Piotr Janik

Matrix metalloproteinases and their tissue inhibitors in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis

Background and purpose:  Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). We investigated the expression of MMPs and tissue inhibitors of matrix metalloproteinases (TIMPs) in serum and cerebrospinal fluid (CSF) correlating the results with age, disease duration and the clinical course.

Anti-neural antibodies in serum and cerebrospinal fluid of amyotrophic lateral sclerosis (ALS) patients

Objectives ‐ An autoimmune basis has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). This hypothesis is supported by the presence of antibodies that interact with motoneuron antigens in serum of these patients. Against autoimmunity are the discrepances in the frequency of the antibodies appearance and also failure of immunosuppression. The aim of our study was to evaluate the titer of antibodies against GM1‐gangliosides, AGM1‐gangliosides and anti‐sulfatides in paired serum and cerebrospinal fluid samples in the ALS patients. Material and methods ‐ Serum of 103 and CSF of 79 patients with ALS was examined. The “disease controls” consisted of 22 cases of other motor neuron diseases and 50 healthy, age‐matched normals. CSF was drawn at the same time from 79 ALS patients, 6 cases of the “disease controls” and 50 normals. To study the titer of antibodies against GM1‐gangliosides, AGM1‐gangliosides and sulfatides the ELISA technique has been applied. Results ‐ An increased titer against GM1‐gangliosides, AGM1‐gangliosides and sulfatides in ALS appeared in serum in 18%, 32% and 11%, resp., in the “disease controls” the increased antibodies titer appeared in single cases. In CSF the appropriate values in ALS were 20%, 15%, 8%, resp. In the “disease controls” a high antibodies titer was a rare finding. Conclusions ‐ It is concluded that in some ALS cases and also in some patients with other motor neuron diseases an autoimmune mechanism may contribute to motor neuron injury.

Novel A18T and pA29S substitutions in α-synuclein may be associated with sporadic Parkinson's disease.

OBJECTIVE Mutations in the α-synuclein-encoding gene SNCA are considered as a rare cause of Parkinsons disease (PD). Our objective was to examine the frequency of the SNCA point mutations among PD patients of Polish origin. METHODS Detection of the known SNCA point mutations A30P (c.88G>C), E46K (c.136G>A) and A53T (c.157A>T) was performed either using the Sequenom MassArray iPLEX platform or by direct sequencing of the SNCA exons 2 and 3. As the two novel substitutions A18T (c.52G>A) and A29S (c.85G>T) were identified, their frequency in a control population of Polish origin was assessed and in silico analysis performed to investigate the potential impact on protein structure and function. RESULTS We did not observe the previously reported point mutations in the SNCA gene in our 629 PD patients; however, two novel potentially pathogenic substitutions A18T and A29S were identified. Each variant was observed in a single patient presenting with a typical late-onset sporadic PD phenotype. Although neither variant was observed in control subjects and in silico protein analysis predicts a damaging effect for A18T and pA29S substitutions, the lack of family history brings into question the true pathogenicity of these rare variants. CONCLUSIONS Larger population based studies are needed to determine the pathogenicity of the A18T and A29S substitutions. Our findings highlight the possible role of rare variants contributing to disease risk and may support further screening of the SNCA gene in sporadic PD patients from different populations.

Serum IgM anti-GM1 ganglioside antibodies in lower motor neuron syndromes

Lower motor neuron syndromes (LMNS) are heterogenous conditions, which include patients with progressive lower motor neuron disease (LMND) and cases with the clinical phenotype of motor neuropathy (MN). The aim of this study was to estimate the IgM anti‐GM1 ganglioside antibodies titer and the ratio of the light chains in order to define the presence of autoimmunity process in particular cases with LMNS. Twenty‐eight patients were diagnosed with LMND and 15 patients were diagnosed with MN (10 patients with multifocal motor neuropathy with conduction block, five patients with MN without conduction block). Total of 103 patients with classical amyotrophic lateral sclerosis (ALS) and 50 healthy, age‐matched persons were also tested. The IgM anti‐GM1 ganglioside titer and the ratio of lambda/kappa light chains in serum were determined using the ELISA technique. High titer of IgM anti‐GM1 antibodies were detected in serum of 46% LMND patients, 80% of MN patients, and 18% of the classical ALS cases. An elevated ratio of lambda/kappa light chains appeared in 18% of LMND patients, and in 67% of the MN cases. The lambda/kappa light chains ratio was normal in all ALS patients. The presence of elevated titer of IgM anti‐GM1 ganglioside antibodies and the changed ratio of the light chains supports the presence of autoimmune process in LMNS and may provide clues for their management.

