Iron promotes α-synuclein aggregation and transmission by inhibiting TFEB-mediated autophagosome-lysosome fusion.

Recent studies have strongly shown that cell-to-cell transmission of neuropathogenic proteins is a common mechanism for the development of neurodegenerative diseases. However, the underlying cause is complex and little is known. Although distinct processes are involved in the pathogenesis of various diseases, they all share the common feature of iron accumulation, an attribute that is particularly prominent in synucleinopathies. However, whether iron is a cofactor in facilitating the spread of α-synuclein remains unclear. Here, we constructed a cell-to-cell transmission model of α-synuclein using SN4741 cell line based on adenovirus vectors. Cells were treated with FeCl2, and α-synuclein aggregation and transmission were then evaluated. In addition, the possible mechanisms were investigated through gene knockdown or over-expression. Our results demonstrated that iron promoted α-synuclein aggregation and transmission by inhibiting autophagosome-lysosome fusion. Furthermore, iron decreased the expression of nuclear transcription factor EB (TFEB), a master transcriptional regulator of autophagosome-lysosome fusion, and inhibited its nuclear translocation through activating AKT/mTORC1 signaling. After silencing TFEB, ratios of α-synuclein aggregation and transmission were not significantly altered by the presence of iron; on the other hand, when TFEB was over-expressed, the transmission of α-synuclein induced by iron was obviously reversed; suggesting the mechanism by which iron promotes α-synuclein transmission may be mediated by TFEB. Taken together, our data reveal a previously unknown relationship between iron and α-synuclein, and identify TFEB as not only a potential target for preventing α-synuclein transmission, but also a critical factor for iron-induced α-synuclein aggregation and transmission. Indeed, this newly discovered role of iron and TFEB in synucleinopathies may provide novel targets for developing therapeutic strategies to prevent α-synuclein transmission in Parkinson's disease.

Association of IGF1 gene polymorphism with Parkinson's disease in a Han Chinese population.

BACKGROUND: Accumulating evidence suggests that insulin-like growth factor 1 (IGF1) plays an important role in Parkinson's disease (PD) pathogenesis. However, it is not clear whether IGF1 polymorphism contributes to PD risk. METHODS: We performed a case-control study in a Han Chinese population that included 512 sporadic PD cases and 535 matched controls. All participants were genotyped for rs972936 using the Sequenom MassARRAY iPLEX platform. Serum IGF1 levels of 61 de novo, drug-naïve PD patients and 55 age- and sex-matched controls were also measured using an enzyme-linked immunosorbent assay. RESULTS: Genotype frequency of rs972936-CC was significantly associated with an increased PD risk (p = 0.009), especially in males (p = 0.024) and late-onset patients (p = 0.013). Serum IGF1 levels were significantly increased in de novo, drug-naïve PD patients compared to controls (p = 0.036), although they were not correlated with motor dysfunction in PD patients (p = 0.220). CONCLUSIONS: The present study shows that rs972936 polymorphism may increase susceptibility to PD, especially in males and late-onset patients. Furthermore, high serum IGF1 levels may be a potential diagnostic biomarker for PD in the Han Chinese population, although they do not correlate with a more severe motor dysfunction.

Association of DNMT3b gene variants with sporadic Parkinson's disease in a Chinese Han population.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Epigenetic modifications, specifically DNA methylation, have been implicated in the development of this disease. Genetic variants of DNA methyltransferase 3b (DNMT3b), one of the most important DNA methyltransferases, were shown to be associated with PD in a Brazilian population. However, it is unclear whether genetic variants of DNMT3b increase the risk of PD in the Chinese Han people. The present study aimed to investigate the association of the DNMT3b variants rs2424913, rs998382 and rs2424932 with PD in a Chinese Han population. METHODS: We studied 487 Chinese Han patients with sporadic PD and 485 healthy age-, sex- and ethnicity-matched controls. DNA was extracted from peripheral blood leukocytes and the individual genotypes were determined using the SNaPshot method. RESULTS: We found that the rs2424932 and rs998382 variants were significantly associated with an increased risk of PD compared to the controls [rs2424932: odds ratio (OR) = 1.632, 95% confidence interval (CI) = 1.108-2.406, p = 0.013; rs998382: OR = 1.612, 95% CI = 1.103-2.382, p = 0.014]. Subgroup analysis suggested that female patients carrying the rs2424932 or rs998382 variants were more likely to develop PD than female controls (rs2424932: OR = 3.863, 95% CI = 2.004-7.445, p < 0.001; rs998382: OR = 3.679, 95% CI = 1.943-6.964, p < 0.001). Haplotype analysis indicated that the three variants comprised one block and that the Trs2424913 -Crs998382 -A rs2424932 haplotype was correlated with an increased risk of PD (p = 0.0046), especially for Chinese Han females (p < 0.0001). CONCLUSIONS: The results of the present study strongly suggest that DNMT3b variants are associated with PD in the Chinese Han people, especially females.

