Cerebrospinal fluid and plasma distribution of anti-α-synuclein IgMs and IgGs in multiple system atrophy and Parkinson's disease.

INTRODUCTION: Ubiquitous naturally occurring autoantibodies (nAbs) against alpha-synuclein (α-syn) may play important roles in the pathogenesis of Multiple System Atrophy (MSA) and Parkinson's disease (PD). Recently, we reported reduced high-affinity/avidity anti-α-syn nAbs levels in plasma from MSA and PD patients, along with distinct inter-group immunoglobulin (Ig)G subclass distributions. The extent to which these observations in plasma may reflect corresponding levels in the cerebrospinal fluid (CSF) is unknown. METHODS: Using competitive and indirect ELISAs, we investigated the affinity/avidity of CSF anti-α-syn nAbs as well as the CSF and plasma distribution of IgG subclasses and IgM nAbs in a cross-sectional cohort of MSA and PD patients. RESULTS: Repertoires of high-affinity/avidity anti-α-syn IgG nAbs were reduced in CSF samples from MSA and PD patients compared to controls. Furthermore, anti-α-syn IgM nAb levels were relatively lower in CSF and plasma from MSA patients but were reduced only in plasma from PD patients. Interestingly, anti-α-syn IgG subclasses presented disease-specific profiles both in CSF and plasma. Anti-α-syn IgG1, IgG2 and IgG3 levels were relatively increased in CSF of MSA patients, whereas PD patients showed increased anti-α-syn IgG2 and reduced anti-α-syn IgG4 levels. CONCLUSIONS: Differences in the plasma/CSF distribution of anti-α-syn nAbs seem to be a common feature of synucleinopathies. Our data add further support to the notion that MSA and PD patients may have compromised immune reactivity towards α-syn. The differing α-syn-specific systemic immunological responses may reflect their specific disease pathophysiologies. These results are encouraging for further investigation of these immunological mechanisms in neurodegenerative diseases.

Serum anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder presenting as acute eosinophilic encephalomyelitis.

We report the case of a 57-year-old man with neuromyelitis optica spectrum disorder (NMOSD) presenting as acute eosinophilic encephalomyelitis. Magnetic resonance imaging revealed central nervous system lesions typical of NMOSD and anti-aquaporin-4 antibodies in the serum were identified; however, eosinophilia was evident in the cerebrospinal fluid (CSF) at the early stage of the disease. The number of eosinophils in the CSF decreased subsequently. Although activation of eosinophils is known to be an important factor in the development of NMOSD lesions, prominent eosinophilia in the CSF at the early stage of the disease has never been reported in patients with NMOSD.

Comparación de adenosina deaminasa y detección de anticuerpos anti-antígeno A60 para el diagnóstico de meningitis tuberculosa / A comparative study for adenosine deaminase and anti-antigen A-60 antibodies detection for the diagnosis of tuberculous meningitis

Background: Diagnosis of tuberculous meningitis (TBM) is hampered by the lack of rapid and accurate diagnostic tools. We evaluated the immunological response to Mycobacterium tuberculosis anti-A60 antibodies in cerebrospinal fluid (CSF) in comparison to adenosine deaminase (ADA) determination, for the diagnosis of TBM. Methods: A total of 63 CSF samples were analyzed by indirect ELISA for the detection of anti- A60 IgG, IgM and IgA. These include samples from 17 patients with confirmed TBM and 46 control patients with other infections. Results: The mean individual anti-A60 IgM, IgG and IgA CSF antibody titers were significantly higher in TBM in comparison with control groups (p < 0.01). The best discriminatory CSF antibody for confirming TBM diagnosis was IgM, with an area under the receiver operating characteristic curve of 0.928 (95%CI 0.834-0.978), compared to 0.863 (95% CI: 0.752-0.936) for ADA testing (p = NS). The sensitivity of anti- A60 IgM CSF antibody titers (cutoff > 0.06 U/ml) was 94.1% compared to 88.2% for ADA (cutoff > 6.2 U/ml), p = NS. Both anti A60 IgM and ADA showed the same moderate specificity (80.4%). Two cases of TBM were correctly identified by anti-A60 IgM but missed by ADA. Conclusion: The ELISA test for anti-antigen A60 antibodies (IgM) is a rapid and sensitive tool for the rapid diagnosis of TBM that can be a complement to ALDA determination. The specificity of both tests is still a limitation in TBM diagnosis.

