Correlation of GABA+ levels in the medial prefrontal cortex and circulating follicular helper T cells in neuromyelitis optica spectrum disorder patients with cognitive impairment.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) associated with cognitive impairment (CI) is acknowledged. However, the underlying pathogenesis and involvement of the immune system remain unclear. OBJECTIVES: This study aimed to investigate the alterations in immune cells, cytokines, and GABA+ levels in NMOSD patients with cognitive deficits. METHODS: Thirty-eight NMOSD patients and 38 healthy controls (HCs) were included. NMOSD patients were stratified as NMOSD-CI and NMOSD-CP groups. The difference in cognitive functions, Tfh and cytokines, and GABA+ levels were assessed, and their correlations were calculated. RESULTS: NMOSD-CI patients showed worse performance on all cognitive tests, and the percentage of circulating follicular helper T cells (cTfh) was significantly elevated. The frequency of cTfh was positively and negatively correlated with Stroop-A and AVLT long-delayed scores, respectively. IL-21 was remarkably higher in NMOSD-CI and NMOSD-CP. The level of GABA+ in medial prefrontal cortex (mPFC) was significantly decreased in NMOSD-CI and was proved positively and negatively correlated with Symbol Digit Modalities Test and the frequency of circulating Tfh cells, respectively. CONCLUSION: In NMOSD-CI patients, all cognitive domains were impacted, , while GABA+ levels in mPFC were decreased. GABA+ levels in NMOSD-CI were negatively correlated with the frequency of cTfh, suggesting the underlying coupling mechanism between immune responses and neurotransmitter metabolism in CI in NMOSD patients.

Reflections from a NMOSD case with serum AQP4-Ab negativity but CSF positivity: narrative review of how to interpret AQP4-Ab test results.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease of the central nervous system. The differential diagnosis of NMOSD in clinical practice is often challenging despite the phenotypical and serological characteristics of the disease. The discovery of anti-aquaporin-4 antibody (AQP4-Ab) enabled clinicians to diagnose NMOSD relatively earlier and more easily, as the AQP4-Ab can mediate the pathogenesis of NMOSD. Testing for AQP4-Ab in the serum of patients can play a crucial role in the diagnosis of NMOSD. Three-quarters of patients with NMOSD have serum immunoglobulin-G (IgG) autoantibodies to the AQP4 channel. Nevertheless, the test results for AQP4-Ab can be affected by several factors, such as assay methods, clinical stages, the types of treatment, sample status, and pre-test error, among others. In patients with seronegative NMOSD, it would be better to test serum and CSF AQP4-Ab together to improve the positive rate, especially when NMOSD is highly suspected. This article aims to update readers on the recent developments in AQP4-Ab testing and how to interpret the results of the AQP4-Ab test.

Altered functional connectivity associated with cognitive impairment in neuromyelitis optica spectrum disorder.

BACKGROUND: Cognitive impairment is one of the common symptoms in patients with neuromyelitis optica spectrum disorder (NMOSD). However, the underlying mechanism remains unclear. Resting-state functional magnetic resonance imaging (rs-fMRI) offers the opportunity to reveal the patterns of brain activity in patients with different cognitive states. Accordingly, this study investigated functional connectivity (FC) abnormalities within and between the main cognitive networks in cognitively impaired (CI) patients with NMOSD and their correlations with cognitive performance. METHODS: Thirty-four patients with NMOSD and 39 healthy controls (HC) were included. Neuropsychological evaluations and rs-fMRI scanning were performed. Patients were classified as CI (n = 16) or cognitively preserved (CP; n = 18) according to neuropsychological evaluations. Seven components representing six main cognitive networks were selected by group independent component analysis. The differences in inter- and intranetwork FC among CI, CP, and HC groups were assessed. The correlation between FC values and neuropsychological data in NMOSD was calculated. RESULTS: The CI group showed decreased intranetwork connectivity in the posterior default mode network (pDMN) compared with the HC group (P < 0.05, GRF corrected), and decreased internetwork connectivity between the salience network (SN) and pDMN, and between the SN and right frontoparietal network (rFPN) compared with CP and HC groups. The altered FC values were significantly correlated with cognitive performance in the whole NMOSD group. CONCLUSION: The disconnection within the pDMN and between the SN and pDMN or rFPN might suggest the neural substrates underlying cognitive impairment in NMOSD.

