Abnormal grey matter structural changes in patients with end-stage kidney disease and mild cognitive impairment: correlations with clinical features.

End-stage kidney disease and mild cognitive impairment (ESKD-MCI) affect the quality of life and long-term treatment outcomes of patients affected by these diseases. Clarifying the morphological changes from brain injuries in ESKD-MCI and their relationship with clinical features is helpful for the early identification and intervention of MCI before it progresses to irreversible dementia. This study gathered data from 23 patients with ESKD-MCI, 24 patients with ESKD and non-cognitive impairment (NCI), and 27 health controls (HCs). Structural magnetic resonance studies, cognitive assessments, and general clinical data were collected from all participants. Voxel-based morphometry analysis was performed to compare grey matter (GM) volume differences between the groups. The patients' GM maps and clinical features were subjected to univariate regression to check for possible correlations. Patients with ESKD-MCI displayed significantly more impairments in multiple cognitive domains, including global cognition, visuospatial and executive function, and memory, compared to patients with ESKD-NCI. Using a more liberal threshold (P < 0.001, uncorrected), we found that compared to patients with ESKD-NCI, patients with ESKD-MCI exhibited clusters of regions with lower GM volumes, including the right hippocampus (HIP), parahippocampal gyrus (PHG), Rolandic operculum, and supramarginal gyrus. The volumes of the right HIP and PHG were negatively correlated with serum calcium levels. ESKD-MCI was associated with a subtle volume reduction of GM in several brain areas known to be involved in memory, language, and auditory information processing. We speculate that these slight morphometric impairments may be associated with disturbed calcium metabolism.

Reversal of neurovascular decoupling and cognitive impairment in patients with end-stage renal disease during a hemodialysis session: Evidence from a comprehensive fMRI analysis.

Neurovascular (NV) decoupling is a potential neuropathologic mechanism of cognitive impairment in patients with end-stage renal disease (ESRD). Hemodialysis improves cognitive impairment at 24 h post-dialysis, which suggests a potential neuroprotective effect of hemodialysis treatment on the brain. We investigated the effects of hemodialysis treatment on the reversal of NV decoupling associated with cognitive improvement. A total of 39 patients with ESRD and 39 healthy controls were enrolled. All patients were imaged twice during a dialysis session: before hemodialysis (T1pre-dialysis ) and at 24 h after dialysis (T2post-dialysis ). The healthy controls were imaged once. NV coupling was characterized based on correlation coefficients between four types of blood oxygen level-dependent signals and cerebral blood flow (CBF). A battery of neuropsychological and blood tests was performed before the imaging. Patients with ESRD showed improvements in memory and executive function at T2post-dialysis compared with that at T1pre-dialysis . At both T1pre-dialysis and T2post-dialysis , patients with ESRD had lower amplitude of low-frequency fluctuation (ALFF)-CBF coupling than healthy controls. Additionally, patients with ESRD had higher ALFF-CBF coupling at T2post-dialysis than at T1pre-dialysis . Higher memory scores, higher hemoglobin level, lower total plasma homocysteine level, lower systolic blood pressure variance, and lower ultrafiltration volume were associated with higher ALFF-CBF coupling in patients with ESRD after a hemodialysis session. These findings indicate that partial correction of anemia and hyperhomocysteinemia, stable systolic blood pressure, and fluid restriction may be closely linked to the reversal of NV decoupling and improvement in cognition in patients with ESRD.

Neurological effects of hemodialysis on white matter microstructure in end-stage renal disease.