Antecedentes: El diagnóstico de meningitis tuberculosa (MTBC) se ve limitado por la ausencia de técnicas diagnósticas rápidas y precisas en líquido cefalorraquídeo (LCR). En este estudio evaluamos la respuesta inmunoló-gica de anticuerpos anti-antígeno A60 de Mycobacterium tuberculosis en LCR en comparación a la determinación de adenosina deaminasa (ADA). Métodos: Un total de 63 muestras de LCR fueron estudiadas mediante ELISA indirecto para detección de IgG, IgM e IgA anti-A60. Estas muestras incluyeron 17 casos de MTBC confirmada y 46 controles con otras infecciones. Resultados: Los títulos de IgG, IgM e IgA anti A-60 resultaron significativamente superiores en casos de MTBC versus controles (p > 0,01). El anticuerpo con mej or poder discriminatorio resultó IgM, con un área bajo la curva ROC de 0,928 (95%IC 0,8340,978), comparado a 0,863 (95% IC: 0,752-0,936) para ADA (p = NS). La sensibilidad de IgM anti-A60 (nivel de corte > 0,06 U/ml) fue de 94,1% versus 88,2% para ADA (nivel de corte > 6,2 U/ml), p = NS. Ambos IgM anti-A60 y ADA presentaron la misma especificidad baja-moderada (80,4%). Dos casos de MMTBC fueron correctamente identificados por IgM anti-A60 pero no por ALDA. Conclusión: La detección de anticuerpos anti-A60 (IgM) puede ser de ayuda en el diagnostico de MTBC en forma complementaria a la determinación de ALDA. La baja especificidad de ambos tests constituye su principal limitante.

Avidity of anti-neurocytoskeletal antibodies in cerebrospinal fluid and serum.

Antibodies have different avidities that can be evaluated using modified enzyme-linked immunosorbent assay (ELISA) techniques. We determined levels and avidities of antibodies to light (NFL) and medium (NFM) subunits of neurofilaments and tau protein in serum and cerebrospinal fluid (CSF) from 26 patients and anti-tau antibody levels and their avidities in 20 multiple sclerosis (MS) patients and 20 age- and sex-matched controls. Each sample was analyzed using both standard ELISA and also using a similar ELISA protocol with the addition of urea. The avidities of anti-neurocytoskeletal antibodies were higher in the CSF than those in serum (anti-NFL, p < 0.0001; anti-tau, p < 0.01; anti-NFM, n.s.). There was no relationship between avidities in serum and CSF for individual anti-neurocytoskeletal antibodies. We did not observe the relationship among the avidities of various anti-neurocytoskeletal antibodies. The avidities of anti-tau antibodies in the CSF were significantly higher in the MS patients than those in the controls (p < 0.0001). The study demonstrates the differences in avidities of CSF or serum neurocytoskeletal antibodies measured as the urea resistance by ELISA method. Avidity determination of anti-neurocytoskeletal antibodies could contribute to the evaluation of the immunological status of patients.

[A comparative study for adenosine deaminase and anti-antigen A-60 antibodies detection for the diagnosis of tuberculous meningitis]. / Comparación de adenosina deaminasa y detección de anticuerpos anti-antígeno A60 para el diagnóstico de meningitis tuberculosa.