Reduced GABA levels in the medial prefrontal cortex are associated with cognitive impairment in patients with NMOSD.

BACKGROUND: Cognitive impairment is a symptom present in part of patients with neuromyelitis optica spectrum disorder (NMOSD) and its pathophysiology is unknown. Dysfunction of the GABAergic/glutamatergic pathways involving inhibitory and excitatory neurotransmitters have been implicated in several neurological disorders. This study aimed to investigate the changes in inhibitory gamma-aminobutyric acid (GABA) and excitatory glutamate and glutamine (Glx) neurotransmitter levels and their correlations with cognitive functions in patients with NMOSD. METHODS: A total of 29 patients with NMOSD and 28 sex-, age-, and education-matched healthy controls (HCs) were included in the study. All participants underwent clinical and cognitive assessments and proton magnetic resonance spectroscopy scanning. Meshcher-Garwood point-resolved spectroscopy was used to measure GABA and Glx levels in the medial prefrontal cortex (mPFC) and left thalamus. Total creatine (tCr) was applied as an internal reference. The GABA and Glx levels in the patient group were compared with those in HCs and correlated with cognitive scores and clinical variables. RESULTS: Patients with NMOSD showed lower GABA+/tCr levels in the mPFC compared with HCs (P = 0.028). The GABA+/tCr levels in the mPFC were significantly associated with verbal memory performance (r = 0.462, P = 0.027) and overall cognition (r = 0.440, P = 0.035) in the NMOSD group. The GABA+/tCr levels in the left thalamus or Glx/tCr levels in both regions were not significantly different between groups, nor were they related to any cognitive domain in patients with NMOSD (all P values > 0.05). CONCLUSION: The GABA+ levels in the mPFC decreased and correlated with cognitive dysfunction in patients with NMOSD, suggesting that the changes in regional GABA+ levels might be a potential metabolic feature of cognitive decline in patients with NMOSD.

LMTK2 regulates inflammation in lipopolysaccharide-stimulated BV2 cells.

Microglia activation plays vital roles in neuroinflammatory pathologys. Lemurs tyrosine kinase 2 (LMTK2) was reported to regulate NF-κB signals. In the present study, the roles of LMTK2 were investigated in lipopolysaccharide (LPS)-treated BV-2 cells. Reverse transcription-quantitative (RT-q)PCR and western blotting (WB) were utilized to analyze LMTK2 levels in LPS-treated BV2 cells. MTT assay determined cell viabilities. Nitric oxide (NO) and prostaglandin E2 (PGE2) levels were assessed through Griess and enzyme-linked immunosorbent assay (ELISA), respectively. The expression level of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) were detected through RT-qPCR and WB. The release of inflammatory mediators under LPS stimulation, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6 and IL-10, were analyzed through ELISA. WB was used to analyze the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/NAD(P)H dehydrogenase quinone 1 (NQO1) signal pathway. The results showed that the levels of the inflammatory mediators, iNOS, NO, COX-2 and PGE2, along with pro-inflammatory factors, TNF-α, IL-1ß and IL-6, were significantly decreased following the induction of exogenous LMTK2 expression by LMTK2 overexpression plasmids in LPS-induced BV2 microglia. In contrast, anti-inflammatory factor IL-10 showed obvious decrease. Additionally, LMTK2 overexpression induced the elevation of Nrf2 in the cytoplasm and nucleus, along with the upregulation of HO-1 and NQO1 expression. In conclusion, LMTK2 is postulated to regulate neuroinflammation possibly through Nrf2 pathway. The present study is essential to reveal the underlying function of LMTK2 and to identify novel therapeutic targets for drug development in treating neuroinflammation.