Multimode MRI Research On Aberrant Brain Of End-Stage Renal Disease Individuals With Neurologically Asymptomatic

Part one:Regional homogeneity abnormalities in ESRD patients with Neurologically Asymptomatic:a resting-state fMRI studyObjective:To investigate the pattern of spontaneous neural activity in end-stage renal disease patients (ESRD) with Neurologically Asymptomatic using resting-state functional magnetic resonance imaging (rs-fMRI) with a regional homogeneity (ReHo) algorithm.Materials and Methods:A total of 31 patients with ESRD (man 24, female 7) were recruited from the renal transplantation department at Guangdong No.2 Provincial People’s Hospital, Guangzhou, China in this study from September 2013 to September 2014. We were recruited 31 health control (man 21, female 10)from the locality, Guangzhou, China. All people will receive the examine with resting state function MRI. Mean age of ESRD is 39.9±9.6years(24-61Y),education time is 11.8 ± 3.3years(3-16Y). Mean age of health control is 42.7 ± 8.5years(26-61Y), education time is10.8 ± 2.8years (6～16 Y). This study was approved by the Research Ethics Review Board of the Institute of Mental Health at the Southern Medical University, and written informed consent was obtained from each participant. Exclusion criteria included: psychiatric disorders or major neurologic disorders (e.g., severe head injury, stroke, epilepsy or visible lesions); ischemic diseases including acute ischemic cerebrovascular disease, acute peripheral arterial occlusion, advanced liver or heart failure; asymptomatic coronary ischemia by electrocardiogram testing; (4) a history of diabetes; and substance abuse including drugs, alcohol and cigarettes, all people are right-handed. In this study, all the patients underwent a neuropsychological test involving a mini-mental state examination (MMSE) and scored^28, which indicated their relatively intact global neurocognition.MRI data were obtained using a 1.5T MR scanner (Achieva Nova-Dual; Philips), The conventional imaging sequences including T1-weighted images and T2-FLAIR images were obtained for every subject to detect clinically lesions. Rs-fMRI data were acquired using EPI sequence. The Rs-fMRI acquisition parameters were as follows:repetition time (TR)= 3,000ms, echo time (TE)=50 ms, In-plane resolution= 128 X 128, FOV=230×230,240 dynamic states, Each Rs-fMRI scan lasted 8 minutes. A total of 33 axial slices of 4.5 mm thickness were collected with no intersection gap. The imaging data were preprocessed mainly using a MATLAB toolbox called Data Processing Assistant for Resting-State data analysis of fMRI. ①We discarded the first 10 time points of each peoples to avoid transient signal changes before magnetization reached steady-state, ②slice timing corrected.③head moving corrected. ④Spatial normalization:High-dimensional spatial normalization was chosen and the T1 images were normalized to an already existing template in MNI space.⑤ Space smooth. Subsequent data preprocessing included removal of linear trends and temporal filtering (band pass,0.01 to 0.08 Hz) to remove the effects of very low-frequency drift and physiological high frequency respiratory and cardiac noise for further ReHo analysis. Using the REST sofe to calculated the Kendall’s coefficient concordance(KCC), and an individual KCC map was obtained for each subject.Two-sample t-tests were performed to assess the differences in age, duration of education and head moving between ESRD and healthy subjects, Analyses were conducted using software (SPSS, version 13.0; Chicago,Ill, USA), and a P value less than 0.05 (two-tailed) was considered statistically significant. Stochastic effect analyze of Reho map will performed by using the SPM8, including two-sample t-test and t-test for decrease the false positive rate, P value less than 0.05 was considered statistically significant. Pearson correlation coefficient was used to analyze the association between ReHo values and the duration of hemodialysis and MMSE in the patient group. Map will display by using Xjview8.1 sofe (www.alivelearn.net/xjview) and REST sofe.Results:(1) Compared with the control group, ESRD patients group showedsignificant increase ReHo value in left Medial Frontal gyrus and bilateral Superior Temporalgyrus (P<0.05;AlphaSim corrected).(2) Compared with the control group, ESRD patients group showed significant decrease ReHo value in right Middle Temporal gyrus (P<0.05; AlphaSim corrected).(3) MMSE score between ESRD group and control group are normal (≥28), and no significantlystatisticsdifferent scores was found between patient and control groups, (P>0.05); Therewas no significant correlations between ReHo values and theduration of hemodialysis in the ESRD group. ConclusionIn conclusion, we found significant change in ReHo values inpatients with ESRD in brain areas located in temporal and frontallobes, which are closely related to the memory and cognition and they are the important component of DMN. Theabnormal spontaneous neuronal activity in those areas may be provide the objective evidence of theneural mechanisms underlying the cognitive impairment inESRD patients, and suggested that an abnormal ReHo valuein certain brain areas may be a potential biomarker to detect theearly cerebral ReHo changes in hemodialysis patients with ESRD.Part two:Structural and Functional Brain Alterations in End StageRenal Disease Patients with Neurologically Asymptomatic:AVoxel-Based Morphome-try and Resting State FunctionalConnectivity StudyObjectiveThe primary focus of this study was to examine structural and functional brain deficits in End-Stage Renal Disease individuals with neurologically asymptomatic by using a voxel-based morphometry and functional connectivity in resting state.Materials and Methods:Inclusion and exclusion criterions of all participants are the same to the Part Ⅰ. Raw data were imported in work-state and to convert NIfTI format. The anatomical images analysis was performed using the SPM8 and VBM8. The detail procedures include:①based on the zero, we will regulation all raw data.