BACKGROUND: Diagnosis of tuberculous meningitis (TBM) is hampered by the lack of rapid and accurate diagnostic tools. We evaluated the immunological response to Mycobacterium tuberculosis anti-A60 antibodies in cerebrospinal fluid (CSF) in comparison to adenosine deaminase (ADA) determination, for the diagnosis of TBM. METHODS: A total of 63 CSF samples were analyzed by indirect ELISA for the detection of anti- A60 IgG, IgM and IgA. These include samples from 17 patients with confirmed TBM and 46 control patients with other infections. RESULTS: The mean individual anti-A60 IgM, IgG and IgA CSF antibody titers were significantly higher in TBM in comparison with control groups (p < 0.01). The best discriminatory CSF antibody for confirming TBM diagnosis was IgM, with an area under the receiver operating characteristic curve of 0.928 (95%CI 0.834-0.978), compared to 0.863 (95% CI: 0.752-0.936) for ADA testing (p = NS). The sensitivity of anti- A60 IgM CSF antibody titers (cutoff > 0.06 U/ml) was 94.1% compared to 88.2% for ADA (cutoff > 6.2 U/ml), p = NS. Both anti A60 IgM and ADA showed the same moderate specificity (80.4%). Two cases of TBM were correctly identified by anti-A60 IgM but missed by ADA. CONCLUSION: The ELISA test for anti-antigen A60 antibodies (IgM) is a rapid and sensitive tool for the rapid diagnosis of TBM that can be a complement to ALDA determination. The specificity of both tests is still a limitation in TBM diagnosis.

Increased intrathecal high-avidity anti-tau antibodies in patients with multiple sclerosis.

BACKGROUND: Antibodies against tau protein indicate an interaction between the immune system and the neurocytoskeleton and therefore may reflect axonal injury in multiple sclerosis (MS). METHODOLOGY/PRINCIPAL FINDINGS: The levels and avidities of anti-tau IgG antibodies were measured using ELISA in paired cerebrospinal fluid (CSF) and serum samples obtained from 49 MS patients and 47 controls. Anti-tau antibodies were significantly elevated intrathecally (p<0.0001) in the MS group. The CSF anti-tau antibody levels were lower in MS patients receiving therapy than those without treatment (p<0.05). The avidities of anti-tau antibodies were higher in the CSF than in the serum (MS group p<0.0001; controls p<0.005). Anti-tau avidities in the CSF were elevated in MS patients in comparison with controls (p<0.05), but not in serum. CONCLUSIONS: MS patients have higher levels of intrathecal anti-tau antibodies. Anti-tau antibodies have different avidities in different compartments with the highest values in the CSF of MS patients.

Anti-Ri-associated paraneoplastic cerebellar degeneration. Report of a case and revision of the literature.

Paraneoplastic cerebellar degeneration associated with anti-Ri antibodies mainly presents with opsoclonus-myoclonus-ataxia. We report here the case of a patient with anti-Ri-antibody paraneoplastic syndrome, who presented four years after treatment for small-cell lung cancer (SCLC) with oscillopsia and gait disorder. On neurological examination vertical nystagmus, ataxic gait and postural tremor of all four limbs was detected. He died one year after the onset of the symptoms because of a acute exacerbation of his severe chronic obstructive pulmonary disease. No SCLC relapse or new cancer has been detected during the one-year follow-up period.To our knowledge, our patient is the first case of anti-Ri associated disorder with oscillopsia and vertical nystagmus as the initially prominent clinical features. The findings of this case study support the variability of anti-Ri-antibody-associated paraneoplastic syndrome. Further studies must be directed to better characterize the mechanisms underlying this syndrome. Finally, paraneoplastic neurological syndromes should be kept in mind also when a neoplastic disease is not demonstrated.

Anti-U1 RNP antibodies in cerebrospinal fluid are associated with central neuropsychiatric manifestations in systemic lupus erythematosus and mixed connective tissue disease.

