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:	ASL MRI brain imaging studies in patients with diabetic retinopathy
Jia-min Nie#, Ju-wei Shao#, Qian He*,Wei Su, Min-jie Zhou, Shu-tian Xiang, Jian-bo Li,Zheng-lin Yang
#These authors have contributed to this work
Corresponding author: 
Qian He
e-mail: ynheqian@sina.com
Department of Radiology, the second people�s hospital of Yunnan province,�the fourth affiliated hospital, Kunming Medical University, Kunming 650000, China
No. 176 of qingnian Street, wuhua District,kunming 650000(China)
Financial support:�
1. Supported, in part, by Core Grant 2018FE001(-267) from Special Joint Fund from Yunnan Provincial Department of Science and Technology and Kunming Medical University, Kunming, Yunnan, China. 
2. Supported, in part, by Grant 2018S181 from kunming medical university graduate innovation fund
Abstract: Objective: To evaluate cerebral perfusion in diabetic retinopathy patients by magnetic resonance ASL (Arterial Spin Labeling) imaging. Methods: Ten diabetic retinopathy patients without hypertension admitted to the Fourth Affiliated Hospital of Kunming Medical University from June 2017 to March 2019 were included in study group A, 24 nonretinopathy patients were included in study group B, and 22 healthy volunteers were included in control group C. Magnetic resonance head scanning, MRA and ASL scanning were performed on the three groups of subjects at rest. SPM software based on MATLAB was used to convert and preprocess the obtained images, and the activation points of each brain region were calculated. The ROI was manually marked in the activated brain region. According to the ROI activation diagrams of different brain regions obtained by preprocessing, the ROI of different groups was manually labeled on the AW4.7 postprocessing workstation, with an area of approximately 20 mm2, and the average CBF value of the corresponding ROI and its mirror ROI was measured. The SPSS 17.0 software package for statistical analysis was used to evaluate three groups of ASL perfusion parameters with a normal distribution and by using an F test. Data conforming to a normal distribution or showing homogeneity of variance were subjected to an analysis of variance (ANOVA), which did not conform to rank and inspection. P < 0.05 was considered to indicate a statistically significant difference. Finally, the data were shown to be statistically significant by the least significant difference (LSD) test and two rank and inspection analyses between the two groups.�
Results: The average CBF values of the left cerebellar hemisphere, left cerebellar tonsil, bilateral inferior temporal gyrus, left straight gyrus, left cingulate gyrus and bilateral median frontal gyrus in group A were lower than those in group B and group C (P<0.05), and the average CBF values of the pons and left anterior central gyrus in group A were higher than those in group B and group C (P<0.05). 
Conclusion: MRI brain ASL imaging showed abnormal perfusion in the cerebral motor center, visual projection area, limbic system and other areas in patients with diabetic retinopathy, indicating that changes in cerebral microcirculation may occur simultaneously in diabetic retinopathy.
Key words: magnetic resonance imaging; arterial spin labeling; diabetic retinopathy; cerebrovascular disease
Introduction
Diabetes is caused by a relative or absolute lack of insulin secretion, affecting the metabolism of sugar, lipids, proteins and other nutrients in individuals with this secretory disease [1]; diabetic retinopathy (DR) is one of the most common microvascular lesions and diabetes complications and is a disease that can cause blindness in adults [2]. Nonproliferative diabetic retinopathy in categorized as stages I-III, depending on the stage of development. Stage e! is used to categorize proliferation diabetic retinopathy [3]. Diabetic non-retinopathy (NDR) involves retinal microcirculation changes and low local capillary perfusion, causing capillary hyperplasia, capillary tumor formation, retinal edema or bleeding, and development into PDR, vascular permeability increase, blood-retinal barrier damage, vitreous clearance before blood leakage into the retina, and macular edema and retinal detachment [4]. Cerebrovascular diseases are one of the causes of death in patients with diabetes. The typical pathological manifestations of diabetic cerebrovascular diseases are microcirculatory disorders, microangiomas and thickening of the basement membrane of microvessels [5]. Both diabetic retinopathy and cerebrovascular disease are caused by pathological changes in capillaries. An increasing number of clinical and basic studies have confirmed that changes in neurons occur before the emergence of characteristic retinal microangiopathy, which not only refers to retinal neurons but also may involve neurons in the central system [6]. Therefore, patients who have developed diabetic retinopathy may also have a high probability and high risk of cerebrovascular disease.
