Prediction of clinical progression in nervous system diseases: plasma glial fibrillary acidic protein (GFAP).

Glial fibrillary acidic protein (GFAP), an intracellular type III intermediate filament protein, provides structural support and maintains the mechanical integrity of astrocytes. It is predominantly found in the astrocytes which are the most abundant subtypes of glial cells in the brain and spinal cord. As a marker protein of astrocytes, GFAP may exert a variety of physiological effects in neurological diseases. For example, previous published literatures showed that autoimmune GFAP astrocytopathy is an inflammatory disease of the central nervous system (CNS). Moreover, the studies of GFAP in brain tumors mainly focus on the predictive value of tumor volume. Furthermore, using biomarkers in the early setting will lead to a simplified and standardized way to estimate the poor outcome in traumatic brain injury (TBI) and ischemic stroke. Recently, observational studies revealed that cerebrospinal fluid (CSF) GFAP, as a valuable potential diagnostic biomarker for neurosyphilis, had a sensitivity of 76.60% and specificity of 85.56%. The reason plasma GFAP could serve as a promising biomarker for diagnosis and prediction of Alzheimer's disease (AD) is that it effectively distinguished AD dementia from multiple neurodegenerative diseases and predicted the individual risk of AD progression. In addition, GFAP can be helpful in differentiating relapsing-remitting multiple sclerosis (RRMS) versus progressive MS (PMS). This review article aims to provide an overview of GFAP in the prediction of clinical progression in neuroinflammation, brain tumors, TBI, ischemic stroke, genetic disorders, neurodegeneration and other diseases in the CNS and to explore the potential therapeutic methods.

The effects of high plasma levels of Aß1-42 on mononuclear macrophage in mouse models of Alzheimer's disease.

More and more evidences are proving that microglia play a crucial role in the pathogenesis of Alzheimer's disease (AD) and the plasma Aß1-42 levels significantly increased 15 years before the onset of dominantly inherited AD. However, the effects of high plasma levels of Aß1-42 on mononuclear macrophage, the peripheral counterparts of microglia, remain unclear. In the present study, we used APP/PS1 transgenic (Tg) mice and a parabiotic model of wild type (Wt) mice and Tg mice (Parabiotic Wt-Tg, Pa (Wt-Tg)) to investigate the effects of high plasma levels of Aß1-42 on peripheral mononuclear macrophage. Our results showed that in the early stage of Tg mice (7 months) and Pa (Wt-Tg) mice (4 months), the proportions of pro-inflammatory macrophages in peritoneal cavity, myeloid derived suppressor cells (MDSCs) in spleen, granulocyte-monocyte progenitors (GMPs) in bone marrow, and the plasma levels of interleukin-6 (IL-6) were significantly decreased. While the proportions of pro-inflammatory macrophages, MDSCs, GMPs, and the plasma levels of IL-6 and tumor necrosis factor (TNF)-α, as well as the numbers of bone marrow-derived macrophages (BMDMs) in mice brain were increased in the late stage of Tg mice (11 months) and Pa (Wt-Tg) mice (8 months). In addition, the proportions of monocytes in spleen and the proliferation of bone marrow cells (BMCs) were enhanced consistently, and the phagocytic function of macrophages kept stably after high plasma levels of Aß1-42 sustaining stimulation. These results demonstrated that high plasma levels of Aß1-42 play a biphasic regulating role at different stages of the disease, namely inhibiting effects on peripheral pro-inflammatory macrophages in the early stage of AD model, while promoting effects in the late stage of AD model. The mechanism behind this may be associated with their effects on MDSCs in spleen and myeloid progenitor cells in bone marrow. Therefore, intervening the effects of plasma Aß1-42 on pro-inflammatory macrophages might offer a new therapeutic approach to AD.

Nuclear factor kappa B inhibitor suppresses experimental autoimmune neuritis in mice via declining macrophages polarization to M1 type.

