Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: Results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study.

BACKGROUND: B cells may be involved in the pathophysiology of multiple sclerosis (MS). Inebilizumab (formerly MEDI-551) binds to and depletes CD19+ B cells. OBJECTIVES: To assess safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of inebilizumab in adults with relapsing MS. METHODS: This phase 1 trial randomised 28 patients 3:1 (21, inebilizumab; 7, placebo) to inebilizumab (2 intravenous (IV) doses, days 1 and 15: 30, 100 or 600 mg; or single subcutaneous (SC) dose on day 1: 60 or 300 mg) or matching placebo, with follow-up until at least week 24 or return of CD19+ B-cell count to ⩾80 cells/µL. RESULTS: Complete B-cell depletion was observed across all doses. Infusion/injection (grade 1/2) reactions occurred in 6/15 patients receiving inebilizumab IV, 2/5 placebo IV and 1/6 inebilizumab SC. Serious adverse events occurred in three patients receiving inebilizumab: pyrexia, mixed-drug intoxication (unrelated to inebilizumab; resulted in death) and urinary tract infection. Mean number of cumulative new gadolinium-enhancing lesions over 24 weeks was 0.1 with inebilizumab versus 1.3 with placebo; mean numbers of new/newly enlarging T2 lesions were 0.4 and 2.4, respectively. CONCLUSION: Inebilizumab had an acceptable safety profile in relapsing MS patients and showed a trend in reductions in new/newly enlarging and gadolinium-enhancing lesions.

PARK2 variability in Polish Parkinson's disease patients--interaction with mitochondrial haplogroups.

AIMS AND OBJECTIVES: A new pathomechanism of Parkinson's disease (PD) involving regulation of mitochondrial functions was recently proposed. Parkin complexed with mitochondrial transcription factor A (TFAM) binds mtDNA and promotes mitochondrial biogenesis, which is abolished by PARK2 gene mutations. We have previously shown that mitochondrial haplogroups/clusters and TFAM common variation influenced PD risk. We investigate the role of PARK2 polymorphisms on PD risk and their interactions with mitochondrial haplogroups/clusters as well as with TFAM variability. METHODS: 104 early-onset PD patients (EOPD, age at onset ≤ 50 years) were screened for PARK2 coding sequence changes including gene dosage alterations. Three selected PARK2 polymorphisms (S167N, V380L, D394N) were genotyped in 326 PD patients and 315 controls using TaqMan allelic discrimination assay. RESULTS: PARK2 screen revealed two heterozygous changes in two EOPD patients: exon 2 deletion and one novel synonymous variation (c.999C > A, P333P). In association study no differences in genotype/allele frequencies of S167N, V380L, D394N were found between analyzed groups. Stratification by mitochondrial clusters revealed higher frequency of V380L G/G genotype and allele G in PD patients, within HV cluster (p = 0.040; p = 0.022, respectively). Moreover, interaction between genotypes G/G V380L of PARK2 and G/G rs2306604 of TFAM, within HV cluster was significant (OR 2.05; CI 1.04-4.04; p = 0.038). CONCLUSIONS: Our results indicate that co-occurrence of G/G V380L PARK2 and G/G rs2306604 TFAM on the prooxidative HV cluster background can contribute to PD risk. We confirm low PARK2 mutation frequency in Polish EOPD patients.

Pharmacokinetic-pharmacodynamic modeling of levodopa in patients with advanced Parkinson disease.

