Anti-GM1 ganglioside antibodies cloned from autoimmune neuropathy patients show diverse binding patterns in the rodent nervous system

We have recently cloned a panel os monoclonal IgM anti-GM1 ganglioside antibodies from peripheral blood lymphocytes of patients with multifocal motor neuropathy and Guillain Barré syndrome. In solid-phase immunoassay, the antibodies all reacted with GM1 and also reacted to different degrees with the structurally related glycolipids asialo-GM1 and GD1b. These antibodies are being used to study the pathogenesis of the anti-GM1 antibody-medicated neuropathy in different experimental systems. In the present immunofluorescence study we report the binding patterns of 5 of these antibodies in the rodent nervous system. The antibodies demonstrated highly diverse binding patterns on tissue sections and teased fibers when compared to one another and between species. The antibodies bound many central and peripheral nervous system structures, including neurons and myelin, motor end plate regions, and muscle spindles. The diversity of binding shown by these antibodies provide evidence that may account for the differing clinical phenotypes, including normality, associated with elevated titers of anti-GM1 antibodies.     

Clinical factors relating to the presence of serum anti-GM1 and GD1b antibodies in demyelinating neuropathy--study using a multivariate analysis

We studied clinical factors relating to the presence of serum anti-GM1 and GD1b antibodies in patients with demyelinating neuropathy using a multivariate analysis. Sera were obtained from 46 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and 33 with Guillain-Barré syndrome (GBS) and kept frozen at -20 degrees C until use. Anti-GM1 and GD1b IgM and IgG antibodies were measured by ELISA at serum dilution of 1:100 and considered to be positive when those values were more than the cut off values determined by means and standard deviations in 35 normal controls. Age, sex, duration, prodromal disease, neurological findings, concentration of CSF protein, nerve conduction, treatment, and outcome were investigated in all patients retrospectively. Multivariate logistic models using all those characteristics were used to clarify the clinical factors relating to the presence of anti-GM1 and GD1b antibodies. In CIDP, anti-GM1 antibodies associated with or without anti-GD1b antibodies were frequently seen in patients with motor dominant neuropathy than those with sensory dominant neuropathy (P = 0.007, odds ratio = 11.6). There was significant difference in anti-GM1 IgM antibodies (P = 0.003, odds ratio = 22.2), but no difference in IgG antibodies. Anti-GM1 antibodies were observed 5 (IgM, 5; IgG, 2) of 7 patients with pure motor neuropathy, 9 (IgM, 8; IgG, 4) of 17 with motor dominant neuropathy, 5 (IgM, 2; IgG, 3) of 16 with sensori-motor neuropathy, and none of 6 with sensory dominant neuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Successful endoscopic transpapillary drainage of an infected pancreatic pseudocyst

Multifocal motor neuropathy (MMN) is a disorder with a highly characteristic clinical picture and one which is defined by a specific electrodiagnostic abnormality, namely, multifocal conduction block which is confined to motor axons. Sensory axons which traverse segments of severe or even complete motor conduction block conduct normally. A proportion of patients with MMN also have elevated levels of antibodies to GM1 ganglioside. However, about one half of MMN patients lack elevated levels of these antibodies and many others have only modest elevations, to a degree often seen in other neurological and even non-neurological disorders. Furthermore, clinical and electrophysiological improvement of MMN in response to treatment with high dose intravenous immunoglobulin is achieved in the absence of any change in antiglycolipid levels. Injection of serum from patients with MMN and elevated GM1 antibody levels produces demyelination in recipient rat nerves, suggesting a pathogenetic role for these antibodies in demyelination. However, sera of patients with identical antibody titers in other motor system diseases produced no demyelination, suggesting that the demyelinating factor resides in some other serum fraction. At present, there is insufficient evidence to support the contention that these antibodies play a critical pathogenetic role in MMN. Until more evidence is available it is important to define MMN on the basis of a characteristic clinical picture and a unique electrodiagnostic abnormality rather than on a pattern of serum antibodies.     

