Altered Brain Functional Connectivity of resting-state networks in Neurologically Asymptomatic Patients with End-Stage Renal Disease Undergoing Maintenance Hemodialysis

doi:10.21203/rs.3.rs-3129835/v1

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Altered Brain Functional Connectivity of resting-state networks in Neurologically Asymptomatic Patients with End-Stage Renal Disease Undergoing Maintenance Hemodialysis

https://doi.org/10.21203/rs.3.rs-3129835/v1

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Purpose: To investigate changes in the functional connectivity (FC) of neurologically asymptomatic patients with end-stage renal disease (ESRD) on haemodialysis (HD) and determine the relationship between these changes and clinical variables.

Methods:Resting-state functional magnetic resonance imaging was performed in 36 neurologically asymptomatic patients with ESRD on HD (ESHD) and 31 healthy control subjects. Using independent component analysis, abnormal resting-state networks and FC regions were identified in the two groups. Partial correlation analysis was performed between abnormal FC regions and clinical variables.

Results: The ESHD group exhibited abnormal FC in multiple regions of three RSNs, including the posterior default mode network (DMN), attention network, and external visual network (VN). Significant correlations were found between the FC values of multiple brain regions (the right supramarginal gyrus, the left angular gyrus, and the left middle occipital gyrus) of the DMN or VN and the neurocognitive scale scores in the ESHD group. Additionally, the FC value of the right median cingulate gyrus was negatively correlated with the serum calcium level.

Conclusion: Our study found that the ESHD group exhibited multiple abnormal FC regions in three RSNs involved in visual–spatial processing, short-term memory, language, attention and executive function; these findings are consistent with the characteristics of cognitive impairment during the HD process. Our findings provided both empirical and complementary evidence indicating that FC changes may be associated with the underlying clinical symptoms of patients with ESHD.

End stage renal disease

Hemodialysis

Resting state magnetic resonance

Independent component analysis

Functional connectivity

Chronic kidney disease (CKD) is a major global public health problem [1]. The final stage of CKD, called end-stage renal disease (ESRD), is one of prime contributors to morbidity and mortality worldwide [2]. Indeed, the number of patients with ESRD requiring replacement therapy will increase to 14.5 million by 2030 [2]. A prospective study suggested that 79.4% of patients undergoing haemodialysis (HD) show increased vulnerability to cognitive impairment [3], including dementia and Alzheimer’s disease (AD) [4]. ESRD patients with cognitive impairment will have an increased risk of the disability rate and mortality[5]. Especially patients with ESRD undergoing HD are at substantial risk of dementia and AD, and these diagnoses are associated with a two-fold higher mortality rate [4]. Therefore, early detection of brain abnormalities in neurologically asymptomatic patients with ESRD undergoing maintenance hemodialysis (ESHD) is essential for early diagnosis, treatment and ultimately reduction of mortality. On the other hand, HD-associated cognitive impairment may lead to acute and chronic brain injury caused by worsening cerebral oedema, the volatility of cerebral blood flow and osmotic shifts [6]. However, the neurobiological mechanism underlying HD-associated cognitive impairment is currently unclear [7, 8].

Resting-state functional connectivity (FC) analysis can noninvasively estimate changes in nerve interactions between brain regions. Independent component analysis (ICA) can determine FC changes of brain-wide resting-state networks (RSNs) related to cognitive tasks without selecting seed regions in advance [9]. ICA has been used to study various neural and mental diseases, including epilepsy[10], schizotypal personality disorder [11], and autism spectrum disorders [12]. Using ICA, Huijuan Chen et al. [13] compared the RSN changes between 22 healthy control (HC) subjects and 37 patients with ESRD before and after kidney transplantation. They found improved FC in the default mode network (DMN) and sensorimotor network (SMN) of patients with ESRD 6 months after kidney transplantation. According to this research, ICA can be used to identify abnormal brain function in the RSNs of ESRD and may provide objective imaging evidence to explain the neuromechanism underlying ESRD and its related symptoms. However, ICA has not yet been established as a method for investigating in ESHD patients.

