Elevated CSF concentration of CCL3 and CCL4 in relapsing remitting multiple sclerosis patients.

CCL3 and CCL4 are considered as inflammatory cytokines and involved in progression of various neurologic disorders as multiple sclerosis (MS). The aim of this study was to evaluate the association between cerebrospinal fluid (CSF) levels of above mentioned inflammatory cytokines and relapsing remitting multiple sclerosis (RRMS. In this case-control study, 40 unrelated patients (without family relationship) with RRMS and 40 age and sex matched subjects as control group were enrolled. CSF samples obtained from all patients and control group and levels of CCL3 and CCL4 were determined in CSF. The mean CSF level of CCL3 was significantly higher in RRMS patients than healthy controls (29.71±18.56 vs. 10.62±6.85, p<0.01). The CSF levels of CCL4 was also higher in RRMS patients compared with healthy controls (33.62±21.50 vs. 13.74±4.90, p<0.01). We found a positive correlation between CSF levels of CCL3 and disease duration (r=+0.32 and p=0.04) and expanded disability status scale (EDSS) (r=+45, p=0.03). We also found a positive correlation between CSF level of CCL4 and disease duration (r=+0.76 and p<0.01) and EDSS (r=+0.73, p<0.01). Present study showed contribution of CCL3 and CCL4 in MS pathogenesis and suggested them as markers of severity of disease. Investigation  of chemokines responsible for attract  of pathogenic T lymphocyte and macrophage in to the central nerves system(CNS) is crucial for therapeutic targets in MS.

Biomarkers of central nervous system inflammation in infantile and juvenile gangliosidoses.

BACKGROUND: The gangliosidoses (Tay-Sachs disease, Sandhoff disease, and GM1-gangliosidosis) are progressive neurodegenerative diseases caused by lysosomal enzyme activity deficiencies and consequent accumulation of gangliosides in the central nervous system (CNS). The infantile forms are distinguished from the juvenile forms by age of onset, rate of disease progression, and age of death. There are no approved treatments for the gangliosidoses. In search of potential biomarkers of disease, we quantified 188 analytes in CSF and serum from living human patients with longitudinal (serial) measurements. Notably, several associated with inflammation were elevated in the CSF of infantile gangliosidosis patients, and less so in more slowly progressing forms of juvenile gangliosidosis, but not in MPS disease. Thirteen CSF and two serum biomarker candidates were identified. Five candidate biomarkers were distinguished by persistent elevation in the CSF of patients with the severe infantile phenotype: ENA-78, MCP-1, MIP-1α, MIP-1ß, and TNFR2. Correspondence of abnormal elevation with other variables of disease-i.e., severity of clinical phenotype, differentiation from changes in serum, and lack of abnormality in other neurodegenerative lysosomal diseases-identifies these analytes as biomarkers of neuropathology specific to the gangliosidosis diseases.

Profiling neuroinflammatory markers and response to nusinersen in paediatric spinal muscular atrophy.

Neuroinflammation is an emerging clinical feature in spinal muscular atrophy (SMA). Characterizing neuroinflammatory cytokines in cerebrospinal fluid (CSF) in SMA and their response to nusinersen is important for identifying new biomarkers and understanding the pathophysiology of SMA. We measured twenty-seven neuroinflammatory markers in CSF from twenty SMA children at different time points, and correlated the findings with motor function improvement. At baseline, MCP-1, IL-7 and IL-8 were significantly increased in SMA1 patients compared to SMA2, and were significantly correlated with disease severity. After six months of nusinersen treatment, CSF levels of eotaxin and MIP-1ß were markedly reduced, while IL-2, IL-4 and VEGF-A were increased. The decreases in eotaxin and MIP-1ß were associated with changes in motor scores in SMA1. We also detected a transient increase in MCP-1, MDC, MIP-1α, IL-12/IL-23p40 and IL-8 after the first or second injection of nusinersen, followed by a steady return to baseline levels within six months. Our study provides a detailed profile of neuroinflammatory markers in SMA CSF. Our data confirms the potential of MCP-1, eotaxin and MIP-1ß as new neuroinflammatory biomarkers in SMA1 and indicates the presence of a subtle inflammatory response to nusinersen during the early phase of treatment.

Cerebrospinal fluid inflammatory markers in Parkinson's disease--associations with depression, fatigue, and cognitive impairment.