OBJECTIVE: To determine the significance of anti-U1 RNP antibodies in the cerebrospinal fluid (CSF) of patients with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MCTD) who have central neuropsychiatric SLE (NPSLE). METHODS: The frequency of antinuclear antibodies including anti-U1 RNP antibodies in the sera and CSF of 24 patients with SLE and 4 patients with MCTD, all of whom had neuropsychiatric syndromes, was determined using an RNA immunoprecipitation assay and an enzyme-linked immunosorbent assay. The frequency of anti-U1 RNP antibodies in the CSF of patients with central NPSLE was examined, and the anti-U1 RNP index ([CSF anti-U1 RNP antibodies/serum anti-U1 RNP antibodies]/[CSF IgG/serum IgG]) was compared with CSF interleukin-6 (IL-6) levels and the albumin quotient (Qalb, an indicator of blood-brain barrier damage). CSF and serum antibodies against U1-70K, U1-A, and U1-C, including autoantigenic regions, were examined, and the U1-70K, U1-A, and U1-C indices as well as the anti-U1 RNP index were calculated. RESULTS: CSF anti-U1 RNP antibodies with an increased anti-U1 RNP index showed 64.3% sensitivity and 92.9% specificity for central NPSLE. The anti-U1 RNP index did not correlate with CSF IL-6 levels or the Qalb. The anti-U1-70K index was higher than the anti-U1-A and anti-U1-C indices in the CSF of anti-U1 RNP antibody-positive patients with central NPSLE. The major autoantigenic region for CSF anti-U1-70K antibodies appeared to be localized in U1-70K amino acid 141-164 residue within the RNA-binding domain. CONCLUSION: The frequency of anti-U1 RNP antibodies in the CSF and the anti-U1 RNP index are useful indicators of central NPSLE in anti-U1 RNP antibody-positive patients. The predominance of anti-U1-70K antibodies in CSF suggests intrathecal anti-U1 RNP antibody production.

Association of anti-triosephosphate isomerase antibody and MRL/MpJ-Faslpr mouse.

The association between anti-triosephosphate isomerase (TPI) antibodies and MRL/MpJ-Fas(lpr) (MRL/lpr) mice was examined. We found that serum anti-TPI antibody levels in MRL/lpr mice, measured by enzyme-linked immunosorbent assay, were significantly higher than that of age-matched Balb/c mice and NZB/WF1 mice. Anti-TPI antibodies were detected in serum and cerebrospinal fluid in MRL/lpr mice by Western blotting. Inoculation of anti-TPI monoclonal antibody-producing hybridoma into the brain of Balb/c mice resulted in immunoglobulin deposition in the regions near the ventricles, hippocampus, and choroid plexus. Anti-TPI antibodies may play a role in the etiology of brain damage and behavioral deficits in MRL/lpr mice.

Anti-Hu antibody neuropathy: a clinical, electrophysiological, and pathological study.

OBJECTIVE: The objective is to report the clinical, electrophysiological, and histopathological features of 16 patients with anti-Hu antibody neuropathy. METHODS: Clinical and electrophysiological data in 16 patients (11 females and 5 males) with positive anti-Hu antibody and nerve biopsy data in 9 cases were analyzed. RESULTS: Cancer was detected in 11 patients, including 9 with small-cell lung cancer. Classical paraneoplastic subacute sensory neuronopathy (SSN) and/or encephalomyelitis (EM) was observed in 7 patients (44%), including 5 with SSN. The most common clinical feature was sensory-motor neuropathy (SMN), accounting for 50% of cases. Though sensory nerve conduction abnormality was the prominent feature in 14 (88%) cases, sensory and motor nerve conduction was abnormal in all cases. Motor nerve conduction findings were typical of axonal degeneration. The most common nerve conduction pattern was that of SMN, with a sensory neuronopathy pattern being observed in only 3 cases. Sural nerve biopsy in 9 patients showed axonal degeneration in all cases and inflammatory cells in 4 cases. CONCLUSIONS: Classical sensory neuronopathy is rarer than expected, both clinically and electrophysiologically. Motor involvement is not uncommon and motor nerve conduction abnormality is frequently seen. A diverse clinical and electrophysiological, and histopathological spectrum was observed in this neuropathy. SIGNIFICANCE: New guidelines for the selection of patients for anti-Hu antibody test are recommended.

Usefulness of anti-GQ1b IgG antibody testing in Fisher syndrome compared with cerebrospinal fluid examination.

Fisher syndrome (FS), a variant of Guillain-Barré syndrome (GBS), is a rare disorder, and there are few reported studies of a large number of patients with FS. Cerebrospinal fluid (CSF) albuminocytological dissociation was found in 59% of 123 FS patients during the first 3 weeks of illness, while serum anti-GQ1b IgG antibody was positive in 85%. Whereas the incidence of CSF albuminocytological dissociation increased from the first to second weeks in FS, anti-GQ1b IgG antibody peaked in the first week, but there was no CSF albuminocytological dissociation. Statistically, anti-GQ1b antibody testing was superior to a CSF examination in supporting a diagnosis of FS during the first 3 weeks of illness, especially in the first week.