[Clinical analysis of subpopulation of peripheral T and B lymphocytes in Chinese Parkinson's disease patients].

OBJECTIVE: To explore the variations of subpopulation of peripheral lymphocytes in Parkinson's disease (PD) and locate its potential biomarkers for clinical evaluations. METHODS: The methods of direct immunostaining and flow cytometry were employed to test the percentages of CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), CD19(+) lymphocytes in blood samples of 77 PD patients and 82 healthy controls. And the percentages of CD3(+)CD4(+) and CD3(+)CD8(+) lymphocytes and the parameters of patients and health controls were analyzed. RESULTS: Compared to controls, the percentages of CD3(+), CD3(+)CD4(+) lymphocytes significantly decreased in PD patients ((62 ± 12)% vs (66 ± 9) %, P = 0.04; (35 ± 9) % vs (38 ± 7) %, P = 0.02), especially in males ((66 ± 9)% vs (61 ± 13) %, P = 0.02; (38 ± 10) % vs (33 ± 9) %, P = 0.01)) . Furthermore, the percentage of CD3(+) lymphocytes had a positive correlation with the course of PD in male patients (r = 0.329, P = 0.013, ß = 1.423). And a negative correlation existed between the percentage of CD3(+)CD4(+) lymphocytes and the course of PD and there was a positive correlation with NMSS scale in female PD patients (r = -0.309, P = 0.045, ß = -0.354; r = 0.370, P = 0.020, ß = 0.486). CONCLUSION: The variants in subpopulation of peripheral lymphocytes in PD patients may serve as a potential biomarker for diagnosing PD and predicting its clinical course.

Apolipoprotein E gene polymorphism in a Chinese population with vascular dementia: a meta-analysis.

BACKGROUND: Apolipoprotein E (ApoE) gene has been reported to be associated with the development of vascular dementia (VD); however, results from observational studies are conflicting. METHODS: We surveyed all case-control studies on ApoE gene and VD patients with comprehensive search and review of the references. A meta-analysis was performed to demonstrate the association of ApoE gene with VD by random effects models. The association was assessed by odds ratio (OR) with 95% confidence intervals (CI). RESULTS: A total of 18 studies including 935 patients and 1,686 controls were eligible and abstracted. ApoE ε3/4 and ε4/4 genotype, as well as ε4 allele (OR = 1.95, 95% CI: 1.52-2.49; OR = 3.47, 95% CI: 1.85-6.51 and OR = 2.12, 95% CI: 1.64-2.74, respectively) were associated with an increased risk of VD, while ApoE ε3/3 genotype and ε3 allele (OR = 0.65, 95% CI: 0.53-0.79 and OR = 0.65, 95% CI: 0.53-0.80, respectively) trended to protect against VD. There was no significant difference in ApoE ε2 allele frequency, ε2/2, ε2/3 or ε2/4 genotype between VD and controls (OR = 0.85, 95% CI: 0.61-1.17; OR = 0.89, 95% CI: 0.39-2.01; OR = 0.82, 95% CI: 0.61-1.09 and OR = 1.03, 95% CI: 0.57-1.84, respectively). CONCLUSIONS: Our results support a genetic association between ApoE polymorphism and VD in the Chinese population.

Association of GLP-1 receptor gene polymorphisms with sporadic Parkinson's disease in Chinese Han population.