Early detection of cerebrovascular diseases in patients with diabetes can reduce the morbidity and mortality of cerebrovascular diseases and improve the survival rate and quality of life of patients with diabetes. Therefore, the early evaluation of changes in cerebral microcirculation is of great significance. For the abnormalities of cerebral microcirculation, the commonly used methods include CT perfusion imaging, positron emission tomography, Doppler contrast ultrasound, single-photon emission computed tomography, and magnetic resonance perfusion weighted imaging [7]. CTP is a fast, economical and quantifiable method for the detection of cerebral hemodynamics. However, it has disadvantages such as no unified index for each parameter threshold, a limited scanning level, unconfirmed reproducibility of results, more patients with radiation and iodine allergies, etc. PET and SPECT are noninvasive, accurate, and parameter-complete perfusion examinations, but they are expensive, radiative, and complex, and lack clear anatomical views [8]. The advantages of TCD include repeatability, noninvasiveness and simplicity of operation. However, due to its low image resolution and reliance on operator technology, the assessment of the brain functional state is not sufficiently accurate [9]. ASL MRI imaging is a noninvasive functional magnetic resonance imaging (fMRI) modality. Without exogenous contrast medium injection, quantitative measurement of blood flow can be performed, obtaining cerebral perfusion images; compared with other imaging examination methods, fMRI is safer, involves no radiation, has the advantage of clearly showing anatomical parts, and is especially suitable for children, individuals with iodine allergy and patients in need of repeated postoperative follow-ups, and thus has become the mainstream of inspection methods [10]. At present, there are few reports about using ASL to study the cerebral microcirculation status of patients with diabetic retinopathy at home and abroad. Therefore, this study aimed to use magnetic resonance ASL to carry out a prospective investigation of the cerebral microvascular status of patients with retinopathy and to evaluate the cerebral microcirculation status of patients with retinopathy.
Materials and methods
Research object
From June 2017 to March 2019, 34 diabetic patients without hypertension were admitted to the Fourth Affiliated Hospital of Kunming Medical University, including 10 diabetic retinopathy patients in group A and 24 nonretinopathy patients in group B. Physical examination, blood pressure measurement, blood biochemical examination and fundus examination were performed on all the patients, and the subjects were determined to be diabetic patients without hypertension and without dyskinesia, dysgraphia, language impairment, visual impairment, etc. Finally, the grouping of retinopathy was determined.
The healthy control group was assigned as group C after undergoing blood pressure, blood biochemistry and fundus examinations. It was confirmed that the 21 volunteers had no diabetes, hypertension, balance movement disorders, dysgraphia, language impairment, visual impairment, etc. This study was approved by the Ethics Committee of the Fourth Affiliated Hospital of Kunming Medical University. Informed consent was signed by each patient.
Magnetic resonance scanning
Routine cranial MRI plain scans and 3D-TOF MRA scans were performed on all subjects, and an ASL scan was performed after ensuring that all subjects had no brain tumors, cerebral infarctions and intracranial large vessel lesions. All subjects were right-handed.
A GE 1.5T Signa HDx Twinspeed superconducting magnetic resonance imager was used with an 8-channel high resolution head and neck combined coil, and a 5.0 mt/m gradient magnetic field was scanned from the skull base to the parietal lobe. The sequence of examination included a routine MRI plain scan, MRA, and ASL. Conventional MR flat scan adopted a fast spin echo pulse (FSE) sequence, including T2WI flair (TR 8000 ms, TE 161 ms), T1WI flair (TR 2100 ms, TE 13 ms), T2WI PROPELLER (TR 4200 ms, TE 110 ms), MRA: 3D TOF (TR 23 ms, TE 3 ms), ASL: TR 4595 ms, TE 10.7 ms), thickness (thickness): 4.0 mm, gap: 0.0 mm, matrix: 512 8, excitation times (NEX): 3.00, field of vision (FOV): 24 24/W, marking delay time (PLD): 1.5 s, scanning time: 4 minutes and 27 seconds.
Image postprocessing
Images were scanned into the postprocessing workstation in GE Advantage Windows 4.7 for CBF map processing to the DICOM format of CBF to identify the statistical parameters based on the MATLAB 7.0 software SPM8 (statistical parametric mapping) software package for image preprocessing, according to the different brain regions of pretreatment for the ROI activation graph. The AW4.7 postprocessing workstation was used for different groups of the object of study to manually mark the ROI, which had an area of approximately 20mm2
 .. The average CBF of the corresponding ROI and its mirror ROI was measured.
Statistical analysis
Using SPSS 17.0 software, the chi-square test was used for the gender of the three groups of subjects. Age, arterial systolic pressure and arterial diastolic pressure were analyzed by homogeneity of variance. An ANOVA and LSD-t test were performed according to whether the homogeneity of variance was met. Fasting blood glucose and glycosylated hemoglobin in group A and group B were tested by an independent sample t test to determine whether age, gender, blood pressure and biochemical index were statistically significant. The average CBF values of the ROI in different brain regions of the three groups were tested for homogeneity of homogeneity or the normality test, homogeneity of homogeneity or normality for variance analysis (ANOVA), and the least significant difference for statistically significant data. The difference method (LSD) was compared between the two groups. The rank-and-score test was used for nonconformity, and the statistically significant data were used to perform a rank-sum test between groups to determine the brain regions with statistically significant differences. The measurement data are expressed using (( EMBED Equation.3 ((� EMBED Equation.3 	�
Results
There were no statistically significant differences in gender, age and arterial blood pressure between the three groups (P>0.05), and no statistically significant differences in course of disease, fasting blood glucose and glyca1c between the diabetic retinopathy group and the non-retinopathy group (P>0.05).