②segment the naive image of all the participants, obtain the *seg.sn.mat profile. ③create GM template with DARTEL.④Normalize.⑤a Jacobian determin-ant was introduced to modulate the resulting GM images so that the voxel’s values indicate the absolute volume of the local GM. ⑥smoothed.⑦transform the GM to the MNI coordinate for SPM analysis. Then analysis these preprocessed GM data by using SPM8. Region of decrease of GM voxel add the structure map and display by using the false color, finally the GM, WM and ventricle volum of whole brain will obtain.After the imaging preprocessing, based-seed function connection will utilize to analyse the BOLD imaging. We defined six region as seeds for functional connectivity, A reference time series for each seed was obtained by averaging the fMRI time series for all voxels within the region withanatomic deficits. Next, each time series was temporally bandpass filtered (0.01-0.08 Hz). Correlation analysis was conducted between the seed reference and the rest of the whole brain in a voxel-wise manner using the realigned images. To combine results across subjects and compute statistical significance, correlation coefficients were converted to a normal distribution by Fisher’s z transform analysis. A random effect one-sample t test by SPM8 to identify voxels showing a significant positive or negative correlation to the seed time series with correlations thresholded using a family-wise error correction at p<0.05.Result(1) A voxel-based morphometry analysis revealed that multiple cortical and subcortical regions exhibited GM atrophy in the patients compared to the HCs (P< 0.05, corrected), which included the bilateral medial orbito-prefrontal cortices, bilateral dorsal lateral prefrontal cortices,, anterior cingulate gyrus, superior temporal gyrus, middle temporal gyrus, lingual gyrus, parahippocampa gyrus, putamen, caudate, insula.(2) When the seed was located in the left dlPFC, the ESRD patients demonstrated enhanced functional connectivity in the superior temporal gyrus compared to controls. When the seed was located in the bilateral medial OFC, the ESRD patients showed reduced functional connectivity in the bilateral posterior cerebellar lobes, right d1PFC, bilateral ACC, and enhanced FC in bilateral OFC, bilateral superior parietal lobe than controls. When the seed was located in the left middle temporal gyrus, enhanced FC was found in the right medial PFC in ESRD patients when compared to controls When the seed was located in the right d1PFC, the ESRD patients demonstrated reduced FC in bilateral posterior cerebellar lobes, the left inferior temporal gyrus, the right d1PFC, and enhanced FC in bilateral OFC, and the left posterior gyrus. When the seed was located in the posterior cingulate, decrease FC was found in the left middle temporal gyrus, right anterior cingulate gyrus, and bilateral medial superior frontal gyrus in ESRD patients when compared to controls. When the seed was located in the ventromedial prefrontal cortex (vmPFC), decrease FC was found in the right thalamus.(3) No significant positive or negative correlation was found between FC and dialysis time and clinic examine.ConclusionIn conclusion, the present study has displayed the structural and functional integrity changes in ESRD patients that will examine by applied morphometry analysis and resting-state functional connectivity. These differences document that patients with ESRD undergoing routine hemodialysis display clear-cut structural alterations in selected gray matter region, Moreover, regions with gray matter volume reduction have significantly altered resting state functional connectivity with other brain regions.Part three:Aberrant Functional Connectome in Neurologically Asymptomatic Patients with End-Stage Renal DiseaseObjective(1) This study aimed to investigate the topological organization of intrinsic functional brain networks in end-stage renal disease (ESRD) patients with neurologically asymptomatic.