The Glucagon Like Peptide 1 Receptor (GLP1R) plays a critical role in selective death of dopaminergic neurons and development of Parkinson's disease (PD). However, little is known about genetic associations of GLP1R gene polymorphisms with PD susceptibility. Therefore, this study aimed to verify whether GLP1R polymorphisms contribute to PD risk in a Chinese Han population. We recruited 518 individuals comprising 259 sporadic PD patients and 259 healthy controls. All of the participants were genotyped for two possibly functional polymorphisms located in GLP1R (rs3765467 and rs6923761) using the Sequenom MassARRAY platform. The frequency of the rs3765467 GG genotype was significantly higher in the PD group compared with that in the control group (OR = 1.444, 95 % CI: 1.015-2.055, p =  0.041). Subgroup analysis revealed that male patients and late-onset patients with the rs3765467 GG genotype suffered an increased risk of PD compared with healthy controls (p =  0.021 and p =  0.012, respectively). However, the genotype and allele frequencies for rs6923761 were not significantly different between PD and healthy subjects. Our results indicate that the GLP1R rs3765467 GG genotype is a potential risk factor for PD, especially for male and late-onset PD patients in the Chinese Han population.

Astrocytic glutamatergic transporters are involved in Aß-induced synaptic dysfunction.

In Alzheimer's disease (AD), dementia severity correlates most strongly with decreased synapse density in the hippocampus and cerebral cortex. Although studies in rodents have established that hippocampal long-term potentiation (LTP) is inhibited by soluble oligomers of beta-amyloid (Aß), the synaptic mechanisms remain unclear. Here, field excitatory postsynaptic potentials (fEPSP) recordings were made in the CA1 region of mouse hippocampal slices. The medium of APP-expressing CHO cells, which contain soluble forms of Aß including small oligomers, inhibited LTP and facilitated long-term depression (LTD), thus making the LTP/LTD curve shift toward the right. This phenomenon could be mimicked by the non-selective glutamate transporter inhibitor, DL-TBOA. More specifically, the Aß impaired LTP and facilitated LTD were occluded by the selective astrocytic glutamate transporter inhibitors, TFB-TBOA. In cultured astrocytes, the Aß oligomers also decrease astrocytic glutamate transporters (EAAT1, EAAT2) expression. We conclude that soluble Aß oligomers decrease the activation of astrocytic glutamate transporters, thereby impairing synaptic plasticity.

MicroRNA expressing profiles in A53T mutant alpha-synuclein transgenic mice and Parkinsonian.

α-synuclein gene mutations can cause α-synuclein protein aggregation in the midbrain of Parkinson's disease (PD) patients. MicroRNAs (miRNAs) play a key role in the metabolism of α-synuclein but the mechanism involved in synucleinopathy remains unclear. In this study, we investigated the miRNA profiles in A53T-α-synuclein transgenic mice and analyzed the candidate miRNAs in the cerebrospinal fluid (CSF) of PD patients. The 12-month A53T-transgenic mouse displayed hyperactive movement and anxiolytic-like behaviors with α-synuclein aggregation in midbrain. A total of 317,759 total and 289,207 unique small RNA sequences in the midbrain of mice were identified by high-throughput deep sequencing. We found 644 miRNAs were significantly changed in the transgenic mice. Based on the conserved characteristic of miRNAs, we selected 11 candidates from the 40 remarkably expressed miRNAs and explored their expression in 44 CSF samples collected from PD patients. The results revealed that 11 microRNAs were differently expressed in CSF, emphatically as miR-144-5p, miR-200a-3p and miR-542-3p, which were dramatically up-regulated in both A53T-transgenic mice and PD patients, and had a helpful accuracy for the PD prediction. The ordered logistic regression analysis showed that the severity of PD has strong correlation with an up-expression of miR-144-5p, miR-200a-3p and miR-542-3p in CSF. Taken together, our data suggested that miRNAs in CSF, such as miR-144-5p, miR-200a-3p and miR-542-3p, may be useful to the PD diagnosis as potential biomarkers.

Peripheral Lymphocyte Subsets as a Marker of Parkinson's Disease in a Chinese Population.