Mapping immunoreactive epitopes in the human peripheral nervous system using human monoclonal anti-GM1 ganglioside antibodies

A series of monoclonal IgM anti-GM1 ganglioside antibodies has been cloned from peripheral blood lymphocytes of patients with multifocal motor neuropathy and Guillain-Barré syndrome. In solid-phase immunoassay, the antibodies react with GMI, and also in differing degrees to the structurally related glycolipids asialo-GM1 (GA1) and GD1b. Here we describe the binding patterns of six human anti-GM I antibodies to epitopes within the human nervous system. Antibodies were observed to bind to motor neurons and spinal grey matter, dorsal and ventral spinal roots, dorsal root ganglion neurons, nodes of Ranvier, neuromuscular junctions and skeletal muscle. The distribution of immunoreactive epitopes, which included sensory structures, extended beyond those sites conventionally regarded as pathologically affected in anti-GM1 antibody-associated motor nerve syndromes. This undermines a model of disease pathogenesis based solely on antigen distribution. Factors other than the presence or absence of antigen, such as the local ganglioside topography, antibody penetration into, and pathophysiological vulnerability of a particular site may also influence the clinicopathological outcome of anti-GM1 antibody-mediated autoimmune attack.     

Peripheral neuropathies associated with monoclonal proteins

Peripheral neuropathies associated with monoclonal proteins have received considerable attention as a clinically important group of chronic late-onset neuropathies. When a monoclonal protein is found in patients with peripheral neuropathy of unknown cause, as occurs in 10% of such cases, usually no associated disease is discovered; hence MGUS. Less often, disorders such as multiple myeloma, AL amyloidosis, Waldenstr?m's macroglobulinemia, osteosclerotic myeloma, and lymphoma are found. Demyelinating neuropathies associated with MGUS of all classes, but particularly IgM, Waldenstr?m's macroglobulinemia, and osteosclerotic myeloma typically follow an indolently progressive course, and frequently respond to treatments aimed at interfering with putative underlying immune mechanisms. By contrast, axonal neuropathies associated with MGUS, multiple myeloma, and AL amyloidosis have generally shown no response to therapy. Recently, IgM monoclonal and polyclonal antibodies directed against human peripheral nerve antigens including MAG and various glycolipids such as GM1 ganglioside have been found in patients with specific neuropathy syndromes. Anti-MAG antibodies occur in predominantly sensory demyelinating neuropathies, whereas elevated titers of anti-GM1 ganglioside antibodies are associated with lower motor neuron syndromes with multifocal motor conduction block. Although the evidence for autoimmune mechanisms in some monoclonal protein-associated neuropathies is mounting, a causal connection between monoclonal proteins and these neurologic syndromes has yet to be established.     

The sword of Damocles: the psychosocial impact of familial spinocerebellar ataxia in South Africa

It has been recently recognized that increased titers of serum anti-GM1 antibodies may be associated with motoneurone diseases or with multiple motor neuropathy with or without conduction block and also with chronic sensorimotor neuropathy and Guillain-Barré syndrome. Santoro et al. were the first to note that anti-GM1 antibodies were able to bind to the nodes of Ranvier of the sural nerve of a patient with clinical signs and symptoms mostly resembling amyotrophic lateral sclerosis who also showed, in nerve conduction studies, multifocal motor nerve fibers conduction block and serum IGM anti-GM1 antibodies. The two patients presented in this report had asymetrical motor neurone disease with signs and symptoms of lower motoneurone involvement, and other signs, in the first patient, which suggested the existence of upper motoneurone damage. Besides, the second patient also had clinical sensory impairment in the lower limbs. Electrophysiologically, none of them had nerve conduction block but both showed inexcitable median and sural nerve sensory fibers. Both had high titers of anti-GM1. A sural biopsy of both patients showed immunoglobulins into the sensory fibers. However, we do not know whether the anti-GM1 antibodies bind to a cross-reactive glycolipid other than the GM1 itself. In any case, it seems that the presence of anti-GM1 antibodies might be a marker signalling a potentially treatable immune disorder which may have signs of lower and upper motor neurone disease and, also, clinical and electrophysiological evidences of peripheral sensory involvement.     