Correlation analysis of the cerebral perfusion parameters in three groups
All the subjects in the three groups showed no obvious abnormalities in routine cranial plain scan and MRA cerebrovascular scan. After manually selecting ROI and measuring CBF, it can be seen that there are some differences in cerebral perfusion in different brain regions.
Diabetic retinopathy group temporal gyrus, straight back, cingulate, back in the left cerebellar hemisphere, the forehead, occipital lobe, the average value of CBF significantly below the retina lesion group and healthy controls (P < 0.05), diabetic retinopathy group left parahippocampal gyrus, pons, significantly better than the average value of CBF precentral gyrus of retinopathy group and healthy controls (P < 0.05).
The abnormal cerebral perfusion in diabetic retinopathy patients is mainly located in the motor center of the brain, visual projection area, limbic system, etc., suggesting that when diabetic retinopathy occurs, cerebral microvascular diseases may also exist. (figure 1-8, table 2)

Discussion
Diabetes mellitus is an endosecretory disease in which the metabolism of nutrients such as sugar, lipid and protein is disturbed due to the relative or absolute deficiency of insulin secretion [1]. Diabetic retinopathy and cerebrovascular disease are two of the complications of diabetes mellitus, both of which are caused by pathological changes in capillaries. An increasing number of clinical and basic studies have confirmed that changes in neurons occur before the emergence of characteristic retinal microangiopathy, which not only refers to retinal neurons but also may involve neurons in the central system [8]. Therefore, patients who have developed diabetic retinopathy also have a high probability and high risk of cerebrovascular disease.
 In mild nonproliferative retinopathy, microaneurysms and hemorrhages appear in the fundus of the patient, and hard exudation and hemorrhage occur as the disease progresses. After the development of proliferative lesions, retinal neovascularization and vitreous hemorrhage occur, and the retina detaches [11]. Some scholars have shown that patients with proliferative retinopathy are more likely to have stroke and skin capillary lesions than patients with nonproliferative retinopathy. The development of retinal vasculopathy may reflect the development of cerebral microvascular disease. [12-13]. Controlling the factors that may cause diabetic retinopathy will cause the probability of developing cerebrovascular disease to also decrease [14-15]. In this study, MRASL was used to evaluate the cerebral perfusion status of diabetic retinal patients. ASL is a noninvasive scan with magnetic molecules in the arterial blood as an endogenous tracer that is magnetically labeled. Before the labeled water molecules flow into the imaging plane, they are labeled with inverted or saturated RF pulses. When the labeled water molecules enter the extracellular space and exchange with water molecules in the static tissue, the net magnetization vector of the tissue is unmarked. The control state of the water molecules is significantly reduced, and the contrast imaging information is subtracted from the labeled imaging information to obtain a perfusion image [16]. The most commonly used parameters are cerebral blood flow (CBF) and postlabeling delay time (PLD). The cerebral blood flow can be judged by comparing the CBF values   of different groups. PLD is the most important parameter in the ASL sequence, which is often based on research. The physiological or pathological state of the subject was modified. The study proved that [17], the general visual effect of 1.5-2 s cerebral blood flow is the best, the spatial resolution and signal-to-noise ratio can be optimized, and the image quality is the best. In this study, a PLD of 1.5 s was employed, aiming to maximize the sensitivity of ASL to the detection of brain microcirculatory disorders.
  In our study, compared with the healthy control group, patients with nonretinopathy exhibited cerebral perfusion abnormalities in the left cerebellar hemisphere, right pons, bilateral inferior temporal gyrus, bilateral middle frontal gyrus, left central anterior gyrus, left cingulate gyrus and left straight gyrus. Regarding the abnormal perfusion area in patients with diabetes, domestic and foreign researchers have obtained different results. Sanne[18] showed that the cerebral blood flow in patients with diabetes decreased in all functional areas, especially in the brain areas related to motor ability and visual function. Heni[19] showed that the cerebral blood flow of white matter and gray matter in the diabetic group was smaller than that in the control group, especially in the frontal lobe, temporal region and occipital parietal region. LAST[20-21] found that cerebral blood flow in the cingulate gyrus decreased in the precuneus and bilateral occipital lobes but increased in the anterior cingulate gyrus. The research results of various scholars are partially consistent with our research results.