OBJECTIVES: To detect the effects of hemodialysis (HD) on the central nervous system (CNS), the present study forces the memory storage capacity and the difference in white matter (WM) microstructure characteristics among end-stage renal disease (ESRD) participants before HD initiation (ESRD-BHD), ESRD participants with maintenance HD (ESRD-MHD), and healthy participants (HCs). METHODS: Between 2016 and 2018, 56 ESRD-BHD, 39 ESRD-MHD, and 56 HCs were recruited for this study. The fractional anisotropy (FA) of tractography streamlines within the working memory network was investigated using a novel along-tracts analysis method. The relationship between WM microstructure and working memory scores, measured from an n-back task, were detected by multiple correlation analysis. RESULTS: As compared with HCs, a significantly lower FA was found along part of the WM in the working memory network in ESRD-BHD. In the group-difference location of ESRD-BHD and HCs, the FA of ESRD-MHD was reversed to normal levels in HCs. However, the FA in a new location was differentially reduced across groups: highest in HCs, intermediate in ESRD-BHD, and lowest in ESRD-MHD. Correlation analysis showed that a longer reaction time correlated to a lower FA, according to the following pattern: ESRD-BHD > ESRD-MHD > HCs. CONCLUSION: Despite the persisting abnormal brain structure, our findings suggest HD has a neuroprotective effect in ESRD patients.

Neurovascular coupling dysfunction in end-stage renal disease patients related to cognitive impairment.

We aimed to investigate the neurovascular coupling (NVC) dysfunction in end-stage renal disease (ESRD) patients related with cognitive impairment. Twenty-five ESRD patients and 22 healthy controls were enrolled. To assess the NVC dysfunctional pattern, resting-state functional MRI and arterial spin labeling were explored to estimate the coupling of spontaneous neuronal activity and cerebral blood perfusion based on amplitude of low-frequency fluctuation (ALFF)-cerebral blood flow (CBF), fractional ALFF (fALFF)-CBF, regional homogeneity (ReHo)-CBF, and degree centrality (DC)-CBF correlation coefficients. Multivariate partial least-squares correlation and mediation analyses were used to evaluate the relationship among NVC dysfunctional pattern, cognitive impairment and clinical characteristics. The NVC dysfunctional patterns in ESRD patients were significantly decreased in 34 brain regions compared with healthy controls. The decreased fALFF-CBF coefficients in the cingulate gyrus (CG) were associated positively with lower kinetic transfer/volume urea (Kt/V) and lower short-term memory scores, and were negatively associated with higher serum urea. The relationship between Kt/V and memory deficits of ESRD patients was partially mediated by the fALFF-CBF alteration of the CG. These findings reveal the NVC dysfunction may be a potential neural mechanism for cognitive impairment in ESRD. The regional NVC dysfunction may mediate the impact of dialysis adequacy on memory function.

White matter characteristics between amygdala and prefrontal cortex underlie depressive tendency in end stage renal disease patients before the dialysis initiation.

Depression is one of the common incidental symptoms in end-stage renal disease (ESRD) patients, empirically overlooked. Reproducible results observed that altered interregional white matter (WM) connections between depression-related brain regions (thalamus, amygdala, and prefrontal cortex (PFC)) in the human brain were closely associated with depression. Whether the depressive tendency of ESRD patients is also association with the WM connections is remains unknown. To address this problem, 56 ESRD patients before dialysis initiation and 56 healthy controls (HCs) were scanned with diffusion tensor imaging. According to the diagnostic and statistical manual of mental disorders, ESRD patients were separated into with and without depressive tendency groups. Twenty-five essential metabolites were tested in ESRD. The tractography atlas-based analysis and multiple regression analysis were implemented to gain features which could map the depressive tendency variability across ESRD. For metabolites, the levels of thrombocytes and calcium have significant differences between with and without depressive tendency groups. For WM microstructure, depressive tendency ESRD patients had abnormal WM diffusion properties along the fiber tracts of the amygdala-PFC. Compared with the features which were extracted from the group-difference of WM or metabolites, only WM features combinations (1000 bootstrap samples; 5000 permutation tests) along the fiber tract of the amygdala-PFC was a significant predictor of either with or without depressive tendency. Our findings suggested that the advanced neuroprotection may be planned before dialysis initiation, and the WM characteristics of amygdala-PFC may be a potential neuromarkers for the early diagnosis of depressive tendency in ESRD patients before dialysis initiation.

