2型糖尿病大鼠模型 z-bio 2021-02-22 363

　　Introduction: This is an exploration that uses a new imaging method, quantitative ultra-short echo time and contrast agent (QUTE-CE) magnetic resonance imaging to assess the permeability of the blood-brain barrier in a rat model of type 2 diabetes. Assume that microvascular disease is a factor of diabetic neuropathy. Methods: Check the blood-brain barrier permeability of BBZDR/Wor rats (type 2 diabetes model) and age-matched control rats. QUTE-CE is a quantitative vascular biomarker, which can generate more than 500,000 voxel angiography images, and is included in the 3D MRI rat brain atlas. It can provide 173 specific locations of the blood brain in various brain regions. Barrier permeability. Results: In this diabetes model, without the support of insulin treatment, more than 84% of the brain showed a significant increase in blood-brain barrier permeability compared with the wild-type control group. The dopaminergic system areas of the cerebellum and midbrain were not significantly affected.

　　 Conclusion: According to the assessment of the permeability of the blood-brain barrier, small vessel diseases are widespread in type 2 diabetes models, including most of the brain. The increased permeability of the blood-brain barrier may be a factor leading to diabetic encephalopathy and dementia.

　　Background: Vascular dementia is a serious consequence of diabetes. Long-term exposure to hyperglycemia (usually type 2 diabetes) can affect the structure, function and permeability of the capillary endothelium. The destruction of the blood-brain barrier is the basis of cerebral microvascular disease and contributes to the development of diabetic encephalopathy. To understand and diagnose the early onset of type 2 diabetic vascular dementia, it is necessary to quantify and identify the changes in the permeability of the blood-brain barrier in the body. Subtle changes in the blood-brain barrier cannot be imaged using standard imaging protocols, but can be assessed by dynamic contrast enhanced (DCE) MRI. However, dynamic dilation MRI has some limitations. DCE-MRI has not proven to be clinically useful. Due to the short acquisition time of the contrast agent and the strong dependence on microstructure properties (vascular size, curvature, direction, etc.), it is difficult to simulate the effect of the contrast agent on T2* and T1. To solve this problem, I used a new imaging method, Quantitative Ultrashort Echo Time and Contrast Enhanced (QUTE-CE) MRI, using BBZDR/Wor rats (inbred strain type 2 diabetic rat model) Blood, I conducted research. Changes in the brain. obstacle.

　　 Animals: This study used non-diabetic BBDR litters (n = 7) (n = 8) age-matched to male Zucker diabetic rats (BBZDR/Wor rats). Obese male BBZDR/Wor rats developed Type 2 diabetes spontaneously at about 10 weeks of age (≥100%) after eating a standard rat diet. BBZDR/Wor diabetic rats showed all the clinical symptoms usually associated with type 2 diabetes, including dyslipidemia, hyperglycemia, insulin resistance and hypertension. Rats can eat and drink freely, and receive intraperitoneal injection of normal saline when there are signs of weight loss. Imaging: The BrukerBiospec 7.0T/20cm USR horizontal magnet and 20G/cm magnetic field gradient insert (ID = 12cm) were used for the study, with a rise time of 120μs. The quadrature volume coil built into the rat restraint is used to send and receive radio frequency signals. All rats were imaged under 1-2% isoflurane while maintaining a breathing rate of 40-50 breaths/min. The rats were imaged before and after intravenous injection of 6 mg/ml iron oxide. Adjust the injection volume of each rat (assuming that blood accounts for 7% of body weight), resulting in an initial blood concentration of 200μg/mlFe (a clinical dose approved for humans). TE? =? 13μs, TR? =? 4ms, flip angle? =? The 20°QUTE-CEMRI image parameters utilize a high RF pulse bandwidth of 200kHz. Therefore, compared with the approximate ferrous phenol concentration of T2 (3.58 mM is 4.58 ms or 200 μg/ml), the pulse duration is shorter (6.4 μs), the signal blur is minimal, the magnetization vector is bent, and the possibility of magnetization is reduced . track. Mz. Using a 3x3x3cm3 field of view, the matrix grid size is 180x180x180, and the isotropic resolution is 167μm. Use the matlabspm12 toolbox developed by UCL to perform image motion correction, spatial alignment and re-segmentation. Set the UTE image before the comparison as the baseline. For each rat in each imaging session, the voxel percentage change in signal intensity was calculated as (after baseline)/(blood intensity change) * 100%, as described in the previous task. Here, the change of blood intensity is normalized. The coefficient obtained by subtracting the baseline blood signal intensity from the blood signal intensity after con. Taking into account the changes in brain size and location, 173 regions of the rat brain atlas were fitted to the T2 enhanced RARE anatomical data set of each rat data set collected through each imaging. Results: Table 1 shows that all brain regions (147/173) between BBZDR/Wor rats and their litter control group have significantly different blood-brain barrier permeability. Note: In all cases, BBZDR/Wor rats showed higher permeability. The location of these regions can be visualized in the surrounding 2D and 3D images generated from the rat MRI atlas shown in Figure 1. Compared with the control group, the permeability of the blood-brain barrier in all red areas of the 2D image of BBZDR/Wor rats was significantly increased. Table 2 shows that there is no significant difference in the permeability of the blood-brain barrier in all brain regions (26/173) between BBZDR/Wor rats and their litter control. These areas are shown in white and are located in the frontal lobe, midbrain and cerebellum. These unaffected areas appear in yellow in the brain.

　　Discussion: QUTE-CEMRI was developed as a quantitative vascular biomarker. The contrast agent is fermoxidol, superparamagnetic iron oxide nanoparticles coated with dextran. Adrenaline will not be eliminated because its size exceeds the critical value of glomerular filtration (≥6m), but it is an excellent contrast agent with an intravascular half-life of about 15 hours. Through a large number of clinical magnetic resonance imaging tests conducted on children and adults, and proved that there are no major side effects, QUTE-CE is easy to be used in clinical studies of blood-brain permeability. obstacle. QUTE-CEMRI can identify high and low angiogenesis, low blood vessel density, blood-brain barrier permeability and vascular reserve, and the responsiveness of blood vessels to single voxel and CO2 stimulation at the regional level. This study focused on preclinical type 2 diabetes model BBZDR/Wor rats, and proved that this imaging technique can be used for clinical diagnosis and assessment of blood-brain barrier permeability and the disease progression of diabetic encephalopathy.

　　 Conclusion: By evaluating the permeability of the blood-brain barrier, it is found that small vessel diseases in type 2 diabetes models are widely distributed, including most of the brain. The increased permeability of the blood-brain barrier may be a factor leading to diabetic encephalopathy and dementia.