Resting-state Functional Magnetic Resonance Imaging In Type2Diabetes Patients

[Objective]To investigate the difference of the functional connectivity between normal person and Type2diabetes mellitus patients.And explore the potential value of resting-state functional magnetic resonance imaging in characterizing normal person and T2DM. The resting-state functional magnetic resonance imaging may provide some evidences for the early diagnosis of AD within T2DM. In addition, the existence of associations between fMRI measures and clinical parameters was examined.[Methods]:1.Subjects:19middle-aged T2DM patients and19non-diabetic non-hypertensive controls were examined by a endocrinologist based on based on the2012version of guideline criteria of The American Diabetes Association. Participants were recruited from the Southern Hospital. There are11men and8women in the T2DM patients, the age range is40to78years and average is58.8; there are9men and10women in normal person, the age range is30to75years and average is52. We evaluated this brain pattern in T2DM patients and healthy control subjects matched for sex、age and education level.We compared T2DM patients (n=19, age=58.8±11.8years, fasting plasma glucose [FPG]=8.80±2.30mmol/L, HbA(lc)=8.62±1.53%) with nondiabetic age-matched control subjects (n=19, age=52±12.30years, FPG=5.34±0.42mmol/L) using resting-state functional magnetic resonance imaging to evaluate functional connectivity strength among DMN regions.All the subjects were right-handedness. Diabetic subjects were on various oral hypoglycemic agents without any history of insulin treatment and hypoglycemic episode. Patients receiving insulin were asked to refrain from taking their insulin on the day of the study. Both patients and controls received detailed examinations, including physical and bed-side neurological examinations (such as checking the cranial nerves, the motor system, and any cerebellar signs)performed by neurologists, a biochemistry study, a chest X-ray, an electrocardiogram, and an electroencephalogram prior to the data acquisition. Conventional brain MR examination was performed in all people to exclude the possibility of ce rebral infarction, hemorrhage, tumor,operation or trauma. To establish that our patients were cognitively intact, we administered a battery of neuropsychological tests before the functional magnetic resonance imaging (fMRI) scan.Participants were excluded if they had a BMI above27kg/m2, current use of drugs affecting cerebral functioning, psychiatric disorders, anemia, epilepsy, thyroid dysfunction, use of glucocorticoids, alcohol abuse (more than20g of alcohol per day), hepatitis, serious cardiovascular diseases, or those with manifestations of stroke (demonstrated by abnormal bedside neurological examination). In both T2DM patients and control subjects, any contraindications to imaging, such as gunshot wound, pacemaker, pregnancy, and claustrophobia, were also exclusionary factors. The study protocol was approved by the Medical Ethics Committee of the Southern Hospital, and written informed consent was obtained from all participants.2. Assessment of cognitive function:Cognitive function was evaluated by Mini-Mental State Examination (MMSE) as well as Clock Drawing Test, which assesses global cortical functions including orientation, attention, memory, calculation, language, and the ability to follow simple verbal and written commands and executive function. Both MMSE scores were based on30total points, and impairment was indicated by a score of24or lower.Additionaly, we administered a bed-side neurological examinations (such as checking the cranial nerves, the motor system, and any cerebellar signs) before the functional magnetic resonance imaging (fMRI) scan to evaluate the cognitive performance.3.MRI acquisition:All imaging data were acquired at Southern Medical University on a GE3.0T scanner(SIGNA EXCITE Ⅱ GE Medical Systems, Milwaukee, Wis) using the standard GE eight-element receiver phased-array head coil for anatomical scans.The conventional MR imaging brain protocol included axial T1weighted images(TR/TE,600/15ms), axial T2weighted images(TR/TE,5200/140ms), axial T2weighted fluid attenuated inversion recovery(TR/TE/IR,9000/120/2100ms), sagittal T1weighted images(TR=550ms, TE=8.4ms).Functional image parameters included gradient-echo planar sequence sensitive to blood oxygen level-dependent (BOLD) contrast (repetition time=2000ms, echo time=20ms, and flip angle=0°), whole-brain volumes with contiguous4mm-thick transverse slices,0.5interslice gap. Patients lay still in the scanner with their eyes closed and not think of anything particular or fall asleep. We asked patients whether in accordance with the requirements when the scheduled scan was completed.4. FMRI image processing and analysis.:The EPI