Anti-GD1a ganglioside antibodies in peripheral motor syndromes

High titers of anti-GD1a antibodies have been found in patients with Guillain-Barre syndrome or motor neuropathy. To determine the possible diagnostic relevance of these antibodies, we measured serum anti-GD1a IgG and IgM antibodies by enzyme-linked immunosorbent assay in 195 patients with different motor syndromes and in 335 control subjects. Moderately high antibody titers (1/1,280-1/5,120) were occasionally found in patients with chronic inflammatory demyelinating polyneuropathy (5%), multifocal motor neuropathy (18%), lower motor neuron disease (3.8%), or amyotrophic lateral sclerosis (1.8%) and in immunological control subjects (1.2%), while titers of 1/20,480 or higher were only found in 2 patients with Guillain-Barre syndrome (IgG in both) and 2 with motor neuropathy and IgM lambda monoclonal gammopathy improving with immunotherapy. In both motor neuropathy patients and the Guillain-Barre syndrome patient who were retested during recovery, anti-GD1a titers decreased concomitantly with clinical improvement. High anti-GD1a antibody titers may be found in several motor syndromes but only markedly increased anti-GD1a titers are strictly associated with potentially treatable dysimmune neuropathies.     

Mitochondria and cells produce reactive oxygen species in virtual anaerobiosis: relevance to ceramide-induced apoptosis

Antibodies reactive with the core glycan of asialoganglioside (GA1), monosialoganglioside (GM1), and disialoganglioside (GD1a) were studied in human sera. In healthy individuals, GA1-, GM1-, and GD1a-reactive antibodies were mainly of the IgM class, but also of the IgA and IgG classes, and were present at low titers in the serum of 68%, 79%, and 91% of the individuals studied, respectively. Levels of anti-GA1 and anti-GM1 antibodies, mainly of the IgA and IgG classes, were significantly elevated (P < 0.001) in 62% and 72% of subjects, respectively, chronically infected with Trypanosoma cruzi, with no association found with the degree of myocardial damage. No significant increase in anti-GA1 and anti-GM1 antibodies was found in dilated cardiomyopathy patients. The level of anti-GD1a antibody was not significantly different between healthy controls and chronic chagasic or dilatatory cardiomyopathy patients. Since the peripheral nervous system is very rich in gangliosides, it is possible that the increases in GA1- and GM1-specific antibodies that develop during chronic T. cruzi infection are involved in the pathology of peripheral neuropathy in Chagas' disease.     

Multifocal motor neuropathy

We present a review of the literature on multifocal motor neuropathy (MMN), a rare neurological disorder which has features in common with both chronic inflammatory demyelinating neuropathy and lower motor neuron disease. Clinically, MMN is characterised by slowly progressive asymmetrical limb weakness, usually most prominent in the forearms. Weakness may be associated with muscle wasting, fasciculations and decreased tendon reflexes. Serum anti-GM1 ganglioside antibody titres may be increased. The diagnostic hallmark of MMN is the electrophysiological demonstration of persistent localised motor conduction blocks, with otherwise normal or near-normal motor and sensory conduction velocities. The pathogenesis of MMN has not been elucidated completely. There is, however, substantial evidence for an autoimmune mechanism. Based on the possible involvement of the immune system in the pathogenesis of MMN the therapeutic efficacy of several immunomodulatory drugs has been tested. Treatment of MMN patients with human immunoglobulin or cyclophosphamide is usually followed by a marked improvement of strength. The finding that MMN is a potentially treatable disorder underscores the importance of distinguishing MMN from lower motor neuron disease, for which no effective therapy is currently available.     