Neuroinflammation may be involved in the pathophysiology of Parkinson's disease (PD) and specifically in non-motor symptoms such as depression, fatigue and cognitive impairment. The aim of this study was to measure inflammatory markers in cerebrospinal fluid (CSF) samples from PD patients and a reference group, and to investigate correlations between non-motor symptoms and inflammation. We quantified C-reactive protein (CRP), interleukin-6, tumor necrosis factor-alpha, eotaxin, interferon gamma-induced protein-10, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein 1-ß in CSF samples from PD patients (N=87) and the reference group (N=33). Sixteen of the PD patients had a dementia diagnosis (PDD). We assessed symptoms of fatigue, depression, anxiety and cognitive function using the Functional Assessment of Chronic Illness Therapy-Fatigue, the Hospital Anxiety and Depression Scale, and the Mini Mental State Examination, respectively. There were no significant differences in mean levels of inflammatory markers between PD patients and the reference group. After controlling for age, gender and somatic illness, patients with PDD had significantly higher levels of CRP compared to non-demented PD patients (p=0.032) and the reference group (p=0.026). Increased levels of inflammatory markers in CSF were significantly associated with more severe symptoms of depression, anxiety, fatigue, and cognition in the entire PD group. After controlling for PD duration, age, gender, somatic illness and dementia diagnosis, high CRP levels were significantly associated with more severe symptoms of depression (p=0.010) and fatigue (p=0.008), and high MCP-1 levels were significantly associated with more severe symptoms of depression (p=0.032). Our results indicate that non-motor features of PD such as depression, fatigue, and cognitive impairment are associated with higher CSF levels of inflammatory markers.

Enhanced expression of cytokines/chemokines in cerebrospinal fluids in mumps meningitis in children.

BACKGROUND: The mumps virus is frequently the causative agent in aseptic meningitis and mumps has still prevailed in Japan. We compared data obtained from patients with mumps meningitis and patients with aseptic meningitis caused by other viruses in order to identify mumps meningitis-specific cytokine/chemokine alterations in cerebrospinal fluid (CSF). METHODS: We elucidated the cytokine/chemokine network based on the cytokine/chemokine profiles in CSF from children with mumps meningitis and meningitis due to other viral infections using multiplex cytokine measurement. Seventeen cytokines/chemokines, namely interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte monocyte colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1ß (MIP-1ß), were measured simultaneously in CSF supernatants from eight children with mumps meningitis, 11 children with other types of viral meningitis and eight children with fever without neurological complications such as convulsion. RESULTS: We found that IL-8, IL-10, IL-12, IL-13 and IFN-γ showed a statistically significant increase in CSF from mumps meningitis when compared to other types of viral meningitis and fever without neurological complications. CONCLUSION: Mumps meningitis may induce a distinct immunological response when compared with other types of viral meningitis.

IL-8 in cerebrospinal fluid from children with acute encephalopathy is higher than in that from children with febrile seizure.

We identify possible differences in the cytokine/chemokine profiles in cerebrospinal fluid (CSF) from children with encephalopathy and febrile seizure. Interleukin (IL)-1beta, 2, 4, 5, 6, 7, 8, 10, 12, 13, 17, interferon-gamma, tumour necrosis factor-alpha, granulocyte colony-stimulating factor, granulocyte monocyte colony-stimulating factor, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1beta were measured simultaneously in CSF supernatants from children with encephalopathy (n = 8), febrile seizure (n = 16) and fever without neurological complications (n = 8). IL-8 in CSF from children with encephalopathy was significantly elevated compared to that in CSF from children with febrile seizure and fever without neurological complications. IL-8 in CSF was also higher than serum IL-8, suggesting that increased IL-8 was generated from glia cells or astrocytes, not by leakage from serum. Increased IL-8 in CSF in encephalopathy may protect against severe brain damage.

Increased cerebrospinal fluid levels of cytokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1ß (MIP-1ß) in patients with amyotrophic lateral sclerosis. / Incremento de las citoquinas proteína quimiotáctica de monocitos-1 (MCP-1) y proteína inflamatoria macrofágica-1ß (MIP-1ß) en líquido cefalorraquídeo de pacientes con esclerosis lateral amiotrófica.