OBJECTIVES: The aims of the present study were to investigate the pharmacokinetic and pharmacodynamic (pk/pd) relationship of levodopa (l-dopa) in patients with advanced Parkinson disease (PD) and also to evaluate the effect of tolcapone on the pk/pd analysis of l-dopa in 1 patient with severe dyskinesias and fluctuations. METHODS: The pharmacokinetics (plasma concentrations of l-dopa and 3-O-methyldopa [3-OMD]) and motor effects (global score of the Unified Parkinson's Disease Rating Scale-III) of a single dose of l-dopa (plus the peripheral decarboxylase inhibitor 1:4) were determined in 14 patients with advanced PD. Patients were classified into 2 groups according to Hoehn and Yahr scale (stages 2 and 3). In 1 patient with severe dyskinesias and fluctuations, pk/pd of l-dopa were evaluated before and after coadministration of tolcapone at 100 mg 2 times daily for 1 month. The pk/pd analysis was based on an estimate of the maximal response model with a semiparametric approach to effect site equilibrium. RESULTS: The highest levels of l-dopa and 3-OMD were observed in patients with stage 3 of Hoehn and Yahr scale. We showed differences in the pk/pd parameters after coadministration of tolcapone in 1 patient as well as the clinical improvement.Univariate analysis showed some significant correlations (P < 0.05) between l-dopa pk/pd parameters and patients' age, duration of l-dopa treatment, and duration of the disease. Multivariate analysis adjusted for patients' age, sex, duration of the disease, and Hoehn and Yahr stage showed that presence of diphasic (dyskinesia-improvement-dyskinesia [DID]) dyskinesias was the only independent predictor of larger threshold level - EC50 (mean concentration at half maximal effect) of l-dopa (P = 0.034). CONCLUSIONS: The motor complications during long treatment therapy in patients with advanced PD especially with stage 3 Hoehn and Yahr scale were correlated to the higher plasma concentrations of l-dopa. In the presented study, patients with motor complications, especially with DID dyskinesias, exhibited a larger threshold level (EC50). The clinical improvement of a patient who received l-dopa and tolcapone can be explained by tolcapone-induced changes of peripheral and central l-dopa pharmacokinetics, which led to a decrease of l-dopa EC50 and 3-OMD concentrations. Our data indicate that pk/pd analysis may be helpful for monitoring the efficiency of therapeutic strategy applied in PD patients.

Mitochondrial transcription factor A variants and the risk of Parkinson's disease.

The mitochondrial transcription factor A (TFAM) has been recently shown to decrease reactive oxygen species (ROS) generation. It is also known that mitochondrial DNA (mtDNA) haplogroups might confer different coupling properties, resulting in different ROS levels. We hypothesized that potentially functional TFAM variants could influence PD risk depending on haplogroup background. To test this we assessed the role of six TFAM variants on PD risk in 326 PD patients and 316 controls, and correlated it with mtDNA haplogroup clusters (HV, JTKU and a putative functionally different group U4U5a1KJ1cJ2, connected previously with partial uncoupling of oxidative phosphorylation). Both genotype and haplotype analysis showed that intronic variant rs2306604 modifies PD risk. Multivariate logistic regression analysis confirmed that rs2306604 G/G genotype is an independent risk factor for PD (OR 1.789, 95% CI 1.162-2.755, p=0.008). There was a borderline interaction between G/G genotype and HV haplogroup (p=0.075). Haplotype analysis showed that all three haplotypes containing rs2306604 allele A occurred at higher frequencies in controls, but only one of them reached statistical significance (chi(2) 4.523, p=0.0334). Conversely, four of five haplotypes containing allele G had higher frequencies in PD group, with no statistical significance.

Association study of GATA-2 transcription factor gene (GATA2) polymorphism and Parkinson's disease.

It was shown that high levels of alpha-synuclein in substantia nigra are essential in pathogenesis of Parkinson disease (PD), and SNCA expression in neurons is controlled by GATA-2 transcription factor, which plays also crucial role in central nervous system development, and erythroid cells differentiation. Recently, significant association of two GATA2 SNPs with early-onset coronary artery disease has been presented. In this case-control study we tested a hypothesis that polymorphism of GATA2 gene may be associated with sporadic PD. Five tag SNPs within GATA2 gene (rs2860228:G > A, rs2335052:G > A, rs11717152:A > C, rs2713604:G > A, and rs3803:C > T) were investigated in 368 PD patients and 349 controls of Caucasian origin from Poland. We did not find any significant differences in the GATA2 allele and genotype frequencies between PD cases and controls, for individual SNPs, neither in haplotype analysis. Elevated frequency of rs3803T allele was observed in early-onset PD patients (vs. controls and vs. late-onset PD), but this difference was not significant (0.05 < p < 0.1). We conclude that GATA2 polymorphism is not an important risk factor for sporadic PD in Caucasians.

[The role of estrogens in Parkinson's disease]. / Rola estrogenów w chorobie Parkinsona.

Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder of the central nervous system. It has a high prevalence, which significantly increases with age. This disease significantly deteriorates the quality of life and, despite treatment, may lead to disability. For these reasons, PD is not only a medical problem, but also a social one. The neuropathological basis of Parkinson's disease is selective degeneration of dopaminergic neurons in the brain's substantia nigra, which results in an imbalance between neurotransmitters in the central nervous system, mainly between dopamine and acetylcholine. The basic symptoms of PD are tremor at rest, extrapyramidal rigidity, bradykinesia, and disturbances of postural reflexes. PD is described as a hypertonic- hypokinetic syndrome. It is also characterized by coexisting vegetative and psychopathological disturbances. In spite of considerable advances in knowledge about the mechanisms of dopaminergic neuron injury, the etiology and pathogenesis of PD are not yet well established. In this paper the authors briefly review agents which influence neurodegenerative processes of the extrapyramidal system based on available literature concerning clinical trials in Parkinson's disease. Since it is known that female sex hormones also influence dopaminergic transmission, special attention is paid to the potential role of estrogens as agents modulating the risk of PD occurrence and their neuroprotective action.

Mitochondrial DNA haplogroups and subhaplogroups are associated with Parkinson's disease risk in a Polish PD cohort.

mtDNA common variation is inconsistently reported to modify the risk of Parkinson's disease (PD). We evaluated the impact of the mitochondrial haplogroups, subhaplogroups, coding and non-coding single-nucleotide polymorphisms on PD risk in 241 PD patients and 277 control subjects. After stratification by gender, we found that haplogroup J (OR 0.19; 95% CI 0.069-0.53; P = 0.0014) was associated with a lower PD risk in males. Unexpectedly, subhaplogroup analysis based on the control region (CR) polymorphisms demonstrated that subcluster K1a was more prevalent in healthy controls, while K1c was more frequent in PD patients (P = 0.025 and P = 0.011, respectively; two-tailed Fisher's exact test). Additionally, we confirmed the hypothesis that sublineages (U4 + U5a1 + K+J1c + J2), previously proposed to partially uncouple oxidative phosphorylation (OXPHOS), decrease PD risk (P = 0.027, chi2 with Yates' correction). The putative protective effect of uncoupling mtDNAs against PD might result from decreased production of reactive oxygen species. We propose that stratification into subhaplogroups or by gender could be necessary to reveal the involvement of specific mtDNA sublineages in PD pathogenesis.

The association of functional catechol-O-methyltransferase haplotypes with risk of Parkinson's disease, levodopa treatment response, and complications.

INTRODUCTION: Differences in catechol-O-methyltransferase (COMT) activity and genotype may determine individual variations in the therapeutic response to levodopa or Parkinson's disease (PD) susceptibility. The role of functional COMT haplotypes in PD susceptibility and treatment response has not been examined. OBJECTIVES: In this case-control study, we investigated the association of the most common COMT gene haplotypes (formed by single nucleotide polymorphisms (SNPs): rs6269:A>G; rs4633C>T; rs4818:C>G; and rs4680:A>G) with PD risk and the association of the COMT haplotypes with the dose and complications of levodopa therapy in PD patients. METHODS: A total of 679 study participants (322 PD and 357 controls) were included. Each participant was genotyped for four SNPs in the COMT gene, located in a common haploblock, that has been shown to influence COMT enzymatic activity. The influence of COMT haplotypes on the dose of levodopa administered during fifth year of treatment, and occurrence of motor complications were examined in PD patients. The EH program (Jurg Ott, Rockefeller University, New York, USA) was used to estimate haplotype frequencies. RESULTS: The estimated frequencies of low (A_C_C_G) and medium (A_T_C_A) activity haplotypes tended to be slightly lower among PD patients when compared with controls (P=0.09, G_C_G_G-high activity haplotype as reference). The frequency of G_C_G_G (high activity) haplotype carriers was higher in late onset PD patients (P=0.04) compared with controls. The mean levodopa dose increased with the activity of the functional haplotypes (low

[Pharmacogenetics in Parkinson's disease treatment]. / Farmakogenetyka - nowe podejscie do leczenia choroby Parkinsona.