[Sensory neuronopathy]. / Neuronopatie czuciowe.

The authors present the question of sensory neuronopathy which are disorders affecting intervertebral ganglia. The neuropathological background and clinical symptoms of sensory neuronopathy are emphasised, as well as diagnostic difficulties resulting from a variety of ethiological conditions: toxic, inflammatory, and autoimmunological ones, and from lack of unequivocal clinical criteria enabling a difference diagnosis along with neuropathy and radiculopathy, which in turn requires a broad spectrum of diagnostic tests and prolonged observation of patients. The authors discuss also the clinical outcome, prognosis, and current therapeutic possibilities focusing on intensive immunosuppressive management.

Changes in the cerebrospinal-fluid monoamines in rats with an immunoneutralization of the subcommissural organ-Reissner's fiber complex by maternal delivery of antibodies.

The subcommissural organ (SCO) is a brain gland secreting glycoproteins into the cerebrospinal fluid (CSF), where they aggregate forming the Reissner's fiber (RF). By the continuous addition of newly released glycoproteins, RF grows along the cerebral aqueduct, fourth ventricle, and central canal of the spinal cord. At the filum, RF-glycoproteins escape from the central canal and reach the local blood vessels. Despite a century of research, the function of the SCO remains elusive. The aim of the present investigation was to test the hypothesis that RF-glycoproteins, by binding and transporting monoamines out of the CSF, participate in the clearance of these compounds. A protocol was designed that led to the permanent immunoneutralization of the SCO through the maternal delivery of antibodies. This was achieved by transplacental transfer to the fetuses, and through the milk to the pups, of specific antibodies against SCO secretory proteins. The antibodies reached the CSF of the fetuses and pups and blocked the RF formation during the first months of life. Some of these animals died during the first postnatal weeks; those who survived displayed a rise in the CSF concentration of several monoamines, l-DOPA being the one with the highest rise. Adult rats transiently deprived of RF by a single injection of anti-RF antibodies into the CSF showed a transient rise in the CSF concentration of l-DOPA. All these results support the hypotheses that the SCO-RF complex participates in the clearance of monoamines from the CSF.

Association of anti-ribosomal P protein antibodies with neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: Although it has been reported that anti-ribosomal P protein antibodies (anti-P) are highly specific for lupus psychosis, there have been discrepancies among the studies regarding the clinical correlation of these antibodies with systemic lupus erythematosus (SLE). The present study was therefore carried out to reappraise the association of anti-P and neuropsychiatric SLE. METHODS: Highly purified synthetic ribosomal P peptides of the carboxyl-terminal 22-amino acid sequence were conjugated to human serum albumin (HSA) with the use of glutaraldehyde. Anti-P in sera from 75 patients with SLE (26 without central nervous system disease [non-CNS], 28 with lupus psychosis, and 21 with nonpsychotic CNS involvement [nonpsychotic CNS lupus]) were analyzed with an enzyme-linked immunosorbent assay (ELISA), using HSA-ribosomal P peptide conjugates as antigens. Anti-P levels were quantitated by subtracting the nonspecific binding activities to HSA. RESULTS: The ELISA was found to be specific for anti-P, as determined by comparison with the results of Western blotting using extracts of HEp-2 cells. Serum anti-P levels were significantly elevated in patients with lupus psychosis, including organic brain syndrome and nonorganic psychosis, compared with those with non-CNS SLE or those with nonpsychotic CNS lupus. There were no significant differences in serum anti-P levels between patients with organic brain syndrome and those with nonorganic psychosis. Anti-P antibodies were not detected in the cerebrospinal fluid of patients with either lupus psychosis or nonpsychotic CNS lupus. CONCLUSION: Our results, obtained from the highly specific ELISA using HSA-ribosomal P peptide conjugates, confirm the correlation of serum anti-P with lupus psychosis. The data also suggest that differences in the purity of the ribosomal P peptides used might be a major reason for the conflicting results in the literature regarding the association of anti-P with lupus psychosis.