N-glycolylneuraminic acid-containing GM1 is a new molecule for serum antibody in Guillain-Barré syndrome

To clarify the pathogenesis of Guillain-Barré syndrome (GBS) after parenteral injections of bovine brain gangliosides, we searched for new molecules in bovine brain gangliosides recognized by sera from GBS patients. Gangliosides fractionated in a Q-Sepharose column were used as the antigens, and the binding of serum IgG or IgM was examined by thin-layer chromatography/immunostaining. Fourteen of 175 serum samples from the patients reacted with the monosialoganglioside fraction 2. In the neutral solvent system, a band in this fraction migrated with N-acetylneuraminic acid-containing GM1 [GM1(NeuAc)], whereas in the alkaline solvent system it migrated slower. This suggested that the band was N-glycolylneuraminic acid-containing GM1 [GM1(NeuGc)]. In both solvent systems, its mobility was almost the same as that of authentic GM1(NeuGc) from mouse liver. Secondary ion mass spectrometry showed that the ganglioside's structure was consistent with that of GM1(NeuGc). IgG anti-GM1(NeuGc) antibodies in sera from the GBS patients were significantly absorbed by GM1(NeuAc), indicative that the anti-GM1(NeuGc) antibodies cross-react with GM1(NeuAc). N-Glycolylneuraminic acid-containing gangliosides are so highly immunogenic in humans that the injection of GM1(NeuGc) could induce the production of IgG anti-GM1(NeuGc) antibody, which cross-reacts with GM1(NeuAc).     

Anti-fucosyl-GM1 ganglioside IgG and IgM autoantibodies in human serum: no link to pathology

Anti-fucosyl-GM1 ganglioside antibodies were detected in sera of five persons: four patients with autoimmune neuropathies and more recently, IgG antibodies in one with Graves' disease (Adler et al., Autoimmunity 18, 149-152, 1994) [1]. In the latter case, we were unable to find any relation between the occurrence of antibodies and thyroid disease. Now we report a detailed study on the anti-glycolipid antibodies in this patient. We found that her serum contained not only IgG but also a high level of anti-FucGM1 IgM antibodies, with a titer stable over a period of 5 years of treatment and follow-up. The carbohydrate structure of the epitope recognized by IgG and some of IgM antibodies seems to consist of Fuc-Gal-GalNAc-Gal- or a part of this sequence. Moreover, this patient's serum contained other IgM antibodies active against FucGM1 and also asialo GM1 glycolipids. Our results indicate that anti-FucGM1 ganglioside antibodies of G and M classes occur in serum of this patient with no apparent adverse health effects.     

Identification of common epitopes on gliadin, enterocytes, and calreticulin recognised by antigliadin antibodies of patients with coeliac disease

Immunopathological studies suggest that the target of immune attack is different in the subtypes of Guillain-Barré syndrome (GBS). In acute motor axonal neuropathy (AMAN), the attack appears directed against the axolemma and nodes of Ranvier. In acute inflammatory demyelinating polyneuropathy (AIDP), the attack appears directed against a component of the Schwann cell. However, the nature of the antigenic targets is still not clear. We prospectively studied 138 Chinese GBS patients and found that IgG anti-GD1a antibodies were closely associated with AMAN but not AIDP. With a cutoff titer of greater than 1:100, 60% of AMAN versus 4% of AIDP patients had IgG anti-GD1a antibodies; with a cutoff titer of greater than 1:1,000, 24% of AMAN patients and none of the AIDP patients had IgG anti-GD1a antibodies. In contrast, low levels of IgG anti-GM1 antibodies (> 1:100) were detected in both the AMAN and the AIDP forms (57% vs 35%, NS). High titers of IgG anti-GM1 (>1:1,000) were more common in the AMAN form (24% vs 8%, NS). Serological evidence of recent Campylobacter infection was detected in 81% of AMAN and 50% of AIDP patients, and anti-ganglioside antibodies were common in both Campylobacter-infected and noninfected patients. Our results suggest that IgG anti-GD1a antibodies may be involved in the pathogenesis of AMAN.     

