Enlarged perivascular spaces, neuroinflammation and neurological dysfunction in NMOSD patients.

Background and objectives: Cerebrospinal fluid (CSF) and interstitial fluid exchange along a brain-wide network of perivascular spaces (PVS) termed the 'glymphatic system'. The aquaporin-4 (AQP4) water channels abundantly expressed on astrocytic endfeet play a key role in the CSF circulation in the glymphatic system. Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating autoimmune disease of the central nervous system (CNS) featured with a specific autoantibody directed against AQP4 in most of patients. Anti-AQP4 antibodies are likely resulting in the impairment of the brain glymphatic system and the enlargement of PVS in NMOSD patients. In the current study, we aimed to demonstrate the features of EPVS detected by MRI and its association with the CSF anti-AQP4 antibody titer, CNS inflammatory markers, and disease severity in NMOSD patients. Methods: We conducted a retrospective review of a consecutive cohort of 110 patients with NMOSD who had brain MRI. We assessed the correlation of EPVS with markers of neuroinflammation, blood-brain barrier (BBB) function and severity of neurological dysfunction in patients. We used multivariate logistic regression analysis to determine the independent variables associated with disease severity. Results: The median number of total-EPVS was 15.5 (IQR, 11-24.2) in NMOSD patients. The number of total-EPVS was significantly related to EDSS score after correcting for the effects of age and hypertension (r=0.353, p<0.001). The number of total-EPVS was also significantly associated with the titer of CSF anti-AQP4 antibody, the albumin rate (CSF/serum ratios of albumin), the CSF albumin, IgG and IgA levels. Logistic regression analysis showed that total-EPVS and serum albumin level were two independent factors to predict disease severity in NMOSD patients (OR=1.053, p=0.028; OR=0.858, p=0.009 respectively). Furthermore, ROC analysis achieved AUC of 0.736 (0.640-0.831, p<0.001) for total-EPVS to determine severe NMOSD (EDSS 4.5-9.5). Discussion: In our cohort, we found a relationship between EPVS and neuroinflammation and BBB function in NMOSD. Moreover, EPVS might independently predict neurological dysfunction in patients with NMOSD.

Human Umbilical Cord Mesenchymal Stem Cells to Treat Neuromyelitis Optica Spectrum Disorder (hUC-MSC-NMOSD): A Study Protocol for a Prospective, Multicenter, Randomized, Placebo-Controlled Clinical Trial.

Background: Neuromyelitis Optica spectrum disorder (NMOSD) is severe relapsing and disabling autoimmune disease of the central nervous system. Its optimal first-line treatment to reduce relapse rate and ameliorate neurological disability remains unclear. We will conduct a prospective, multicenter, randomized, placebo-controlled clinical trial to study the safety and effectiveness of human umbilical cord mesenchymal stem cells (hUC-MSCs) in treating NMOSD. Methods: The trial is planned to recruit 430 AQP4-IgG seropositive NMOSD patients. It consists of three consecutive stages. The first stage will be carried out in the leading center only and aims to evaluate the safety of hUC-MSCs. Patients will be treated with three different doses of hUC-MSCs: 1, 2, or 5 × 106 MSC/kg·weight for the low-, medium-, and high-dose group, respectively. The second and third stages will be carried out in six centers. The second stage aims to find the optimal dosage. Patients will be 1:1:1:1 randomized into the low-, medium-, high-dose group and the controlled group. The third stage aims to evaluate the effectiveness. Patients will be 1:1 randomized into the optimal dose and the controlled group. The primary endpoint is the first recurrent time and secondary endpoints are the recurrent times, EDSS scores, MRI lesion numbers, OSIS scores, Hauser walking index, and SF-36 scores. Endpoint events and side effects will be evaluated every 3 months for 2 years. Discussion: Although hUC-MSC has shown promising treatment effects of NMOSD in preclinical studies, there is still a lack of well-designed clinical trials to evaluate the safety and effectiveness of hUC-MSC among NMOSD patients. As far as we know, this trial will be the first one to systematically demonstrate the clinical safety and efficacy of hUC-MSC in treating NMOSD and might be able to determine the optimal dose of hUC-MSC for NMOSD patients. Trial registration: The study was registered with the Chinese Clinical Trial Registry (CHICTR.org.cn) on 2 March 2016 (registration No. ChiCTR-INR-16008037), and the revised trial protocol (Protocol version 1.2.1) was released on 16 March 2020.