(2) This study aimed to Investigate the relationships between he topological organization of intrinsic functional brain networks and renal function and hemodialysis time.MethodsThis study was approved by the Research Ethics Review Board of the Institute of Mental Health at the Southern Medical University, and written informed consent was obtained from each participant. A total of 25 patients with ESRD (all right-handed) were recruited from the renal transplantation department at Guangdong No.2 Provincial People’s Hospital, Guangzhou, China in this study from September 2013 to September 2014. Exclusion criteria is same as the part one. The final study population included 22 patients with ESRD (16 males,6 females; mean age 38 ± 10.5 years, range 18-61 years).All the patients completed biochemical tests within 24 hours before the MR imaging. In this study, all the patients underwent a neuropsychological test involving a mini-mental state examination (MMSE) and scored>= 28, which indicated their relatively intact global neurocognition. Twenty-nine age-and gender-matched HCs (all right handed; 19 males,10 females; mean age 42.1 ± 8.4years, range 28-61 years) were recruited from the local community. All the HCs had normal renal function as determined by no abnormal findings in the abdominal MR imaging and had no physical diseases or history of psychiatric or neurologic diseases.Instrumentation is same as part one MRI data were obtained using a l.5T MR scanner (Achieva Nova-Dual; Philips), The conventional imaging sequences including T1-weighted images and T2-FLAIR images were obtained for every subject to detect clinically lesions. Rs-fMRI data were acquired using EPI sequence. The Rs-fMRI acquisition parameters were as follows:repetition time (TR)/echo time (TE)= 3,000/50 ms, In-plane resolution= 128×128, FOV=230×230,240 dynamic states, The data preprocessing was performed using the SPM8 package (http://www.fil.ion.ucl.ac. uk/spm/software/spm8)and included the following:i) removal of the first five volumes to allow T1 equilibration; ii) realignment to correct for spatial displacements due to head motion; iii) spatial normalization into the Montreal Neurological Institute space; iv) removal of linear trend; v) temporal band-pass filtering (0.01-0.1 Hz); and vi) regression of several nuisance signals of white matter signal, cerebrospinal fluid signal and head-motion profiles.Briefly, the cerebrum were first parceled into 1,024 equal-sized regions of interest (ROIs).This random parcellation method ensures higher functional homogeneity within the ROIs compared with anatomically defined atlases, and the spatial scale. We then calculated the Pearson correlation coefficients of the mean regional time series between any pair of ROIs, which generated a 1,024×1,024 connectivity matrix for each participant. To further de-noise spurious interregional correlations, only those correlations whose corresponding P-values passed through a statistical threshold (P< 0.05, Bonferroni-corrected over connections) were retained. Such a significance level-based thresholding procedure effectively avoids erroneous evaluations of network topology, then Whole-brain functional networks were obtained by calculating the interregional correlation of low-frequency fluctuations in spontaneous brain activity among 1,024 parcels that cover the entire cerebrum. We would calculate four globe parameters of global efficiency(Eglob)andlocal efficiency(Eloc),normalized globalefficiency(Eglob)and local efficiency (Eloc)and a local parameter of Nodal efficiency (Ei-glob) of whole brain, further four functional modules were identified in the mean network of HC whole brain including the Default Mode network (DMN,317 ROIs), executive control network (ECN,250 ROIs), sensorimotor network (SMN,289 ROIs) and visual network (VN,168 ROIs). Under the framework of this modular architecture, we contrasted the intra- and inter-module connectivity strength between the ESRD patients and the HCs. Finally, Significant correlations were observed between the small-world parameters of whole-brain networks and the clinical variables in the patients.Result(1) A graph-based network efficiency analysis revealed that all the networks obeyed small-world organizations, statistical comparisons revealed signific-ant differences in the quantitative network measures between the two groups. Compared to the HC group, the ESRD patients showed significantly decreased local efficiency, global efficiency and normalized global efficiency (P<0.05)(2)Compared with the HCs, the ESRD patients showed an overall decrease in the mean nodal strength of DMN and VN. These regions enclosed predominately the lateral and medial prefrontal cortex, motor cortex, anterior and middle cingulate gyri, precuneus, angular gurus, superior parietal lobule, lateral temporal lobe and occipital regions, bilaterally. In addition, result of module indicated that ESRD patients showed decreased local efficiency, global efficiency and normalized global efficiency of four modules (P<0.05). Meanwhile Compared with the HC group, the patients with ESRD showed significantly (P< 0.05, False Discovery Rate corrected) decreased functional connectivity within the DMN.(3) Abnormal topological attribute of brain functional network in ESRD positively correlated with the hemoglobin level (P<0.05); For modules, only the SMN module exhibited significantly positive correlations with the hemoglobin level in the local efficiency and global efficiency and negative correlation with the hemoglobin level in the normalized local efficiency. ConclusionESRD have the alteration of nervous activity and aberrant brain functional connectome, these founds indicated brain functional integration deficit. Meanwhile, we also found DMN would play an important role in ESRD, Our findings provide evidence for the disconnection nature of ESRD’s brain and therefore have important implications for understanding the neuropathologic substrate of the disease from disrupted network organization perspective.