Abnormal rich club organization in end-stage renal disease patients before dialysis initiation and undergoing maintenance hemodialysis.

BACKGROUND: End-stage renal disease (ESRD) patients are at a substantially higher risk for developing cognitive impairment compared with the healthy population. Dialysis is an essential way to maintain the life of ESRD patients. Based on previous research, there isn't an uncontested result whether cognition was improved or worsened during dialysis. METHODS: To explore the impact of dialysis treatment on cognitive performance, we recruited healthy controls (HCs), predialysis ESRD patients (predialysis group), and maintenance hemodialysis ESRD patients (HD group). All ESRD patients performed six blood biochemistry tests (hemoglobin, urea, cystatin C, Na+, K+, and parathyroid hormone). Neuropsychological tests were used to measure cognitive function. By using diffusion tensor imaging and graph-theory approaches, the topological organization of the whole-brain structural network was investigated. Generalized linear models (GLMs) were performed to investigate blood biochemistry predictors of the neuropsychological tests and the results of graph analyses in the HD group and predialysis group. RESULTS: Neuropsychological analysis showed the HD group exhibited better cognitive function than the predialysis group, but both were worse than HCs. Whole-brain graph analyses revealed that increased global efficiency and normalized shortest path length remained in the predialysis group and HD group than the HCs. Besides, a lower normalized clustering coefficient was found in the predialysis group relative to the HCs and HD group. For the GLM analysis, only the Cystatin C level was significantly associated with the average fiber length of rich club connections in the predialysis group. CONCLUSIONS: Our study revealed that dialysis had a limited effect on cognitive improvement.

Larger regional volume of the thalamus in diarrhea-predominant irritable bowel syndrome: a cross-sectional study.

As a relay center between the cerebral cortex and various subcortical brain areas, the thalamus is repeatedly associated with the dysfunction of brain-gut interaction in patients with irritable bowel syndrome (IBS). However, the regional morphological alterations of the thalamus in IBS are not well defined. We acquired structural magnetic resonance data from 34 patients with IBS and 34 demographically similar healthy subjects. Data processing was performed using FMRIB's Integrated Registration and Segmentation Tool (FIRST). Volumetric analysis and surface-based vertex analysis were both carried out to characterize the morphology of the thalamus and other subcortical structures. Our results suggested that the majority (31 cases) of the patients with IBS had diarrhea-predominant symptoms. Volumetric analysis revealed a larger normalized volume of the right thalamus and left caudate nucleus in patients with IBS than in healthy controls. Surface analysis indicated that the difference arose mainly from the laterodorsal nucleus of the right thalamus, and the body of the left caudate nucleus. In addition, patients with IBS had different hemispheric asymmetries of the thalamus (rightward) and caudate nucleus (leftward) from controls (leftward for the thalamus and rightward for the caudate nucleus). In general, our results indicated that patients with diarrhea-predominant IBS had enlarged thalamus and caudate nucleus volumes, as well as altered hemispheric asymmetries of these two structures, compared with healthy controls. The neuroimaging evidence of these structural alterations helps clarify the underlying pathophysiology of diarrhea-predominant IBS.

The variation of motor-related brain structure and its relation to abnormal motor behaviors in end-stage renal disease patients with restless legs syndrome.