Reportedly, reorganisation of brain structure is associated with the pathophysiology of ESRD [14–16], thus, we hypothesised that ESHD would alter the FC of RSNs. Therefore, in this study; we compared the FC of RSNs defined by ICA between ESHD and a HC group. Furthermore, we determined the correlation of the FC of RSNs with the cognitive and laboratory indicators of patients with ESHD. We aimed to understand the relationship between disease severity and abnormal FC in patients with ESHD.

Subjects

Approval was provided by the Guangdong Second Provincial General Hospital Human Research Ethics Committee, and each participant provided informed consent. From 2016 to 2021, 36 neurologically asymptomatic participants with ESRD who were treated with hemodialysis (dialysis duration > 3 months, 3–4 times a week) were enrolled from the renal transplantation department of the Second People’s Hospital of Guangdong Province. 31 age-, sex- and education level-matched HC subjects were recruited through the community. Eligible participants were aged 20–65 years and right-handed.

All patients with ESRD were diagnosed by two physicians with ≥ 15 years of experience, and ESRD (CKD stage 5) was classified per the K/DOQI classification-i.e. glomerular filtration rate < 15 ml/min/1.73 m². The primary disease of all ESRD patients is chronic glomerulonephritis. All patients with ESRD had undergone conventional HD for minimum 3 months. All patients were asymptomatic and without history of neurologic or psychiatric disease. HD aetiology and duration were collected from the patients’ electronic medical records. Exclusion criteria were drug or alcohol abuse history, known severe neurological disorders (e.g. stroke and epilepsy, etc.) and psychiatric disorders, traumatic brain injury, obvious brain lesions or intolerance to magnetic resonance (MR).

Neurocognitive Testing

A series of neuropsychological tests were performed before MR data acquisition, including the digital connections test types A and B (NCT-A/B), line-tracing test (LTT), serial dot test (SDT), digit symbol test (DST), the Folstein version of the mini-mental state examination (MMSE) [17] and the Montreal cognitive assessment (MoCA) [18]. NCT-A/B, DST, SDT, and LTT assess attention, psychomotor speed, and visual memory [19]. NCT-A tested visual perception and motor speed abilities, whereas NCT-B tested of visual perception, working memory, attention and executive control. LTT is a test of visual discrimination and attention. SDT is a test of spatial ability, reaction speed and fine motor skills. DST is a test of short-term memory, reaction speed and attention accuracy.

Laboratory tests

All ESRD patients completed blood biochemical examinations including haemoglobin, serum calcium, serum potassium, serum urea nitrogen and serum creatinine tests, within 24h of MR examination. Blood laboratory tests were not performed on HC group. All blood samples and MR data acquisitions were obtained before dialysis.

MR Data Acquisition

MR was performed for all patients with ESRD and HC subjects using a Philips Ingenia 3.0T MR scanner system with a 32-channel phased-array head coil at the Department of Medical Imaging, Guangdong Second Provincial General Hospital. All patients were in a supine and fixed state during scanning, as described previously [20]. EPI was used with the following parameters: axial slices, 33; repetition time (TR), 2000 ms; echo time (TE), 30 ms; flip angle (FA), 90◦; slice thickness, 3.5 mm with no gap; matrix, 64 × 64; field of view (FOV), 230 mm × 230 mm. 240 vol per participant were obtained. Besides, individual three-dimensional T1WI were acquired by an EPI sequence (160 sagittal slices; TR, 25 ms; TE, 4.1 ms; FA, 30◦; slice thickness, 1.0 mm with no gap; field-of-view (FOV), 230 × 230mm²; and matrix, 230 mm × 230 mm, total volume = 240. The duration of each rs-fMRI scan was 8min.

All subjects were interviewed after completing the scan to clarify their cooperation level. Each subject underwent a routine MR sequence including T1WI and T2 FLAIR to detect unknown diseases. Conventional MR images were reviewed by two physicians with ≥ 15 years of experience who did not know whether the image was a patient case or a HC.