INTRODUCTION: Neuroinflammation has recently been described in amyotrophic lateral sclerosis (ALS). However, the precise role of such proinflammatory cytokines as monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1ß (MIP-1ß) in ALS has not yet been determined. In this study, we determined cerebrospinal fluid (CSF) MCP-1 and MIP-1ß levels and assessed their association with the duration and severity of ALS. METHODS: Concentrations of MCP-1 and MIP-1ß were determined in the CSF of 77 patients diagnosed with ALS and 13 controls. Cytokine levels were analysed in relation to ALS duration (<12months vs. >12months) and severity (<30points vs. >30points on the ALS Functional Rating Scale administered at hospital admission). RESULTS: Higher CSF MIP-1ß (10.68pg/mL vs. 4.69pg/mL, P<.0001) and MCP-1 (234.89pg/mL vs. 160.95pg/mL, P=.011) levels were found in the 77 patients with ALS compared to controls. There were no differences in levels of either cytokine in relation to disease duration or severity. However, we did observe a significant positive correlation between MIP-1ß and MCP-1 in patients with ALS. CONCLUSIONS: The increase in MIP-1ß and MCP-1 levels suggests that these cytokines may have a synergistic effect on ALS pathogenesis. However, in our cohort, no association was found with either the duration or the clinical severity of the disease.

Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III.

We report three siblings with Gaucher disease type III, born between 1992 and 2004. During this period, new developments resulted in different potential therapies, changing clinical practice. The two eldest siblings received enzyme replacement therapy (ERT) from the age of 24 and 5 months respectively, later followed by an increase in dosage. ERT was combined with substrate reduction therapy (SRT) from the ages of 12 and 8 years, respectively. In the youngest sibling the combination of high-dose ERT and SRT was given from the age of 5 months. The two eldest siblings showed significant neurological impairment from the age of 1.5 years, starting with a convergent strabismus and partial oculomotor apraxia, followed by cognitive decline and an abnormal EEG and BAER. In contrast, the neurological development in the youngest sibling is almost completely normal. At the age of 3 years, cognitive development, EEG and BAER are all normal. Disturbed saccadic eye movements, which were already present at the start of therapy, remained stable. In addition to the clinical efficacy, we report on the biochemical response to therapy. Based on our results, the combination of high-dose ERT and SRT should be considered as a possible therapeutic approach for GD III, especially if started at a young age. Further follow-up studies are necessary to explore the long-term therapeutic effects.

Intrathecal upregulation of IFN-gamma and MIP-1beta in juvenile muscular atrophy of the distal upper extremity.

Juvenile muscular atrophy of the distal upper extremity (JMADUE) is associated with airway allergy and hyperIgEaemia, suggesting the involvement of immunological processes. In this study we aimed to clarify the changes in various cytokines/chemokines in cerebrospinal fluid (CSF) from JMADUE patients. We simultaneously measured 17 cytokines/chemokines in sera and CSF from 6 patients with JMADUE before treatment and from 14 patients with cervical spondylosis (CS) as a disease control (mean age at examination 23+/-7 and. 57+/-16 years, respectively), using a fluorescent bead-based immunoassay. We also assayed CSF from a JMADUE patient before and after plasma exchanges. In sera, only an increase of MIP-1beta (CCL3) in the JMADUE patients had a marginal significance as compared with the CS patients. In the CSF, IFN-gamma and MIP-1beta (CCL3) were significantly elevated in JMADUE patients compared with controls (1.5 and 2-fold increases, respectively), while no other cytokines/chemokines showed any significant differences. Moreover, the upregulated cytokines decreased after plasma exchanges in accord with improvement of distal upper limb weakness. The intrathecal upregulation of proinflammatory Th1 cytokines/chemokines, such as IFN-gamma and MIP-1beta (CCL3), in the CSF of JMADUE patients indicates the possible involvement of intrathecal immunological processes in this condition.

CSF chemokine alterations related to the clinical course of amyotrophic lateral sclerosis.

We measured the levels of 27 cytokines/chemokines and growth factors in cerebrospinal fluid (CSF) from 42 patients with sporadic amyotrophic lateral sclerosis (ALS), 12 patients with lower motor neuron disease (LMND), and 34 control patients with non-inflammatory neurological diseases (OND), using a multiplexed fluorescent bead-based immunoassay. Among cytokines/chemokines elevated in ALS, CCL2 and CXCL8 levels were negatively correlated with the revised ALS functional rating scale (ALSFRS-R) score, while CCL4 showed a positive correlation with ALSFRS-R score. CCL4 and CXCL10 showed negative correlations with disease progression rate. These chemokine alterations are assumed to somehow correlate with the clinical course of ALS.