The authors present the current opinion on the significance of molecular biology in individualized therapy. Pharmacogenetics is a new branch of clinical pharmacology dealing with the influence of genetic factors on drugs with special focus on interpersonal differences to drug response. The article includes basic rules of pharmacogenetics as well as its use in clinical practice. Individualized treatment of Parkinson's disease is not widely known although interpersonal differences to drug response is clearly stated. There is some evidence that varied efficacy of treatment and risk of motor and mental complications can be of genetic origin. Some results concerning the relationship between genetic polymorphism of COMT, DRD2, DAT, CCK, MTHFR and successful and safe treatment of Parkinson's disease are presented.

Interleukin-10 gene polymorphism in Parkinson's disease patients.

BACKGROUND: The etiology of sporadic Parkinson's disease (PD) is not well established. Recent studies revealed that inflammatory processes might also play an important role in the pathogenesis of PD. We hypothesized that genetically determined differences in the immune response, especially in anti-inflammatory cytokines production, might influence the risk of sporadic PD development and/or onset. To prove this hypothesis, two DNA polymorphisms at IL-10 promoter (-1082 and -519) were examined in sporadic PD patients. METHODS: The study enrolled 341 patients with diagnosed idiopathic PD. All cases of secondary parkinsonism were excluded from the study. For the purpose of this study the patients were also divided into two subgroups: group 1: patients with onset of Parkinson's disease, i.e., <50 years of age (early onset) included 60 patients, as well as group 2: patients with onset of Parkinson's disease >50 years of age (late onset) comprising 281 subjects. Control samples were from 315 randomly selected healthy individuals from the same geographical region who were free from signs of parkinsonism as evaluated by consultant neurologists. PCR-RFLP methods were used for genotyping. RESULTS: No statistically significant differences between PD patients and controls were found in the frequency of a single locus (-1082, -519) of IL-10 promoter. Likewise, haplotype analysis did not demonstrate any significant differences between evaluated groups. The frequency of the evaluated IL-10 genotypes was also similar in EOPD and LOPD patients. CONCLUSIONS: Results from our study revealed that the IL-10 (-1082G>A, -592C>A) polymorphism is not a risk factor of sporadic Parkinson's disease in a Polish population.

CARD15 variants in patients with sporadic Parkinson's disease.

Recent reports have proven the importance of genetic factors and inflammation in the pathogenesis of sporadic Parkinson's disease (PD). In the current study, the frequency of CARD15/NOD2 gene variants (R702W, G908R, L1007fs), previously associated with Crohn's disease--a common inflammatory bowel disease, have been examined in a group of 308 sporadic PD patients and 220 healthy controls. Significantly higher frequency of total CARD15 variant alleles in PD patients (13.0%) compared to the controls (8.0%, p<0.02) was observed. 24.0% of PD patients carried at least one CARD15 variant allele compared to 15.5% of healthy controls (p<0.02, OR=1.73). The results of the study suggest, that the polymorphism in CARD15/NOD2 gene may be a risk factor for sporadic PD development, and support the concept of inflammatory pathogenesis of PD.

Corticobasal degeneration -- clinico-pathological considerations.

Corticobasal degeneration (CBD) is a rare sporadic 4-repeat tauopathy. We report here the first Polish case of pathologically proven CBD. Our patient developed clumsiness of the right hand at age 63 years. During the course of his illness he suffered from progressive asymmetric parkinsonism unresponsive to dopaminergic therapy. Focal dystonia affecting right upper extremity, non-fluent aphasia, dysphagia, supranuclear vertical gaze palsy, imbalance and myoclonus ensued. The patient died of pneumonia at age 71 years. Head magnetic resonance imaging revealed the presence of asymmetric cortical atrophy contralateral to the clinically more affected right side. Median somatosensory evoked potentials performed bilaterally demonstrated significant reduction of cortical evoked potential amplitudes recorded from the left scalp electrodes. Neuropathological examination showed cortical atrophy of the frontal and parietal lobes with superficial spongiosis and diffuse cortical gliosis. Numerous ballooned neurons were found in frontal and parietal cortices. The most remarkable pathology was extensive tau-immunoreactivity of glial and neuronal cell processes, significantly pronounced in the frontotemporal cortex, basal ganglia, thalamus and brainstem. Recent research studies have resulted in better clinical, pathological and genetic characterization of sporadic tauopathies. It is hoped that similar progress will ensue in the development of symptomatic and eventually curative treatments for these rare conditions.

