Autoimmune astrocytopathy double negative for AQP4-IgG and GFAP-IgG: Retrospective research of clinical practice, biomarkers, and pathology.

OBJECTIVE: The objective of this study is to investigate the presence of astrocyte antibodies in patients, excluding aquaporin-4 or glial fibrillary acidic protein (GFAP) antibodies, while evaluating associated biomarkers and pathologies. METHODS: Patient serum and cerebrospinal fluid (CSF) were tested for antibodies using tissue- and cell-based assays. Neurofilament light chain (NFL) and GFAP in the CSF were detected using single-molecule array (SIMOA). RESULTS: 116 patients accepted SIMOA. Fifteen functional neurological disorders patients without antibodies were designated as controls. Thirty-five patients were positive for astrocyte antibodies (Anti-GFAP: 7; Anti-AQP4: 7; unknown antibodies: 21, designed as the double-negative group, DNAP). The most frequent phenotype of DNAP was encephalitis (42.9%), followed by myelitis (23.8%), movement disorders (19.0%), and amyotrophic lateral sclerosis-like (ALS-like) disease (14.2%). The levels of CSF GFAP and NFL in DNAP were higher than in the control (GFAP: 1967.29 [776.60-13214.47] vs 475.38 [16.80-943.60] pg/mL, p < 0.001; NFL: 549.11 [162.08-2462.61] vs 214.18 [81.60-349.60] pg/mL, p = 0.002). GFAP levels decreased in DNAP (n = 5) after immunotherapy (2446.75 [1583.45-6277.33] vs 1380.46 [272.16-2005.80] pg/mL, p = 0.043), while there was no difference in NFL levels (2273.78 [162.08-2462.61] vs 890.42 [645.06-3168.06] pg/mL, p = 0.893). Two brain biopsy patterns were observed: one exhibited prominent tissue proliferation and hypertrophic astrocytes, with local loss of astrocytes, while the other showed severe astrocyte depletion with loss of neurofilaments around the vessels. Eighteen patients received immunotherapy, and improved except one with ALS-like symptoms. We identified anti-vimentin in this patient. DISCUSSION: There are unidentified astrocyte antibodies. The manifestations of double-negativity are heterogeneous; nevertheless, the pathology and biomarkers remain consistent with astrocytopathy. Immunotherapy is effective.

PPARγ Dysfunction in the Medial Prefrontal Cortex Mediates High-Fat Diet-Induced Depression.

Epidemiological studies suggest a bidirectional association between depression and obesity; however, the biological mechanisms that link the development of depression to a metabolic disorder remain unclear. Even though nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) agonists show anti-depressive effect, and high-fat diet-(HFD)-induced PPARγ dysfunction is involved in the pathogenesis of metabolic disorders, the neuronal PPARγ has never been studied in HFD-induced depression. Thus, we aimed to investigate the effect of neuronal PPARγ on depressive-like behaviors in HFD-induced obese mice.We fed male C57BL/6 J mice with HFD to generate obese mice and conducted a series of behavioral tests to assess the effects of HFD feeding on depression. We generated neuron-specific PPARγ knockout mice (NKO) to determine whether neuronal PPARγ deficiency was correlated with depressive-like behaviors. To further prove whether PPARγ in the medial prefrontal cortex (mPFC) neurons is involved in depressive-like behaviors, we applied AAV- CaMKIIα-Cre approach to specifically knockout PPARγ in the mPFC neurons of LoxP mice and used AAV-syn-PPARγ vectors to overexpress PPARγ in the mPFC neurons of NKO mice.We observed a low mPFC PPARγ level and an increase in depressive-like behaviors in the HFD-fed mice. Moreover, neuronal-specific PPARγ deficiency in mice induced depressive-like behaviors, which could be abolished by imipramine. Furthermore, overexpressing PPARγ in the mPFC reversed the depressive-like behaviors in HFD-fed mice as well as in neuronal-specific PPARγ knockout mice.These results implicate that dysregulation of neuronal PPARγ in the mPFC may contribute to an increased risk for depression in obese populations.

Serological biomarkers in autoimmune GFAP astrocytopathy.

Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a newly defined meningoencephalomyelitis. The pathogenesis of GFAP-A is not well understood. The present study measured the expression levels of 200 serological cytokines in GFAP-A patients, NMOSD patients and healthy controls (HCs). The correlations between serum cytokine levels and clinical information in GFAP-A patients were analyzed. A total of 147 serological proteins were differentially expressed in GFAP-A patients compared to HCs, and 33 of these proteins were not observed in NMOSD patients. Serum levels of EG-VEGF negatively correlated with GFAP antibody titers, MIP-3 alpha positively correlated with clinical severity in GFAP-A patients, and LIGHT positively correlated with WBC counts and protein levels in the CSF of GFAP-A patients. These results suggest that GFAP and AQP4 astrocytopathy share some common pathology related to TNF signaling. Serum MIP 3 alpha may be a biomarker to assess clinical severity and a potential target for therapy of autoimmune GFAP astrocytopathy.

Serum molecular biomarkers in neuromyelitis optica and multiple sclerosis.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare and severe inflammatory demyelinating disorder of the central nervous system (CNS), which mainly affects the optic nerves and spinal cord. The aims of this study were to determine whether the expression levels of serological cytokines could distinguish 1) NMOSD from healthy controls (HCs); and 2) NMOSD patients with and without the aquaporin-4 (AQP4) antibody biomarker from each other; and 3) NMOSD patients without the antibody to AQP4 from MS patients. METHODS: The expression levels of 200 proteins in serum from 41 NMOSD (32 with antibodies to AQP4, 9 without antibodies to AQP4), 12 MS patients, and 34 HCs were measured using glass-based antibody arrays. None of the patients received any immunosuppressive treatment. In parallel, the correlation between protein expression in NMOSD/MS patients and clinical traits was determined with Weighted Gene Co-expression Network Analysis (WGCNA). RESULTS: Thirty-nine serological proteins were differentially expressed in NMOSD patients compared to HCs, with 29 of these proteins not observed in MS patients. In addition, the data reveal 15 differentially-expression proteins (DEPs) between AQP4-IgG seronegative and AQP4-IgG seropositive NMOSD patients, and 9 DEPs between NMOSD and MS patients who did not have AQP4-IgG. CONCLUSION: Serological IL-17B is significantly upregulated in both NMOSD and MS patients compared to HCs, and could be a key biomarker of NMOSD and MS. Serological VEGF, MPIF-1 and NrCAM were positively associated with AQP4-IgG titer. We also demonstrate that EGF may be involved in the breakdown of the BBB by downregulating Claudin-5.