Guillain-Barré syndrome (GBS) is an acute inflammatory and immune-mediated demyelinating disease of the peripheral nervous system (PNS). Macrophages play a central role in its animal model, experimental autoimmune neuritis (EAN), which has been well accepted. Additionally, nuclear factor (NF)-κB inhibitors have been used to treat cancers and have shown beneficial effects. Here, we investigated the therapeutic effect of M2 macrophage and the NF-κB pathway's correlation with macrophage activation in EAN in C57BL/6 mice. We demonstrate that M2 macrophage transfusion could alleviate the clinical symptoms of EAN by reducing the proportion of M1 macrophage in the peak period, inhibiting the phosphorylation of NF-κB p65. The NF-κB inhibitor (BAY-11-7082) could alleviate the clinical symptoms of EAN and shorten the duration of symptoms by reducing the proportion of M1 macrophages and the expression of proinflammatory cytokines. Consequently, BAY-11-7082 exhibits strong potential as a therapeutic strategy for ameliorating EAN by influencing the balance of M1/M2 macrophages and inflammatory cytokines.

Co-occurrence of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids and posterior reversible encephalopathy syndrome: a case report.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare inflammatory disorder, mainly involving the brainstem. Posterior reversible encephalopathy syndrome (PRES) is a syndrome that affects the bilateral parietal-occipital region. Here, we describe a rare case of CLIPPERS with PRES. A 47-year-old woman presented with subacute, progressive ataxia symptoms, and radiological and pathological findings were consistent with CLIPPERS. In addition, she had acute convulsions and was unconscious, and brain magnetic resonance imaging fluid-attenuated inversion recovery showed patchy high-intensity posterior cerebral white matter signals, with imaging lesions showing vasogenic oedema, a typical manifestation of PRES. The imaging lesions showed vasogenic oedema in bilateral parietal and occipital lobes and typical 'pepper-like' punctate gadolinium enhancement in pons and bilateral cerebellar hemispheres, which were considered to be caused by merger of CLIPPERS and PRES. Clinical manifestations and imaging lesions disappeared after two months of steroids and symptomatic treatment, supporting the diagnosis of CLIPPERS with PRES. When patients with CLIPPERS show unusual symptoms or atypical vasogenic oedema lesions in the posterior cerebral white matter, the coexistence of PRES should be considered.

The effects of IVIg therapy on serum levels of neuropeptide Y and cytokines in Guillain-Barré syndrome.

BACKGROUND: Guillain-Barré syndrome (GBS) is a common acute immune-mediated inflammatory disorder affecting the peripheral nervous system (PNS) of humans. Studies in humans and in animal models revealed that neuropeptide Y (NPY) levels are altered in some neurodegenerative and neuroimmune disorders. Herein, we investigated the levels of NPY and cytokines in the serum of GBS patients and explored the roles of NPY in the disease severity and its short-term prognosis. METHODS: Twenty patients with GBS (case group) and twenty healthy individuals (control group) were enrolled in this study. NPY levels were analyzed by enzyme-linked immunosorbent assay (ELISA). The levels of pro- and anti-inflammatory cytokines (including interferon-γ (IFN-γ), interleukin (IL)-4, IL-10, IL-12p70, IL-17A, and tumor necrosis factor-α (TNF-α)) were analyzed using cytometric beads array (CBA). The clinical characteristics, disease severity, and short-term prognosis were compared between the two groups. RESULTS: Compared with the control group, the levels of NPY and cytokines were significantly increased in the serum of patients with GBS. NPY levels in the serum of GBS patients were correlated with the disease severity. CONCLUSION: Our results suggest that NPY and cytokines are involved in the pathogenesis of GBS. The levels of NPY can help to predict the severity of the disease.

Beneficial or Harmful Role of Macrophages in Guillain-Barré Syndrome and Experimental Autoimmune Neuritis.

Guillain-Barré syndrome (GBS), an immune-mediated demyelinating peripheral neuropathy, is characterized by acute weakness of the extremities and areflexia or hyporeflexia. Experimental autoimmune neuritis (EAN) is a common animal model for GBS, which represents a CD4+ T cell-mediated inflammatory autoimmune demyelination of the peripheral nervous system (PNS), and is used to investigate the pathogenic mechanism of GBS. It has been found that macrophages play a critical role in the pathogenesis of both GBS and EAN. Macrophages have been primarily classified into two major phenotypes: proinflammatory macrophages (M1) and anti-inflammatory macrophages (M2). The two different macrophage subsets M1 and M2 may play a decisive role in initiation and development of GBS and EAN. However, recently, it has been indicated that the roles of macrophages in immune regulation and autoimmune diseases are more complex than those suggested by a simple M1-M2 dichotomy. Macrophages might exert either inflammatory or anti-inflammatory effect by secreting pro- or anti-inflammatory cytokines, and either inducing the activation of T cells to mediate immune response, resulting in inflammation and demyelination in the PNS, or promoting disease recovery. In this review, we summarize the dual roles of macrophages in GBS and EAN and explore the mechanism of macrophage polarization to provide a potential therapeutic approach for GBS in the future.