In this study, we conducted a clinical analysis of lymphocyte subtypes in 268 patients with Parkinson's disease (PD) to assess their clinical impact as a potential marker of advanced PD in Chinese patients. The participants comprised 268 sporadic PD patients and 268 healthy controls. The numbers of natural killer (NK) cells and CD3+, CD3+CD4+, CD3+CD8+, and CD19+ lymphocytes from peripheral blood were determined by immunostaining and flow cytometric analysis and the percentages of these CD+ T cells were calculated. The ratio of regulatory T (Treg)/helper T 17 (Th17) lymphocytes from 64 PD patients and 46 controls was determined by flow cytometric analysis. The results showed that the percentage of NK cells was higher in advanced PD patients than in controls (22.92% ± 10.08% versus 19.76% ± 10.09%, P = 0.006), while CD3+ T cells are decreased (62.93% ± 9.27% versus 65.75% ± 9.13%, P = 0.005). The percentage of CD19+ B cells in male patients was lower (P = 0.021) than in female patients, whereas NK cells were increased (P < 0.0001). The scores on the Unified Parkinson's Disease Rating Scale (UPDRS) and the Non-Motor Symptoms Scale in late-onset PD patients were significantly higher than those in early-onset patients (P = 0.024 and P = 0.007, respectively). The percentage of CD19+ B cells in patients with UPDRS scores >24 was lower than in those with scores <24 (10.17% ± 4.19% versus 12.22% ± 5.39%, P = 0.009). In addition, the Treg/Th17 ratio in female patients was higher than that in female controls (13.88 ± 6.32 versus 9.94 ± 4.06, P = 0.042). These results suggest that the percentages of NK cells, CD3+ T cells, and CD19+ B cells along with the Treg/Th17 ratio in peripheral blood may be used to predict the risk of PD in Chinese individuals and provide fresh avenues for novel diagnostic biomarkers and therapeutic designs.

Enhancing Beta-Catenin Activity via GSK3beta Inhibition Protects PC12 Cells against Rotenone Toxicity through Nurr1 Induction.

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic (DA) neurons in the substantial nigra pars compacta. Increasing evidence showed that Wnt/ß-catenin pathway and the orphan nuclear receptor Nurr1 play crucial roles in the survival and functional maintenance of DA neurons in the midbrain and GSK-3ß antagonists LiCl and SB216763 were used to activate Wnt/ß-catenin pathway experimentally. However, the detail mechanism underlying the neuroprotection against apoptosis on DA neuron is still unclear and the interaction between Wnt/ß-catenin and Nurr1 remains undisclosed. In this study, using cell biological assay we investigated the function of Wnt/ß-catenin and its crosstalk with Nurr1 on the course of PC12 cell degeneration in vitro. Our data showed that PC12 cell viability was inhibited by rotenone, but attenuated by GSK-3ß antagonists LiCl or SB216763. The activity of Wnt/ß-catenin pathway was deregulated on exposure of rotenone in a concentration-dependent manner. After the interference of ß-catenin with siRNA, LiCl or SB216763 failed to protect PC12 cells from apoptosis by the rotenone toxicity. Our data confirmed that Wnt/ß-catenin signaling activated by LiCl or SB216763 enhanced Nurr1 expression to 2.75 ± 0.55 and 4.06 ± 0.41 folds respectively compared with control detected by real-time PCR and the interaction of ß-catenin with Nurr1 was identified by co-immunoprecipitate analysis. In conclusion, the data suggested that Wnt/ß-catenin and Nurr1 are crucial factors in the survival of DA neurons, and the activation of Wnt/ß-catenin pathway exerts protective effects on DA neurons partly by mean of a co-active pattern with Nurr1. This finding may shed a light on the potential treatment of Parkinson disease.

The biomarkers of immune dysregulation and inflammation response in Parkinson disease.

Parkinson's disease (PD) is referring to the multi-systemic α-synucleinopathy with Lewy bodies deposited in midbrain. In ageing, the environmental and genetic factors work together and overactive major histocompatibility complex pathway to regulate immune reactions in central nerve system which resulting in neural degeneration, especially in dopaminergic neurons. As a series of biomarkers, the human leukocyte antigen genes with its related proteomics play cortical roles on the antigen presentation of major histocompatibility complex molecules to stimulate the differentiation of T lymphocytes and i-proteasome activities under their immune response to the PD-related environmental alteration and genetic variation. Furthermore, dopaminergic drugs change the biological characteristic of T lymphatic cells, affect the α-synuclein presentation pathway, and inhibit T lymphatic cells to release cytotoxicity in PD development. Taking together, the serum inflammatory factors and blood T cells are involved in the immune dysregulation of PD and inspected as the potential clinic biomarkers for PD prediction.

Association of DYRK1A polymorphisms with sporadic Parkinson's disease in Chinese Han population.