Treatment of immune deficient neuropathies with intravenous polyvalent immunoglobulins. An open study of 16 cases

Between June 1989 and February 1992, in an open controlled study 16 patients with various types of polyneuropathy were treated with high-dose intravenous immunoglobulins (IgIV). Every month during 3 months, each patient received three courses of IgIV in doses of 0.4 g/kg/day during 5 successive days. The trial was discontinued in case of no response or if the neuropathy was considered as being in remission. In the other cases, at most one course of IgIV was given once a month if there was significant improvement (assessed by previously published clinical functional scales, electrophysiological examinations and titers of specific antibodies), or spaced at intervals which varied according to each patient, and sometimes in low doses. Results: 1) A first group of 6 patients had chronic demyelinating polyneuropathy with severe motor disability. The first infusions of IgIV resulted, in 4/6 cases, in a dramatic improvement which lasted under regularly spaced courses in lower doses. 2) Four patients had chronic neuropathy associated with monoclonal IgM gammopathy of undetermined significance (3 had anti-MAG and anti-SPG antibodies, and 1 had anti-GD1a and GD1b antibodies) and had not been improved by the usual immunosuppressive treatments. In 1 case the IgIV treatment had to be discontinued because of skin allergy. In the remaining 3 patients the clinical disorders (mainly the sensory ones) were reduced, but no significant improvement of neurophysiological or immunological data was observed. 3) Three patients had a purely multifocal motor neuropathy with persistent conduction blocks at EMG and high titers of anti-GM1 antibodies in 2/3 cases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anti-ganglioside antibodies in patients with rheumatoid arthritis complicated by peripheral neuropathy

Gangliosides are a diverse class of glycolipids found in the plasma membrane of mammalian cells and are particularly abundant in cells of the nervous system. Serum antibodies to gangliosides have been detected in various neurological disorders with some evidence that they play a pathogenic role. In this study, we have investigated whether anti-ganglioside antibodies were elevated in a group of patients with rheumatoid arthritis (RA) who developed peripheral neuropathy (PN). An ELISA technique was used to test sera from 28 patients with RA and PN. 38 RA patients without PN and 20 normal controls for the presence of IgG and IgM anti-GM1 and sulphatide antibodies. The patients with RA and PN had higher pain scores (P < 0.005), more extra-articular features (P < 0.05), higher erosive scores (P < 0.0001), lower haemoglobin (P < 0.005), higher ESR (P < 0.001) and were more often on disease-modifying drugs (P < 0.05). Twelve RA patients with PN (43%), but only two RA controls (5%), had positive titres against one or more gangliosides (P < 0.001). The neurologic disability score (NDS) correlated with RA duration (P < 0.05), and with levels of IgM anti-GM1 (P < 0.001) and IgM anti-sulphatide (P < 0.05) antibodies. We conclude that PN is more common in patients with severe rheumatoid disease, and a significant proportion have elevated levels of anti-ganglioside antibodies.     

Serological follow-up of patients with paracoccidioidomycosis treated with itraconazole using Dot-blot, ELISA and western-blot

Twenty-seven mycologically proven cases of paracoccidioidomycosis (PCM) were treated with itraconazole (100-200 mg/day in month 1 and 100 mg/day until month 6-8) and evaluated clinically and serologically, up to 3.5 years post-therapy, using Dot-blot and ELISA for measuring the titers of IgG, IgA and IgM anti-P.brasiliensis antibodies and Western-blot for determining IgG, IgA and IgM antibodies against the antigen components of the fungus. Before treatment, 81.5% (Dot-blot) and 84% (ELISA) of the patients presented elevated IgG anti-P.brasiliensis antibody titers which dropped slightly with treatment. On the other hand, the percentages of pre-treatment high-titered sera for IgA and IgM anti-P.brasiliensis were lower (51.9% and 51.8%: Dot-blot; 16.5 and 36%: ELISA, respectively) but the titers tended to become negative more frequently with treatment. Prior to treatment, the percentages of positivity for IgG, IgA and IgM anti-P.brasiliensis antibodies in Western-blot were 96%, 20.8% and 41.6%, respectively. Antigens with molecular weights varying from 16-78 kDa, from 21-76 kDa and from 27-78 kDa were reactive for IgG, IgA and IgM antibodies, respectively. The most frequently reactive antigenic components had molecular weights of 27, 33 and 43 kDa for IgG, and 70 for IgA and IgM antibodies. During the period of study, the patients responded well to treatment. The present data confirm the diversity and complexity of the humoral response in PCM, and the importance of utilizing different serological tests to detect IgG, IgA and IgM anti-P. brasiliensis antibodies.     