Polymorphism in semaphorin 5A (Sema5A) gene is not a marker of Parkinson's disease risk.

A SNP rs7702187 within the semaphorin 5A gene (Sema5A) has been recently associated with sporadic Parkinson's disease (PD) risk in American Caucasians. In the present study frequencies of rs7702187 was determined in two independent populations involving 427 sporadic PD patients (235 Polish Caucasians and 192 Asians from Singapore) and 412 healthy controls (220 Caucasians and 192 Asians), with the use of PCR-RFLP assay. The frequencies of the minor allele were found to be very similar in PD patients and healthy controls in both populations studied: 0.147 versus 0.143 in Caucasian, and 0.224 versus 0.221 in Asian, respectively. Our research does not confirm the previous observation, as no relationship was found between polymorphism within Sema5A gene and the risk of PD. It can be concluded that rs7702187 SNP in Sema5a gene is not a marker of PD risk in the studied populations.

[The role of environmental factors in Parkinson's disease may depend on disease onset age]. / Wplyw czynników srodowiskowych moze zalezec od wieku zachorowania na chorobe Parkinsona.

BACKGROUND AND PURPOSE: Various factors are suspected to participate in PD onset and include environment-related factors and workplace exposure to pesticides, metals and hydrocarbons. Nevertheless, results of epidemiological research are inconsistent. Some authors emphasize hydrocarbons exposure to younger patients. Our aim was to compare PD risk factors to onset age. MATERIAL AND METHODS: Of 174 patients with idiopathic PD, without dementia, two subgroups were isolated: 65 patients with early onset PD (EOPD) below 50 (n=65, age 52.8+/-7.6 years, onset 42.8+/-5.3 years) and 109 patients with late onset (LOPD) above 50 (n=109, age 67.8+/-7.0, onset 60.8+/-6.7 years). Various environmental factors reported in literature were analyzed. RESULTS: The univariate analysis showed that factors significantly predisposing to EOPD are vocational education (OR 3.24, 95%CI 1.50-7.00, p<0.003), smoking (OR 1.94, 95%CI 1.02-3.69, p<0.05), well water consumption at 20-40 (OR 2.77, 95%CI 1.31-5.86, p<0.008), and after 40 (OR 4.84, 95%CI 1.95-11.99, p<0.0007), side-effects following exposure to paints (OR 2.26, 95%CI 1.10-4.66, p<0.03) and exposure to solvents (OR 1.98, 95%CI 0.96-4.07, p<0.07) on borderline significance. Drinking well water both between 20-40 and after 40 involved a substantial increase in EOPD (OR 6.57, 95%CI 2.43-17.75, p<0.0002). Education only at a primary level proved to be protective against EOPD (OR 0.20, 95%CI 0.07-0.55, p<0.002). The multivariate logistic regression model demonstrated that independent EOPD risk factors are smoking (OR 2.20, 95%CI 1.07-4.53, p<0.04) and well water consumption both between 20-40 and after 40 (OR 8.29, 95%CI 2.73-25.23, p<0.0002), whilst the independent protective factor is education only at a primary level (OR 0.17, 95%CI 0.05-0.53, p<0.003). CONCLUSIONS: Our research demonstrated that a number of independent environmental factors significantly affect the risk of PD onset at younger ages. Presumably, some of the observed differences in the results of research of various authors into PD risk factors may be caused by ignoring onset age within the researched patients.

Analysis of LRRK 2 G 2019 S and I 2020 T mutations in Parkinson's disease.