α-Synuclein plays important roles in the development of Parkinson's disease (PD) pathologies. The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has a wide range of phosphorylation targets including α-synuclein. Posphorylated α-synuclein is more neurotoxic to dopamine (DA) neurons, but little is known about the genetic variation of DYRK1A in patients with PD. The present investigation aimed to explore the possible association of DYRK1A gene with PD in Chinese Han population. A total of 268 PD patients and 268 healthy-matched individuals in Chinese Han population were enrolled. Genotyping of rs8126696, rs2835740, and rs1137600 single nucleotide polymorphisms (SNPs) were performed on the Sequenom MassARRAY platform. Results revealed TT genotype in SNP rs8126696 denoted a significant difference between PD patients and controls (OR=1.710, 95% CI=1.116-2.619, P=0.014), and the frequency of rs8126696 TT genotype was significantly higher in male PD patients than male controls (OR=2.012, 95%CI: 1.125-3.599, p=0.018). The genotypes in rs2835740 and rs1137600 showed no significant difference between PD patients and controls. These results suggest that TT genotype derived from SNP rs8126696 of DYRK1A gene is a possible risk factor for sporadic PD, especially for males in this Chinese Han population.

Association Analysis of Proteasome Subunits and Transporter Associated with Antigen Processing on Chinese Patients with Parkinson's Disease.

BACKGROUND: Proteasome subunits (PSMB) and transporter associated with antigen processing (TAP) loci are located in the human leukocyte antigen (HLA) Class II region play important roles in immune response and protein degradation in neurodegenerative diseases. This study aimed to explore the association between single nucleotide polymorphisms (SNPs) of PSMB and TAP and Parkinson's disease (PD). METHODS: A case-control study was conducted by genotyping SNPs in PSMB8, PSMB9, TAP1, and TAP2 genes in the Chinese population. Subjects included 542 sporadic patients with PD and 674 healthy controls. Nine identified SNPs in PSMB8, PSMB9, TAP1, and TAP2 were genotyped through SNaPshot testing. RESULTS: The stratified analysis of rs17587 was specially performed on gender. Data revealed that female patients carry a higher frequency of rs17587-G/G versus (A/A + G/A) compared with controls. But there was no significant difference with respect to the genotypic frequencies of the SNPs in PSMB8, TAP1, and TAP2 loci in PD patients. CONCLUSION: Chinese females carrying the rs17587-G/G genotype in PSMB9 may increase a higher risk for PD, but no linkage was found between other SNPs in HLA Class II region and PD.

Association analysis of HLA-DRA in Chinese patients with sporadic Parkinson's disease.

Our aim is to explore the linkage between single nucleotide polymorphisms (SNPs) in human leukocyte antigen (HLA)-DRA and Parkinson's disease (PD). 542 sporadic PD patients and 674 healthy controls were recruited to investigate this association in the Chinese population by the screening of 15 SNPs in HLA-DRA, and the association of rs3129882 was further re-evaluated by performing meta-analysis and meta-regression analysis. No SNPs in HLA-DRA were significantly associated with PD in the Chinese patients. Although the rs3129882 allele-G frequency in the Caucasian population was lower than that in Chinese population, meta-analysis showed no association of rs3129882 allele-G with PD in the Chinese or Caucasian population. In consideration of the heterogeneity (I(2)=78.6%, Q=66.33, p<0.000), subgroup analysis was performed, revealing a significant association between rs3129882 and PD in the Caucasian patients from the genome-wide association studies (OR=1.22, 95% CI: 1.16, 1.27); however, this association was not consistently observed in the studies performed using other DNA sequencing techniques. Meta-regression analysis, which accounted for 58.3% of the heterogeneity, revealed that the impact of the sequencing technique used was significant (p=0.027) compared with ethnicity. Regression analysis of the Caucasian population further showed that the sequencing technique used contributed to 71.2% of the heterogeneity (p=0.033). Our data support the absence of a linkage between the risk loci in HLA-DRA and PD in Chinese patients. The different DNA sequencing techniques used in PD studies may largely account for the controversial conclusions concerning rs3129882.

Dopamine Agonists Exert Nurr1-inducing Effect in Peripheral Blood Mononuclear Cells of Patients with Parkinson's Disease.