  In the areas with abnormal perfusion, the mean CBF values of the inferior temporal gyrus, straight gyrus, cingulate gyrus, left cerebellar hemisphere, middle frontal gyrus and occipital lobe in the diabetic retinopathy group were significantly lower than those in the control group, and the mean CBF values of the parahippocampal gyrus, pons and left anterior central gyrus were significantly higher than those in the control group. These brain regions cover multiple functional areas, such as vision, movement, language and cognition, which reflect that diabetic retinopathy may lead to functional diseases in the body. Type 2 diabetes mellitus may lead to atrophy of multiple cerebral cortex and subcortical regions and weakened vascular reactivity, leading to abnormal cerebral perfusion and reduced cerebral blood flow [22-23]. The cerebellum plays a key role in regulating balance movement and muscle tension. In addition to processing information from the primary motor cortex, it also processes "nonmotor" information from the prefrontal cortex and the posterior parietal cortex [24]. The frontal lobe mainly includes the anterior central gyrus, superior frontal gyrus, middle frontal gyrus and inferior gyrus, which is the premotor area and the location of the writing center. The occipital lobe mainly processes visual information. When the occipital lobe is damaged, not only visual symptoms but also memory defects and motor perception disorders may occur. The inferior temporal gyrus is the language motor center. The cingulate gyrus is part of the limbic system and is associated with memory. The white matter nerve fibers in the pons connect to the cerebellar cortex, transmitting nerve impulses from one side of the cerebellar hemisphere to the other, enabling it to coordinate muscle activity on both sides of the body. The anterior central gyrus receives proprioception from the skin, joints, tendons and skeletal muscles and controls voluntary movement of the contralateral body. The parahippocampal gyrus has an important relationship with cognition and emotion and is related to higher nervous functions, such as emotion, learning and memory. The cause of a decrease in cerebral perfusion is unclear, and the possible reasons include high blood sugar conditions for a long period, the patient�s oxidative stress reaction, capillary wall thickening of the basement membrane, endothelial cell damage, deep brain white matter atherosclerosis, vascular basement membrane sugar deposits, fat sample changes and hyaline degeneration, and narrow microvascular occlusion [25]. With the progression of the disease, disorders of the microcirculation occur, the endothelial cells are further involved, and capillary barrier function is damaged; furthermore, intravascular material extravasation and microvascular structure destruction occur, causing vascular occlusion and resulting in reduced cerebral perfusion. Some brain regions show increased perfusion, which some scholars believe [26-27] may be a compensatory phenomenon of the organism. High perfusion often appears in the area related to nerve function, with the development of the disease. When the local function is impaired, the body attempts compensatory activities to maintain the normal function of the body, which some researchers have found [28] in diabetic patients with frontal lobe, parietal lobe, and parahippocampal gyrus activity; this result is similar to the results of our research, supporting neural compensation claims.
  Therefore, our study showed that MRASL imaging of the brain in patients with diabetic retinopathy could detect changes in cerebral blood flow before the occurrence of the symptoms of cerebrovascular diseases, which has certain guiding significance for the development of treatment plans in the early clinical stage.
In addition, due to the small sample size, patients with diabetic retinopathy were not further divided on the basis of proliferative phase and nonproliferative phase. Moreover, in this study, the mean cerebral perfusion values were measured by manual selection of ROIs, and voxel-based analysis (VBA) is planned to be adopted in the future to accurately locate the ROI of different research objects.
Acknowledgements
Appreciation is expressed to Xiao Yuanyuan, from the Department of Statistics, Kunming Medical University, for the assistance in the statistical analysis.
References
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Figure 4: Difference diagram of whole brain perfusion, the green area is the area with decreased cerebral blood flow compared with that of the control group, and the red area is the area with increased cerebral blood flow compared with that of the control group.(p=0.001), activated cluster >332 after FDR correction
Figure 5: Difference diagram of whole brain perfusion, the green area is the area with decreased cerebral blood flow compared with that of the control group, and the red area is the area with increased cerebral blood flow compared with that of the control group. (p=0.001), activated cluster >332 after FDR correction
Figure 6: 3D display of whole-brain perfusion results (sag.), the green area is the area with decreased cerebral blood flow compared with that of the control group, and the red area is the area with increased cerebral blood flow compared with that of the control group.
Figure 7: 3D display of whole-brain perfusion results (Cor.) the green area is the area with decreased cerebral blood flow compared with that of the control group, and the red area is the area with increased cerebral blood flow compared with that of the control group.
Figure 8: 3D display of whole-brain perfusion results (Ax.), the green area is the area with decreased cerebral blood flow compared with that of the control group, and the red area is the area with increased cerebral blood flow compared with that of the control group.
Table 1 clinical characteristics ( EMBED Equation.3 )
Table 2 CBF results of all brain regions in ASL ( EMBED Equation.3 >�����������Ḭ̇������������
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