Imaging analysis

All resting-state functional MR imaging (fMRI) functional datasets were preprocessed using the DPARSFA 4.4 Advanced Edition plugin software within DPABI 6.2_220915 (http://rfmri.org/dpabi) [21]. The first 10 images were discarded to eliminate interference and ensure steady-state longitudinal magnetisation. The remaining 230 images were corrected for temporal differences and head motion. A movement threshold of head motion of > 1.5 mm or 1.5° was set during the procedure; however, no subject was eliminated because head movements did not exceed the threshold. To normalise all functional images, the standard Montreal Neurological Institute template was used with the DARTEL method at a resolution of 3×3×3 mm³. After spatial normalisation, linear trends were filtered using a typical temporal bandpass (0.01–0.08 Hz). An 8 mm ‘full width at half maximum’ Gaussian kernel was used to spatially smoothen resulting time series. Two radiologists ≥ 15 years of experience checked the images to ensure segmentation quality and registration.

Group ICA analysis

All preprocessed images were analysed using the Group ICA (GIFT) of the fMRI Toolbox to identify large-scale patterns of FC. According to the automatic score estimation of the GIFT software, we used ICA to reduce the dimensions of all subjects’ fMRI images into 24 spatial components, after which we calculated the cross-correlations of the 24 networks with a well-identified template. Using the brain network template provided by Smith et al. [22], the following six brain RSNs of interest were identified for all subjects according to the order of correlation and visual inspection: the anterior DMN (aDMN), posterior DMN (pDMN), SMN, attention network (AN), lateral visual network (LVN) and external visual network (EVN) (Fig. 1). We decomposed all fMRI images into different numbers of networks ( i.e. 10, 15, 20, 25, 30, 35, 40, 45, and 50 components). Correlation coefficients calculated according to the segmentation of the different number of components were consistent.

Statistical analysis

SPSS 20.0 software (SPSS Inc., Chicago, USA) was used to conduct comparative analysis of demographic and clinical characteristics. First, we compared the demographic and clinical characteristics of HD and HC subjects using the Mann–Whitney U test. Shapiro–Wilk test was used to ensure data normality. Chi-square test was conducted to compare the intergroup qualitative variables of gender. Two-sample t-tests were used to assess intergroup differences in age, education, neuropsychological test scores and clinical laboratory indicators.

As in a previous study [11], a one-sample t-test was used to analyse the RSNs of each group and select significant clusters, P < 0.05 for the family-wise error (FWE) correction indicated statistical significance (P < 0.05, FWE). A ESRD and HC group maps combination was used as a mask of each individual RSN component group analysis. The statistical maps were analysed using the combination mask to ensure that only each RSN-relevant alteration was analysed. Two-sample t-tests were conducted to analyse the FC according to each spatial component of the six RSNs identified via Group ICA. Clusters of > 20 voxels exhibiting P < 0.05 with FWE correction were statistically significant. After an intergroup comparison, partial correlation analysis was performed within the HD group with age, sex and years of education removed as covariates.

Demographic and Clinical Features

Thirty-six patients with ESRD (without clinical neurological disease), including 16 with minimal mild cognitive impairment and 20 without cognitive impairment. No significant differences in age, sex, education and SDT, DST, LTT and MMSE scores (all P > 0.05), whereas the NCT-A/B of the ESHD group was significantly higher than that of the HC group (P < 0.05), and the MoCA score of the ESHD group was significantly lower than that of the HC group (P < 0.05) (Table ).

Compared with the HC group, patients with ESHD exhibited abnormal FC in multiple brain regions of three RSNs: the pDMN, AN, and EVN. No significant intergroup differences were noted in the FC of the SMN between the ESRD and HC groups (P > 0.05). Compared with the HC group, the FC of the right supramarginal gyrus (SMG) and right median cingulate gyrus (MCC) of the pDMN was increased in the ESHD group (P < 0.05, FWE) (Fig. 2). In addition, decreased FC regions were located in the pDMN, including the bilateral angular gyrus (ANG), and bilateral precuneus gyrus (PCUN) (P < 0.05, FWE) (Fig. 3A). Decreased FC regions were observed in the right middle frontal gyrus (MFG) of the AN and in the left middle occipital gyrus (MOG) of the EVN (P < 0.05, FWE) (Fig. 3B-3C).