Restless legs syndrome (RLS) is common in the end-stage renal disease (ESRD) population; however, their interrelationship remains largely unclear. In the current study, we aimed to investigate the brain structure variation in ESRD patients with RLS (ERSD-RLS) and its potential relation with the severity of RLS. Diffusion tensor imaging and T1-weighted imaging were obtained from 64 ERSD-RLS and 64 matched healthy controls. Voxel-based morphometry (VBM) analysis and tractography atlas-based analysis (TABS) were used to detect the alteration of gray matter (GM) volume and white matter (WM) microstructural characterization. The corticospinal tract (CST), which is a main motor-pathway, was selected as a fiber bundle of interest in the TABS analysis. The severity of RLS was evaluated by using the International RLS Study Group scale. Lastly, a correlation analysis was performed to explore the interrelationship between RLS rating scores and brain structure measurements. For the results, ERSD-RLS showed abnormal GM volume of motor-related brain regions located in the bilateral superior frontal gyri, precentral gyrus, and putamen. Significant differences in the diffusion properties were found at the posterior limb of the internal capsule. Furthermore, the severity of RLS was only significantly associated with the diffusion properties, which was not found in the motor-related regions of GM. Our results suggest that the motor-related brain structure was altered in ERSD-RLS. The abnormal WM microstructure of the CST may serve as an imaging marker correlated with the severity of motor dysfunction in ERSD-RLS, indicating that WM neuroprotection should be considered when improving motor function in ERSD-RLS.

Altered white matter microstructure mediates the relationship between hemoglobin levels and cognitive control deficits in end-stage renal disease patients.

The brain-kidney crosstalk theory suggested that the brain and kidneys may be considered end organs on parallel trajectories and subject to shared risk factors, which are receiving increasing attention. Cognitive control deficits were frequently presented in patients with end-stage renal disease (ESRD). Whether or not cognitive control impairment is concerned with brain-kidney crosstalk is in need of further research. To detect the relationship between ESRD and cognitive control impairment, diffusion tensor imaging was collected in 64 healthy controls (HCs) and 64 patients with ESRD. Tract-based spatial statistics and fixel-based analysis were used to detect the difference of white matter (WM) microstructure and morphology between ESRD patients and HCs in the whole brain. Tractography atlas-based analysis was also used to investigate the difference of diffusional characteristics along fiber bundles of interest between the two groups. For the whole-brain analysis, ESRD patients showed WM microstructural alteration and fiber density variation in the cingulum. In addition, ESRD patients exhibited higher MD and RD than HCs along the anterior cingulum. Among all of the blood biochemistry tests that represent kidney disease to a degree, the stepwise regression analysis showed that only hemoglobin significantly contributed to the cognitive control deficits in ESRD patients. Mediation analysis proved that the relationship between hemoglobin and cognitive control deficits of ESRD patients was mediated by WM microstructural alteration of the cingulum. Our results indicated that the anterior cingulum was correlated with cognitive control deficits and mediated the impact of hemoglobin on cognitive control.

Association between abnormal thalamic metabolites and sleep disturbance in patients with end-stage renal disease.

Sleep disturbances are common in end-stage renal disease (ESRD) patients. However, the underlying neuropathological mechanisms are largely unclear. Previous studies have revealed the important role of the thalamus in the potential mechanisms of sleep disorders. We hypothesized that the sleep disturbances in ESRD patients may correspond to metabolic changes of thalamus and the uremic factors may have a vital contribution on these changes. We performed multi-voxel 1H-MRS of bilateral thalami in 27 ESRD patients who currently receiving hemodialysis treatment and 21 age-matched healthy volunteers. ESRD patients underwent Pittsburgh Sleep Quality Index (PSQI) scale and restless legs syndrome (RLS) rating scale assessment. Laboratory blood tests including serum creatinine, serum urea, cystatin-C, serum parathyroid hormone (PTH), calcium and phosphorus levels, hemoglobin and hematocrit were performed in all ESRD patients close to the time of the MR examination. We found correlations among elevated PTH, higher PSQI score and RLS rating score in ESRD patients. ESRD patients displayed decreased N-acetylaspartate and creatine ratio (NAA/Cr) of thalami compared with controls. There were significantly negative correlation between NAA/Cr and serum PTH level or PSQI score. The metabolic changes of thalami played an important role in the neuropathological mechanisms of lower sleep quality in ESRD patients. Secondary hyperparathyroidism as one of the main uremia-related factors was closely related to abnormal metabolites of the thalamus in patients with ESRD, revealing the crosstalk procedure between renal impairment and brain function.

