perfusion MRI images. The rCBV was served as an index to correlate with progression to psychosis (8). Nevertheless, the relationship between CRMP-1 deficiency and the rCBV in hippocampus remains unclear. The purpose of this study was to quantify the rCBV value of hippocampus and explore the difference of vascular distribution in wild type (WT) and aging CRMP-1 knockout (KO) mice.
Methods
Twenty-two 15-month-old C57BL/6 mice (WT=11, KO=11) was recruited in this study. The CRMP-1 gene was knockout based on the methods described previously (1). Dynamic images were acquired in a 7-Tesla MR scanner (ClinScan, Bruker) by echo-planar imaging (EPI) with TR/TE=500/18 ms, FOV=24x24 mm2, matrix size=96x96, slice thickness=0.6 mm, temporal resolution=0.5 s, and scanning time=120 s. The EPI images were acquired in a transverse view at bregma=-2.7 mm. Gadolinium (0.1 mmol/kg) was intravenously injected at via tail vein at t=20s. T2WI was acquired for determining the region-of-interests (ROI) of the left and right hippocampus (TR/TE=2600/42 ms, FOV=20x20 mm2, matrix size=256x256, slice thickness=0.6 mm).Figure 1 demonstrates the flowchart of rCBV calculation. Dynamic EPI signals were converted to ΔR2* as follows (7):
$$\triangle R2^{*}=\frac{-ln(\frac{S}{S_{0}})}{TE} $$
, where ΔR2* is the change of T2* relaxation rate, S is the signal intensity and S0 is the baseline signal generated from the 5th ~14th frame of the EPI images. The rCBV maps were obtained by pixelwise integration of ΔR2*. The ROIs of the left and right hippocampus determined in T2WI were overlaid on the rCBV maps and the mean rCBV values within the ROIs were computed. Student t test was performed when appropriate and p<0.05 was considered statistically significant.
Results
The T2WI, EPI, and rCBV maps of a WT and KO mouse overlaid with hippocampus ROIs were displayed in Figure 2. The KO mouse demonstrated higher rCBV values in hippocampus than WT mouse.Table 1 lists the mean rCBV of the left, right, and total (left + right) hippocampus in WT and KO mice. The mean rCBV of left, right and total hippocampus of KO group were higher than the WT group (left: 248.7±186.5 vs. 122.4±57.7 (a.u.), p=0.044, right: 215.6±148.5 vs. 107.9±67.1 (a.u.), p=0.040, total: 230.5±159.9 vs. 116.2±60.0 (a.u.), p=0.038). The ratio of rCBV in left to right hippocampus was higher than 1 in both of WT and KO groups, describing the higher rCBV in left hippocampus in the two mice models. Interestingly, the asymmetry of rCBV was more evident in WT (1.43±0.94) than in KO (1.11±0.50) groups.
Discussion
In this study, KO mice possessed significantly higher rCBV in the hippocampus than WT mice, indicating the increased blood volume in the hippocampus of KO mice. Other than the hippocampus region, KO mice generally displayed elevated rCBV in other brain regions. We also found that WT mice exhibited more distinct asymmetry of rCBV than KO mice.CRMP-1 KO mice were reported to be related with memory and spatial learning dysfunction (1). In addition, the increased CBV in hippocampus, especially in the left CA1 region of hippocampus, was found in patients with psychosis (9,10). Therefore, the results of higher rCBV shown in the hippocampus of KO mice might provide as a supportive information of altered angiogenesis and potential relationship between CRMP-1 gene knockout and psychotic disorder.
In conclusion, this study demonstrated that the deficient CRMP-1 gene of an aging mouse model may result in abnormal cerebral blood volume in the hippocampus region.
Acknowledgements
No acknowledgement found.References
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