Negative correlations were found between the FC value of the right MCC and the serum calcium level (r = − 0.362, P = 0.038) (Fig. 4B), and the FC value of the right SMG and the NCT-A score(r= -0.502, P = 0.003), (Fig. 5A) and the FC value of the left ANG and NCT-B score (r= -0.438, P = 0.011) (Fig. 5B). In addition, a significant positive correlation was found between the FC value of the left MOG and the MoCA score (r = 0.464, P = 0.007) (Fig. 4A).There were no significant correlations between the FC values and MMSE, LTT, or DST scores.

Based on ICA, we found FC changes in multiple regions of three RSNs. Significant correlations were found between the FC values of multiple brain regions (i.e. the right SMG, the left ANG and left MOG) and the neurocognitive scale scores in patients with ESRD. Additionally, the FC values of the right MCC were significantly correlated with the serum calcium level. These results provide both empirical and complementary evidence indicating that the underlying clinical symptoms of patients with ESHD are associated with changes in the FC of several different RSNs.

We found that the ESHD group exhibited abnormal FC regions in the DMN involving the bilateral PCUN and inferior parietal lobule (IPL, including the bilateral ANG and right SMG). The dysfunctional connection of the DMN may lead to learning/memory retrieval and self-reference processing disorders, behavior defects of external orientation consciousness, and loss and weakening of emotion, leading to possible abnormalities of the VN, the AN and/or the SMN [23]. Furthermore, the PCUN plays a central role in a range of integrated self-awareness tasks, including self-processing operations, visual–spatial processing and episodic memory retrieval [24, 25]. The ANG integrates visual, auditory and somatosensory inputs; thus, it is involved in visual–spatial abilities, language and reading comprehension, self-awareness and memory retrieval functions [26, 27]. The SMG is associated with episodic memory encoding, short-term auditory memory, memory processing [28–30]. Our results agree with many previous studies [13, 31–35]. For example, Huijuan Chen et al. identified the abnormal spontaneous activity of the DMN in the PCUN and IPL/ANG using the amplitude of low-frequency fluctuations (ALFFs)[33] and regional homogeneity [35] analysis, respectively, in patients undergoing HD. Using degree centrality (DC) and seed-based FC analyses, Peina Chen et al. [36] found that patients with ESRD and cognitive impairment exhibited increased DC values in the left SMG. Using diffusion-tensor imaging technology, Longjiang Zhang et al. [31] found many changes in the fibre bundles connecting the posterior cingulate cortex and the PCUN to the bilateral IPL in patients with ESRD following renal transplantation as well as positive correlations between these changes and NCT-A scores. In summary, previous studies and our study indicate that the abnormal PCUN and IPL (including the ANG and SMG) may be the characteristics of brain spontaneous activities in patients with ESHD. Furthermore, our results revealed that negative correlations existed between the increased FC values of the right SMG and the NCT-A score, and the decreased FC value of the left ANG and NCT-B score. This result provides further evidence to support the notion that the increased FC of the SMG may reflect a compensatory mechanism that helps maintain cognitive function, and the decreased FC of the ANG may be a critical signature associated with the progression of cognitive decline of patients with ESHD.

We also observed abnormal FC regions in the right MFG. Peina Chen et al.[36] found a positive correlation between the DC values of the right superior frontal gyrus and neurocognitive scores in ESRD with cognitive impairment. TingYu Chang et al. [32] used graph theory analysis to evaluate patients with ESRD without cognitive decline that were receiving peritoneal dialysis, finding many abnormal FC regions of the frontal gyrus and cingulate gyrus. We confirmed that the FC values of the MFG in the ESHD group are abnormal, which is inconsistent with the superior frontal gyrus reported in most previous studies. According to previous studies [37, 38], We speculate that the observed difference may be related to different treatments (i.e. conventional treatment, HD and peritoneal dialysis) or the severity of the disease. Melissa et al.[39] found that patients undergoing HD are more vulnerable to damage to their visual–spatial processing, deductive reasoning, executing, and verbal skills than their short-term memory, and these findings support our speculation; however, a study with a larger sample size will be required to validate our findings. Nevertheless, our discovery of FC regions in the right MFG may provide additional brain imaging markers for cognitive impairment in patients with ESHD.