Altered intrinsic brain activity and memory performance improvement in patients with end-stage renal disease during a single dialysis session.

Memory deficits are considered to have a great influence on self-management, dietary restriction and therapeutic regimen for end-stage renal disease (ESRD) patients with dialysis treatment. This study was aim to investigate the spontaneous brain activity and its relationship with memory performance in ESRD patients before dialysis (T1) and after 24 h (T2) during a single dialysis session. 23 ESRD patients and 25 matched healthy controls (HCs) were scanned using functional magnetic resonance imaging (fMRI) at T1, and all patients were also scanned at T2. Amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) methods were used to evaluate the spontaneous brain activity between two groups. The Auditory Verbal Learning Test-Huashan version (AVLT-H) was performed to assess memory function. Compared with HCs, ESRD group showed a significant decreases in the immediate recall total score (IR-S), short-term delayed recall score (SR-S), and long-term delayed recall score (LR-S) at T1. IR-S, SR-S, LR-S and recognition score (REC-S) were significantly increased at T2. Compared with HCs at T1, ESRD patients showed that the lower mean ALFF (mALFF) values were mainly located in dorsolateral prefrontal cortex (DLPFC), medial frontal gyrus, and precuneus. Higher ReHo in the bilateral inferior temporal gyrus and left hippocampus and lower ReHo in the right precentral gyrus, anterior cingulate cortex were found at T1 too. The mALFF values of the DLPFC and precuneus were significantly increased during a dialysis session, while no significantly difference of ReHo region was found. Furthermore, the increased mALFF values of the DLPFC were significantly positively correlated with the improvement in the IR-S. Our results indicated that increased regional spontaneous activity of the DLPFC may reflect memory performance improvement after a single dialysis treatment, which may provide insight into the effect of hemodialysis on spontaneous brain function during a single dialysis session.

The relationship between putamen-SMA functional connectivity and sensorimotor abnormality in ESRD patients.

The basal ganglia (BG) are composed of several nuclei involved in neural processing associated with integration of sensory and motor information. Recent neuroimaging studies implicated its key role in control of voluntary motor function. As the sensorimotor abnormality is common among the end-stage renal disease (ESRD) population, in the current study, we aimed to investigate the abnormal structure and functional connectivity patterns of BG in ESRD patients. Twenty-nine ESRD and twenty-nine age and gender-matched healthy controls (HC) were enrolled to compare the volume of the subsets in the BG (e.g., caudate nucleus, putamen and globus pallidus) by using the VBM analysis; resting-state functional connectivity was analyzed by a seed-based method. Compared with the HC group, ESRD patients had a smaller volume in the right putamen. Taking the right putamen as a seed region, we further found reduced functional connectivity in patients mainly between the putamen and supplementary motor area (SMA), insula, posterior mid-cingulate gyrus, and primary motor cortex. In ESRD group, the severity score of restless legs syndrome was negatively correlated with putamen-SMA functional connectivity, while the hemoglobin level was positively correlated with functional connectivity degree between the putamen and SMA. Our results revealed an abnormal volume of the putamen and its decreased functional connectivity patterns during resting state in ESRD with sensorimotor abnormalities. These preliminary results indicated that the decreased functional connectivity in putamen-SMA was associated with sensorimotor abnormalities, and anemia was correlated with this abnormal functional pattern in ESRD patients.

Abnormal interaction between cognitive control network and affective network in patients with end-stage renal disease.