Serum albumin level is associated with the severity of neurological dysfunction of NMOSD patients.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system. Serum albumin (SA) has antioxidant, immunomodulatory and anti-inflammatory effects. However, the roles of SA in NMOSD have not been studied. The current study aimed to clarify the association of SA with disease severity and prognosis in NMOSD patients. METHODS: Serum levels of albumin were measured by Bromcresol Green method. Serum level measurements of interleukins were performed using enzyme-linked immunoassay (ELISA) method. RESULTS: Of all the 130 NMOSD patients, 96 patients were in the acute phase while 34 patients were in the remission phase of disease at the time of sampling. SA concentration was significantly correlated with EDSS score in patients in the acute phase but not in remission phase (r = - 0.388, p < 0.001 and r = - 0.467, p = 0.809, respectively). Logistic analysis revealed that SA was the only significant factor to predict severe NMOSD (EDSS 8.0-9.5) OR = 0.698, 95%CI 0.563-0.865, p = 0.001) after adjustment of other confounding factors. Furthermore, SA was negatively correlated with the serum level of IL-33 (r = -0.438, p = 0.016) in the acute phase of NMOSD patients. CONCLUSION: The current study found that low level of SA was an independent indicator of more severe neurological deficit in patients in acute phase of NMOSD. SA concentration was negatively correlated with the serum level of IL-33 in the acute phase of the disease, which implies that SA might participate in the immunopathology of NMOSD partly through its interaction with IL-33.

Th2 axis-related cytokines in patients with neuromyelitis optica spectrum disorders.

AIMS: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system. Increasing evidence indicates that NMOSD is a Th2- and Th17-dominant disease. IL-25, IL-31, and IL-33 are three newly found Th2-related cytokines, and their roles in the pathogenesis of NMOSD have not been studied. This study aimed to measure the serum levels of IL-25, IL-31, and IL-33 in patients with NMOSD and evaluate their clinical implications. METHODS: Serum was collected from patients with NMOSD (n = 48) and healthy controls (HC, n = 28). Serum level measurements of IL-25, IL-31, IL-33, IL-17A, and IL-6 were performed using enzyme-linked immunoassay (ELISA) method. RESULTS: The serum levels of IL-25, IL-31, and IL-33 were significantly higher in patients with NMOSD as compared to HC. The serum level of IL-31 was significantly correlated with IL-17A (r = 0.382,P = 0.009) in patients with NMOSD; the latter is a critical cytokine in the pathogenesis of NMOSD. The serum level of IL-33 was higher in patients with characteristic brain lesions than patients without (307 pg/mL vs 166 pg/mL, P = 0.028). Furthermore, the serum level of IL-33 in the acute phase of the disease was positively correlated with annualized relapse rate (r = 0.364, P = 0.04). CONCLUSION: We found higher serum levels of IL-25, IL-31, and IL-33 in patient with NMOSD as compared to healthy controls. The serum level of IL-33 during acute phase was associated with more past attacks in patients with NMOSD.

Study on hippocampal volume with quantitative 3T magnetic resonance imaging in Chinese patients with epilepsy.

BACKGROUND: It was still rare for the quantitative magnetic resonance imaging (MRI) research of regional changes in hippocampus sclerosis (HS) in Chinese patients with epilepsy. This study aimed to study the hippocampal volumes (HVs) with quantitative MRI measurement in Chinese patients with epilepsy. METHODS: Forty-six Chinese patients with epilepsy (intractable epilepsy (IE), n = 21; non-intractable epilepsy (NIE), n = 25) and 25 normal controls were collected between July 2007 and March 2008. All of the subjects underwent a 3T high-resolution MRI with oblique coronal thin sections oriented perpendicular to the hippocampal long axis. Hippocampal structures were assessed by visual detection, and HVs were quantitatively studied with a Picture Archiving and Communication System (PACS). RESULTS: Our study suggested that there was no significant difference in gender (P > 0.05) while the right hippocampal head volume (HHV), hippocampal body volume (HBV), and the whole hippocampal volume (HCV) were greater than the left one (P < 0.05), but no significant difference was found in bilateral hippocampal tail volume (HTV) (P > 0.05) in normal controls. That unilateral/diffuse (64%/21%) and bilateral/focal (86%/20%) hippocampal atrophy (HA) were significant in IE and NIE patients, respectively. Anterior hippocampus, especially HHV (26% in IE and 20% in NIE) and HBV (29% in IE and 12% in NIE), had more significant atrophy than the HTV (5% in IE and 0% in NIE) in patients with epilepsy. CONCLUSION: By assessing the volumes of the regional hippocampus with 3T MRI, we could better define the range and distribution of HS, since regional or subtle changes in HVs could be detected earlier with 3T MRI.