data were preprocessed with the REST that works with SPM5on the Matlab7.0platform. The datas were transformed from DICOM to NIFTI.The first ten volumes of the scanning sessions were removed to allow for scanner calibration and participants’ adaptation to the scanning environment. The remaining volumes were analyzed. For each subject, the EPI images were slice-time corrected and realigned. All of the subjects’ head movements were less than2mm maximum displacement in any direction of x, y and z and less than1.5°in any angular dimension. After realignment, all of the data were normalized to Montreal Neurological Institute (MNI) space and resampled with3x3x3mm3resolution. Next, smoothing with a Gaussian kernel of4-mm full-width at half-maximum (FWHM) and removal of linear trends were performed. No band-pass filtering was implemented during preprocessing such that the entire frequency band could be examined in the subsequent analysis. ALFF and fALFF analyses were performed using the REST software as previously described.After the above preprocessing, the fMRI data were temporally band-pass filtered (0.01<f<0.08Hz) to reduce low-frequency drift and high-frequency respiratory and cardiac noise. The time series of each voxel was transformed into the frequency domain, and the power spectrum was obtained. Because the power of a given frequency is proportional to the square of the amplitude of that frequency component, the square root was calculated at each frequency of the power spectrum, and the averaged square root was then obtained across0.01-0.08Hz at each voxel. We assessed functional connectivity between the PCC/hippocampus and all other regions in the brain using Automatic Anatomy Labeling template. The average time course of the BOLD signal was extracted from the PCC/hippocampus seed region and used as the model predictor in a general linear model analysis to determine brain regions temporally correlated with it.5. Statistical Data analysis.:Between-group t tests, were used to compare demographic and clinical characteristics between T2DM and control subjects. All tests were conducted using a two-sided a-level of0.05. Demographic and cognitive data are presented as mean (SD); between-groups comparisons are presented as mean±SEM. A general linear model was used to assess functional connectivity strengths (using β-weights), and Pearson correlation was used to determine whether insulin resistance were correlated with β-weights.[Results]1. The fALFF in control was significantly increased in the left prefrontal lobe%left anterior cingulated、left temporal lobe%right superior parietal lobule with no group differences in cognition.;2. The right medial frontal gyrus,right superior gyrus,left inferior frontal gyrus,bilateral middle temporal gyrus,bilateral inferior parietal lobule, precuneus were not as strongly correlated with the PCC seed region in T2DM patients compared with control subjects; the value of HbAlc were negatively correlated with the functional connectivity between PCC and right medial frontal gyrus and precuneus;3. The right fusiform gyrus, bilateral inferior Frontal Gyrus,,bilateral anterior cingulate gyrus,left posterior cingulate gyrus,bilateral precuneus were not as strongly correlated with the left hippocampus seed region in T2DM patients compared with control subjects;4. The left middle frontal gyrus,right right anterior cingulated gyrus, left superior temporal gyrus,bilateral posterior cingulate gyrus, right superior frontal gyrus, right inferior parietal lobule,left precuneus were not as strongly correlated with the right hippocampus seed region in T2DM patients compared with control subjects;5. The scores of Clock Drawing Test were negativey correlated to the value of HbAlc and the functional connectivity between right hippocampus and left middle frontal gyrus.. the connectivity between right hippocampus and left middle frontal gyrus was inversely correlated with the value of HbAlc. the value of HbAlc were negatively correlated with the functional connectivity between PCC and right medial frontal gyrus and precuneus.[Conclusion]The changes of default network and functional connectivity provide new idea for the early diagnosis of AD within T2DM patients. T2DM patients showed reduced functional connectivity in the DMN compared with control subjects, which was associated with HbA1c. Impaired cognitive performance of CDT were observed in T2DM patients. It is important that because level of insulin resistance is modifiable, it may be a variable under patient control. Thus, diet and exercise may ameliorate reduced functional connectivity in the DMN and lessen the risk for AD in this population. As this research field evolves, a clearer protocol will emerge out-lining what steps can be taken to reduce AD risk in people with insulin resistance.