End-stage renal disease (ESRD) is a common complicated disorder that is generally associated with an altered central nervous system and cognitive impairment. Neuroimaging studies have recorded aberrant brain circuits in patients with ESRD that were closely associated with abnormal clinical manifestations. However, whether the altered interaction was within and/or between these circuits is largely unclear. We investigated brain topological organization and/or module interaction by employing resting-state functional magnetic resonance imaging (rs-fMRI) and modularity network analysis in 24 patients with ESRD and 20 age- and gender-matched healthy control (HC) subjects. Stroop task was used to evaluate the performance of cognitive control in all subjects. At the global level, ESRD patients exhibited significantly decreased global and local efficiency which were mainly related to abnormal functional connectivity of the amygdala and inferior frontal gyrus (IFG). Stepwise regression analysis was applied to estimate the relationships between network efficiency and blood biochemistry level (urea, creatine, phosphate, Ca2+, hematocrit, cystatin, hemoglobin levels, parathyroid hormone, K+ and Na+), and only the hematocrit level was significantly associated with global efficiency in patients with ESRD. At the modular level, we discovered an aberrant brain interaction between the amygdala- and IFG-related circuits in the ESRD group, and the regional efficiency of the amygdala was observably relative to the performance of cognitive control in patients with ESRD. Our results suggested that ESRD exhibited aberrant brain functional topological organization and module-level interaction between the affective and cognitive control circuits, providing crucial insights into the pathophysiological mechanism of ESRD patients.

Abnormal structure and functional connectivity of the anterior insula at pain-free periovulation is associated with perceived pain during menstruation.

Neuroimaging studies have demonstrated the critical role of the insula in pain pathways and its close relation with the perceived intensity of nociceptive stimuli. We aimed to identify the structural and functional characteristics of the insula during periovulatory phase in women with primary dysmenorrhea (PDM), and further investigate its association with the intensity of perceived pain during menstruation. Optimized voxel-based morphometry and functional connectivity (FC) analyses were applied by using 3-dimensional T1-weighted and resting functional magnetic resonance imaging (fMRI) in 36 patients at the peri-ovulation phase and 29 age-, education-, and gender-matched healthy controls (HC). A visual analogue scale (VAS) was used to examine the intensity of the abdominal pain at periovulation and menstruation. In our results, PDM patients had significant higher VAS-rating during menstruaion than periovulation. Compared with the HC, PDM patients had lower gray matter density in the left anterior insula (aINS). Taken the left aINS as a seed region, we further found hypoconnectivity between aINS and medial prefrontal cortex (mPFC), which showed negative relation with the VAS during menstruation. As the aINS is a key site of the salience network (SN) and the mPFC is a critical region in the default mode network (DMN), it's implicated a trait-related central-alteration that communications between pain attention and perception networks were disrupted without the ongoing menstrual pain. Moreover, result of correlation analysis, at least in part, suggested a possible role of altered FC (pain-free period) in predicting pain perception (menstruation).

Neuroprotection of Osthole against Cerebral Ischemia/Reperfusion Injury through an Anti-apoptotic Pathway in Rats.

Cerebral ischemia/reperfusion (I/R) injury is a major cause of acute brain injury. The pathogenetic mechanisms underlying I/R injury involve apoptosis, inflammation and oxidative stress. Osthole-a plant coumarin compound-has been reported to protect against focal cerebral I/R-induced injury in rats. However, the mechanism remains unknown. Here we hypothesize that osthole acts through inhibition of apoptosis during focal cerebral I/R injury in rats. We induced cerebral I/R injury by middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion. We randomly assigned 60 rats to three groups (20 rats per group): sham-operated, vehicle-treated I/R, and osthole-treated I/R. We treated rats intraperitoneally with osthole (40 mg/kg) or vehicle 30 min before cerebral ischemia. We harvested the brains for infarct volume, brain water content, histological changes and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining as well as cleaved caspase-3, bax, and bcl-2 levels 24 h after reperfusion. Osthole treatment significantly attenuated cerebral dysfunction and histologic damage induced by I/R injury. Moreover, osthole-treated rats had a dramatic decrease in apoptotic neuronal cells along with a decrease in bax and cleaved caspase-3. The bcl-2 levels increased. Osthole treatment protects the brain from cerebral I/R injury by suppressing cell apoptosis. Thus, osthole may represent a novel practical strategy to prevent cerebral I/R injury.