Mutations in the leucine-rich repeat kinase 2 (LRRK 2), encoding dardarin protein, have been demonstrated to be linked to autosomal dominant Parkinson's disease (PD). In the present study the entire exon 41 of LRRK 2 gene was evaluated in a series of 174 PD patients recruited from Polish population, aged at the time of diagnosis 54.0+/-39.1 years, 21 of them had positive family history of PD with mean onset of the disease of 51.9+/-11.7 years as well as in 190 healthy controls aged 73.7+/-6.0 years. The mutations were evaluated by direct sequencing for mutations in exon 41 of LRRK 2 gene. In the studied patients no known mutations in exon 41 of LRRK 2 gene, including G 2019 S and I 2020 T were found, both in PD patients as well as in the controls. It can be concluded that the G 2019 S and I 2020 T mutations in exon 41 of LRRK 2 gene are rare causes of Parkinson disease in a Polish population.

[Polymorphism of N-acetyltransferase-2 and pathogenesis of neoplastic diseases]. / Polimorfizm N-acetylotransferazy 2 a patogeneza chorób nowotworowych.

Pathogenesis of many diseases is connected with influence of environmental factors with individual genetic sensitivity dependent among others on detoxification enzymes. Mutations of N-acetyltransferase-2 lead to decreased enzyme function. In this review the focus is on discussion about the connection between the polymorphic N-acetyltransferase-2 and increase in the risk of cancer, atopic disease and adverse drug effects.

Catechol-O-methyltransferase and monoamine oxidase B genes and susceptibility to sporadic Parkinson's disease in a Polish population.

Recent reports have proved that genetic factors play a role in the pathogenesis of sporadic Parkinson's disease (PD). It has been suggested that polymorphisms in monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) might increase the risk of PD. A total of 210 Polish patients with sporadic PD and 152 healthy controls were studied. The MAOB and COMT polymorphisms were identified using the polymerase chain reaction-restriction fragment length polymorphism method. The MAOB allele and genotype frequencies in PD patients did not differ significantly from the controls. A statistically lower frequency of the COMTLL genotype in patients with parkinsonism was found. The combined haplotype of the MAOB G (G/G) and COMTHL genotype showed a fourfold increase (p < 0.05) in the risk of PD in female patients in this Polish population.

Analysis of MDR1 haplotypes in Parkinson's disease in a white population.

The MDR1 multidrug transporter is important in regulating environmental xenobiotics and hence may play a causative role in Parkinson's disease (PD). MDR1 haplotype comprising 2677 G > T/A and 3435 C > T may be protective against PD. Using a case control methodology, we investigated the association of MDR1 haplotypes (single nucleotide polymorphisms (SNPs) 2677 G > T/A and 3435 C > T) in a Polish PD population. Seven SNPs, extending from the promoter to exon 28 of the MDR1 gene in 158 PD patients and 139 healthy controls were evaluated. Specifically we examined the association of haplotypes containing SNPs 2677 G > T/A and 3435 C > T and risk of PD. The multivariate logistic regression model was used to evaluate the effects of the covariates on the phenotypes. Haplotypes' frequencies were estimated using the Expectation-Maximization algorithm. The frequency of each individual SNPs; -41 A > G (intron -1), -145 C > G (exon 1), -129 T > C (exon 1), 1236 T > C (exon 12), 2677 G > T/A (exon 21), 3435 C > T (exon 26), and 4036 A > G (exon 28) did not differ between PD and controls. However, there was a trend towards significance in PD patients having the haplotype 2677G-3435C (p < 0.09, chi-square 2.85, odds ratio 0.25, 95% CI 0.06-1.08). Haplotype constructs of the other loci did not differ significantly between the two groups. There was a weak protective effect of the haplotype 2677G-3435C in our white population. However, the MDR1 haplotypes did not generally modulate the risk of PD.

[The role of N-acetyltransferase polymorphism in the pathogenesis of Parkinson's disease]. / Rola polimorfizmu N-acetylotransferazy 2 w patogenezie choroby parkinsona.

Pathogenesis of many diseases is related to the influence of noxious environmental agents coupled with individual genetic sensitivity that depends on the function of detoxificating enzymes. One of the latter is N-acetyltransferase 2 whose mutations lead to an impairment of the enzyme function. Genetically determined acetylation rate reduction with exposure to neurotoxins may contribute to the development of Parkinson's disease (PD). While both genetic and environmental factors are implicated in etiology of PD, genetic factors may play a crucial role in early-onset Parkinson's disease (in patients aged under 50).