Dystrophia myotonica type 1 presenting with dysarthria: A case report and literature review.

Dystrophia myotonica (DM) type 1 is an autosomal dominant disorder, caused by a trinucleotide CTG repeat expansion in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene (chromosome 19q13.3). The disorder affects different organ systems, including the skeletal muscles, ocular lens, lungs, heart and gastrointestinal tract, as well as the endocrine and central nervous systems. The skeletal muscles are most frequently involved, whereby the disorder manifests as myotonia, muscle weakness and amyotrophy. However, DM type 1 presenting with dysarthria is rare. The current study presents a case of a 28-year-old male with DM type 1 presenting with dysarthria and associated multifocal hyperintense lesions in the white matter. Although electromyogram measurements identified myotonic discharges in all extremities, a muscle biopsy failed to detect the characteristic pathological features of DM type 1. A lack of a positive family history for DM type 1 also obscured diagnosis. However, genetic analysis detected a single allele in the P12 segment of the DMPK gene that included a CTG expansion of 13 repeats and a three-base gradient fragment in the P134 segment that included a CTG expansion of >600 repeats. According to the characteristics of dysarthria, multifocal hyperintense lesions in the white matter, electromyogram measurement results and genetic testing results, a diagnosis of DM type 1 was confirmed.

Vascular spinal cord obstruction associated with superior vena cava syndrome: A case report and literature review.

RATIONALE: Superior vena cava syndrome (SVCS) is the obstruction of blood flow through the SVC, causing complete or partial blockade of the collateral circulation of returning venous blood. SVCS is frequently presented with facial, neck, trunk, and upper limbs swelling and so on. However, to the best of our knowledge, the obstruction of the venous return in the spinal veins is rarely a manifestation of SVCS. PATIENT CONCERNS: We presented a rare case of a 52-year-old male patient with 2-month history of progressive right upper limb numbness and swelling and 10-day history of extremities malfunctioning. Cervical magnetic resonance imaging (MRI) detected obstruction of the spinal venous return. Lung computed tomography (CT) revealed lesions in the esophagus, which indicated esophageal cancer with mediastinal lymph nodes metastasis and signified SVCS. DIAGNOSES: With the results of laboratory findings, cervical MRI, lung CT findings, and physical examination, the patient was diagnosed with SVCS manifesting as spinal vein obstruction. INTERVENTIONS AND OUTCOMES: The family abandoned further treatment, and the patient passed away 2 months after discharge. LESSONS: The case indicates that SVCS can induce systemic and spinal cord diseases affecting the venous return. Further studies are necessary to reveal the mechanism for SVCS inducing spinal veins obstruction and to explore whether SVCS patients with and without vascular spinal cord obstruction have different prognoses.

Effect of bone marrow stromal cell transplantation on neurologic function and expression of VEGF in rats with focal cerebral ischemia.

There is evidence that the transplantation of mesenchymal stem cells into rat models of cerebral ischemia reduces ischemic damage; however, the mechanism remains to be elucidated. The present study aimed to assess the effect of transplantation of human bone marrow stromal cells (hBMSCs) on neurologic function and the expression of vascular endothelial growth factor (VEGF) in a rat model of focal cerebral ischemia. The left middle cerebral artery of adult Wistar rats was occluded for 90 min using a nylon thread, followed by reperfusion for 1 h. hBMSCs labeled with 5-bromo-2-deoxyuridine (BrdU) were stereotaxically injected into the ischemic boundary zone. Behavioral analysis using the Neurological Severity Score (NSS) was conducted on days 1, 3, 7 and 28, and a histologic evaluation was performed simultaneously. VEGF was detected by immunofluorescence staining and western blot analysis. Fifty rats were divided equally into five groups: Normal control, sham­operated, operated (no transplantation), Dulbecco's medium Eagle's medium (DMEM)-injected (received only serum-free DMEM), and hBMSC-transplanted. The hBMSC-transplanted group showed significantly improved behavioral recovery compared with the operated and DMEM-transplanted groups on days 3, 7 and 28. Histological examination showed that transplanted cells migrated from the injection site into nearby areas including the cortex. Expression of VEGF was significantly greater in the hBMSC group compared with the other four groups on each assessment day. The expression of VEGF was found to be beneficial for functional recovery following cerebral ischemic injury and hBMSC transplantation stimulated the expression of VEGF. Transplantation of BMSCs may be a promising therapeutic strategy for treating cerebral infarction.