Singular DYT6 phenotypes in association with new THAP1 frameshift mutations

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Singular DYT6 phenotypes in association with new THAP1 frameshift mutations Arnaud Blanchard, Agathe Roubertie, Marion Simonetta-Moreau, Vuthy Ea, Coline Coquart, Melissa Y. Frederic, Gael Gallouedec, Jean-Paul Adenis, Isabelle Benatru, Michel Borg, et al.

Association of ADORA1 rs2228079 and ADORA2A rs5751876 Polymorphisms with Gilles de la Tourette Syndrome in the Polish Population

Background Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterized by motor and vocal tics. Hyperactivity of dopaminergic transmission is considered a prime abnormality in the pathophysiology of tics. There are reciprocal antagonistic interactions between adenosine and dopamine transmission. The aim of the study was to analyze the association of two polymorphisms, rs2228079 in ADORA1 and rs5751876 in ADORA2A, with the risk of GTS and co-morbid disorders. Material and Methods A total of 162 Polish GTS patients and 270 healthy persons were enrolled in the study. Two polymorphisms were selected on the basis of knowledge of SNPs frequencies in ADORA1 and ADORA2A. Chi-square test was used for allelic and genotypic association studies. Association of genotypes with age of tic onset was analyzed with Mann-Whitney test. Multivariate logistic regression was used to find independent predictors of GTS risk. Results We found that the risk of GTS was associated with rs2228079 and rs5751876 polymorphisms. The GG+GT genotypes of rs2228079 in ADORA1 were underrepresented in GTS patients (p = 0.011), whereas T allele of rs5751876 in ADORA2A was overrepresented (p = 0.017). The GG genotype of rs2228079 was associated with earlier age of tic onset (p = 0.046). We found also that the minor allele G of rs2228079 was more frequent in GTS patients with depression as compared to the patients without depression (p = 0.015). Also the genotype GG was significantly more frequent in patients with obsessive compulsive disorder/behavior (OCD/OCB, p = 0.021) and depression (p = 0.032), as compared to the patients without these co-morbidities. The minor allele T frequency of rs5751876 was lower in GTS patients with co-morbid attention deficit hyperactivity disorder (p = 0.022), and TT+TC genotypes were less frequent in the non-OCD anxiety disorder group (p = 0.045). Conclusion ADORA1 and ADORA2A variants are associated with the risk of GTS, co-morbid disorders, and may affect the age of tic onset.

Coprolalia and copropraxia in patients with Gilles de la Tourette syndrome

BACKGROUND AND PURPOSE Involuntary expression of socially unacceptable words (coprolalia) or gestures (copropraxia) is the best-known symptom of Gilles de Tourette syndrome (GTS) that contributes to the social impairment. The aim of the study was to assess the prevalence, age at onset and co-occurring symptoms of coprophenomena. MATERIALS AND METHODS One hundred and sixty-eight consecutive subjects with GTS including 94 adults and 74 children and aged between 4 and 54 years (mean: 18.0±8.3) were studied. Demographic and clinical data were obtained from medical history and neurological examination. RESULTS Coprolalia or copropraxia appeared in 44 patients. Both coprophenomena were present in 9 patients. Coprolalia occurred in 25.0% (n=42) and copropraxia in 6.5% (n=11) of patients. Mean age at onset was 12.2±5.7 years (range: 4-33) for coprolalia and 12.4±4.9 years (range: 7-24) for copropraxia. Coprolalia started 4.4±3.7 years (range: 0-16) after the onset of disease; copropraxia started 6.1±4.0 years (range: 1-12) after the onset of the disease. Coprolalia began in adulthood in six patients only, and copropraxia in one person. In six patients, coprolalia appeared in the first year of the disease. Copropraxia was never seen in the first year of the disease. Coprophenomena were more frequent in patients with comorbid mental disorders, behavioral problems and severe tics. Three quarters of patients reported significant influence of coprophenomena on daily living. CONCLUSIONS Coprophenomena affect one quarter of GTS patients, appear in the time when tics are most severe, and are positively associated with comorbidity and more severe form of disease. Coprophenomena may reflect more widespread dysfunction of brain in GTS.