BACKGROUND: Nurr1 plays an essential role in the development, survival, and function maintenance of midbrain dopaminergic (DA) neurons, and it is a potential target for Parkinson's disease (PD). Nurr1 mRNA can be detected in peripheral blood mononuclear cells (PBMCs), but whether there is any association of altered Nurr1 expression in PBMC with the disease and DA drug treatments remains elusive. This study aimed to measure the Nurr1 mRNA level in PBMC and evaluate the effect of Nurr1 expression by DA agents in vivo and in vitro. METHODS: The mRNA levels of Nurr1 in PBMC of four subgroups of 362 PD patients and 193 healthy controls (HCs) using real-time polymerase chain reaction were measured. The nonparametric Mann-Whitney U-test and Kruskal-Wallis test were performed to evaluate the differences between PD and HC, as well as the subgroups of PD. Multivariate linear regression analysis was used to evaluate the independent association of Nurr1 expression with Hoehn and Yahr scale, age, and drug treatments. Besides, the Nurr1 expression in cultured PBMC was measured to determine whether DA agonist pramipexole affects its mRNA level. RESULTS: The relative Nurr1 mRNA levels in DA agonists treated subgroup were significant higher than those in recent-onset cases without any anti-PD treatments (de novo) (P < 0.001) and HC groups (P < 0.010), respectively. Furthermore, the increase in Nurr1 mRNA expression was seen in DA agonist and L-dopa group. Multivariate linear regression showed DA agonists, L-dopa, and DA agonists were independent predictors correlated with Nurr1 mRNA expression level in PBMC. In vitro, in the cultured PBMC treated with 10 µmol/L pramipexole, the Nurr1 mRNA levels were significantly increased by 99.61%, 71.75%, 73.16% in 2, 4, and 8 h, respectively (P < 0.001). CONCLUSIONS: DA agonists can induce Nurr1 expression in PBMC, and such effect may contribute to DA agonists-mediated neuroprotection on DA neurons.

Cerebrospinal fluid τ protein in differential diagnosis of Alzheimer's disease and vascular dementia in Chinese population: a meta-analysis.

BACKGROUND: To assess whether biomarker τ protein could differentiate between Alzheimer's disease (AD) and vascular dementia (VaD). METHODS: We conducted a comprehensive search to identify studies on τ protein, patients with AD, and patients with VaD. Cerebrospinal fluid (CSF) τ protein levels were compared to discriminate among patients with AD, healthy controls, and patients with VaD by a meta-analysis. RESULTS: Patients with AD exhibit significantly higher CSF τ protein levels than healthy controls or patients with VaD in the Chinese population. CONCLUSION: Our findings suggested that CSF τ protein levels were found to be significantly associated with AD in the Chinese population. Measurement of τ protein could help in attenuating the strict distinction between AD and VaD.

Serum uric acid levels in patients with multiple sclerosis: a meta-analysis.

BACKGROUND: Serum uric acid (UA), a natural scavenger of peroxynitrite, has been found to be of lower levels in patients with multiple sclerosis (MS) in some recent preliminary studies. OBJECTIVE: To evaluate the correlation between serum UA levels and several clinical parameters of MS reliably. METHODS: We surveyed studies on the serum UA levels and MS patients with comprehensive search and review of the references. A meta-analysis was performed to demonstrate the potential association between serum UA levels in MS patients and their clinical characteristics by random effects models. Results The serum UA levels were lower in patients with MS than in healthy controls (standardized mean difference (SMD) = -0·68; 95% confidence interval (CI): -0·82 to -0·55), as well as in other inflammatory neurological diseases (OINDs) (SMD = -0·45; 95% CI: -0·60 to -0·30). Similarly, the serum UA levels decreased in MS patients with clinical activity when compared to MS with clinical inactivity (SMD = -0·29; 95% CI: -0·48 to -0·10), as well as in relapsing-remitting MS (RRMS) patients with relapse in comparison to RRMS patients with remission (SMD = 0·64; 95% CI: 0·39 to 0·89). However, the results suggested that serum UA levels did not correlate with higher (or lower) expanded disability status scale (SMD = -0·09; 95% CI: -0·10 to 0·27) and magnetic resonance imaging (MRI) activity (SMD = -0·14; 95% CI: -0·13 to 0·41). In the subtypes of MS group, there were significant differences in serum UA levels between secondary progressive MS (SPMS) and RRMS (SMD = -0·34; 95% CI: 0·16 to 0·52), or primary progressive MS (PPMS) (SMD = -0·58; 95% CI: -0·89 to -0·27), but no significant difference between RRMS and PPMS (SMD = -0·18; 95% CI: -0·44 to 0·08). CONCLUSIONS: Our study suggests that UA is relevant to MS. Future research is needed to determine whether the administration of UA levels by inosine might be considered as a novel treatment strategy for MS.