Influence of viraemia and genotype upon serological reactivity in screening assays for antibody to hepatitis C virus

Ganglioside GM2, expressed on the surface of some human cancers, is a promising target for immune therapy, since GM2 antibodies are cytotoxic, can be induced in humans by vaccination, and the presence of GM2 antibodies is associated with a better prognosis in melanoma patients. In our efforts to induce long-lived, cytotoxic GM2 antibodies, we investigated lipopolysaccharides (LPS) containing "GM2-like" oligosaccharides. LPS were prepared from Campylobacter jejuni serotypes O:1, O:23, or O:36 (all sharing the oligosaccharide structure GalNAcbeta1-4Gal(113NeuAc)-Hex with ganglioside GM2), and tested for their ability to induce GM2-reactive antibodies. Immunization of NZW rabbits (2 animals per vaccine) with LPS from C. jejuni serotype O:1 in Freund's adjuvant resulted in production of high-titer IgG antibodies reactive with purified bovine brain GM2 in ELISA, dot-blot immune strains and immune thin-layer chromatography, and with GM2 derived from various human tumors by immune thin-layer chromatography. These rabbit antibodies bound to cancer cell lines expressing GM2 on their cell surface, as determined by mixed hemadsorption assays, mediating strong antibody-dependent cellular cytotoxicity (ADCC) with tumor cells expressing cell-surface GM2. Antibodies induced by vaccination with C. jejuni serotype O:1 were higher-titer (IgG ELISA titer > 1:60,000) than antibodies induced by immunization with purified GM2 (IgG ELISA titer > 1:200). Immunization with LPS from C. jejuni serotype O:36 resulted in production of moderately high-titer IgM and low-titer IgG GM2 antibodies. Immunization with LPS from C. jejuni serotype O:23 did not elicit GM2-reactive antibodies. No clinical symptoms were observed in animals immunized with these LPS preparations, with purified GM2 ganglioside, or with LPS derived from C. jejuni serotype O:19 (containing a GM1-like oligosaccharide). Our results indicate that lipopolysaccharides sharing carbohydrate epitopes with gangliosides may be useful immunogens for inducing antibodies to ganglioside antigens.     

Chimeric anti-ganglioside GM2 antibody with antitumor activity

Ganglioside GM2, which is one of the major gangliosides expressed on the cell surface of human tumors of neuroectodermal origin, has been focused on as a target molecule for passive immunotherapy. GM2 is thought to be one of the T-cell-independent antigens and to elicit only IgM antibody responses in rodents and humans. We have previously established two murine anti-GM2 monoclonal antibodies with high specificity and strong binding activity, KM696 and KM697, both of which are of the IgM class. Variable heavy and light chain complementary DNAs of these two murine monoclonal antibodies were cloned and used in the construction of mouse/human IgG1 chimeric antibodies, KM966 and KM967, respectively, in this study. One of the chimeric antibodies, KM966, retained strong and specific reactivity with GM2 and showed the similarity of the binding activity with tumor cell lines to that of the original murine monoclonal antibody. Indirect immunofluorescence staining of tumor cell lines with the chimeric KM966 revealed that the antigen was expressed in substantial amounts on pulmonary tumor cells and leukemia cells as well as neuroectodermal origin tumor cells. When human serum and human peripheral blood mononuclear cells were used as effectors in complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity, respectively, chimeric KM966 was fully effective in killing GM2-expressing tumor cells. In addition, i.v. injection of chimeric KM966 markedly suppressed the establishment of human tumor xenografts in nude mice. Taken together, chimeric KM966 is the first antibody of the human IgG class to ganglioside GM2 and has strong antitumor activity both in vitro and in vivo. It is likely that chimeric KM966 will be a useful agent for passive immunotherapy of human cancer.     