Extraction of biomedical traits for patients with Amyotrophic Lateral Sclerosis using parallel and hierarchical classifiers

This paper concerns the analysis and interpretation of results obtained from biomedical experiments. The biomedical approach allows differentiating patients by testing their EPO concentration in serum and cerebrospinal fluids. The diagnostic tests can be applied in patient monitoring, or future therapeutic research. The paper presents the possibility of recognition of the clinical status of patients with Amyotrophic Lateral Sclerosis (ALS) by the use of parallel and hierarchical classifiers. The proposed method can be used in biometric identification of ALS patients. The results demonstrate that the pattern recognition methods may be helpful in evaluation of the clinical progress of ALS.

Immunochemical quantification of glycoconjugates in serum and cerebrospinal fluid of amyotrophic lateral sclerosis patients.

Glycoconjugates in the serum of 73 patients with amyotrophic lateral sclerosis (ALS), 21 cases of other motor neuron diseases and 20 healthy controls were determined. Cerebrospinal fluid (CSF) was studied in 64, 7 and 10 of these subjects. respectively. The level of sialic acid containing glycoconjugates, detected by Maakia amurensis agglutinin (M.AA), was decreased in the serum of 61.6% of the ALS patients, while in the CSF it was decreased, on average, in 75% of these cases. Only in single ALS cases was the concentration of these glycoconjugates increased. There was no correlation between the content of MAA‐labelled glycoconjugates both in serum and CSF and the titre of sialic acid containing antiGMI gangliosides. The glycoconjugates, detected by peanut agglutinin (PNA) which recognizes the disaccharide galactose β(1‐3)N‐acetylgalactosamine (GGN), were decreased in the serum of 78.1% of ALS patients, while in CSF they were increased in 54.7% of these cases. There was no correlation between the concentration of PNA‐labelled glycoconjugates both in serum and CSF as well as the titre of antibodies against GGN‐containing anti‐GM1 and anti‐AGM1 gangliosides. Changes in the level of the MAA‐ and PNA‐labelled glycoconjugates, as well as the titre of anti‐GM1 and anti‐AGM1 gangliosides antibodies were not specific for ALS. They were also observed in some cases of other motor neuron diseases. The low level of the lectin‐labelled glycoconjugates in serum and party in CSF of the majority of ALS patients is possibly the consequence of their accelerated clearance and/or specific inactivation by the formation of immune complexes or epitope binding. Degeneration of neurons and muscle cells could also be responsible. The relatively low incidence of high anti‐glycolipids antibodies titre may be, at least partly, connected with the low concentration of the appropriate antigens. The increased content of PNA‐labelled glycoconjugates in the CSF of the majority of ALS patients, together with the low incidence of high titre of antibodies against the appropriate glycolipids, could indicate that in CSF this lectin binds to the GGN epitope of glycoproteins rather than to the GGN epitope of glycolipids.

The analysis of selected neurotransmitter concentrations in serum of patients with Tourette syndrome

BACKGROUND AND PURPOSE Metabolic disturbances of excitatory and inhibitory neurotransmitters are implicated in pathogenesis of Tourette syndrome (TS). The aim of the study was to measure serum concentrations of glutamic acid, g-aminobutyric acid (GABA) and glycine in TS patients and evaluate any correlation between neurotransmitter levels and age at onset, actual age, gender, tic severity, duration of the disease and concomitant psychiatric disorders. MATERIAL AND METHODS Sixty-seven TS patients, aged 16-59, and 57 healthy controls, aged 19-37, were enrolled in the study. Information regarding medical history and physical investigation was collected using a short questionnaire. Sixty-seven percent of patients were medication-free at the time of examination and the rest had withheld treatment for 24 hours before. Blood samples were taken after a 12-hour fasting period. HPLC technique was used. RESULTS The TS group had higher glutamic acid and lower GABA levels. Glycine concentrations were comparable. No differences regarding neurotransmitter concentrations between treated and non-treated patients were found. Patients with concomitant obsessive-compulsive disorder and severe tics had higher glutamate levels. Glutamate concentrations correlated positively with the number of comorbid psychiatric disorders and GABA concentrations correlated negatively with the number of behavioural problems in patients with comorbidities. There was no correlation between analysed neurochemicals and age, gender, age at onset or disease duration. CONCLUSIONS Imbalance between excitatory and inhibitory systems in the brains of TS patients may be reflected by glutamate and GABA serum level changes. Glutamate and GABA may be biomarkers of the disease and high concentration of glutamate may indicate more severe course of TS.