We also found decreased FC in the left MOG, which has rarely been reported in previous studies. Indeed, we found only one related study, conducted by Waverly Harrell et al.[40] where functional MRI was performed during a visual–spatial working memory task in 21 children with CKD in which several brain regions in the frontal cortex, occipital cortex, temporal cortex, insula and cingulate cortex were activated, and these regions were important elements of visual working memory and visual–spatial processing in these children. The abnormal MOG of the ESHD group could have various explanations. First, previous studies [41, 42] have shown that patients with ESRD/CKD are more vulnerable to visual impairment and eye disease; therefore, we speculate that the abnormal FC of the occipital lobe may be related to the visual impairment of patients with ESHD. Second, the dysfunctional DMN connection may cause abnormalities in the VN, AN and SMN [43], which may be related to the feedback mechanism of neural impulses in the frontoparietal and occipital cortex of the DMN. Third, the MOG belong to the occipital cortex, which is mainly associated with vision, language, executive function and visual–spatial processing [44]. The functions of these regions are consistent with the vulnerable aspects of cognitive impairment during HD. Therefore, we speculate that the intrinsic FC changes of the MOG may be related to the cognitive decline of patients with ESHD. Moreover, our speculation is supported by the positive correlations between the MOCA scores and the decreased FC values of the left MOG. These positive correlations suggest that the FC changes of the MOG might be critical signatures associated with the progression of cognitive decline. In summary, the FC changes of the MOG may provide additional sensitive brain imaging markers for the cognitive impairment of patients with ESHD.

We also found a negative correlation between the increased FC value of the right MCC and the serum calcium level. A previous study [14] found that changes to the white matter structure of the left anterior thalamic radiation were positively correlated with the serum calcium level. Hypocalcaemia is common in patients with ESRD [45] and may lead to neurotoxicity and neurotransmitter imbalance as well excessive parathyroid hormone stimulation and neuron 1,25(OH)₂D₃ deficiency[46]. Moreover, 1,25(OH)₂D₃ deficiency leads to neurotoxicity acting on the cingulate cortex and prefrontal cortex. Several other studies [47–50] have indicated that the MCC is an important transit station connecting the anterior and posterior cingulate cortex in the limbic system, which play important roles in working memory, attention and execution, emotional perception, reward and punishment. Therefore, based on previous findings and our study, we suggested that hypocalcaemia may directly or indirectly affect abnormal changes in the spontaneous activity of the MCC in patients with ESHD and may affect cognitive function through changes in the FC of the MCC.

Our research has several limitations. First, this is a cross-sectional study. We did not determine whether the relationship between HD and cognitive impairment changes with dialysis time; longitudinal research may help solve this problem. Second, the size of our research sample may limit the generalisability of our results. In addition, our results do not exclude the effects of the ultrafiltration rate and other dialysis parameters during dialysis or complications in patients with ESRD (including hypertension, hypotension, transient ischemic attack, diabetes, the level of parathyroid gland or thyroid hormone, depression and anxiety). Finally, in patients with ESRD, the types and measurement time (dialysis day and nondialysis day) of neurocognitive scales used in our study may have affected the sensitivity of different brain regions to cognitive function evaluation.

In conclusion, this study found that the ESHD group exhibited multiple abnormal FC regions in three RSNs involved in visual–spatial processing, short-term memory, language, attention and executive function; these findings are consistent with the characteristics of cognitive impairment during the HD process. Overall, our results provide both empirical and complementary evidence indicating that the underlying clinical symptoms of the ESHD group are associated with FC changes. Moreover, these results begin to improve our understanding of the underlying the clinical symptoms of ESHD from the perspective of RSNs.

