Journal of Peking University (Health Sciences) ›› 2020, Vol. 52 ›› Issue (2): 362-367. doi: 10.19723/j.issn.1671-167X.2020.02.026

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Effect of convection enhanced delivery on the microstructure of brain extracellular space in aged rats

Yu SONG1,2,Hong-bin HAN2,3,4,(),Jun YANG5,Ai-bo WANG3,4,Qing-yuan HE3,4,Yuan-yuan LI3,4,Guo-mei ZHAO3,4,Ya-juan GAO3,4,Rui WANG3,4,Yi-xing HAN3,4,Ai-lian LIU1,(),Qing-wei SONG1,()   

  1. 1. Department of Radiology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning, China
    2. Institute of Medical Technology, Peking University Health Science Center, Beijing 100191, China
    3. Beijing Key Lab of Magnetic Resonance Imaging Device and Technique, Beijing 100191, China
    4. Department of Radiology, Peking University Third Hospital, Beijing 100191, China
    5. Department of Neurosurgery, Peking University Third Hospital, Beijing 100191, China
  • Received:2019-09-02 Online:2020-04-18 Published:2020-04-18
  • Contact: Hong-bin HAN,Ai-lian LIU,Qing-wei SONG E-mail:hanhongbin@bjmu.edu.cn;cjr.liuailian@163.com;songqw1964@163.com
  • Supported by:
    Supported by the Beijing Municipal Science & Technology Commission(Z181100001518004);the National Major Scientific Research Instrument Development Project(61827808);the Program for Training Capital Science and Technology Leading Talents(Z181100006318003)

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Abstract:

Objective: To compare the changes of extracellular space (ECS) structure and local drug distribution in adult brain and aged brain at different drug delivery rates in minimally invasive treatment of encephalopathy by convection enhanced delivery (CED) via ECS pathway.Methods: Thirty-six SD male rats were divided into adult rats group (2-8 months, n=18) and aged rats group (18-24 months, n=18) according to the age of the month. According to the drug rates (0.1 μL/min, 0.2 μL/min, and 0.3 μL/min), they were randomly divided into 3 subgroups, 6 in each subgroup. Gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) with a concentration of 10 mmol/L were introduced into the caudate nucleus of each group of rats by stereotactic injection. Tracer-based magnetic resonance imaging (MRI) was used to dynamically monitor the diffusion and distribution images of the Gd-DTPA in the brain interstitial system (ISS). Using the self-developed MRI image measurement and analysis system software to process and analyze the obtained images, the diffusion coefficient, clearance rate, volume fraction, and half-life of each group of rats in the caudate nucleus ECS could be acquired. The effects and differences of drug clearance and ECS structural function in the brain of aged rats and adult rats were compared and analyzed at different drug delivery rates. Magnetic tracer DECS-mapping technique was used to observe the distribution and drainage of tracer in caudate nucleus.Results: At the injection rate of 0.1 μL/min, the volume fraction in the aged rats was increased compared with that in the adult rats (18.20%±0.04% vs. 17.20%±0.03%, t=3.752, P=0.004), and the degree of tortuosity was decreased (1.63±0.04 vs. 1.78±0.09, t=-3.680, P=0.004), the drug clearance rate was decreased [(1.94±0.68) mm 2/s vs. (3.25±0.43) mm 2/s, t=-3.971, P=0.003], and the molecular diffusion in ECS was increased [(3.99±0.21)×10 -4 mm 2/s vs. (3.36±0.37)×10 -4 mm 2/s, t=3.663, P=0.004]. When the rate of injection increased to 0.2 μL/min, the drug clearance in ECS of the aged rats was slowed down [(2.53±0.45) mmol/L vs. (3.37±0.72) mmol/L, t=-1.828, P=0.021]. However, there were no significant differences in volume fraction,molecular diffusion in ECS and macroscopic drug metabolism parameters. When the rate of injection increased to 0.3 μL/min, the volume fraction in the aged rats was decreased (17.20%±0.03% vs. 18.20%±0.05%, t=-0.869, P=0.045), and the drug clearance rate in ECS was significantly accelerated [(4.04±0.76) mmol/L vs. (3.26±0.55) mmol/L, t=1.786, P=0.014], and there was no significant difference in tortuosity and the rate of molecular diffusion in the ECS. Conclusion: The drug clearance and ECS structural parameters of brain ECS in aged brain with CED administration were changed at different rates, and it has the least effect on ECS in the aged brain at the injection rate of 0.2 μL/min. For the application of CED for the treatment of encephalopathy, we should consider the influence of factors such as age and injection rate, and provide reference for the development of individualized clinical treatment plan for minimally invasive treatment of encephalopathy via ECS pathway.

Key words: Radioactive tracers, Brain, Extracellular space, Convection enhanced delivery, Magnetic resonance imaging

CLC Number: 

  • R814.4

Figure 1

Diffusion distribution of tracer in the caudate nucleus of adult rats"

Figure 2

Diffusion distribution of tracer in the caudate nucleus of aged rats"

Figure 3

The distribution and drainage of magnetic tracer were different in adult rats (A) and aged rats (B) brain DECS-mapping images"

Figure 4

Contour map of DECS-mapping of magnetic tracer measurement shows the changes of morphology and amplitude of diffusion coefficient of adult rats (A) and aged rats (B)"

Table 1

Comparison of structural and functional parameters of ECS between adult rats and aged rats at different drug delivery rates"

Items 0.1 μL/min 0.2 μL/min 0.3 μL/min
Volume fraction, $\bar{x}±s$
Adult rats 17.20%±0.03% 17.60%±0.04% 18.20%±0.05%
Aged rats 18.20%±0.04% 17.70%±0.03% 17.20%±0.03%
P 0.004 0.261 0.045
Degree of tortuosity, $\bar{x}±s$
Adult rats 1.78±0.09 1.77±0.07 1.76±0.10
Aged rats 1.63±0.04 1.69±0.06 1.79±0.11
P 0.004 0.135 0.896
Diffusion coefficient/(×10-4 mm2/s), $\bar{x}±s$
Adult rats 3.36±0.37 3.42±0.37 3.40±0.43
Aged rats 3.99±0.21 3.70±0.26 3.31±0.55
P 0.004 0.155 0.723
Clearance rate/(×10-4 mm2/s), $\bar{x}±s$
Adult rats 3.25±0.43 3.37±0.72 3.26±0.55
Aged rats 1.94±0.68 2.53±0.45 4.04±0.76
P 0.003 0.021 0.014
Half-life/min, $\bar{x}±s$
Adult rats 81.12±5.12 81.89±3.81 86.51±3.35
Aged rats 141.83±7.25 105.95±8.67 88.61±3.71
P 0.002 0.154 0.328
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