Microembolic signals detected with transcranial doppler sonography differ between symptomatic and asymptomatic middle cerebral artery stenoses in Northeast China.

Although microembolus monitoring has been widely used for ischemic cerebrovascular disease, the clinical significance of microembolic signal (MES) in asymptomatic middle cerebral artery (MCA) stenosis remains unclear. We aim to investigate the frequency of MES and the value of MES in predicting ischemic stroke secondary to asymptomatic MCA stenosis. From June 2011 to December 2012, microembolus monitoring was performed in 83 asymptomatic and 126 symptomatic subjects. By comparing the demographics and risk factors between the symptomatic and asymptomatic subjects, we found that the ratio of male sexuality and smoking history differed (101/126 vs 43/83, and 88/126 vs 38/83, respectively, p<0.01). The frequency of MES was significantly higher in the symptomatic group than in the asymptomatic group (49/126 vs 2/108, p<0.01). Specifically, the frequency of MES in the symptomatic and asymptomatic groups with mild stenosis, moderate stenosis, severe stenosis and occlusion groups was 4/18 (22.22%) vs 0/30 (0), 13/31 (41.94%) vs 1/28 (3.57%), 30/62 (48.39%) vs 1/39 (2.56%), 2/15 (13.33%) vs 0/11 (0), respectively. Except for the occlusive group, the frequency of MES is correlated with stenosis degree and symptom. Two patients in the asymptomatic group were found positive for MES, and the MES number was 1 for both. During the one-year follow-up, neither of them developed ischemic stroke. In conclusion, MES detected with TCD differs between symptomatic and asymptomatic MCA stenoses. Due to the low frequency, the value of MES as a predictor of subsequent ischemic stroke in patients with asymptomatic MCA stenosis might be limited.

Clinical presentation and differential diagnosis of Lambert-Eaton myasthenic syndrome.

Lambert-Eaton myasthenic syndrome (LEMS) is frequently associated with malignancy, especially small cell lung cancer (SCLC). Here, we describe a patient with a 5-year history of cervical myelopathy who presented with recurrent limb weakness of her limbs and complained of recent progressive weakness. Following an examination that included electromyography, a chest CT scan, and a bronchofiberscopy examination with brushing biopsy, the patient was diagnosed with LEMS and SCLC. This case report highlights the ongoing need for clinicians to be observant for cases of LEMS, to consider both patient history and physical examination data, and to accurately obtain a differential diagnosis between LEMS and other diseases, which also cause weakness.

Human mesenchymal stem cells increases expression of α-tubulin and angiopoietin 1 and 2 in focal cerebral ischemia and reperfusion.

Angiogenesis is associated with improved neurologic recovery after cerebral ischemia. Human bone marrow mesenchymal stem cells (hMSCs) have been successfully used to treat ischemic stroke and were shown to induce the expression of a number of neurotrophic factors including VEGF, epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) in a rat middle cerebral artery occlusion (MCAO) ischemia model. In this study, we aimed to understand the mechanism underlying the improvement of neurological function following hMSCs transplantation into MCAO rats. We established a rat MCAO model and used immunofluorescence to evaluate α-tubulin expression in the hippocampus. We used RT-PCR to determine the expression of Ang-1 and Ang-2 mRNAs after transplantation of hMSCs into MCAO rats. We showed a significant decrease in α-tubulin expression in rats with cerebral ischemia, suggesting that α-tubulin is a protective protein in cerebral ischemia Transplantation of hMSCs significantly upregulated α-tubulin levels in the hippocampus. Transplantation of hMSCs also resulted in a significant upregulation of Ang-1 and Ang-2 mRNAs in MCAO rats. Ang-2 expression was upregulated earlier than Ang-1, suggesting that (1) transplantation of hMSCs promotes angiogenesis and that (2) Ang-2 may be an initiator of angiogenesis. Our results provide a theoretical basis for the therapeutic use of hMSCs in cerebral ischemia.