CKD=Chronic kidney disease

ESRD =end-stage renal disease

HC= healthy control

HD=haemodialysis

ESHD = neurologically asymptomatic patients with ESRD undergoing maintenance hemodialysis

ICA=independent component analysis

RNS= abnormal resting-state networks

FC= functional connectivity

Ethical approval Institutional Review Board approval was obtained from the Guangdong Second Provincial General Hospital Human Research Ethics Committee.

Competing interests The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.

Authors' contributions

project administration—YW,GJ; writing-original draft—YW; MRI data were obtained, writing-review & editing—YW, ML; clinical data were obtained—SM, MC, HS; MRI data were obtained and sorted out by—JL,QL,WX; supervision—XM,ML；visualization—ZZ, YW; data curation—SF, SX； investigation—SF, XM; and software—YC, RL, BX.

Funding This study was funded by grants from the Science and Technology Planning Project of Guangzhou (Grant No.202201010865) and the basic and applied basic research project of high-level uni-versity/Dengfeng Hospital of the municipal university (college) joint funding project of Guang-zhou Basic Research Plan (Grant No. 2023A03J0277,and the National Natural Science Foundation of China (Grant No. 81901729 ).

Informed consent Written informed consent was obtained from all subjects

(patients) in this study.

Availability of data and materials Data and materials from the current study are not publicly available but are available from the corresponding author by reasonable request.

Acknowledgements We would like to thank all the participants involved in this project.

Funding This study was funded by grants from the National Natural Science Foundation of China (Grant No. U1903120 and 81901729 ) and the Science and Technology Planning Project of Guangzhou(Grant No.202201010865),and the basic and applied basic research project of high-level uni-versity/Dengfeng Hospital of the municipal university (college) joint funding project of Guang-zhou Basic Research Plan (Grant No. 2023A03J0277）.

Compliance with ethical standards

Guarantor The scientific guarantor of this publication is Guihua Jiang.

Conflict of interest The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.

Informed consent Written informed consent was obtained from all subjects

(patients) in this study.

Ethical approval Institutional Review Board approval was obtained.

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Table Demographics and Clinical Characteristics of All Participants

Characteristic	ESRD participants on hemodialysis (n = 36)	HC participants (n = 31)	P value
Age (years)	44.33± 10.61	44.13±10.63	0.685
Sex (male/female)	25/11	18/13	0.444
Duration of education (yeas)	10.4± 3.5	9.7± 4.1	0.417
Hemodialysis duration (months)	13.4± 12.0	/	/
MMSE (score)	28.00(27.00,30.00)	29.00(28.00,29.00)	0.106
MoCA (score)	25.00(21.00,28.00)	27.00(26.00,29.00)	<0.001
NCT-A (s)	46.00(32.00,71.00)	45.00(38.00,55.00)	0.001
NCT-B (s)	74.00(54.00,132.00)	74.00(37.00,71.00)	<0.001
DST (score)	46.00(42.00,50.50)	52.00(47.00,55.00)	0.331
SDT (s)	58.00(51.00,69.75)	46.00(40.00,53.00)	0.186
LTT (s)	50.00(44.25,57.00)	46.00(44.00,49.00)	0.110
Hemoglobin (g/dl)	94.00± 18.83	/	/
serum urea nitrogen (mg/dl)	25.24 ± 6.94	/	/
serum creatinine (mg/dl)	1012.23± 316.64	/	/
serum Kalium (mg/dl)	4.70 ± 0.68	/	/
serum Calcium (mg/dl)	2.19 ± 0.23	/	/
Note.—Unless otherwise noted, data are expressed as mean ± SD. MMSE=the Folstein version of the Mini-Mental State Examination, MoCA=the Montreal Cognitive Assessment , NCT-A/B=Test Types A and B, DST =the digit symbol test, SDT= the Serial Dot Test, LTT =the Line Tracing Test, ESRD= End-stage renal disease, HC = healthy control.

No competing interests reported.

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Altered Brain Functional Connectivity of resting-state networks in Neurologically Asymptomatic Patients with End-Stage Renal Disease Undergoing Maintenance Hemodialysis

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