Efficacy of traditional rice-lentil-yogurt diet, lactose free milk protein-based formula and soy protein formula in management of secondary lactose intolerance with acute childhood diarrhoea

Gangliosides were found to be present in Entamoeba histolytica. They were extracted from lyophilized trophozoites of the pathogenic strain HM-1:IMSS and purified by high performance thin-layer chromatography. Two resorcinol-positive bands, comigrating with GM2 and GD1a were demonstrated, revealing the existence of ganglioside molecules in Entamoeba histolytica. The GM2 content, determined as lipid-bound sialic acid, was 1.5 micrograms/10(8) amoebae, the content of the GD1a comigrating band was 0.32 microgram/10(8) amoebae. The identity of the GM2 comigrating band was confirmed by TLC immunostaining, using the monoclonal anti-GM2 antibody GMB28. Furthermore, six out of ten anti-amoeba positive sera selectively reacted with the GM2 comigrating band, as revealed by immunostaining on TLC plates. Absorption tests revealed that preincubation of anti-amoeba positive sera with standard GM2 was followed by a significant decrease in the reaction with amoeba trophozoites by indirect immunofluorescence. These results demonstrate that a GM2 comigrating component of Entamoeba histolytica may be one of the antigens responsible for the appearance of circulating antibodies in patients with amoebiasis.     

Parkinson's disease: improved function with GM1 ganglioside treatment in a randomized placebo-controlled study

BACKGROUND/OBJECTIVE: Studies in animal models of Parkinson's disease (PD) suggest that GM1 ganglioside treatment can restore neurologic and dopaminergic function. In view of positive preclinical findings and the results of a previous open-label study demonstrating efficacy of GM1 in PD patients, this study compared effects of GM1 ganglioside and placebo on motor functions in PD patients. METHODS: Forty-five patients with mild to moderate PD were studied. The primary efficacy measure was change in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score. After three independent baseline assessments, patients received IV infusion of the test drug (1,000 mg GM1 or placebo) and then self-administered either GM1 or placebo twice daily (200 mg/day, subcutaneously) for 16 weeks. Patients were examined during monthly follow-up visits. RESULTS: There was a significant difference between groups in UPDRS motor scores at 16 weeks (p=0.0001). The activities of daily living portion of the UPDRS (off-period assessment) also showed a significant effect in favor of the GM1-treated patients (p=0.04). GM1-treated patients also had significantly greater mean improvements than placebo-treated patients in performance of timed motor tests including tests of arm, hand, and foot movements, and walking. GM1 was well tolerated and no serious adverse events were reported. CONCLUSIONS: This study demonstrates that GM1 ganglioside treatment enhances neurologic function significantly in PD patients. Further study is warranted to evaluate long-term effects of GM1 in PD patients and to elucidate further the mechanisms underlying patient improvements.     

Cholinergic neuron-specific ganglioside GQ1b alpha a possible target molecule for serum IgM antibodies in some patients with sensory ataxia

In neurological diseases the presence of certain anti-glycosphingolipid antibody species is associated with the clinical features. We recently isolated the novel cholinergic neuron-specific gangliosides GQ1b alpha and GT1a alpha from bovine brain. A monoclonal antibody specific for GQ1b alpha and GT1a alpha reacted strongly with the dorsal born of human spinal cord but not with human motor neurons. We investigated the serum antibodies to these minor gangliosides in a number of neurologic diseases and found that 4 patients with sensory ataxic neuropathy had a remarkably high IgM anti-GQ1b alpha antibody titer. GQ1b alpha may be a target molecule for serum IgM antibodies in some patients with sensory ataxic neuropathy.