There were three vital findings in our study. First, compared with HCs,GMV in hemodialysis patients were diffusely decreased. Some regional GMV in hemodialysis patients at follow-up were also decreased compared to those patients at baseline. These findings indicate that hemodialysis patients suffered from brain atrophy over time. Second, the MMSE and MoCA scores of hemodialysis patients significantly lower than those in HCs. The MMSE scores in patients at follow-up were also significantly lower than those in patients at baseline. Furthermore, decreased GMV of left caudate nucleus showed significant positive correlation with reduced MMSE scores for the interval time between baseline and follow-up examinations, indicating that brain atrophy was associated with neurocognitive impairment. Third, long hemodialysis duration, increased serum urea, and increased parathyroid hormone were independent risk factors for regional GMV changes in hemodialysis patients by longitudinal analysis.
Our study found diffusely decreased GMV in hemodialysis patients compared with HCs, furthermore, decreased GMV in patients at follow-up compared with patients at baseline. These findings suggested that hemodialysis patients are more likely to suffer from GM atrophy over time. In our study, age, sex, and TIV of all subjects were taken as covariates to exclude the effects of these factors. The reasons for GM atrophy may be: First, hemodialysis patients are more likely to suffer from cerebrovascular diseases28 due to anemia29, oxidative stress30, and inflammation30. Cerebrovascular diseases have been reported as one of the factors to affect regional brain volumes. The occurrence of cerebrovascular diseases results in ischemia and hypoxia of regional brain tissues, which could further lead to brain tissue damage and showed the brain atrophy31. In our study, we found that the more increased parathyroid hormone, the more increased GM atrophy, which supported this reason. The increased parathyroid hormone can cause the secondary hyperparathyroidism and cause the metabolic disorder of calcium and phosphorus. These further increase the cerebrovascular diseases risk28. Second, renal failure leads to abnormal accumulation of organic toxic substances, such as urea, uric acid, guanidine compounds, and creatinine32. Some studies have found that creatinine and guanidine compounds existed in the cerebrospinal fluid of uremia patients29,33. These neurotoxic substances may cause atrophy or death of glial cells and neurons, which further induce brain atrophy15. Our study also found that elevated serum urea can cause more decreased GM volumes, also supporting this finding. Third, a previous study had shown that iron deposition occurred in some brain regions of hemodialysis patients24, which can cause oxidative stress, further damage brain tissues and cause brain atrophy17. Fourth, we found that follow-up duration was a risk factor for reginal GMV decrease in hemodialysis patients. Patients were prone to cerebral ischemic vascular diseases due to the hemodynamic instability and decreased vascular autoregulation during the hemodialysis session34.
Our findings of decreased regional GMV in hemodialysis patients were partially consistent with some cross-sectional studies15,16. However, there were still a few differences between our study and other studies15,16. In Zhang et al.’s study, they also found increased GMV of kidney failure patients mainly located in right extra-nuclear, right caudate, and right thalamus15. Gong et al.35 revealed increased regional GMV of hemodialysis patients in bilateral thalamus16, and bilateral caudate35. There are several possible explanations for these different findings: First, in the Gong et al.’s study35, all the hemodialysis patients were diagnosed with secondary hyperparathyroidism, However, the patients in our study were just hemodialysis patients. Although they had the increased parathyroid hormone levels, they cannot diagnose as the secondary hyperparathyroidism due to the clinical diagnostic criteria. Second, some studies have also suggested that different dialysis modalities have different effects on the incidence and degrees of cerebrovascular diseases, which may also cause different degrees of brain atrophy36. The study by Zhang et al.15 included both hemodialysis and peritoneal dialysis patients. However, the patients in our study were all hemodialysis patients. The comparison of effects of different dialysis modalities on the brain atrophy will need further investigation in the future.
We found that MMSE scores of patients at follow-up were significantly lower compared with patients at baseline, and the volumes changes of left caudate nucleus between two examinations were positively correlated with MMSE scores changes, indicating that brain atrophy was associated with the progressive neurocognitive impairment as the result of hemodialysis therapy. The caudate nucleus is an important part of frontostriatal brain circuit and it plays a role in cognitive function, especially executive function37. Some studies had found that caudate nucleus with discrete lesions caused executive function isolated deficits38. Some studies also demonstrated that the caudate nucleus was involved in complicated processes such as complex sentences and ambiguity resolution39. The MMSE test contained the high proportion of language test items, so it can correctly reflect the cognitive-related impairment caused by the decreased GMV of left caudate nucleus.
There were some limitations in our study. First, although our study explored longitudinal changes in brain volumes of hemodialysis patients, the HCs did not have follow-up examinations. The purpose of our study to observe the longitudinal changes of brain volumes in hemodialysis patients over time, so we mainly compared the brain volumes changes between patients at follow-up and baseline, between patients at baseline and HCs in our study. In order to avoid the effect of follow-up interval time on brain volumes, we also considered age, sex and TIV as covariates in the analysis. Second, the sample size of longitudinal study was relatively small, and a larger sample size is needed to explore the longitudinal brain volumes changes in hemodialysis patients. Third, our longitudinal study only relied on MMSE test, which may be not sensitive enough to mild cognitive impairment. MMSE also has some advantages including low false negative rate, short time consumption and simple operation in evaluation of moderate to severe cognitive impairment. It has been reported that the prevalence of mild to moderate cognitive impairment, severe impairment in patients were about 50% and 37%40. Besides, the MMSE had also been applied in some longitudinal studies to evaluate the cognitive function of some other diseases41. In the future, we will add other neuropsychological tests to evaluate cognitive function of patients.